Conditions: Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 578
Healthy volunteers: no

Brief summary:
This is a randomized, Phase III, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab in combination with cisplatin or carboplatin + pemetrexed compared with treatment with cisplatin or carboplatin + pemetrexed in participants who are chemotherapy-naive and have Stage IV non-squamous NSCLC. Eligible participants will be randomized by a 1:1 ratio into 2 groups: Arm A (Atezolizumab + Carboplatin or Cisplatin + Pemetrexed) and Arm B (Carboplatin or Cisplatin + Pemetrexed). The study will be conducted in two phases: Induction Phase and Maintenance Phase.

Detailed description:

Arms:
arm 1: Participants received intravenous (IV) infusion of 1200 milligrams (mg) of atezolizumab on Day 1 every 3 weeks (q3w), IV infusion of 500 milligrams per meter square (mg/m\^2) pemetrexed on Day 1 q3w, and as per investigator's choice either IV infusion of carboplatin on Day 1 q3w with a dose calculated using 'Calvert formula' to obtain area under concentration versus time (AUC) = 6 milligrams per milliliter per minute (mg/mL/min) or IV infusion of 75 mg/m\^2 cisplatin q3w on Day 1 q3w, during induction dosing period of 4 or 6 cycles (Cycle length=21 days). Participants who experienced clinical benefit during the induction phase began maintenance therapy. Participants will receive IV infusion of 1200 mg of atezolizumab and 500 mg/m\^2 of pemetrexed on Day 1 q3w until disease progression in the maintenance period. arm 2: Participants received IV infusion of 500 mg/m\^2 pemetrexed on Day 1 q3w, and as per investigator's choice of either IV infusion of carboplatin on Day 1 q3w with a dose calculated using 'Calvert formula' to obtain AUC =6 mg/mL/min or IV infusion of 75 mg/m\^2 cisplatin q3w on Day 1 q3w, during induction dosing period for 4 or 6 cycles (Cycle length=21 days). Participants who did not experience disease progression during the induction phase began maintenance therapy. Participants will receive IV infusion of 500 mg/m\^2 of pemetrexed on Day 1 q3w until disease progression in the maintenance period.

Interventions: intervention 1: Atezolizumab intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: Pemetrexed
Intervention descriptions: intervention 1: Participants received IV infusion of 1200 mg atezolizumab on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period and until disease progression on Day 1 q3w in the maintenance dosing period. intervention 2: Participants received IV infusion of carboplatin on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period with doses calculated using Calvart formula. intervention 3: Participants received IV infusion of 75 mg/m\^2 cisplatin on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period. intervention 4: Participants received IV infusion of 500 mg/m\^2 pemetrexed on Day 1 q3w for 4 or 6 cycles (Cycle length=21 days) in induction dosing period and until disease progression on Day 1 q3w in the maintenance dosing period.

Protocol document:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol GO29438, Version 7
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY OF ATEZOLIZUMAB (MPDL3280A, 
ANTI–PD-L1 ANTIBODY) IN COMBINATION WITH 
CARBOPLATIN OR CISPLATINPEMETREXED
COMPARED WITH CARBOPLATIN OR 
CISPLATINPEMETREXED IN PATIENTS WHO 
ARE CHEMOTHERAPY-NAIVE AND HAVE 
STAGE IV NON-SQUAMOUS NON–SMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29438
VERSION NUMBER:
7
EUDRACT NUMBER:
2015-003605-42
IND NUMBER:
117296
NCT NUMBER:
NCT02657434
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  19 September 2015
DATES AMENDED:
Version 2:  24 November 2015
Version 3:  9 June 2016
Version 4:  10 October 2016
Version 5:  9 October 2017
Version 6:  2 November 2018
Version 7:  See electronic date stamp below.
 
11-Feb-2020 00:33:32
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GO29438, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol GO29438 has been amended to reflect a change in the definition for the end of 
study and to align with current atezolizumab risk language. Changes to the protocol, 
along with a rationale for each change, are summarized below.

Background information on atezolizumab has been updated to account for additional 
approved indications (Section 1.2).

Language has been added to clarify that, after withdrawal of consent for 
participation in the Roche Clinical Repository (RCR), remaining RCR samples will 
be destroyed or will no longer be linked to the patient (Section 4.5.11.6).

The list of atezolizumab risks has been updated to include myositis for consistency 
with the list of identified risks in the Atezolizumab Investigator's Brochure 
(Section 5.1.1).

To align with the Atezolizumab Investigator's Brochure, Version 15, 
"immune-related" has been changed to "immune-mediated" when describing events 
associated with atezolizumab (Sections 1.3.2.1, 4.4.2, 4.6.2, 5.1.1, 5.1.6.2, 5.1.9, 
and Appendix 15).

To address a request by the French National Agency for the Safety of Medicines 
and Health Products (ANSM), systemic immune activation has been replaced by 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome in the 
list of potential risks for atezolizumab (Section 5.1.1) and the management 
guidelines for systemic immune activation have been replaced with management 
guidelines for hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome (Section 5.1.7 has been deleted; management guidelines have been 
added to Appendix 15).  In addition, systemic immune activation has been removed 
from the list of adverse events of special interest (Section 5.2.3).

Language has been updated to indicate that therapeutic or elective abortions are 
not considered adverse events unless performed because of an underlying maternal 
or embryofetal toxicity.  In such cases, the underlying toxicity should be reported as 
a serious adverse event.  Language has also been added to clarify that all abortions 
are to be reported on the paper Clinical Trial Pregnancy Reporting Form
(Section 5.4.3.3).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

The Appendix 11 (Anaphylaxis Precautions) has been modified to remove the 
requirement for use of a tourniquet.  The application of a tourniquet is no longer 
recommended due to the limited therapeutic benefit and risk of losing time for more 
important measures (Ring J, Beyer K, Biedermann T, et al. Allergo J Int. 
2014;23:96112).


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
To address a request by the French ANSM, the atezolizumab adverse event 
management guidelines have been revised to add laboratory (e.g., B-type natriuretic 
peptide) and cardiac imaging abnormalities as signs or symptoms that are 
suggestive of myocarditis (Appendix 15).

Guidelines for managing patients who experience atezolizumab-associated adverse 
events have been revised to include myositis (Appendix 15).

The management guidelines for infusion-related reactions associated with 
atezolizumab have been updated to include guidelines for cytokine-release 
syndrome (CRS) to align with the definition, grading, and management of CRS 
reflected in a recent publication (Lee et al. 2019) (Appendix 15).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Atezolizumab—F. Hoffmann-La Roche Ltd
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 27
1.1
Background on Lung Cancer................................................. 27
1.1.1
First-Line Treatment for Advanced NonSmall 
Cell Lung Cancer with an EGFR Mutation or ALK 
Rearrangement...................................................................... 28
1.1.2
First-Line Treatment for Advanced NSCLC 
without an EGFR Mutation or ALK 
Rearrangement...................................................................... 28
1.1.3
Platinum-Based Regimen for First-Line NSCLC.................... 31
1.1.4
Pemetrexed ........................................................................... 31
1.1.4.1
Pemetrexed plus Platinum Compounds in 
First-Line NSCLC .................................................................. 31
1.1.4.2
Pemetrexed Maintenance Therapy in NSCLC....................... 32
1.1.5
Targeted Therapy for NSCLC................................................ 33
1.2
Background on Atezolizumab................................................ 33
1.2.1
Summary of Nonclinical Studies............................................ 34
1.3
Clinical Experience with Atezolizumab .................................. 34
1.3.1
Ongoing Clinical Studies........................................................ 34
1.3.2
Clinical Safety........................................................................ 35
1.3.2.1
Single-Agent Clinical Safety in Patients with 
NSCLC in Study PCD4989g.................................................. 35
1.3.2.2
Single-Agent Clinical Safety in Patients with 
NSCLC in the POPLAR Study............................................... 37
1.3.2.3
Clinical Safety in Combination Platinum-Based 
Doublet Chemotherapy.......................................................... 39
1.3.3
Clinical Activity....................................................................... 41
1.3.3.1
Single-Agent Clinical Activity in Patients with 
NSCLC in Study PCD4989g.................................................. 41
1.3.3.2
Single-Agent Clinical Activity in Patients with 
NSCLC in the POPLAR Study............................................... 42


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1.3.3.3
Clinical Efficacy in Combination with 
Platinum-Based Doublet Chemotherapy in 
Patients with NSCLC ............................................................. 44
1.3.4
Clinical Pharmacokinetics and Immunogenicity..................... 44
1.3.5
Rationale for Atezolizumab Dosage ...................................... 44
1.4
Study Rationale and Benefit-Risk Assessment...................... 45
1.4.1
Rationale for Testing Atezolizumab in 
Combination with Carboplatin or Cisplatin and 
Pemetrexed ........................................................................... 46
2.
OBJECTIVES.............................................................................................. 48
2.1
Efficacy Objectives ................................................................ 48
2.1.1
Co-Primary Efficacy Objectives ............................................. 48
2.1.2
Secondary Efficacy Objectives .............................................. 48
2.2
Safety Objectives................................................................... 48
2.3
Pharmacokinetic Objectives .................................................. 49
2.4
Exploratory Objectives........................................................... 49
3.
STUDY DESIGN......................................................................................... 50
3.1
Description of Study .............................................................. 50
3.1.1
Independent Data Monitoring Committee .............................. 52
3.2
End of Study and Length of Study......................................... 53
3.3
Rationale for Study Design.................................................... 53
3.3.1
Rationale for Testing Atezolizumab in Patients 
with PD-L1Unselected NSCLC............................................ 53
3.3.2
Rationale for Control Arm ...................................................... 54
3.3.3
Rationale for Open-Label Study ............................................ 54
3.3.4
Rationale for Progression-Free Survival and 
Overall Survival as Co-Primary Endpoints............................. 55
3.3.5
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment until Loss of Clinical 
Benefit ................................................................................... 55
3.3.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 56
3.3.7
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens ................................................................. 56
3.3.8
Rationale for Blood Sampling for Biomarkers........................ 57


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3.4
Outcome Measures ............................................................... 57
3.4.1
Efficacy Outcome Measures.................................................. 57
3.4.1.1
Co-Primary Efficacy Outcome Measures............................... 57
3.4.1.2
Secondary Efficacy Outcome Measures................................ 57
3.4.2
Safety Outcome Measures .................................................... 58
3.4.3
Pharmacokinetic Outcome Measures.................................... 58
3.4.4
Exploratory Outcome Measures ............................................ 58
4.
MATERIALS AND METHODS .................................................................... 59
4.1
Patients.................................................................................. 59
4.1.1
Inclusion Criteria.................................................................... 59
4.1.2
Exclusion Criteria................................................................... 62
4.1.2.1
Cancer-Specific Exclusions ................................................... 62
4.1.2.2
General Medical Exclusions .................................................. 63
4.1.2.3
Exclusion Criteria Related to Medications ............................. 64
4.1.2.4
Exclusion Criteria Related to Chemotherapy......................... 65
4.2
Method of Treatment Assignment and Blinding..................... 65
4.3
Study Treatment.................................................................... 66
4.3.1
Formulation, Packaging, and Handling.................................. 66
4.3.1.1
Atezolizumab......................................................................... 66
4.3.1.2
Carboplatin or Cisplatin Pemetrexed .................................. 66
4.3.2
Dosage, Administration, and Compliance.............................. 67
4.3.2.1
Atezolizumab......................................................................... 68
4.3.2.2
Pemetrexed Carboplatin or Cisplatin .................................. 70
4.3.3
Investigational Medicinal Product Accountability ................... 71
4.3.4
Post-Study Access to Atezolizumab ...................................... 71
4.4
Concomitant Therapy ............................................................ 72
4.4.1
Permitted Therapy................................................................. 72
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 73
4.4.3
Prohibited Therapy ................................................................ 73
4.5
Study Assessments ............................................................... 74
4.5.1
Informed Consent Forms and Screening Log........................ 74
4.5.2
Medical History and Demographic Data ................................ 74


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4.5.3
Physical Examinations........................................................... 75
4.5.4
Vital Signs.............................................................................. 75
4.5.5
Tumor and Response Evaluations......................................... 76
4.5.6
Laboratory Assessments and Biomarker 
Samples................................................................................. 77
4.5.7
Tumor Tissue Samples.......................................................... 79
4.5.7.1
Archival or Freshly Collected Tumor Tissue 
Samples at Screening............................................................ 79
4.5.7.2
Optional Tumor Samples at the Time of 
Radiographic Progression ..................................................... 79
4.5.7.3
Tumor Samples at Other Timepoints..................................... 80
4.5.7.4
Use and Storage of Remaining Samples from 
Study-Related Procedures..................................................... 80
4.5.8
Anti-Therapeutic Antibody Testing......................................... 80
4.5.9
Electrocardiograms................................................................ 81
4.5.10
Patient-Reported Outcomes .................................................. 81
4.5.11
Samples for Roche Clinical Repository.................................. 83
4.5.11.1
Overview of the Roche Clinical Repository............................ 83
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 83
4.5.11.3
Sample Collection.................................................................. 83
4.5.11.4
Confidentiality........................................................................ 84
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 85
4.5.11.6
Withdrawal from the Roche Clinical Repository..................... 85
4.5.11.7
Monitoring and Oversight....................................................... 85
4.5.12
Timing of Assessments.......................................................... 86
4.5.12.1
Screening and Baseline Assessments .................................. 86
4.5.12.2
Assessments during Treatment............................................. 86
4.5.12.3
Assessments at Study Drug Discontinuation Visit ................. 87
4.5.12.4
Follow-Up Assessments ........................................................ 87
4.5.12.5
Assessments at Unplanned Visits ......................................... 88
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 88
4.6.1
Patient Discontinuation.......................................................... 88


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4.6.2
Study Treatment Discontinuation........................................... 89
4.6.3
Study and Site Discontinuation.............................................. 91
5.
ASSESSMENT OF SAFETY....................................................................... 91
5.1
Safety Plan ............................................................................ 91
5.1.1
Risks Associated with Atezolizumab ..................................... 92
5.1.2
Risks Associated with Pemetrexed 
Administration........................................................................ 92
5.1.3
Risks Associated with Carboplatin......................................... 92
5.1.4
Risks Associated with Cisplatin Chemotherapy..................... 93
5.1.5
General Plan to Manage Safety Concerns ............................ 93
5.1.5.1
Monitoring.............................................................................. 93
5.1.6
Dose Modification.................................................................. 93
5.1.6.1
General Notes Regarding Dose Modification......................... 93
5.1.6.2
Atezolizumab Dose Modification and 
Management of Specific Adverse Events .............................. 94
5.1.7
Pemetrexed Dose Modification and Management 
of Specific Adverse Events.................................................... 95
5.1.8
Platinum Chemotherapy Dose Modification and 
Management of Specific Adverse Events .............................. 97
5.1.8.1
Cisplatin................................................................................. 97
5.1.8.2
Carboplatin ............................................................................ 99
5.1.9
Potential Overlapping Toxicities .......................................... 100
5.2
Safety Parameters and Definitions ...................................... 101
5.2.1
Adverse Events ................................................................... 101
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 102
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 103
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 103
5.3.1
Adverse Event Reporting Period ......................................... 104
5.3.2
Eliciting Adverse Event Information..................................... 104
5.3.3
Assessment of Severity of Adverse Events ......................... 104
5.3.4
Assessment of Causality of Adverse Events ....................... 105
5.3.5
Procedures for Recording Adverse Events.......................... 106


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5.3.5.1
Diagnosis versus Signs and Symptoms............................... 106
5.3.5.2
Adverse Events That are Secondary to Other 
Events.................................................................................. 106
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 107
5.3.5.4
Abnormal Laboratory Values ............................................... 107
5.3.5.5
Abnormal Vital Sign Values ................................................. 108
5.3.5.6
Abnormal Liver Function Tests............................................ 108
5.3.5.7
Deaths ................................................................................. 109
5.3.5.8
Preexisting Medical Conditions............................................ 109
5.3.5.9
Worsening of NSCLC .......................................................... 110
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 110
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 110
5.3.5.12
Patient-Reported Outcome Data ......................................... 111
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 111
5.4.1
Emergency Medical Contacts.............................................. 111
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 112
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 112
5.4.2.2
Events That Occur after Study Drug Initiation...................... 112
5.4.3
Reporting Requirements for Pregnancies............................ 113
5.4.3.1
Pregnancies in Female Patients.......................................... 113
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 113
5.4.3.3
Abortions ............................................................................. 114
5.4.3.4
Congenital Anomalies and Birth Defects ............................. 114
5.5
Follow-Up of Patients after Adverse Events ........................ 114
5.5.1
Investigator Follow-Up......................................................... 114
5.5.2
Sponsor Follow-Up .............................................................. 115
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 115
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 115


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 116
6.1
Determination of Sample Size ............................................. 116
6.2
Summaries of Conduct of Study.......................................... 118
6.3
Summaries of Treatment Group Comparability ................... 118
6.4
Efficacy Analyses ................................................................ 118
6.4.1
Co-Primary Efficacy Endpoints............................................ 118
6.4.2
Secondary Efficacy Endpoints............................................. 120
6.4.2.1
Objective Response Rate.................................................... 120
6.4.2.2
Duration of Response.......................................................... 120
6.4.2.3
Overall Survival Rate at Landmark Timepoints.................... 120
6.4.2.4
Patient-Reported Outcomes ................................................ 120
6.4.3
Handling of Missing Data..................................................... 121
6.5
Safety Analyses................................................................... 121
6.6
Pharmacokinetic Analyses................................................... 122
6.7
Exploratory Analyses........................................................... 122
6.7.1
Exploratory Analyses of Progression-Free 
Survival................................................................................ 122
6.7.1.1
Progression-Free Survival Rate at Landmark 
Timepoints........................................................................... 122
6.7.1.2
NonProtocol-Specified Anti-Cancer Therapy..................... 122
6.7.1.3
Subgroup Analysis............................................................... 123
6.7.1.4
Sensitivity Analyses............................................................. 123
6.7.2
Exploratory Analyses of Overall Survival............................. 123
6.7.2.1
Loss to Follow-Up................................................................ 123
6.7.2.2
Subgroup Analysis............................................................... 123
6.7.2.3
Overall Survival Rate at 3-Year Landmark .......................... 124
6.7.2.4
Milestone Overall Survival Analysis..................................... 124
6.7.2.5
NonProtocol-Specified Anti-Cancer Therapy..................... 124
6.7.3
Exploratory Biomarker Analysis........................................... 124
6.7.4
EQ-5D-5L Health Status Data ............................................. 124
6.7.5
Exploratory Patient-Reported Outcome Analyses ............... 125
6.8
Interim Analyses .................................................................. 125
6.8.1
Planned Interim Analyses.................................................... 125
6.8.2
Optional Interim Analysis..................................................... 126


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6.9
China Subpopulation Analysis............................................. 126
7.
DATA COLLECTION AND MANAGEMENT ............................................. 127
7.1
Data Quality Assurance....................................................... 127
7.2
Electronic Case Report Forms............................................. 127
7.3
Electronic Patient-Reported Outcome Data......................... 128
7.4
Source Data Documentation................................................ 128
7.5
Use of Computerized Systems ............................................ 129
7.6
Retention of Records........................................................... 129
8.
ETHICAL CONSIDERATIONS.................................................................. 129
8.1
Compliance with Laws and Regulations .............................. 129
8.2
Informed Consent................................................................ 130
8.3
Institutional Review Board or Ethics Committee.................. 131
8.4
Confidentiality...................................................................... 131
8.5
Financial Disclosure ............................................................ 132
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 132
9.1
Study Documentation .......................................................... 132
9.2
Protocol Deviations.............................................................. 132
9.3
Site Inspections ................................................................... 133
9.4
Administrative Structure....................................................... 133
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 133
9.6
Protocol Amendments ......................................................... 134
10. REFERENCES ......................................................................................... 135


Atezolizumab—F. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Randomized Phase III Studies in Patients with Previously 
Untreated NSCLC....................................................................... 29
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades................................................................ 36
Table 3
Adverse Events Reported in at Least 10% of Patients in 
the POPLAR Study ..................................................................... 38
Table 4
Study GP28328:  All Reported Adverse Events.......................... 40
Table 5
Patients with NSCLC in Study PCD4989g:  Investigator-
Assessed Confirmed Objective Response Rate by Tumor 
PD-L1 Expression, Duration of Response, and 6-Month 
Progression-Free Survival Rates (per RECIST Version 1.1)....... 42
Table 6
Efficacy Results in the POPLAR Study:  Intent-to-Treat 
Population................................................................................... 43
Table 7
Study GO29438 Treatment Arms................................................ 51
Table 8
Premedication for Pemetrexed.................................................... 67
Table 9
Treatment Regimen for Pemetrexed Platinum-Based 
Chemotherapy ............................................................................ 68
Table 10
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 69
Table 11
Vital Sign Measurements at Cycle 1 and All Subsequent 
Cycles ......................................................................................... 75
Table 12
Pemetrexed Dose Modification for Hematologic Toxicities ......... 95
Table 13
Pemetrexed Dose Modification for Non-Hematologic 
Toxicities..................................................................................... 96
Table 14
Cisplatin Dose Modification for Hematologic Toxicities............... 97
Table 15
Cisplatin Dose Modification for Non-Hematologic Toxicities 
(Excluding Neurotoxicity) ............................................................ 98
Table 16
Cisplatin Dose Modification for Associated Neurotoxicity ........... 98
Table 17
Carboplatin Dose Modification for Hematologic Toxicities .......... 99
Table 18
Carboplatin Dose Modification on the Basis of 
Non-Hematologic Toxicities in the Preceding Cycle.................. 100
Table 19
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 105
Table 20
Analysis Timing and Stopping Boundary of Overall Survival..... 126


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LIST OF FIGURES
Figure 1
Study Schema............................................................................. 50
Figure 2
Criteria for Continuing Atezolizumab in Presence of 
Increased Radiographic Tumor Size (Atezolizumab Arms)......... 90
Figure 3
Overview of the Alpha Control Strategy .................................... 117
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 143
Appendix 2
Schedule of Pharmacokinetic, Biomarker, and Anti-
Therapeutic Antibody Assessments.......................................... 149
Appendix 3
American Joint Committee on Cancer NonSmall Cell Lung 
Cancer Staging, 7th Edition ...................................................... 152
Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication ............................... 154
Appendix 5
Modified Response Evaluation Criteria in Solid Tumors ........... 166
Appendix 6
AntiPD-L1 Immunohistochemistry........................................... 173
Appendix 7
EORTC QLQ-C30..................................................................... 174
Appendix 8
EORTC QLQ-LC13................................................................... 176
Appendix 9
EQ-5D-5L.................................................................................. 177
Appendix 10
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 180
Appendix 11
Anaphylaxis Precautions........................................................... 181
Appendix 12
Preexisting Autoimmune Diseases ........................................... 182
Appendix 13
Symptoms in Lung Cancer........................................................ 183
Appendix 14
Additional Guidance on Chemotherapy Administration............. 186
Appendix 15
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 188


Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol GO29438, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY OF ATEZOLIZUMAB (MPDL3280A, 
ANTI–PD-L1 ANTIBODY) IN COMBINATION WITH
CARBOPLATIN OR CISPLATINPEMETREXED
COMPARED WITH CARBOPLATIN OR 
CISPLATINPEMETREXED IN PATIENTS WHO 
ARE CHEMOTHERAPY-NAIVE AND HAVE 
STAGE IV NON-SQUAMOUS NON–SMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29438
VERSION NUMBER:
7
EUDRACT NUMBER:
2015-003605-42
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy to 
the Sponsor or their designee.  Contact details will be provided to the investigator prior 
to study start.


Atezolizumab—F. Hoffmann-La Roche Ltd
15/Protocol GO29438, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (MPDL3280A, ANTI–PD-L1 ANTIBODY) 
IN COMBINATION WITH CARBOPLATIN OR 
CISPLATINPEMETREXED COMPARED WITH CARBOPLATIN 
OR CISPLATINPEMETREXED IN PATIENTS WHO ARE 
CHEMOTHERAPY-NAIVE AND HAVE STAGE IV 
NON-SQUAMOUS NON–SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29438
VERSION NUMBER:
7
EUDRACT NUMBER:
2015-003605-42
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
III
INDICATION:
Non-squamous nonsmall cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab in 
combination with carboplatin or cisplatinpemetrexed compared with carboplatin or 
cisplatinpemetrexed in patients who are chemotherapy-naive and have Stage IV 
non-squamous nonsmall cell lung cancer (NSCLC).  Specific objectives and corresponding 
endpoints for the study are outlined below.
Efficacy Objectives
The co-primary objectives of this study are:

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1)

To evaluate the efficacy of atezolizumab as measured by overall survival (OS)
The secondary efficacy objectives for this study are:

To evaluate the efficacy of atezolizumab as measured by investigator-assessed objective 
response rate (ORR) according to RECIST v1.1

To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response (DOR) according to RECIST v1.1

To evaluate the OS rate at 1 and 2 years

To determine the impact of atezolizumab as measured by the change from baseline in
patient-reported lung cancer symptoms of cough, dyspnea (single-item and multi-item 
subscales), chest pain, or arm/shoulder pain, using the European Organization for 
the Research and Treatment of Cancer (EORTC) Quality-of-Life QuestionnaireCore 30 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13)


Atezolizumab—F. Hoffmann-La Roche Ltd
16/Protocol GO29438, Version 7

To determine the impact of atezolizumab as measured by the change from baseline in 
patient-reported lung cancer symptoms (chest pain, dyspnea, and cough) scores using the 
Symptoms in Lung Cancer (SILC) scale symptom severity scores
Safety Objectives
The safety objectives for this study are:

To evaluate the safety and tolerability of atezolizumab when given in combination with 
carboplatin or cisplatin pemetrexed or as maintenance therapy with pemetrexed alone

To evaluate the incidence and titers of anti-therapeutic antibody against atezolizumab and 
to explore the potential relationship of the immunogenicity response with pharmacokinetics, 
safety, and efficacy
Pharmacokinetic Objectives
The PK objectives for this study are:

To characterize the pharmacokinetics of atezolizumab when given in combination with 
carboplatin or cisplatinpemetrexed or pemetrexed alone

To characterize the pharmacokinetics of carboplatin when given in combination with 
atezolizumab and pemetrexed

To characterize the pharmacokinetics of cisplatin when given in combination with 
atezolizumabpemetrexed

To characterize the pharmacokinetics of pemetrexed when given in combination with 
atezolizumabcarboplatin or cisplatin
Exploratory Objectives
The exploratory objectives for this study are:

To evaluate the PFS rate at 6-month and 1-year landmark timepoints

To evaluate the OS rate at 3 years in each treatment arm

To evaluate the efficacy of atezolizumab as measured by OS and investigator-assessed 
PFS according to RECIST v1.1 in subgroups based on demographic and baseline 
characteristics

To evaluate the efficacy of atezolizumab as measured by milestone survival

To evaluate the relationship between biomarkers in tumors and blood (including but not 
limited to programmed deathligand 1 (PD-L1), programmed death1 (PD-1), somatic 
mutations and others), as defined by immunohistochemistry (IHC), quantitative reverse 
transcriptasepolymerase chain reaction (qRT-PCR), next-generation sequencing, and/or 
other methods and measures of efficacy

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease status, mechanisms 
of resistance, and/or response to study treatment

To evaluate and compare patient’s health status as assessed by the EuroQoL 
5 Dimensions 5-Level questionnaire to generate utility scores for use in economic models 
for reimbursement

To determine the impact of atezolizumab in each of the treatment comparisons as 
measured by change from baseline in patient-reported outcomes (PROs) of health-related 
quality of life, lung cancerrelated symptoms, and health status as assessed by the EORTC
QLQ-C30 and QLQ-LC13


Atezolizumab—F. Hoffmann-La Roche Ltd
17/Protocol GO29438, Version 7
Study Design
Description of Study
This is a randomized, Phase III, multicenter, open-label study (IMpower 132) designed to 
evaluate the safety and efficacy of atezolizumab in combination with cisplatin or 
carboplatin pemetrexed compared with treatment with cisplatin or carboplatin pemetrexed in 
patients who are chemotherapy-naive and have Stage IV non-squamous NSCLC.
Eligible patients will be stratified by sex (male vs. female), smoking status (never vs. current 
and/or former), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1) and 
chemotherapy regimen (carboplatin vs. cisplatin) and randomized by a 1:1 ratio to receive one 
of the following treatment regimens:

Induction phase (four or six 21-day cycles):
Arm A: atezolizumabcarboplatin or cisplatinpemetrexed
Arm B:  carboplatin or cisplatinpemetrexed

Maintenance phase (21-day cycles):
Arm A:  atezolizumab pemetrexed
Arm B:  pemetrexed
Treatment with chemotherapy (both in Arm A and B) should be discontinued in all patients who 
exhibit evidence of progressive disease by RECIST 1.1.  During induction or maintenance 
treatment, patients randomized to Arm A may continue treatment with atezolizumab beyond 
progressive disease by RECIST v1.1, provided they are experiencing clinical benefit as 
assessed by the investigator.
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 48 weeks 
following Cycle 1, Day 1, regardless of dose delays.  After the completion of the Week 48 tumor 
assessment, tumor assessment will be required every 9 weeks.  Patients will undergo tumor 
assessments until radiographic disease progression per RECIST v1.1 or loss of clinical benefit 
(for atezolizumab-treated only patients who continue treatment after radiographic disease 
progression according to RECIST v1.1), withdrawal of consent, study termination by Sponsor, 
or death, whichever occurs first.  Patients who discontinue treatment for reasons other than 
radiographic disease progression (e.g., toxicity) will continue scheduled tumor assessments 
until radiographic disease progression per RECIST v1.1 or loss of clinical benefit (for 
atezolizumab-treated patients who continue treatment after radiographic disease progression 
according to RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, 
whichever occurs first, regardless of whether patients start a new anti-cancer therapy.
All primary imaging data used for tumor assessment will be collected by the Sponsor to enable 
centralized, independent review of response endpoints. The independent reviews of the stored 
scans will be performed when requested.
Number of Patients
Approximately 568 patients will be enrolled across all sites during the global enrollment phase 
of the study.  If at least 1 patient is enrolled in China during the global enrollment phase, 
additional patients will be enrolled in a subsequent China extension phase as needed to ensure 
a total enrollment of approximately 164 patients in the China cisplatin subpopulation.
Target Population
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Male or female, 18 years of age or older

ECOG performance status of 0 or 1


Atezolizumab—F. Hoffmann-La Roche Ltd
18/Protocol GO29438, Version 7

Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 
7th edition; Detterbeck et al. 2009)
Patients with tumors of mixed non-small cell histology (i.e., squamous and 
non-squamous) are eligible if the major histological component appears to be 
non-squamous.

No prior treatment for Stage IV non-squamous NSCLC
Patients with a sensitizing mutation in the epidermal growth factor receptor (EGFR) 
gene are excluded given that erlotinib, gefitinib, or another EGFR tyrosine kinase 
inhibitor is the appropriate initial treatment of EGFR-mutant NSCLC.
Patients with an anaplastic lymphoma kinase (ALK) fusion oncogene are excluded 
given that crizotinib or other ALK inhibitors is the appropriate initial treatment of 
NSCLC in patients having an ALK fusion oncogene.
Patients with unknown EGFR and ALK status require test results at screening. ALK
and/or EGFR may be assessed at a local or central laboratory.

Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy or 
chemoradiotherapy with curative intent for non-metastatic disease must have experienced a 
treatment-free interval of at least 6 months from randomization since the last dose of 
chemotherapy and/or radiotherapy.

Patients with a history of treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
randomization
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study

Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, these 
patients may then be eligible without the need for an additional brain scan prior to 
randomization, if all other criteria are met.

Patients should submit a pre-treatment tumor tissue sample (if available).  If tumor tissue is 
not available (e.g., depleted for prior diagnostic testing), patients are still eligible.
If tumor tissue is available, a representative formalin-fixed paraffin-embedded (FFPE) 
tumor specimen in paraffin block or unstained, freshly cut, serial sections (preferably at 
least 10) from an FFPE tumor specimen, are preferred.  If 10 sections are not available, 
fewer can be submitted.
If FFPE specimens described above are not available, any type of specimens 
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural effusion], and 
lavage samples) are also acceptable.
This specimen should be accompanied by the associated pathology report.
Any available tumor tissue sample should be submitted before or within 4 weeks 
after enrollment.

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease.


Atezolizumab—F. Hoffmann-La Roche Ltd
19/Protocol GO29438, Version 7

Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 14 days prior to randomization:
ANC 1500 cells/L without granulocyte colony-stimulating factor support
Lymphocyte count 500/L
Platelet count 100,000/L without transfusion
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
INR or aPTT 1.5upper limit of normal (ULN)
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
AST, ALT, and alkaline phosphatase 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase 
5ULN.
Serum bilirubin 1.25ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN may 
be enrolled.
Calculated creatinine clearance (CRCL) 45 mL/min or, if using cisplatin, 
calculated CRCL must be 60 mL/min

For patients enrolled in the extended China enrollment phase: current resident of mainland 
China, Hong Kong, or Taiwan and of Chinese ancestry

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the treatment period and for at least 5 months after the last dose of 
atezolizumab and 6 months after the last dose of cisplatin, carboplatin, or pemetrexed.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of 1% per year during the chemotherapy treatment period and for at least 6 months 
after the last dose of chemotherapy.
With pregnant female partners, men must remain abstinent or use a condom during 
the chemotherapy treatment period and for at least 6 months after the last dose of 
chemotherapy.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.


Atezolizumab—F. Hoffmann-La Roche Ltd
20/Protocol GO29438, Version 7
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-Specific Exclusions

Patients with a sensitizing mutation in the EGFR gene or an ALK fusion oncogene

Active or untreated CNS metastases as determined by CT or magnetic resonance imaging 
evaluation during screening and prior radiographic assessments

Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for 2 weeks prior to randomization

Leptomeningeal disease

Uncontrolled tumor-related pain
Patients requiring pain medication must be receiving a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to randomization.  
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not currently associated 
with spinal cord compression) should be considered for loco-regional therapy, if 
appropriate, prior to randomization.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or 
calcium 12 mg/dL or corrected serum calcium ULN)
Patients who are receiving denosumab prior to randomization must be willing and 
eligible to discontinue its use and replace it with a bisphosphonate instead while in 
the study.

Malignancies other than NSCLC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS 90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous-cell skin cancer, localized prostate cancer treated surgically with 
curative intent, ductal carcinoma in situ treated surgically with curative intent)

Known tumor PD-L1 expression status as determined by an IHC assay from other clinical 
studies (e.g., patients whose PD-L1 expression status was determined during screening for 
entry into a study with anti-PD-1 or antiPD-L1 antibodies but were not eligible are excluded)
General Medical Exclusions

Women who are pregnant, lactating, or intending to become pregnant during the study

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study.


Atezolizumab—F. Hoffmann-La Roche Ltd
21/Protocol GO29438, Version 7
Patients with controlled Type I diabetes mellitus who are receiving a stable dose of 
insulin regimen are eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and only requiring low potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids)

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test for HIV
All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the clinical study.

Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody and absence of HBsAg) are 
eligible only if they are negative for HBV DNA.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) 
are eligible.

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
Patients with known coronary artery disease, congestive heart failure not meeting 
the above criteria, or left ventricular ejection fraction 50% must be receiving a 
stable medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate.

Major surgical procedure other than for diagnosis within 28 days prior to randomization or 
anticipation of need for a major surgical procedure during the course of the study

Prior allogeneic bone marrow transplantation or solid organ transplant

Administration of a live attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study

Any other diseases, 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 or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications

Illness or condition that may interfere with a patient’s capacity to understand, follow, and/or 
comply with study procedures


Atezolizumab—F. Hoffmann-La Roche Ltd
22/Protocol GO29438, Version 7
Exclusion Criteria Related to Medications

Prior treatment with EGFR inhibitors or ALK inhibitors

Any approved anti-cancer therapy, including hormonal therapy within 21 days prior to 
initiation of study treatment.

Treatment with any other investigational agent with therapeutic intent within 28 days prior to 
randomization

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, antiPD-1, 
and antiPD-L1 therapeutic antibodies
Patients who have had prior anticytotoxic T-lymphocyte associated antigen 4 
(CTLA-4) treatment may be enrolled, provided the following requirements are met:
Last dose of anti-CTLA-4 at least 6 weeks prior to randomization
No history of severe immune-mediated adverse effects from anti-CTLA-4 
(National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] Grade 3 and 4)

Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
interleukin [IL]-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to 
randomization
Prior treatment with cancer vaccines is allowed.

Treatment with systemic immunosuppressive medications (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor agents) within 2 weeks prior to randomization
Patients who have received acute, low-dose (10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in the 
study.
The use of corticosteroids (10 mg oral prednisone or equivalent), for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension, and low-dose supplemental corticosteroids 
for adrenocortical insufficiency are allowed.
Exclusion Criteria Related to Chemotherapy

History of allergic reactions to cisplatin, carboplatin, or other platinum-containing 
compounds

Patients with hearing impairment (cisplatin)

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 (cisplatin)

CRCL 60 mL/min for cisplatin or 45 mL/min for carboplatin
End of Study and Length of Study
The end of study is defined as the date of the last follow-up visit of the last patient or when all 
patients have been enrolled into an extension study.  The Sponsor may decide to terminate the 
study at any time.  If the Sponsor decides to end the study, patients who are still receiving study 
treatment or are in survival follow-up may be offered enrollment in an extension study or a 
non-interventional study.
Investigational Medicinal Products
The investigational medicinal products for this study are atezolizumab and pemetrexed.  
Depending on local classification, in this study, cisplatin and carboplatin may either be 
considered a non-investigational medicinal product or an investigational medicinal product.
Test Product (Investigational Drug)
Patients randomized to atezolizumab will receive 1200 mg of atezolizumab administered by IV 
infusion every 21 days in a monitored setting where there is immediate access to trained 
personnel and adequate equipment/medicine to manage potentially serious reactions.


Atezolizumab—F. Hoffmann-La Roche Ltd
23/Protocol GO29438, Version 7
Comparator
Institutions should follow their standard administration procedures for pemetrexed.  
The premedication doses administered should be in compliance with the prescribing information.  
All patients eligible for pemetrexed therapy should avoid taking non-steroidal anti-inflammatory 
drugs with long elimination half-lives for at least 5 days prior to, on the day of, and at least 
2 days following pemetrexed administration.
Non-Investigational Medicinal Products
Cisplatin should be administered by IV infusion approximately 30 minutes after completion of 
the pemetrexed infusion at a dose of 75 mg/m² over 1–2 hours or per standard of care at the 
institution.  Patients must receive adequate anti-emetic treatment and appropriate hydration 
prior to and/or after receiving cisplatin.
Carboplatin should be administered 30 minutes after completion of pemetrexed administration 
by IV infusion over 3060 minutes to achieve an initial target area under the concentrationtime 
curve of 6 mg/mL/min (Calvert formula dosing) with standard anti-emetics per local practice 
guidelines.
Statistical Methods
Primary and Secondary Efficacy Analyses
The primary efficacy analyses for PFS and OS will include randomized patients in the ITT 
population.  ORR will be analyzed using all randomized patients.  DOR will be assessed in 
patients who have an objective response.  PRO measures will be conducted on all patients with 
a non-missing baseline PRO assessment.  Change from baseline analysis for PRO measures 
will be performed using the patients who have both a non-missing baseline assessment and at 
least one non-missing post-baseline assessment.
Determination of Sample Size
Determination of sample size is based on patients enrolled in the global enrollment phase.  
This study will randomize approximately 568 patients during the global enrollment phase.  
Additional patients may be randomized during the China extension phase if at least one patient 
is enrolled in China during the global enrollment phase.
Interim Analyses
There are no interim analyses planned for PFS in this study.  An external independent Data 
Monitoring Committee (iDMC) will be set up to evaluate safety data on an ongoing basis.  
All summaries and analyses by treatment arm for the iDMC’s review will be prepared by an 
independent Data Coordinating Center.  Members of the iDMC will be external to the Sponsor 
and will follow a charter that outlines their roles and responsibilities.  Any outcomes of these 
safety reviews that affect study conduct will be communicated in a timely manner to the 
investigators for notification of the Institutional Review Boards and Ethics Committees.  
A detailed plan will be included in the iDMC Charter. 
One interim efficacy analysis of OS is planned and will be performed by the Sponsor.  The first 
interim OS analysis will be conducted at the time of the final PFS analysis.  It is expected that 
there will be approximately 312 OS events in the ITT population but the exact timing of this 
analysis will depend on the actual number and timing of PFS events.  If there are significantly 
fewer than the expected 312 OS events at the time of the final PFS analysis, a nominal 
two-sided of 0.01% (negligible impact on overall type I error rate) will be spent on the OS 
analysis at the time of the final PFS analysis and a second interim OS analysis will then be 
conducted after approximately 312 OS events have occurred.


Atezolizumab—F. Hoffmann-La Roche Ltd
24/Protocol GO29438, Version 7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ALK
anaplastic lymphoma kinase
ASCO
American Society of Clinical Oncology
ATA
anti-therapeutic antibody
AUC
area under the concentrationtime curve
BSC
best supportive care
Cmax
maximum observed serum concentration
Cmin
minimum observed serum concentration
CR
complete response
CRC
colorectal cancer
CRCL
creatinine clearance
CT
computed tomography
ctDNA
circulating tumor DNA
Ctrough
trough concentration
CTLA-4
cytotoxic T-lymphocyte associated antigen 4
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EORTC
European Organization for Research and Treatment of Cancer
ePRO
electronic PRO
EQ-5D-5L
EuroQoL 5 Dimensions 5-Level Version
FDA
U.S. Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
GFR
glomerular filtration rate
HBcAb
hepatitis B core antibody
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life
IC
tumor-infiltrating immune cell


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Abbreviation
Definition
ICH
International Conference for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
IRF
Independent Review Facility
ITT
intent to treat
IV
intravenous
IxRS
interactive voice/Web response system
KRAS
GTPase Krase
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
Pac Cb Bev
paclitaxel carboplatinbevacizumab
PD-1
programmed death1
PD-L1
programmed deathligand 1
Pem Cb
pemetrexed carboplatin
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
q3w
every 3 weeks
QLQ-C30
Quality-of-Life QuestionnaireCore 30
QLQ-LC13
Quality-of-Life Questionnaire Lung Cancer Module
qRT-PCR
quantitative reverse transcriptasepolymerase chain reaction
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
Statistical Analysis Plan


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Abbreviation
Definition
SILC
Symptoms in Lung Cancer
TC
tumor cell
TKI
tyrosine kinase inhibitor
TNF
tumor necrosis factor
TTD
time to deterioration
UBC
urothelial bladder cancer
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON LUNG CANCER
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most 
common cancer in both men and women and accounted for approximately 13% of all 
new cancers in 2008 (Jemal et al. 2011).  In 2012, it was estimated that there would be 
226,160 new cases of lung cancer and 160,340 lung cancer deaths in the United States 
alone (Siegel et al. 2012).  Similar data from Europe estimate that there were 
288,000 new cases of lung cancer and 253,000 deaths in 2008 (GLOBOCAN 2008).
Nonsmall cell lung cancer (NSCLC) is the predominant subtype of lung cancer, 
accounting for approximately 85% of all cases (Molina et al. 2008; Howlader et al. 2011).  
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% 
(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 is 2%4%, 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 
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 will reveal cytological differences 
between the squamous cell type (keratinization, intracellular bridges, and central necrosis) 
and adenocarcinoma (glandular architecture).  In cases where the tumor sample is poorly 
differentiated or there is limited tissue available, immunohistochemical markers may 
support the histologic diagnosis.  Thyroid transcription factor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), the rearrangement in the 
anaplastic lymphoma kinase (ALK) genes, and mutations in the GTPase Kras (KRAS)
gene.  The rates of these mutations differ between squamous cell carcinoma and 
adenocarcinoma.  For example, EGFR kinase domain mutations have been reported 


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in 10%40% of patients with adenocarcinoma NSCLC but are infrequently observed in 
patients with squamous NSCLC (Herbst et al. 2008).  Similarly, the ALK fusion oncogene, 
recognized as a driver of lung tumorigenesis, is observed in approximately 7% of patients 
with adenocarcinoma but is very rare in the squamous histology (Herbst et al. 2008; 
Langer et al. 2010).  In addition, KRAS mutations are very rare in squamous NSCLC, 
while they can be observed in up to 30% of cases of adenocarcinoma NSCLC 
(Travis et al. 2011).
1.1.1
First-Line Treatment for Advanced NonSmall Cell Lung 
Cancer with an EGFR Mutation or ALK Rearrangement
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC characterized by alterations of 
driver oncogenes, including sensitizing EGFR mutations and ALK rearrangements.  
However, these mutations are more prevalent in adenocarcinoma NSCLC and are very 
rare in squamous NSCLC.  Randomized Phase III studies of gefitinib (IPASS), erlotinib 
(EURTAC), and afatinib (LUX-Lung 3) showed significant improvement of 
progression-free survival (PFS) and objective response rate (ORR) compared with 
platinum doublet chemotherapy (Fukuoka et al. 2011; Rosell et al. 2012; 
Yang et al. 2012; respectively).  Similarly, the ALK inhibitor crizotinib has demonstrated 
efficacy in patients with NSCLC that is positive for ALK rearrangement as defined by 
fluorescence in situ hybridization (Crino et al. 2011; Camidge et al. 2012; 
Shaw et al. 2012; XALKORI® U.S. Package Insert [USPI]).  Both EGFR tyrosine kinase 
inhibitors (TKIs) and crizotinib have been shown to be generally well tolerated.
1.1.2
First-Line Treatment for Advanced NSCLC 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).  More recently, 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 who were 
allocated to chemotherapy had a significantly longer median survival than did those who 
were managed with BSC (8 vs. 5.7 months; hazard ratio [HR]0.77, 95% CI: 0.66, 0.89).
The benefit conferred by platinum-based chemotherapy regimens appears to have 
reached a plateau in ORR (approximately 15%22%) and median survival 
(710 months).  More recently, the addition of bevacizumab to carboplatin and paclitaxel 
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 NSCLC
First-Line Therapy Regimen
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 (n434)
35
6.5
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 NSCLC (cont.)
First-Line Therapy Regimen
ORR
(%)
Median PFS
(months)
Median OS
(months)
OS HR
(95% CI)
Phase III studies 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
HRhazard ratio; NRnot reported; ORRobjective response rate; OSoverall survival; PFSprogression-free survival.
a Schiller JH, Harrington D, Belani CP, et al. Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for
advanced non–small-cell lung cancer. N Engl J Med 2002;346:928.
b Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for nonsmall cell lung cancer. N Engl J Med 
2006;355:254250.
c Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in 
chemotherapy-naive patients with advanced-stage nonsmall cell lung cancer. J Clin Oncol 2008;26:354351.
d 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.
e Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an 
open-label randomised Phase III trial. Lancet 2009;373:152531.


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Despite the limited survival benefit conferred by cytotoxic chemotherapy, platinum-based 
regimens remain the standard first-line option for most patients with locally advanced 
and metastatic NSCLC that was not harboring an activating EGFR mutation or ALK gene 
rearrangement.  In particular, for newly diagnosed advanced stage non-squamous 
NSCLC, the standard of care is a platinum doublet with either cisplatin or carboplatin 
and a taxane or pemetrexed, with or without bevacizumab.  However, these regimens 
are associated with substantial toxicities (such as febrile neutropenia, myelosuppression, 
nausea, alopecia, nephropathy, and neuropathy) and are generally poorly tolerated 
by elderly and poor-performance-status patients.  Therefore, novel therapies that deliver 
an improved therapeutic index are urgently needed for non-squamous NSCLC.
1.1.3
Platinum-Based Regimen for First-Line NSCLC
Several meta-analyses have compared the use of cisplatin and carboplatin as 
treatments for NSCLC.  In general, although the ORR was higher in patients treated 
with cisplatin than in those treated with carboplatin, the 1-year and OS rates were 
comparable.  When given in combination with a third-generation chemotherapy, 
cisplatin may result in longer survival than carboplatin (overall response of 
30% vs. 24%, respectively; Hotta et al. 2004; Ardizzoni et al. 2007), but overall benefit 
was quite marginal, and subgroup analyses including additional, more recent studies 
indicate that there may be no difference between the two agents (Jiang et al. 2007; 
Azzoli et al. 2009).
As to safety, cisplatin-based chemotherapy has been associated with more severe 
nausea and vomiting and nephrotoxicity, while severe thrombocytopenia has been 
more frequent during carboplatin-based chemotherapy (Hotta et al. 2004; 
Ardizzoni et al. 2007). The risk of treatment-related deaths was greater in the cisplatin 
arm, but this increase was not statistically significant (Jiang et al. 2007).
Currently, the standard of care for newly diagnosed advanced stage non-squamous 
NSCLC is a platinum doublet with either cisplatin or carboplatin and a taxane or
pemetrexed, with or without bevacizumab.  In particular, the combination of platinum 
doublet with pemetrexed has been used more widely because of a better tolerability 
and safety profile.
1.1.4
Pemetrexed
Pemetrexed disodium (ALIMTA®, pemetrexed) is a novel pyrrolo[2,3 d]pyrimidinebased
folic acid analogue.  In vitro studies, pemetrexed inhibited multiple folate-dependent 
enzymes (thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide 
formyl-transferase) crucial in the de novo biosynthesis of thymidine and purine 
nucleotides (Shih et al. 1997).
1.1.4.1
Pemetrexed plus Platinum Compounds in First-Line NSCLC
Two Phase II studies demonstrated that the combination of pemetrexed and carboplatin 
is tolerable and that its activity in first-line treatment of advanced-stage NSCLC is 


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comparable with other standard platinum doublets commonly used in clinical practice 
(Kelly et al. 2001; Scagliotti et al. 2002; Fossella et al. 2003; Reck et al. 2010).  
The toxicity profile of the pemetrexed/carboplatin combination appears to be more 
favorable than that seen with other standard regimens in first-line NSCLC.
A Phase III non-inferiority study comparing the efficacy of cisplatin/pemetrexed (n862) 
versus cisplatin/gemcitabine (n863) in patients with incurable Stage IIIB or IV NSCLC 
who had received no prior chemotherapy.  Median OS, PFS, and time to progression 
were comparable between the two treatment groups.  However, among patients who 
had adenocarcinoma or large-cell carcinoma, patients treated with cisplatin/pemetrexed 
had significantly better median OS than patients treated with cisplatin/gemcitabine 
(12.6 vs. 10.9 months for adenocarcinoma [HR0.84; 95% CI: 0.71, 0.99; p0.03]); 
10.4 vs. 6.7 months for large-cell carcinoma [HR0.67; 95% CI: 0.48, 0.96; p0.03]).  
In addition, cisplatin/pemetrexed was associated with better tolerability and safety and 
necessitated less supportive care (Scagliotti et al. 2008).
In addition, a supportive study named PRONOUNCE was designed to assess the 
efficacy and safety of pemetrexedcarboplatin (PemCb) followed by pemetrexed 
maintenance versus paclitaxelcarboplatinbevacizumab followed by bevacizumab 
maintenance (PacCbBev) in patients with advanced non-squamous NSCLC.  The 
median PFS was 4.44 months for PemCb versus 5.49 months for PacCbBev 
(HR1.06; 95% CI: 0.84, 1.35; p0.610).  The median OS for PemCb was 10.5 
months versus 11.7 months for PacCbBev (HR1.07; 95% CI: 0.83, 1.36; p0.615).  
One- and 2-year survival rates were not significantly different between the arms and 
were 43.7% and 18.0% for PemCb and 48.8% and 17.6% for PacCbBev.  
Response rate and disease control rate (DCR) were 23.6% and 59.9% for PemCb and 
27.4% and 57.0% for PacCbBev (p0.414 and 0.575, respectively).
1.1.4.2
Pemetrexed Maintenance Therapy in NSCLC
A Phase III, randomized, double-blind, placebo-controlled, study that explored the use of 
pemetrexed as switch maintenance in first-line patients with NSCLC after four cycles of 
induction therapy using one of six standard platinum doublets (gemcitabine, paclitaxel, or 
docetaxel with either carboplatin or cisplatin).  Patients who achieved a complete 
response (CR), partial response (PR), or stable disease were then randomized to 
maintenance therapy with pemetrexed plus BSC or placebo plus BSC until progression 
(Ciuleanu et al. 2009).  A significant improvement in PFS was reported for patients who
received pemetrexed maintenance therapy compared with those who received placebo 
(4.04 vs. 1.97 months; unadjusted HR, 0.50; 95% CI: 0.42, 0.61; p0.00001).  In patients 
with non-squamous histology, the median PFS for patients receiving pemetrexed versus 
placebo was 4.5 months versus 2.6 months (unadjusted HR, 0.44; 95% CI: 0.36, 0.55; 
p0.00001).  The median follow-up for OS was 11.2 months for patients in the 
pemetrexed group and 10.2 months for those receiving placebo.  The median OS 
following induction chemotherapy in the overall study population was 13.4 months 
with pemetrexed and 10.6 months with placebo (unadjusted HR, 0.798; 95% CI: 0.65, 


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0.95; p0.012).  In the non-squamous population, the median OS was 15.5 months 
for pemetrexed-treated patients and 10.3 months for patients on placebo (unadjusted 
HR, 0.70; 95% CI: 0.56 to 0.88; p0.002).
A second study also explored the value of pemetrexed in the continuous maintenance 
setting.  In this study, patients who had not received prior treatment for lung cancer 
received four cycles of pemetrexedcisplatin.  Maintenance therapy was continued if 
stable disease, a PR, or a CR was documented.  Patients were then randomized in a 
2:1 fashion to either pemetrexedBSC or placeboBSC.  The median PFS in patients 
who received pemetrexed was 4.1 months (range: 3.2–4.6 months) compared with the 
median PFS of 2.8 months (range: 2.6–3.1 months) in patients who received placebo.  
The HR for PFS as assessed by the investigator was 0.62 (95% CI: 0.49, 0.79; 
p0.00006).  The PFS benefit was internally consistent, and benefit was seen 
across all clinically important subgroups.  OS data from this study are pending 
(Paz-Ares et al. 2012).
1.1.5
Targeted Therapy for NSCLC
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC (mainly non-squamous histology) 
characterized by alterations of driver oncogenes, including sensitizing EGFR mutations 
and ALK rearrangement.  However, these mutations are more prevalent in 
adenocarcinoma NSCLC and are very rare in squamous NSCLC.  Randomized Phase III 
studies of gefitinib (IPASS), erlotinib (EURTAC), and afatinib (LUX-Lung 3) showed 
significant improvement of PFS and ORR compared with platinum-doublet 
chemotherapy (Fukuoka et al. 2011; Rosell et al. 2012; Yang et al. 2012).  Similarly, the 
ALK inhibitors crizotinib and ceritinib have demonstrated efficacy in patients with NSCLC 
positive for ALK rearrangement as defined by fluorescence in situ hybridization 
(Crino et al. 2011; Camidge et al. 2012; Shaw et al. 2012; Shaw and Engelman 2014; 
XALKORI® USPI; ZYKADIAUSPI).
Despite progress with new targeted treatments and new chemotherapy combinations, 
survival rates for advanced disease remain low and acquired resistance to targeted 
agents is a major clinical problem.  Therefore, alternative treatment options that yield 
durable responses and enhance OS remain an important focus of research.  Against this 
background, immunotherapeutic agents, such as cancer vaccines and antibodies that 
modulate immune cell activity, offer an alternative treatment approach that could 
potentially improve the prognosis of patients with this disease.
1.2
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab (MPDL3280A) is a humanized immunoglobulin G1 monoclonal antibody 
consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids) 
and is produced in Chinese hamster ovary cells.  Atezolizumab was engineered to 
eliminate Fc-effector function via a single amino acid substitution at position 298 on the 


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heavy chain, which results in a non-glycosylated antibody that has minimal binding to 
Fc receptors and prevents Fc-effector function at expected concentrations in humans.  
Atezolizumab targets human programmed deathligand 1 (PD-L1) and inhibits its 
interaction with its receptors, programmed death1 (PD-1) and B7.1 (CD80, B7-1).  
Both of these interactions are reported to provide inhibitory signals to T cells.
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.  Atezolizumab is approved for the treatment of 
urothelial carcinoma, NSCLC, small-cell lung cancer, and triple-negative breast cancer.
1.2.1
Summary of Nonclinical Studies
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab.
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid 
in projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.
Overall, the nonclinical pharmacokinetics 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.
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.3
CLINICAL EXPERIENCE WITH ATEZOLIZUMAB
1.3.1
Ongoing Clinical Studies
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  Safety and efficacy data 
are summarized below from the following studies:

Study PCD4989g (GO27831):  A Phase Ia, multicenter, first-in-human, open-label,
dose-escalation study evaluating the safety, tolerability, immunogenicity,
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of
biologic activity of atezolizumab administered as a single agent by IV infusion
every 3 weeks (q3w) to patients with locally advanced or metastatic solid
malignancies or hematologic malignancies


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
Study GO28753 (hereinafter POPLAR):  A randomized, Phase II, open-label study 
assessing the clinical benefit of atezolizumab as a single agent versus docetaxel in 
PD-L1 unselected patients with locally advanced or metastatic NSCLC that has 
progressed during or following treatment with a platinum-containing regimen

Study GP28328:  A Phase Ib study of the safety and pharmacology of atezolizumab 
(antiPD-L1 antibody) administered with bevacizumab and/or with chemotherapy in 
patients with advanced solid tumors

Study GO28915 (OAK): A randomized, Phase III, open-label study assessing the 
efficacy and safety of atezolizumab as a single agent versus docetaxel in patients 
with locally advanced or metastatic NSCLC that has progressed during or following 
treatment with a platinum-containing regimen
1.3.2
Clinical Safety
1.3.2.1
Single-Agent Clinical Safety in Patients with NSCLC in 
Study PCD4989g
Study PCD4989g, in which atezolizumab is being used as a single agent in patients with 
locally advanced or metastatic solid tumors or hematologic malignancies, provides the 
majority of data (with 558 safety-evaluable patients as of the data extraction date of 
11 May 2015) for the safety profile of atezolizumab as monotherapy.
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined.
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications.  The most common cancer types for these patients include NSCLC, 
urothelial bladder cancer (UBC), melanoma, and renal cell carcinoma (RCC).  Safety 
data for NSCLC are also derived from Studies GO28625 (FIR) and the POPLAR study.
Adverse Events
Of the 558 patients, 520 patients (93.2%) experienced at least one adverse event, 
including 376 patients (67.4%) who experienced one treatment-related adverse event.  
Commonly reported events (reported in 10% of all patients) included fatigue, 
decreased appetite, nausea, pyrexia, constipation, and cough (see Table 2).


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Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades
Preferred Term
All Grades
n (%)
All Grades 
Related
n (%)
Grade 34
n (%)
Grades 34 
Related
n (%)
Any adverse event
520 (93.2)
376 (67.4)
239 (42.8)
66 (11.8)
Fatigue
192 (34.4)
115 (20.6)
13 (2.3)
6 (1.1)
Decreased appetite
142 (25.4)
62 (11.1)
4 (0.7)
0 (0.0)
Nausea
136 (24.4)
65 (11.6)
5 (0.9)
2 (0.4)
Pyrexia
117 (21.0)
63 (11.3)
2 (0.4)
0 (0.0)
Constipation
116 (20.8)
8 (1.4)
2 (0.4)
0 (0.0)
Cough
113 (20.3)
11 (2.0)
1 (0.2)
1 (0.2)
Dyspnea
112 (20.1)
18 (3.2)
18 (3.2)
4 (0.7)
Diarrhea
110 (19.7)
53 (9.5)
2 (0.4)
1 (0.2)
Anemia
104 (18.6)
26 (4.7)
23 (4.1)
5 (0.9)
Vomiting
96 (17.2)
28 (5.0)
3 (0.5)
2 (0.4)
Asthenia
88 (15.8)
53 (9.5)
8 (1.4)
4 (0.7)
Back pain
85 (15.2)
9 (1.6)
8 (1.4)
1 (0.2)
Headache
83 (14.9)
32 (5.7)
2 (0.4)
1 (0.2)
Arthralgia
79 (14.2)
35 (6.3)
2 (0.4)
0 (0.0)
Pruritus
75 (13.4)
55 (9.9)
0 (0.0)
0 (0.0)
Rash
73 (13.1)
53 (9.5)
0 (0.0)
0 (0.0)
Abdominal pain
63 (11.3)
12 (2.2)
8 (1.4)
0 (0.0)
Insomnia
62 (11.1)
7 (1.3)
1 (0.2)
0 (0.0)
Peripheral edema
59 (10.6)
7 (1.3)


Chills
57 (10.2)
31 (5.6)
0 (0.0)
0 (0.0)
Note:  “” refers to missing Common Terminology Criteria grade.
Grade 34 adverse events (on the basis of National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 [NCI CTCAE v4.0]) were reported 
in 239 patients (42.8%), of which 66 (11.8%) were considered related.  Grade 3 and 4 
adverse events considered related by the investigator included dyspnea, pneumonitis, 
increased ALT, increased AST, increased gamma-glutamyl transferase, lymphocyte 
count decreased, cardiac tamponade, asthenia, autoimmune hepatitis, pneumonia, 
influenza, and hypoxia.
Refer to the Atezolizumab Investigator’s Brochure for details on adverse events 
observed in patients treated with atezolizumab.


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Immune-Mediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
atezolizumab clinical program.  These include potential dermatologic, hepatic, endocrine, 
gastrointestinal, and respiratory events.
Refer to the Atezolizumab Investigator’s Brochure for details on immune-mediated
adverse events that were observed in patients treated with atezolizumab.  Guidelines for 
the management of immune-mediated adverse events are described in Section 5.1.6.2.
1.3.2.2
Single-Agent Clinical Safety in Patients with NSCLC in the 
POPLAR Study
As of the 8 May 2015 data cutoff date, the Phase II POPLAR study included data from 
142 patients treated with atezolizumab as a fixed dose of 1200 mg IV q3w and 
135 patients treated with docetaxel 75 mg/m2 IV q3w. The frequency of patients in the 
POPLAR study who reported any adverse event regardless of attribution was 96.3% for 
the atezolizumab arm and 95.8% for the docetaxel arm.  A higher number of Grade 3 
adverse events were observed in the docetaxel arm (56.3% vs. 44.4%), explained 
primarily by the difference in adverse events due to bone marrow suppression.  Adverse 
events reported in at least 10% of patients in either treatment arm are listed in Table 3.


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Table 3
Adverse Events Reported in at Least 10% of Patients in 
the POPLAR Study
MedDRA Preferred Term
Atezolizumab
n142
(%)
Docetaxel
n135
(%)
Fatigue
55 (38.7)
54 (40.0)
Decreased appetite
49 (34.5)
28 (20.7)
Nausea
31 (21.8)
45 (33.3)
Cough
38 (26.8)
33 (24.4)
Dyspnoea
38 (26.8)
27 (20.0)
Diarrhea
24 (16.9)
38 (28.1)
Constipation
29 (20.4)
32 (23.7)
Alopecia
3 (2.1)
52 (38.5)
Anemia
23 (16.2)
26 (19.3)
Pyrexia
24 (16.9)
16 (11.9)
Asthenia
14 (9.9)
22 (16.3)
Vomiting
18 (12.7)
18 (13.3)
Arthralgia
22 (15.5)
12 (8.9)
Rash
15 (10.6)
16 (11.9)
Insomnia
19 (13.4)
11 (8.1)
Back pain
16 (11.3)
11 (8.1)
Musculoskeletal pain
19 (13.4)
7 (5.2)
Myalgia
8 (5.6)
18 (13.3)
Neutropenia
2 (1.4)
17 (12.6)
Pneumonia
15 (10.6)
4 (3.0)
Neuropathy, peripheral
2 (1.4)
16 (11.9)
For additional information, refer to the Atezolizumab Investigator’s Brochure.


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1.3.2.3
Clinical Safety in Combination Platinum-Based 
Doublet Chemotherapy
Study GP28328 is a Phase Ib study of atezolizumab in combination with bevacizumab or 
cytotoxic chemotherapy in patients with multiple tumor types including NSCLC, 
triple-negative breast cancer, and colorectal cancer (CRC).  As of 10 February 2015, 
144 patients had been enrolled in this study:  39 in Arm A (atezolizumabbevacizumab), 
36 in Arm B (atezolizumabbevacizumab and FOLFOX [oxaliplatin, leucovorin, and 
5-fluorouracil]), 14 in Arm C (atezolizumabcarboplatin and paclitaxel), 24 in Arm D 
(atezolizumabcarboplatin and pemetrexed), 20 in Arm E (atezolizumabcarboplatin 
and nab-paclitaxel), and 11 in Arm F (atezolizumabnab paclitaxel).  The treatment 
combinations have been generally well tolerated.  No DLTs have been reported during 
the dose-escalation stage in any study arm.  Patients are being enrolled in safety and 
biopsy expansion cohorts in Arms A and B as well as in additional arms testing 
atezolizumab in combination with commonly used NSCLC chemotherapy doublets.
A total of 141 of 144 patients (97.9%) reported at least one adverse event while 
receiving study drug.  The majority of these events were Grade 2 and 3 in severity.  The 
five most commonly reported adverse events across the study arms (10% in patients) 
included fatigue, nausea, diarrhea, decreased appetite, and pyrexia.  The adverse 
events were consistent with the known safety profile of each agent (atezolizumab 
monotherapy and chemotherapy).  No additive effects were observed when 
atezolizumab was administered with chemotherapy.  See Table 4 for all adverse events 
reported in each treatment arm of Study GP28328.


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Table 4
Study GP28328:  All Reported Adverse Events
Parameter
Arm A
(n39)
No. (%)
Arm B
(n36)
No. (%)
Arm C
(n14)
No. (%)
Arm D
(n24)
No. (%)
Arm E
(n20)
No. (%)
Arm F
(n12)
No. (%)
All Patients
(n145)
No. (%)
Any AEs
39 (100)
36 (100)
14 (100)
24 (100)
19 (95.0)
10 (83.3)
142 (97.9)
Related AEs
29 (74.4)
28 (77.8)
12 (85.7)
19 (79.2)
19 (95.0)
6 (50.0)
113 (77.9)
Grade 35 AEs
20 (51.3)
29 (80.6)
12 (85.7)
17 (70.8)
18 (90.0)
6 (50.0)
102 (70.3)
Related Grade 35 AEs
1 (2.6)
7 (19.4)
4 (28.6)
4 (16.7)
11 (55.0)
4 (33.3)
31 (21.4)
Serious AEs
14 (35.9)
15 (41.7)
5 (35.7)
10 (41.7)
8 (40.0)
3 (25.0)
55 (37.9)
Related serious AEs
0 (0)
1 (2.8)
1 (7.1)
2 (8.3)
2 (10.0)
2 (16.7)
8 (5.5)
AEs leading to discontinuation
1 (2.6)
4 (11.1)
0 (0)
1 (4.2)
1 (5.0)
0 (0)
8 (5.6)
AEs leading to death (Grade 5)
0 (0)
2 (2.8)
1 (7.1)
2 (8.3)
2 (10.0)
1 (8.3)
7 (4.8)
Related AEs leading to death (Grade 5)
0 (0)
0 (0)
0 (0)
1 (4.2)
0 (0)
0 (0)
1 (0.7)
Immune-mediated AEs
12 (30.8)
28 (77.8)
8 (57.1)
11 (45.8)
11 (55.0)
2 (16.7)
72 (49.7)
AEadverse event.


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All 39 patients who were enrolled in Arm A reported one or more adverse event.  
The five most frequently reported events were consistent with the overall population 
and included fatigue, nausea, diarrhea, decreased appetite, and pyrexia.  There were 
36 patients enrolled in Arm B, and 97% of patients reported at least one adverse event.  
The most frequently reported adverse events (20% of patients) included fatigue, 
pyrexia, peripheral neuropathy, neutropenia, anemia, diarrhea, decreased appetite, 
temperature intolerance, constipation, vomiting, and nausea.
All patients who were enrolled in Arms C and D experienced an adverse event; 95% of 
patients who were enrolled in Arm E experienced an adverse event, and 83.3% of 
patients enrolled in Arm F experienced an adverse event.  The adverse events 
commonly reported in 2 or more patients in Arms C, D, and E included anemia, 
decreased appetite, hypomagnesemia, nausea, neutropenia, constipation, vomiting, 
fatigue, rash, cough, and diarrhea.  Adverse events commonly reported in 2 or more 
patients in Arm F included dermatitis, upper respiratory infection, alopecia, peripheral 
sensory neuropathy, fever, constipation, neutrophil count decreased, anemia, diarrhea, 
headache, nausea, and fatigue.
1.3.3
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)based responses (i.e., RECIST v1.1 responses), have been observed in 
patients with different tumor types treated with atezolizumab monotherapy in 
Study PCD4989g.
Refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in all 
patients treated to date, regardless of tumor type.
1.3.3.1
Single-Agent Clinical Activity in Patients with NSCLC in 
Study PCD4989g
As of the clinical data cutoff of 2 December 2014, the efficacy evaluable population 
included 88 patients with locally advanced or metastatic NSCLC.  The median age was 
60.5 years (range: 2484 years), and represented a heavily pre-treated patient 
population:  97% of the patients had received 2 prior systemic therapies, and 77.3% 
had received 4 prior systemic therapies.
Overall, responses were recorded for 20 of 88 (22.7%) patients with NSCLC, and 
included responses in patients with squamous and non-squamous NSCLC (4 in 
21 patients and 16 in 67 patients, respectively).  A total of 8 of the 20 responding 
patients have continued to respond at the time of the clinical data cutoff.
Table 5 displays the investigator-assessed confirmed ORR, confirmed duration of 
response (DOR), and 6-month PFS rates by PD-L1 expression for patients with NSCLC.  
These results are based on investigator assessed RECIST v1.1.  Analyses of 


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tumor-infiltrating immune cells (IC) and tumor cells (TC) for PD-L1 expression on 
baseline tumor tissue from NSCLC patients have been performed.
Refer to the Atezolizumab Investigator’s Brochure for details on the clinical activity in 
patients with NSCLC treated to date.
Table 5
Patients with NSCLC in Study PCD4989g:  Investigator-Assessed 
Confirmed Objective Response Rate by Tumor PD-L1 Expression, 
Duration of Response, and 6-Month Progression-Free Survival 
Rates (per RECIST Version 1.1)
PD-L1 IHC 
Expression 
Category
ORR by RECIST, 
Version 1.1
n 88
SD
(n/N)
PD
(n/N)
DOR (range 
in months)
6-month 
PFS 
% (95% CI)
TC3 or IC3
50.0% (11 of 22)
(95% CI: 28.22%, 
71.78%)
13.6%
(3/22)
31.8%
(7/22)
7.1625.26
50.0
(29.1, 70.9)
TC3 or IC2/3
37.5% (15 of 40)
(95% CI: 22.73%
54.2%)
12.5%
(5/40)
45.0%
(18/40)
7.1626.74+
44.9
(29.4, 60.3)
TC2/3 or IC2/3
33.3% (16 of 48)
(95% CI: 20.40%, 
48.41%)
22.9%
(11/48)
37.5%
(18/48)
7.1626.74+
41.6
(27.6, 55.5)
TC0/1/2 and IC0/1/2
15.5% (9 of 58)
(95% CI: 7.35%, 
27.42%)
37.9%
(22/58)
37.9%
(22/58)
7.1626.74+
41.1 
(28.4, 53.8)
TC0/1/2 and IC0/1
12.5% (5 of 40)
(95% CI: 4.19%, 
26.8%)
37.5%
(15/40)
40.0%
(16/40)
9.9224.74
42.3
(27, 57.7)
TC0/1 and IC0/1
12.5% (4 of 32)
(95% CI: 3.51%, 
28.99%)
43.8%
(14/32)
34.4%
(11/32)
9.9224.74
46.7
(29.3, 64.0)
DORduration of response; ICtumor-infiltrating immune cell; IHCimmunohistochemistry; 
NSCLCnonsmall cell lung cancer; ORRobjective response rate; PFSprogression-free 
survival; PRpartial response; PDprogressive disease; PD-L1programmed deathligand 1; 
RECIST Response Evaluation Criteria in Solid Tumors; SDstable disease; TCtumor cell.
Notes: This table is based on a data cutoff of 2 Dec 2014 of NSCLC patients. ORR includes 
confirmed responses. “” denotes a censored value.
1.3.3.2
Single-Agent Clinical Activity in Patients with NSCLC in the 
POPLAR Study
The primary OS analysis in the POPLAR study was conducted when 173 deaths had 
occurred (clinical cutoff, 8 May 2015).  Demographic characteristics were comparable 
between treatment arms in the intent-to-treat (ITT) population.  The median age was 
62 years (range: 4282 years for the atezolizumab arm, range: 3684 years for the 
docetaxel arm), and the majority of patients had one prior therapy (64.6% for 


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atezolizumab and 67.1% for docetaxel), non-squamous histology (66.0% for 
atezolizumab and 66.4% for docetaxel), and Eastern Cooperative Oncology Group
(ECOG) performance status of 1 (67.6% for atezolizumab and 68.3% for docetaxel).  
More females were enrolled in the docetaxel arm (46.9% vs. 35.4%).
Key efficacy results for the ITT population and the PD-L1selected subgroup categories 
are shown in the section below.  Atezolizumab showed significant improvement in 
overall survival compared with docetaxel in patients with advanced, previously treated 
NSCLC unselected for PD-L1 expression.  OS in the ITT population was 12.6 months 
(95% CI: 9.7, 16.4) for atezolizumab versus 9.7 months (95% CI: 8.6, 12.0) for docetaxel 
(HR0.73; 95% CI: 0.53, 0.99; p0.04).  PFS was similar between groups (2.7 months 
with atezolizumab vs. 3.0 months with docetaxel). Objective responses with 
atezolizumab were durable, with a median duration of 14.3 months (95% CI: 11.6, not 
estimable) compared with 7.2 months (95% CI: 5.6, 12.5) for docetaxel 
(Fehrenbacher et al. 2016).
Table 6
Efficacy Results in the POPLAR Study:  Intent-to-Treat 
Population
Efficacy Endpoint
Atezolizumab
(n144)
Docetaxel
(n143)
Overall survival
No. of deaths (%)
78 (54.2)
95 (66.4)
Median (months)
95% CI
12.6
9.7, 16.4
9.7
8.6, 12.0
Stratified hazard ratio
95% CI
0.73
0.53, 0.99
Progression-free survival
No. of events (%)
124 (86.1)
121 (84.6)
Median (months)
95% CI
2.7
2.0, 4.1
3.0
2.8, 4.1
Stratified hazard ratio
95% CI
0.94
0.72, 1.23
Objective response rate (confirmed)
14.6%
14.7%
Duration of response
Median (months)
14.3
7.2
95% CI
11.6, NE
5.6, 12.5
NEnot estimable.
In summary, the data from the POPLAR study show that atezolizumab provides survival 
benefit in previously treated patients with NSCLC.


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1.3.3.3
Clinical Efficacy in Combination with Platinum-Based Doublet 
Chemotherapy in Patients with NSCLC
As of the 10 February 2015 data cutoff, 58 patients with NSCLC who were enrolled into 
Arms C, D, or E of the Phase Ib Study GP28328.  Patients who had received their first 
dose of atezolizumab by 10 November 2014 were evaluable for efficacy (n41).  
Patients who were enrolled into Arms C, D, and E received 15 mg/kg atezolizumab 
administered q3w in combination with carboplatinpaclitaxel, carboplatinpemetrexed, 
and carboplatinnab-paclitaxel, respectively.  All patients had histologically or 
cytologically documented Stage IIIB, Stage IV, or recurrent NSCLC and had not received 
prior chemotherapy for advanced disease.  The median age was 65 years, and 79% of 
patients had non-squamous histology.  The overall response rate in all three arms 
combined was 63% (26 of 41 patients).
Within each cohort, the ORR was 50% (95% CI: 16%, 84%) in Arm C (4 PRs among 
8 patients), 77% (95% CI: 50%, 93%) in Arm D (13 PRs among 17 patients), and 56%
(95% CI: 30%, 80%) in Arm E (5 PRs and 4 complete responses [CRs] among 
16 patients).  Patients with high levels of PD-L1 expression appeared to have higher 
response rates, but responses were also seen in patients with lower PD-L1 expression 
levels. Careful attention was paid to the use of steroid premedication with pemetrexed in 
Arm A of this study because of the potential for steroids to hinder atezolizumab activity.  
Specifically, efforts to reduce prophylactic steroid use were successful without resulting 
in any significant increase in the incidence of rash, nausea, or other related toxicities 
(Liu et al. 2015).
1.3.4
Clinical Pharmacokinetics and Immunogenicity
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab appeared 
to show linear pharmacokinetics at doses 1 mg/kg.  For the 1-mg/kg and 20-mg/kg 
dose groups, the mean apparent clearance and the mean volume of distribution under 
steady-state conditions had a range of 3.11 to 4.14 mL/kg and 48.1 to 67.0 mL/kg, 
respectively, which is consistent with the expected profile of an IgG1 antibody in humans.
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses from 10 to 20 mg/kg.  
Patients in the 10-, 15-, and 20-mg/kg dose cohorts have maintained the expected target 
trough levels of drug despite the detection of ATAs.  To date, no clear relationship 
between the detection of ATAs and adverse events or infusion reactions or efficacy has 
been observed.
1.3.5
Rationale for Atezolizumab Dosage
The fixed dose of 1200 mg (equivalent to an average body weightbased dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below.


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The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors. The 
target trough concentration (Ctrough) was projected to be 6 g/mL on the basis of several 
assumptions, including the following:  1) 95% tumor-receptor saturation is needed for 
efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue 
distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, PK, and 
immunogenicity data. Anti-tumor activity has been observed across doses from 1 mg/kg 
to 20 mg/kg. The MTD of atezolizumab was not reached, and no DLTs have been 
observed at any dose in Study PCD4989g. Currently available PK and ATA data 
suggest that the 15-mg/kg atezolizumab q3w regimen (or fixed-dose equivalent) for 
Phase II and Phase III studies would be sufficient to both maintain Ctrough 6 g/mL and 
further safeguard against both interpatient variability and the potential effect of ATAs that 
could lead to subtherapeutic levels of atezolizumab relative to the 10-mg/kg 
atezolizumab q3w regimen (or fixed-dose equivalent).  From inspection of available 
observed Ctrough data, moving further to the 20-mg/kg atezolizumab q3w regimen does 
not appear to be warranted to maintain targeted Ctrough levels relative to the proposed 
15-mg/kg atezolizumab q3w level.
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in
exposure following a fixed dose or a dose adjusted for weight.  Therefore, a fixed dose 
of 1200 mg has been selected (equivalent to an average body weightbased dose of 
15 mg/kg).  Selection of an every-21-day dosing interval is supported by this preliminary 
pharmacokinetics evaluation.
Refer to the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012).
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1. PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is sustained in 
states of chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008). Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of 
T cells.  B7.1 is a molecule expressed on antigen-presenting cells and activated T cells.  
PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate 


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downregulation of immune responses, including inhibition of T-cell activation and 
cytokine production (Butte et al. 2007; Yang et al. 2011).
Overexpression of PD-L1 on TCs has been reported to impede anti-tumor immunity, 
resulting in immune evasion (Blank and Mackensen 2007).  Therefore, interruption of the 
PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific 
T-cell immunity.
PD-L1 expression is prevalent in many human tumors, and elevated PD-L1 expression 
is associated with a poor prognosis in patients with NSCLC (Mu et al. 2011).
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies and who have failed standard of care therapies.  At the time 
of Study GO29438 initiation, Study PCD4989g, a Phase Ia dose-escalation and 
expansion study of patients treated with atezolizumab as a single agent had the 
following clinical activity:  345 evaluable patients were dosed by 21 October 2013 
(data cutoff date as of 21 April 2014) with a minimum of 6 months of follow-up; 
62 patients experienced objective responses per RECIST v1.1 with an ORR of 18.0% 
(95% CI: 14.1%, 22.3%).  Objective responses were observed across a broad range of 
malignancies, including NSCLC, RCC, melanoma, and UBC.
In addition, as explained above, the POPLAR study key efficacy results for the ITT 
population and the PD-L1−selected subgroup categories indicate that an OS benefit in 
the atezolizumab arm was observed, with a stratified HR of 0.78 (95% CI: 0.59, 1.03) 
even though PFS and ORR for the atezolizumab arm were similar to those for the 
docetaxel arm.
1.4.1
Rationale for Testing Atezolizumab in Combination with 
Carboplatin or Cisplatin and Pemetrexed
Platinum-based regimens remain the standard first-line option for patients with locally 
advanced or metastatic NSCLC that is not harboring EGFR mutations or ALK gene 
rearrangements.  However, the survival benefit conferred by cytotoxic chemotherapy has 
reached a plateau, with overall response rates of approximately 20% and 1-year survival 
ranging from 31% to 36% (Schiller et al. 2002), leaving considerable room for 
improvement in outcomes.  TC killing by cytotoxic chemotherapy can reasonably be 
expected to expose the immune system to high levels of tumor antigens, and 
invigorating tumor-specific T-cell immunity in this setting by inhibiting PD-L1/PD-1 
signaling may result in deeper and more durable responses compared with standard 
chemotherapy alone (Merritt et al. 2003; Apetoh et al. 2007).  Evaluating the safety and 
efficacy of these treatment combinations in NSCLC patients will enable future tests of 
this hypothesis.
The combination of platinum-based doublet chemotherapy and atezolizumab in NSCLC 
was evaluated in the Phase Ib study GP28328 as detailed in Section 1.3.3.3.  On the 


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basis of results observed in GP28328, Study GO29438 is designed to evaluate whether 
the anti-tumor effect seen in atezolizumab-treated patients would translate into
statistically significant and clinically relevant improvement in PFS and OS when used in 
combination with carboplatin or cisplatinpemetrexed compared with carboplatin or 
cisplatinpemetrexed in patients with non-squamous NSCLC. This study will allow for 
the evaluation of the efficacy of atezolizumab in the ITT population.
This study will enroll patients with Stage IV non-squamous NSCLC who are naive to 
chemotherapy treatment and for whom the experimental arm can represent a valuable 
treatment option and a reasonable benefit-risk balance.  Patients whose tumors are 
known to harbor sensitizing EGFR mutations or ALK rearrangements are excluded given 
that the appropriate and current standard-of-care treatments of these patients is with an 
EGFR tyrosine kinase or ALK inhibitor. 
In order to account for the possibility of pseudoprogression and tumor-immune infiltration 
(i.e., radiographic increase in tumor volume due to the influx of immune cells) 
(Hales et al. 2010) and the potential for delayed anti-tumor activity, this study will allow
patients treated with atezolizumab to receive treatment beyond the initial apparent 
radiographic progression (see Section 3.3.5 and Section 4.6) and will use modified 
RECIST (in addition to RECIST v1.1) to evaluate clinical benefit.  Because it is not yet 
possible to reliably differentiate pseudoprogression and tumor-immune infiltration from
true tumor progression, the risk exists that some patients who are not responding to 
treatment but yet continuing to receive atezolizumab may experience further progression 
of NSCLC and delay treatment with subsequent therapies for which they are eligible.  
Investigators should make every effort to fully inform patients of this risk.
Atezolizumab has been generally well tolerated (see Section 1.3.2); adverse events with 
potentially immune-mediated causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis, 
have been observed in Study PCD4989g.  To date, these events have been 
manageable with treatment.
In summary, treatment with atezolizumab offers the potential for clinical benefit in 
NSCLC patients, in addition to platinum-based chemotherapy.  Patients will be fully 
informed of the risk of continuing study treatment in spite of apparent radiographic 
progression, and investigators should make a careful assessment of the potential 
benefit of doing so, considering radiographic data, biopsy results, and the clinical status 
of the patient.


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2.
OBJECTIVES
Unless stated otherwise, the following objectives will be assessed in patients who are 
chemotherapy-naive and have stage IV non-squamous NSCLC (the ITT population) 
treated with atezolizumabcarboplatin or cisplatinpemetrexed (Arm A) in comparison 
with carboplatin or cisplatinpemetrexed (Arm B).
2.1
EFFICACY OBJECTIVES
2.1.1
Co-Primary Efficacy Objectives
The co-primary objectives of this study are:

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
PFS according to RECIST v1.1

To evaluate the efficacy of atezolizumab as measured by OS
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are:

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
ORR according to RECIST v1.1

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
DOR according to RECIST v1.1

To evaluate the OS rate at 1 and 2 years

To determine the impact of atezolizumab as measured by time to deterioration (TTD) 
in patient-reported lung cancer symptoms of cough, dyspnea (single-item and 
multi-item subscales), chest pain, or arm/shoulder pain using the European 
Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life 
QuestionnaireCore 30 (QLQ-C30) and the supplemental lung cancer module 
(QLQ-LC13)

To determine the impact of atezolizumab as measured by the change from baseline
in patient-reported lung cancer symptoms (chest pain, dyspnea, and cough) scores 
using the Symptoms in Lung Cancer (SILC) scale symptom severity scores
2.2
SAFETY OBJECTIVES
The safety objectives for this study are:

To evaluate the safety and tolerability of atezolizumab when given in combination 
with carboplatin or cisplatinpemetrexed or as maintenance therapy with 
pemetrexed alone

To evaluate the incidence and titers of ATAs against atezolizumab and to explore 
the potential relationship of the immunogenicity response with pharmacokinetics, 
safety, and efficacy


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2.3
PHARMACOKINETIC OBJECTIVES
The PK objectives for this study are:

To characterize the pharmacokinetics of atezolizumab when given in combination 
with carboplatin or cisplatinpemetrexed or pemetrexed alone

To characterize the pharmacokinetics of carboplatin when given in combination with 
atezolizumab and pemetrexed

To characterize the pharmacokinetics of cisplatin when given in combination with 
atezolizumabpemetrexed

To characterize the pharmacokinetics of pemetrexed when given in combination 
with atezolizumabcarboplatin or cisplatin
2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are:

To evaluate the PFS rate at 6-month and 1-year landmark timepoints

To evaluate the OS rate at 3 years in each treatment arm

To evaluate the efficacy of atezolizumab as measured by OS and 
investigator-assessed PFS according to RECIST v1.1 in subgroups based on 
demographic and baseline characteristics

To evaluate the efficacy of atezolizumab as measured by milestone survival

To evaluate the relationship between biomarkers in tumors and blood (including, but 
not limited to, PD-L1, PD-1, somatic mutations and others), as defined by
immunohistochemistry (IHC), quantitative reverse transcriptasepolymerase chain 
reaction (qRT-PCR), next-generation sequencing (NGS), and/or other methods and 
measures of efficacy

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in 
archival and/or fresh tumor tissue and blood and their association with disease 
status, mechanisms of resistance, and/or response to study treatment

To evaluate and compare patient’s health status as assessed by the EuroQoL 
5 Dimensions 5-Level (EQ-5D-5L) questionnaire to generate utility scores for use in 
economic models for reimbursement

To determine the impact of atezolizumab in each of the treatment comparisons 
described in Section 2.1.1 as measured by change from baseline in patient-reported 
outcomes (PROs) of health-related quality of life (HRQoL), lung cancerrelated
symptoms, and health status as assessed by the EORTC QLQ-C30 and QLQ-LC13


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3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a randomized, Phase III, multicenter, open-label study (IMpower 132) designed to 
evaluate the safety and efficacy of atezolizumab in combination with cisplatin or 
carboplatinpemetrexed compared with treatment with cisplatin or 
carboplatinpemetrexed in patients who are chemotherapy-naive and have Stage IV 
non-squamous NSCLC. Figure 1 illustrates the study design.  Schedules of 
assessments are provided in Appendix 1 and Appendix 2.
Figure 1
Study Schema
ECOG PSEastern Cooperative Oncology Group performance status; NSCLCnonsmall cell 
lung cancer; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.


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Eligible patients will be stratified by sex (male vs. female), smoking status (never vs. 
current and/or former), ECOG performance status (0 vs. 1) and chemotherapy regimen 
(carboplatin vs. cisplatin) and randomized by a 1:1 ratio to receive one of the following 
treatment regimens as shown in Table 7.
Table 7
Study GO29438 Treatment Arms
Treatment Arm
Induction
(Four or Six 21-Day Cycles)
Maintenance
(21-Day Cycles)
A
Atezolizumabcarboplatin or 
cisplatinpemetrexed
Atezolizumabpemetrexed
B
Carboplatin or cisplatinpemetrexed
Pemetrexed
The number of cycles of induction treatment (four or six) will be at the discretion of the 
investigator and will be determined and documented prior to randomization.  Induction 
treatment will be administered on a 21-day cycle until the following occurs (whichever 
occurs first):  1) administration of four or six cycles, 2) unacceptable toxicity, or 
3) documented disease progression.
Following the induction phase, patients who have not experienced disease progression 
or unacceptable toxicity will continue treatment with maintenance therapy as shown in 
Table 7.  Patients randomized to either Arm A or B will continue treatment with 
pemetrexed maintenance until progressive disease, unacceptable toxicity, or death.  
During induction or maintenance treatment, patients randomized to Arm A may continue 
treatment with atezolizumab beyond progressive disease by RECIST v1.1, provided they 
are experiencing clinical benefit as assessed by the investigator as described below:
For Treatment Arm A
During treatment (induction or maintenance), patients who show evidence of clinical 
benefit will be permitted to continue atezolizumab after RECIST v1.1 for progressive 
disease are met if they meet all of the following criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating 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 (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Patients must provide written consent to acknowledge deferring other treatment 
options in favor of continuing study treatment at the time of initial progression.


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Treatment with chemotherapy (both in Arm A and B) should be discontinued in all 
patients who exhibit evidence of progressive disease by RECIST v1.1.
Patients will undergo tumor assessments at baseline and every 6 weeks for the 
first 48 weeks following Cycle 1, Day 1, regardless of dose delays.  After the completion 
of the Week 48 tumor assessment, tumor assessment will be required every 9 weeks.  
Patients will undergo tumor assessments until radiographic disease progression per
RECIST v1.1 or loss of clinical benefit (for atezolizumab-treated only patients who 
continue treatment after radiographic disease progression according to RECIST v1.1), 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
Patients who discontinue treatment for reasons other than radiographic disease 
progression (e.g., toxicity) will continue scheduled tumor assessments until radiographic 
disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab-treated 
patients who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever 
occurs first, regardless of whether patients start a new anti-cancer therapy.
All primary imaging data used for tumor assessment will be collected by the Sponsor to 
enable centralized, independent review of response endpoints. The independent 
reviews of the stored scans will be performed when requested.  
This study will initially enroll approximately 568 patients across all sites in a global 
enrollment phase.  If at least 1 patient is enrolled in China during the global enrollment 
phase, additional patients will be enrolled in a China extension phase as needed to 
ensure a total enrollment of approximately 164 patients in China treated with cisplatin 
and pemetrexedatezolizumab.  The China subpopulation will include patients enrolled 
at sites in China during both the global enrollment phase and the China extension phase.
3.1.1
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will be used to evaluate safety data 
when a minimum of 12 patients receiving cisplatin-based chemotherapy have been 
enrolled into each treatment arm with a minimum follow-up of approximately 60 days, 
and then approximately every 6 months thereafter until the study is unblinded for primary 
efficacy analyses or the study is terminated by the Sponsor.
The Sponsor will remain blinded to the efficacy results until the final PFS analysis.  
All summaries and analyses by treatment arm for the iDMC review will be prepared by 
an external independent Data Coordinating Center (iDCC).  The safety data will include 
disposition, demographic data, adverse event data (e.g., serious adverse events and 
adverse events of special interest), study conduct data, and relevant laboratory data. 
Efficacy data (excluding data on deaths) will not be included in the iDMC safety data 
reviews.  Following the safety data review, the iDMC will provide a recommendation as 
to whether the study may continue, whether amendment(s) to the protocol should be 


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implemented, or whether the study should be stopped.  The final decision will rest with 
the Sponsor.
Members of the iDMC will be external to the Sponsor and will follow a separate iDMC 
Charter that outlines their roles and responsibilities.
Any outcomes of these safety or efficacy reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the Institutional 
Review Boards (IRBs) and Ethics Committees (ECs).
3.2
END OF STUDY AND LENGTH OF STUDY
The end of study is defined as the date of the last follow-up visit of the last patient or 
when all patients have been enrolled into an extension study.  The Sponsor may decide 
to terminate the study at any time.  If the Sponsor decides to end the study, patients who 
are still receiving study treatment or are in survival follow-up may be offered enrollment 
in an extension study or a non-interventional study.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Testing Atezolizumab in Patients with 
PD-L1Unselected NSCLC
Despite recent improvements in treatment, the prognosis for patients with advanced 
NSCLC remains dismal, with a median OS of approximately 12.3 months 
(Sandler et al. 2006).  Patients who receive second-line treatment for their disease 
have an even more limited prognosis, with a median survival duration of 
approximately 89 months (Stinchcombe et al. 2008).  Approved therapies are 
associated with significant toxicities (e.g., neuropathy, febrile neutropenia, 
myelosuppression, and alopecia) that negatively affect 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, and expression of PD-L1 by TCs in several tumor types 
(including NSCLC) correlates with response to therapy (Topalian et al. 2012).
Atezolizumab monotherapy has demonstrated clinical efficacy and is generally 
well-tolerated in patients with squamous or non-squamous NSCLC (Besse et al. 2015; 
Horn et al. 2015; Spigel et al. 2015; Fehrenbacher et al. 2016).  In the second- and 
third-line setting, the POPLAR study, the first randomized Phase II study of atezolizumab 
in advanced NSCLC, showed significant improvement in OS with atezolizumab 
(12.6 vs. 9.7 months; HR0.73, 95% CI: 0.53, 0.99, p0.04) versus docetaxel 
(Fehrenbacher et al. 2016).  In patients with squamous and non-squamous disease, 
OS was 10.1 versus 8.6 months (HR0.80, 95% CI: 0.49, 1.30) and 15.5 versus 
10.9 months (HR0.69, 95% CI: 0.47, 1.01), respectively, in the atezolizumab arm
compared with the docetaxel arm (Fehrenbacher et al. 2016).


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On the basis of promising efficacy activity of atezolizumab as a single agent (POPLAR,
Study PCD4989g) and in combination with platinum-doublet therapy (Study GP28328) 
and the safety findings from Study GP28328 indicating no additive toxicity of 
atezolizumab in combination with platinum-based chemotherapy or bevacizumab, this 
study will evaluate atezolizumab in combination with platinum-based chemotherapy.  
TC killing by cytotoxic chemotherapy may expose the immune system to high levels of 
tumor antigens, and invigorating tumor-specific T-cell immunity in this setting by 
inhibiting PD-L1/PD-1 signaling may result in deeper and more durable responses 
compared with standard chemotherapy alone (Merritt et al. 2003; Apetoh et al. 2007),
and this may reasonably occur in tumors regardless of PD-L1 expression.
3.3.2
Rationale for Control Arm
A common standard of care in first-line treatment for advanced stage non-squamous 
NSCLC is a platinum doublet with either cisplatin or carboplatin and pemetrexed.  In this 
study, all patients in the experimental arm will receive the platinum doublet of carboplatin 
or cisplatin with pemetrexed with atezolizumab followed by maintenance 
pemetrexedatezolizumab.  The control group will receive the combination of 
carboplatin or cisplatinpemetrexed followed by pemetrexed maintenance.  This control 
group is recognized as a standard of care for the first-line treatment of non-squamous
NSCLC based on the results of the two previous Phase III studies as stated above 
and is the most commonly used first-line regimen in the United States and Europe 
(see Section 1.1).
3.3.3
Rationale for Open-Label Study
An open-label study design was chosen for this study for the following reasons:  
a blinded study would require prolonged administration of placebo during the 
maintenance phase, which could pose a significant burden to patients. Furthermore, 
because of the potential for pseudoprogression in patients randomized to atezolizumab-
containing arms, a blinded study would require the option that all patients continue 
treatment until loss of clinical benefit regardless of whether they were receiving 
atezolizumab. In the absence of pseudoprogression, this could then delay subsequent 
treatment with approved therapies for NSCLC in patients assigned to any treatment arm, 
as well as increase the complexity of treatment decisions.
Adequate steps have been taken to ensure the validity of data in an open-label study 
design. This includes performing a sensitivity analysis to demonstrate the robustness of 
the co-primary endpoints, defining progression using established response evaluation 
criteria (RECIST v1.1), performing tumor assessments at the same frequency in all arms, 
adhering to protocol-defined schedules, and determining the strategy for the final 
analysis of the co-primary endpoints prior to study start, including predefined methods 
for handling missing data and censoring rules. Final efficacy analyses will only be 
performed at the prespecified analysis timepoints in the protocol.


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3.3.4
Rationale for Progression-Free Survival and Overall Survival
as Co-Primary Endpoints
The co-primary endpoint of OS has been added to the PFS primary endpoint because 
recent data suggest that OS may be a more sensitive endpoint for cancer 
immunotherapy than PFS.  For example, in the randomized Phase II POPLAR study in 
patients with advanced NSCLC, an OS benefit in the atezolizumab arm compared with 
the docetaxel arm was observed, with a stratified HR of 0.73 (95% CI: 0.53, 0.99) 
(Fehrenbacher et al. 2016).  In addition, OS is the most objective and best measure of 
clinical benefit for patients with advanced, unresectable, or metastatic lung cancer.
However, given that the majority of patients in this study will likely receive subsequent 
therapies and/or palliative care (Temel et al. 2010), the OS analysis may be 
confounded (Miller et al. 2012). Therefore, investigator-assessed PFS is being retained 
as a co-primary endpoint, and crossover from the control arm to the experimental arm 
will not be permitted with the aim of preserving the study’s ability to potentially 
demonstrate treatment benefit of atezolizumab on OS.
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; in addition, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents a 
direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the 
effect and the benefit-risk of the new treatment compared with available therapies 
(Guidance for Industry 2007; European Medicines Agency 2012).  To ensure the validity 
of investigator-assessed PFS as a co-primary endpoint, a number of measures have 
been implemented:  a substantial, clinically meaningful target magnitude of benefit 
(target HR of 0.65 in the ITT population), and study assessments that will allow a robust 
evaluation of risk-benefit (standard RECIST to define progression with fixed assessment 
intervals that are identical in all treatment arms and a robust definition of PFS and 
prospectively defined methods to assess, quantify, and analyze PFS, including 
sensitivity analyses).
New treatment modalities, such as targeted therapies and immunotherapy, are emerging 
as highly effective regimens that are providing improvements in patient outcomes far 
beyond what was achieved before (Ellis et al. 2014).  In particular, immunotherapy has 
been correlated or associated with durable responses, significant prolongation of PFS, 
and improvement of quality of life.  In addition, meta-analyses have indicated that PFS 
can be considered a good measure of clinical benefit for patients with locally advanced
and/or metastatic NSCLC (Laporte et al. 2013).
3.3.5
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment until Loss of Clinical Benefit
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure.  Because of the potential for 


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pseudoprogression and tumor-immune infiltration, this study will allow patients 
randomized to the atezolizumab treatment arms to remain on atezolizumab after 
apparent radiographic progression, provided the benefit-risk ratio is judged to be 
favorable.  Patients should be discontinued for unacceptable toxicity or symptomatic 
deterioration attributed to disease progression as determined by the investigator after an 
integrated assessment of radiographic data and clinical status (see Section 3.1). 
3.3.6
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 effects on HRQoL
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).  This is 
especially true for studies that use PFS as a primary endpoint, where it is important 
to better understand in what regard the delay in disease progression is meaningful 
to patients.
Chest pain, dyspnea, and cough have been regarded as the most frequent and clinically 
relevant disease-related symptoms experienced by patients with NSCLC.  The BR.21 
study (erlotinib vs. BSC in second- or third-line NSCLC) demonstrated that longer TTD in 
the pain, dyspnea, and cough scales of the EORTC QLQ-C30 and EORTC QLQ-LC13 
was consistent with superior PFS, OS, and QoL 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 first-line study also reported significant delay of TTD in 
lung cancer symptoms (chest pain, dyspnea, and cough) as measured by the EORTC 
QLQ-C30 and EORTC QLQ-LC13 (Yang et al. 2013).  In this study, the validated 
EORTC QLQ-C30 and EORTC QLQ-LC13 will be used to assess HRQoL and 
symptom severity.
In addition, the SILC scale will be used to assess the effect and impact of atezolizumab 
as measured by the change from baseline in patient-reported specific lung cancer 
symptoms (chest pain, dyspnea, and cough) in patients with Stage IV, non-squamous 
NSCLC in the first-line setting.
The EQ-5D-5L (see Appendix 9) is included in the study to generate utility scores for use 
in economic models for reimbursement.  Results from the EQ-5D-5L are not planned to 
be used for market authorization.
3.3.7
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPD-1 therapy (Topalian et al. 2012).  This correlation was also 
observed with atezolizumab in Study PCD4989g (Herbst et al. 2014; Horn et al. 2015), 
and the FIR (Spiegel et al. 2015), BIRCH (Study GO28754) (Besse et al. 2015), and 
POPLAR (Fehrenbacher et al. 2016) studies. In this study, although tumor tissues are 
not required for enrollment, baseline archival and/or fresh tumor specimens from 


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patients will be obtained if available and may be tested (retrospectively) for PD-L1 
expression by a central laboratory.
In addition to the assessment of PD-L1 status, other exploratory markers, such as 
potential predictive and prognostic markers related to the clinical benefit of atezolizumab, 
tumor immunobiology, mechanisms of resistance, or tumor type, may also be analyzed.  
DNA and/or RNA extraction and analysis may be performed to enable identification of 
somatic mutations by use of NGS and to evaluate expression of genes (including, but 
not limited to, PD-L1, PD-1, T-effector cells, and others) to assess their association with 
efficacy and to increase understanding of disease pathobiology.
3.3.8
Rationale for Blood Sampling for Biomarkers
An exploratory objective of this study is to evaluate surrogate biomarkers (that may 
include circulating tumor DNA [ctDNA], gene expression, and others) in blood samples.  
Evaluation of blood biomarkers may provide evidence for biologic activity of 
atezolizumab in patients with NSCLC and may allow for the development of blood-based 
biomarkers to help predict which patients may benefit from atezolizumab.
In addition, potential correlations of these biomarkers with the safety and activity of 
atezolizumab will be explored.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
3.4.1.1
Co-Primary Efficacy Outcome Measures
The primary efficacy outcome measures for this study are:

PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator using RECIST v1.1 or death from any 
cause, whichever occurs first.  Patients who have not experienced disease 
progression or death at the time of analysis will be censored at the time of last tumor 
assessment.  Patients with no post-baseline tumor assessment will be censored at 
the randomization date plus 1 day.

OS, defined as the time from randomization to death from any cause
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are:

Objective response, defined as PR or CR as determined by the investigator 
according to RECIST v1.1

DOR, defined as the time interval from first occurrence of a documented objective 
response to the time of disease progression as determined by the investigator using 
RECIST v1.1 or death from any cause, whichever comes first

OS at 1- and 2-year landmark timepoints


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
TTD in patient-reported lung cancer symptoms, defined as time from randomization 
to deterioration (10-point change) on each of the EORTC QLQ-C30 and 
EORTC QLQ-LC13 symptom subscales 

Change from baseline in patient-reported lung cancer symptoms (cough, dyspnea, 
or chest pain) with use of the SILC scale symptom score
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are:

Incidence, nature, and severity of adverse events graded according to the 
NCI CTCAE v4.0

Changes in vital signs, physical findings, and clinical laboratory results during and 
following study treatment administration

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are the following:

Maximum observed serum atezolizumab concentration (Cmax) after infusion (Arm A)

Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at 
selected cycles, at treatment discontinuation, and at 120 days (30 days) after the 
last dose of atezolizumab (Arm A)

Plasma concentrations for carboplatin or cisplatin (Arm A)

Plasma concentrations for pemetrexed (Arm A) 
See Appendix 2 for specific sample collection times.
3.4.4
Exploratory Outcome Measures
The exploratory outcome measures for this study are:

PFS at 6-month and 1-year landmark timepoints

OS rate at 3-year landmark timepoint

Milestone survival

OS and investigator-assessed PFS according to RECIST v1.1 in subgroups based 
on demographic and baseline characteristics

Status of PD-L1, immune- and NSCLC-related and other exploratory biomarkers in 
archival and/or fresh tumor tissues, and blood (or blood derivatives) collected before, 
during, or after treatment with atezolizumab or at progression and association with 
disease status and/or response to atezolizumab in combination with chemotherapy

Utility scores of the EQ-5D-5L

Change from baseline in PROs of HRQoL, lung cancerrelated symptoms, and 
health status as assessed by the EORTC QLQ-C30 and QLQ-LC13


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients may be eligible if they are chemotherapy-naive and have Stage IV, 
non-squamous NSCLC.  Approximately 568 patients will be enrolled during the global 
enrollment phase of the study.  If at least 1 patient is enrolled in China during the global 
enrollment phase, additional patients will be enrolled in a subsequent China extension 
phase as needed to ensure a total enrollment of approximately 164 patients in the China 
cisplatin subpopulation.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Male or female, 18 years of age or older

ECOG performance status of 0 or 1 (see Appendix 10)

Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the 
Union Internationale contre le Cancer/American Joint Committee on Cancer staging 
system, 7th edition; Detterbeck et al. 2009; see Appendix 3)
Patients with tumors of mixed non-small cell histology (i.e., squamous and 
non-squamous) are eligible if the major histological component appears to be 
non-squamous.

No prior treatment for Stage IV non-squamous NSCLC
Patients with a sensitizing mutation in the EGFR gene are excluded given that 
erlotinib, gefitinib, or another EGFR TKI is the appropriate initial treatment of 
EGFR-mutant NSCLC.
Patients with an ALK fusion oncogene are excluded given that crizotinib or 
other ALK inhibitors is the appropriate initial treatment of NSCLC in patients 
having an ALK fusion oncogene.
Patients with unknown EGFR and ALK status require test results at screening. 
ALK and/or EGFR may be assessed at a local or central laboratory.

Patients who have received prior neo-adjuvant, adjuvant chemotherapy, 
radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease 
must have experienced a treatment-free interval of at least 6 months from 
randomization since the last dose of chemotherapy and/or radiotherapy

Patients with a history of treated asymptomatic CNS metastases are eligible, 
provided they meet all of the following criteria:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 7 days or whole-brain radiation within 14 days 
prior to randomization


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No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening scan 
must receive radiation therapy and/or surgery for CNS metastases.  Following 
treatment, these patients may then be eligible without the need for an additional 
brain scan prior to randomization, if all other criteria are met.

Patients should submit a pre-treatment tumor tissue sample (if available).  If tumor 
tissue is not available (e.g., depleted for prior diagnostic testing), patients are still 
eligible. 
If tumor tissue is available, a representative formalin-fixed paraffin-embedded 
(FFPE) tumor specimen in paraffin block or unstained, freshly cut, serial sections 
(preferably at least 10) from an FFPE tumor specimen are preferred.  If 10 sections 
are not available, fewer can be submitted. 
If FFPE specimens described above are not available, any type of specimens 
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural effusion], 
and lavage samples) are also acceptable.
This specimen should be accompanied by the associated pathology report.  
See Section 4.5.7.1 for further details.
Any available tumor tissue sample should be submitted before or within 
4 weeks after enrollment.

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can only be considered as measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of disease.

Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to randomization:
ANC 1500 cells/L without granulocyte colony-stimulating factor support
Lymphocyte count 500/L
Platelet count 100,000/L without transfusion
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
INR or aPTT 1.5upper limit of normal (ULN)
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be receiving a stable 
dose.
AST, ALT, and alkaline phosphatase 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase 
5ULN


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Serum bilirubin 1.25ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN 
may be enrolled.
Calculated creatinine clearance (CRCL) 45 mL/min or, if using cisplatin, 
calculated CRCL must be 60 mL/min

For patients enrolled in the extended China enrollment phase: current resident of 
mainland China, Hong Kong, or Taiwan and of Chinese ancestry
For women of childbearing potential:  agreement to remain abstinent (refrain 
from heterosexual intercourse) or use contraceptive methods that result in 
a failure rate of 1% per year during the treatment period and for at least
5 months after the last dose of atezolizumab and 6 months after the last dose of 
cisplatin, carboplatin, or pemetrexed.  Women must refrain from donating eggs 
during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of non-hormonal contraceptive methods with a failure rate of 
1% per year include bilateral tubal ligation, male sterilization, established, 
proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below:
With partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure 
rate of 1% per year during the chemotherapy treatment period and for at least 
6 months after the last dose of chemotherapy.
With pregnant partners, men must remain abstinent or use a condom during the 
chemotherapy treatment period and for at least 6 months after the last dose of 
chemotherapy.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.


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4.1.2
Exclusion Criteria
Patients who meet any of the criteria below will be excluded from study entry.
4.1.2.1
Cancer-Specific Exclusions

Patients with a sensitizing mutation in the EGFR gene or an ALK fusion oncogene

Active or untreated CNS metastases as determined by CT or magnetic resonance 
imaging (MRI) evaluation during screening and prior radiographic assessments

Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 2 weeks prior to randomization

Leptomeningeal disease

Uncontrolled tumor-related pain
Patients requiring pain medication must be receiving a stable regimen at study 
entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to randomization.  Patients should be recovered from the effects of radiation.  
There is no required minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy, if appropriate, prior to randomization.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or 
calcium 12 mg/dL or corrected serum calcium ULN)
Patients who are receiving denosumab prior to randomization must be willing 
and eligible to discontinue its use and replace it with a bisphosphonate instead 
while in the study.

Malignancies other than NSCLC within 5 years prior to randomization, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 
5-year OS 90%) treated with expected curative outcome (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized 
prostate cancer treated surgically with curative intent, ductal carcinoma in situ 
treated surgically with curative intent)

Known tumor PD-L1 expression status as determined by an IHC assay from other 
clinical studies (e.g., patients whose PD-L1 expression status was determined 
during screening for entry into a study with anti-PD-1 or antiPD-L1 antibodies 
but were not eligible are excluded)


Atezolizumab—F. Hoffmann-La Roche Ltd
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4.1.2.2
General Medical Exclusions

Women who are pregnant, lactating, or intending to become pregnant during the 
study

History of severe allergic, anaphylactic, or other hypersensitivity reactions 
to chimeric or humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary cells or any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, 
multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 12 for a 
comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-related hypothyroidism who are receiving
a stable dose of thyroid-replacement hormone are eligible for this study.
Patients with controlled Type 1 diabetes mellitus who are receiving a stable 
dose of insulin regimen are eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions:
Rash must cover less than 10% of body surface area.
Disease is well controlled at baseline and only requiring low-potency topical 
steroids.
No acute exacerbations of underlying condition within the last 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral 
steroids)

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test for HIV
All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the clinical study.

Patients with active hepatitis B (chronic or acute; defined as having a positive 
hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of 
HBsAg) are eligible only if they are negative for HBV DNA.


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Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible.

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
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or left ventricular ejection fraction 50% must be 
receiving a stable medical regimen that is optimized in the opinion of the 
treating physician, in consultation with a cardiologist if appropriate.

Major surgical procedure other than for diagnosis within 28 days prior to 
randomization or anticipation of need for a major surgical procedure during the 
course of the study

Prior allogeneic bone marrow transplantation or solid organ transplant

Administration of a live attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study

Any other diseases, 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 or that may affect the 
interpretation of the results or renders the patient at high risk from treatment 
complications

Illness or condition that may interfere with a patient’s capacity to understand, follow, 
and/or comply with study procedures
4.1.2.3
Exclusion Criteria Related to Medications

Prior treatment with EGFR inhibitors or ALK inhibitors

Any approved anti-cancer therapy, including hormonal therapy within 21 days prior 
to initiation of study treatment.

Treatment with any other investigational agent with therapeutic intent within 28 days 
prior to randomization

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
antiPD-1, and antiPD-L1 therapeutic antibodies


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Patients who have had prior anticytotoxic T-lymphocyte associated antigen 4 
(CTLA-4) treatment may be enrolled, provided the following requirements 
are met:
Last dose of anti-CTLA-4 at least 6 weeks prior to randomization
No history of severe immune-related adverse effects from anti-CTLA-4 
(NCI CTCAE Grade 3 and 4)

Treatment with systemic immunostimulatory agents (including, but not limited to,
interferons, interleukin 2) within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to randomization
Prior treatment with cancer vaccines is allowed.

Treatment with systemic immunosuppressive medications (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization
Patients who have received acute, low-dose (10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in 
the study.
The use of corticosteroids (10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) 
for patients with orthostatic hypotension, and low-dose supplemental 
corticosteroids for adrenocortical insufficiency are allowed.
4.1.2.4
Exclusion Criteria Related to Chemotherapy

History of allergic reactions to cisplatin, carboplatin, or other platinum-containing 
compounds

Patients with hearing impairment (cisplatin)

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 (cisplatin)

CRCL 60 mL/min for cisplatin or 45 mL/min for carboplatin
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label study.
After written informed consent has been obtained and eligibility has been established, 
the study site will enter demographic and baseline characteristics in the interactive 
voice/Web response system (IxRS).  For patients who are eligible for enrollment, the 
study site will obtain the patient’s randomization number and treatment assignment from 
the IxRS.  The number of cycles of induction treatment (four or six) will be determined by 
the investigator and documented prior to randomization.
Randomization to one of the two treatment arms 
(carboplatin/cisplatinpemetrexedatezolizumab or carboplatin/cisplatinpemetrexed) 
will occur in a 1:1 ratio.  Permuted-block randomization will be applied to ensure a 


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balanced assignment to each treatment arm.  Randomization will be stratified by the 
following criteria:

Sex (male vs. female)

Smoking status (never vs. current or former)

ECOG performance status (0 vs. 1)

Chemotherapy (cisplatin vs. carboplatin)
Patients should receive their first dose of study drug on the day of randomization if 
possible.  If this is not possible, the first dose should occur within 5 business days after 
randomization.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab
The atezolizumab drug product is provided as a sterile liquid in 20-mL glass vials.  
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may 
contain more than the stated volume to enable delivery of the entire 20-mL volume.
For further details on the formulation and handling of atezolizumab, see the Pharmacy 
Manual and Investigator’s Brochure.
4.3.1.2
Carboplatin or CisplatinPemetrexed
The comparator arm includes a platinum-based regimen (carboplatin or cisplatin 
based on investigator’s choice)pemetrexed.  This study will randomize approximately
568 patients in the global enrollment phase.
After the global enrollment phase, additional patients may be enrolled in China to ensure 
a total of approximately 164 patients in the China cisplatin subpopulation, including 
those enrolled in China in the global enrollment phase.  Patients enrolled in the China 
extension phase will receive cisplatin.
Each study drug will be used in the commercially available formulation (with the 
exception of atezolizumab) and will be provided by the Sponsor if it is considered an 
Investigational Medical Product (IMP) by local regulations (see Section 4.3.3).
For information on the formulation, packaging, and handling of cisplatin, carboplatin, and 
pemetrexed, see the local prescribing information for each drug.


 
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4.3.2 
Dosage, Administration, and Compliance 
The induction phase of the study will consist of four or six cycles of chemotherapy, each 
cycle being 21 days in duration.  On Day 1 of each cycle, all eligible patients will receive 
drug infusions in the following order: 
Arm A:  Atezolizumab  [carboplatin or cisplatin  pemetrexed] 
Arm B:  [carboplatin or cisplatin  pemetrexed] 
 
During the induction phase, a chemotherapy cycle counts toward the prespecified 
number of induction chemotherapy cycles (4 or 6) as long as at least one chemotherapy 
component has been administered at least once during a 21-day cycle.  Cycles in which 
no chemotherapy component is given do not count toward the total number of induction 
chemotherapy cycles.  Additional guidance is provided in Appendix 14. 
Patients who experience no further clinical benefit (for patients enrolled into Arm A, see 
Section 3.1 for definition) or disease progression (for patients enrolled into Arm B) at any 
time during the induction phase will discontinue all study treatment.  In the absence of 
the above criteria, after the 4 or 6-cycle induction phase, patients will begin maintenance 
therapy (atezolizumab  pemetrexed in Arm A or pemetrexed in Arm B). 
During treatment (induction or maintenance), Arm A patients who show evidence of 
clinical benefit will be permitted to continue atezolizumab after RECIST v1.1 for 
progressive disease are met if they meet all criteria listed in Section 3.1.  However, 
treatment with chemotherapy should be discontinued. 
Patients should receive anti-emetics and IV hydration for platinum-pemetrexed 
treatments according to the local standard of care and manufacturer’s instruction.  
However, due to their immunomodulatory effects, premedication with steroids should be 
limited when clinically feasible.  In addition, in the event of pemetrexed-related skin rash, 
topical steroid use is recommended as front-line treatment whenever is clinically feasible.  
Table 8 lists the premedication for pemetrexed.  Table 9 lists the suggested infusion 
times for treatment administration for pemetrexed  platinum during the induction and 
maintenance phases. 
Table 8 
Premedication for Pemetrexed 
Premedication 
Dose and Route 
Timing 
Folic acid 
350–1000 g PO 
Once daily beginning at least 5–7 days before 
Cycle 1, Day 1 and continuing until 3 weeks after 
discontinuation of pemetrexed 
Vitamin B12 
1000 g IM 
q9w beginning Cycle 1, Day 1 and continuing until 
3 weeks after discontinuation of pemetrexed 
Dexamethasone 
(suggested) 
4 mg PO 
Twice daily the day before, the day of, and the day 
after pemetrexed administration 
IM  intramuscular; PO  oral; q9w  every 9 weeks. 


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Table 9
Treatment Regimen for PemetrexedPlatinum-Based 
Chemotherapy
Study Drug
Dose and 
Route
Induction Period 
(Four or Six Cycles)
Maintenance Period 
(Until PD)
Pemetrexed
500 mg/m2 IV
Over approximately10 minutes 
on Day 1 q3w
Over approximately 
10 minutes on Day 1 q3w
Carboplatin
AUC 6 IV
Over approximately 
3060 minutes on Day 1 q3W
Not applicable
OR
Cisplatin
75 mg/m²
Over 1–2 hours on Day 1 q3w
Not applicable
AUCarea under the concentrationtime curve; IVintravenous; PDprogressive disease; 
q3wevery 3 weeks.
Guidelines for dose modification and treatment interruption or discontinuation for 
carboplatin or cisplatin and pemetrexed are provided in Section 5.1.6.1, Section 5.1.8, 
and Section 5.1.9.
4.3.2.1
Atezolizumab
Patients randomized to atezolizumab will receive 1200 mg of atezolizumab administered 
by IV infusion every 21 days in a monitored setting where there is immediate access to 
trained personnel and adequate equipment and medicine to manage potentially serious 
reactions.
Atezolizumab infusions will be administered per the instructions outlined in Table 10.


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Table 10 Administration of First and Subsequent Infusions 
of Atezolizumab
First Infusion
Subsequent Infusions

No premedication administered for 
atezolizumab specifically is permitted

Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.

Infuse atezolizumab (1200 mg in a 250 mL 
0.9% NaCl IV bag) over 60 (15) minutes.

If clinically indicated, record patient’s vital 
signs (pulse rate, respiratory rate, blood 
pressure, and temperature) during the 
infusion at 15, 30, 45, and 60 minutes 
(5-minute windows are allowed for all 
timepoints).

If clinically indicated, record patient’s vital 
signs (pulse rate, respiratory rate, blood
pressure, and temperature) at 
30 (10) minutes after the infusion.

Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If patient experienced infusion-related 
reaction during any previous infusion, 
premedication with antihistamines may be 
administered for Cycles 2 at the 
discretion of the treating physician.

Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.

If the patient tolerated the first infusion 
well without infusion-associated adverse 
events, the second infusion may be 
delivered over 30 (10) minutes.

If no reaction occurs, subsequent 
infusions may be delivered over 
30 (10) minutes.
Continue to record vital signs within 
60 minutes before starting infusion.  
Record vital signs during and after the 
infusion, if clinically indicated.

If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be delivered 
over 60 (15) minutes.
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) every 15 (5) minutes 
during the infusion if clinically indicated or 
patient experienced symptoms during the 
previous infusion.
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) 30 (10) minutes after the 
infusion if clinically indicated or patient 
experienced symptoms during the
previous infusion.
IVintravenous; NaClsodium chloride.
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are 
provided in Section 5.1.6.2 and Appendix 15.
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.


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4.3.2.2
PemetrexedCarboplatin or Cisplatin
4.3.2.2.1
Pemetrexed
Institutions should follow their standard administration procedures for pemetrexed.  
The premedication doses administered should be in compliance with the 
prescribing information.  All patients eligible for pemetrexed therapy should avoid taking 
non-steroidal anti-inflammatory drugs with long elimination half-lives for at least 5 days 
prior to, on the day of, and at least 2 days following pemetrexed administration.
4.3.2.2.2
Cisplatin
IV infusion should be administered approximately 30 minutes after completion of the 
pemetrexed infusion at a dose of 75 mg/m² over 1–2 hours or per standard of care at the 
institution.  Patients must receive adequate anti-emetic treatment and appropriate 
hydration prior to and after receiving cisplatin.
Refer to local clinical practice guidelines for further details.
4.3.2.2.3
Carboplatin
Carboplatin should be administered 30 minutes after completion of pemetrexed 
administration by IV infusion over 3060 minutes to achieve an initial target area under 
the concentrationtime curve (AUC) of 6 mg/mL/min (Calvert formula dosing) with 
standard anti-emetics per local practice guidelines.
The carboplatin dose of AUC 6 will be calculated using the Calvert formula 
(Calvert et al. 1989):
Calvert Formula
Total dose (mg)(target AUC)(glomerular filtration rate [GFR]25)
NOTE:  The GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min.
For the purposes of this protocol, the GFR is considered to be equivalent to the CRCL.  
The CRCL is calculated by institutional guidelines or by the method of Cockcroft and 
Gault (1976) using the following formula:
CRCL
(140 – age) (wt)
(0.85 if female)
72 Scr
Where:
CRCLcreatinine clearance in mL/min
agepatient’s age in years 
wtpatient’s weight in kg
Scrserum creatinine in mg/dL


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NOTE:  For patients with an abnormally low serum creatinine level, estimate the GFR 
through use of a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 
125 mL/min.
If a patient’s GFR is estimated based on serum creatinine measurements by the isotope 
dilution mass spectroscopy method, the U.S. Food and Drug Administration (FDA)
recommends that physicians consider capping the dose of carboplatin for desired 
exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert 
formula described in the carboplatin label, the maximum doses can be calculated 
as follows:
Maximum carboplatin dose (mg)target AUC (mg min/mL)(GFR25 mL/min)
The maximum dose is based on a GFR estimate that is capped at 150 mL/min for 
patients with normal renal function.  No higher estimated GFR values should be used.
For a target AUC6, the maximum dose is 6 150900 mg.
For a target AUC5, the maximum dose is 5 150750 mg.
For a target AUC4, the maximum dose is 4 150600 mg.
Refer to the FDA’s communication regarding carboplatin dosing at the following Web site
for more details:
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/
ucm228974.htm
4.3.3
Investigational Medicinal Product Accountability
The investigational medicinal products for this study are atezolizumab and pemetrexed.  
Depending on local classification, in this study, cisplatin and carboplatin may either be 
considered a non−investigational medicinal product or an IMP.
The study site will acknowledge receipt of the IMPs using IxRS to confirm 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 returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Atezolizumab
The Sponsor will evaluate the appropriateness of continuing to provide atezolizumab to 
patients assigned to this treatment after evaluating the primary and secondary efficacy 
outcome measures and safety data gathered in the study and in accordance with the 


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Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
These analyses may be conducted prior to completion of the study.
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs or homeopathic remedies, nutritional supplements) used by a patient from 7 days 
prior to screening until the treatment discontinuation visit.  All such medications should be 
reported to the investigator.
4.4.1
Permitted Therapy
Premedication with antihistamines may be administered for any atezolizumab infusions 
after Cycle 1.
The following therapies should continue while patients are in the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level)

Palliative radiotherapy (e.g., treatment of known bony metastases) provided it does 
not interfere with the assessment of tumor target lesions (e.g., the lesion being 
irradiated is not the only site of disease, as that would render the patient not 
evaluable for response by tumor assessments according to RECIST v1.1)
It is not a requirement to withhold atezolizumab during palliative radiotherapy.

Inactive influenza vaccinations

Megestrol administered as an appetite stimulant

Inhaled corticosteroids for chronic obstructive pulmonary disease

Mineralocorticoids (e.g., fludrocortisone)

Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2-receptor antagonist per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local practice).  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 


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respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 11). 
All medications must be recorded on the appropriate Concomitant Medications electronic 
Case Report Form (eCRF).
4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations where 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered first by the treating physician.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the treating physician except in the case of patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance) (see also Section 4.4.3).
Systemic corticosteroids are recommended, with caution at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with 
atezolizumab therapy.  Guidelines for the management of immune-mediated adverse 
events are described in Section 5.1.6.2 and Appendix 15.
4.4.3
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment, depending on the anti-cancer agent (see Section 4.1.2), and 
during study treatment until disease progression is documented and patient has 
discontinued study treatment.  This includes, but is not limited to, chemotherapy, 
hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal 
therapy (unless otherwise noted).
The following medications are prohibited while the patient is in the study, unless 
otherwise noted:

Denosumab; patients who are receiving denosumab prior to enrollment must be 
willing and eligible to receive a bisphosphonate instead.

Any live attenuated vaccine (e.g., FluMist®) within 4 weeks prior to randomization or 
during treatment or within 5 months following the last atezolizumab dose (for 
patients randomized to atezolizumab).

Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, non-contrast CT scans of the chest and non-contrast CT scans or 
MRIs of the abdomen and pelvis should be performed.


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The concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, their use for patients in the study is allowed at the discretion of the 
investigator provided that there are no known interactions with any study treatment.  
As noted above, herbal therapies intended for the treatment of cancer are prohibited.
4.5
STUDY ASSESSMENTS
Flowcharts of scheduled study assessments are provided in Appendix 1 and Appendix 2.
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.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  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.
Patients who are treated with atezolizumab and who show apparent radiographic 
progression at a tumor response evaluation must sign consent to acknowledge deferring 
other treatment options before continuing treatment with atezolizumab beyond apparent 
radiographic progression.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to the screening visit.
NSCLC cancer history will include prior cancer therapies, procedures, and an 
assessment of tumor mutational status (e.g., sensitizing EGFR mutation, ALK fusion 
status).  For patients not previously tested for tumor mutational status, testing will be 
required at screening.  For these patients, testing can either be performed locally or 
submitted for central evaluation during the screening period.  If EGFR mutations or ALK
status testing is not performed locally, additional tumor sections may be required for 


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central evaluation of the mutational status of these genes.  Review tissue requirements 
for central evaluation in the central laboratory instruction manual.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of temperature, pulse rate, respiratory rate, and 
systolic and diastolic blood pressures while the patient is in a seated position.
Vital signs will be measured and recorded at screening and as described in Table 11.
Table 11 Vital Sign Measurements at Cycle 1 and All Subsequent Cycles
Treatment Arm
Cycle 1
Timepoints
Arm A

Within 60 minutes prior to atezolizumab infusion

During the atezolizumab infusion (every 15 [5] minutes) if clinically 
indicated

Within 30 (10) minutes after atezolizumab infusion if clinically indicated
Arms A and B
Within 30 (10) minutes after carboplatin or cisplatin infusion
Treatment Arm
Subsequent Cycles
Timepoints
Arm A

Within 60 minutes prior to atezolizumab infusion

During the atezolizumab infusion (every 15 [5] minutes) if clinically 
indicated or symptoms occurred during prior infusion

Within 30 (10) minutes after atezolizumab infusion if clinically indicated 
or symptoms occurred during prior infusion
For patients in the atezolizumab arm, also refer to Section 4.3.2.1.


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4.5.5
Tumor and Response Evaluations
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRIs of the chest and abdomen.  A CT or MRI scan of the pelvis is
required at screening and as clinically indicated or as per local standard of care at 
subsequent response evaluations.  A spiral CT scan of the chest may be obtained but is 
not a requirement.
A CT (with contrast if not contraindicated) or MRI scan of the head must be done at 
screening to exclude CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.  
Patients with active or untreated CNS metastases are not eligible for the study 
(see Section 4.1.2.1).
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET) or CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan.
Bone scans and CT scans of the neck should also be performed if clinically indicated.  
At the investigator’s discretion, other methods of assessment of measurable disease as 
per RECIST v1.1 may be used.
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days of Cycle 1, Day 1, may be used rather than repeating tests.  
All known sites of disease must be documented at screening and re assessed at each 
subsequent tumor evaluation.  Patients with history of irradiated brain metastases at 
screening are not required to undergo imaging brain scans at subsequent tumor 
evaluations, unless scans are clinically indicated.  The same radiographic procedure 
used to assess disease sites at screening should be used throughout the study (e.g., the 
same contrast protocol for CT scans).  Response will be assessed by the investigator
using RECIST v1.1 (see Appendix 4) and modified RECIST (see Appendix 5) for 
patients in Arm A and RECIST v1.1 in Arm B. Assessments should be performed by the 
same evaluator, if possible, to ensure internal consistency across visits.  Results must 
be reviewed by the investigator before dosing at the next cycle. 
Tumor assessments should occur every 6 weeks (7 days) for 48 weeks following Cycle 
1, Day 1 and then every 9 weeks (7 days) thereafter, after the completion of the 
Week 48 tumor assessment, regardless of treatment delays, until radiographic disease 
progression per RECIST v1.1 (loss of clinical benefit for atezolizumab-treated patients 
who continue treatment beyond disease progression according to RECIST v1.1 only), 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.
Patients who discontinue treatment for reasons other than radiographic disease 
progression per RECISTv1.1 (e.g., toxicity, symptomatic deterioration) will continue 
scheduled tumor assessments until radiographic disease progression per RECIST v1.1 


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(or loss of clinical benefit for atezolizumab-treated patients who had continued treatment 
with atezolizumab after radiographic disease progression according to RECIST v1.1), 
withdrawal of consent, death, or study termination by Sponsor, whichever occurs first.
Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 will continue scheduled tumor assessments until 
radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who had continued treatment with atezolizumab after 
radiographic disease progression according to RECIST v1.1), withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first.
Patients who are treated with atezolizumab who continue to experience clinical benefit, 
despite evidence of radiographic progression, will continue tumor assessments as per 
the schedule listed above.
Scans will be submitted to an IRF.
4.5.6
Laboratory Assessments and Biomarker Samples
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin)

Coagulation (aPTT or INR)

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed at Day 1 of each 
cycle during treatment prior to administration of study treatment.  If a urine 
pregnancy test result is positive, it must be confirmed by a serum pregnancy test.
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, or bilateral oophorectomy or not being postmenopausal 
(12 months of amenorrhea).

Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood); dipstick 
permitted

Thyroid function testing (thyroid-stimulating hormone, free T3, free T4)
Total T3 (instead of free T3) will be tested only at sites where free T3 testing 
cannot be performed.


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
HBV serology:  HBsAg, antibodies against HBsAg (HBsAb or anti-HBs), and 
hepatitis B core antibody (HBcAb)
If the patient has a negative serology for HBsAg and a positive serology for 
HBcAb, an HBV DNA test must be obtained prior to randomization and must be 
negative.

HCV serology:  HCV antibody (anti-HCV)
If the patient tests positive for anti-HCV, an HCV RNA must be obtained prior to 
randomization and be negative.

HIV testing
All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the clinical study.
A central laboratory will coordinate the sample collection of tissue and blood samples for 
research-related testing at central laboratories or at the Sponsor. Instruction manuals 
and supply kits will be provided for all central laboratory assessments.  Samples for the 
following laboratory tests will be sent to one or several central laboratories or to the 
Sponsor for analysis:

ATA assays (all atezolizumab-treated patients)
Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of validated immunoassays.  Accompanying PK samples will be collected 
at the same timepoints.

PK assays
Blood samples for PK assessments will be obtained according to the schedule 
in Appendix 2.
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.
At selected sites, a subset of 20 patients in Arm A will undergo additional PK 
assessments for carboplatin, cisplatin, and pemetrexed.
Plasma carboplatin, cisplatin, and pemetrexed concentrations will be 
assayed using validated methods.

Biomarker assays in blood samples
Blood samples will be obtained for biomarker evaluation (including, but not 
limited to, biomarkers that are related to NSCLC or tumor immune biology) from 
all eligible patients according to the schedule in Appendix 2.  Samples will be 
processed to obtain EDTA plasma and serum for the determination of changes 
in blood-based biomarkers (e.g., ctDNA, cytokines).  Whole blood samples may 
be processed to obtain their derivatives (e.g., RNA and DNA) and evaluated for 
immune-related, tumor typerelated, and other exploratory biomarkers 
(e.g., alterations in gene expression or single nucleotide polymorphisms).


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Residual PK and ATA samples will be retained for further method development, 
validation, and characterization.  Samples will be stored for up to 5 years after 
the date of final completion of the Clinical Study Report.

For patients who consent to the optional collection of samples for the Roche Clinical 
Repository (RCR) any leftover material from the above sample collection will be 
stored and used for exploratory analyses as indicated in Section 4.5.11.  For 
patients who consent to RCR optional future research on their whole blood samples 
collected at screening but are determined to be ineligible for study participation, 
these samples and their derivatives (e.g., DNA, RNA, protein) may be used for 
future development of biomarker and/or diagnostic tests as indicated in 
Section 4.5.11.
4.5.7
Tumor Tissue Samples
4.5.7.1
Archival or Freshly Collected Tumor Tissue Samples at 
Screening
A pre-treatment tumor tissue (archival or freshly obtained) sample (if available) should 
be submitted before or within 4 weeks after enrollment.  This specimen must be 
accompanied by the associated pathology report.  Although any available tumor tissue 
sample can be submitted, it is strongly encouraged that the sites submit representative 
tumor specimens in paraffin blocks (preferred) or 10 (or more) serial, freshly cut,
unstained slides exploratory biomarker analysis (including, but not limited to, markers 
related to immune or NSCLC biology, such as T-cell markers or non-inherited 
biomarkers identified through NGS on extracted DNA and/or RNA).
The preferred sample types include resections, core needle, excisional, incisional, punch, 
or forceps biopsies. If specimens described above are not available, any type of 
specimens (including fine-needle aspiration, cell pellet specimens e.g., from pleural 
effusion, and lavage samples) are also acceptable.
Tumor tissue should be of good quality based on total and viable tumor content.  Tumor 
tissue from bone metastases that is subject to decalcification is not advisable.  If tumor 
tissue is not available, the patient is still eligible.
For archival samples, the remaining tumor tissue block for all patients enrolled will be 
returned to the site upon request or 18 months after final closure of the study database, 
whichever is sooner.  Tissue samples from patients who are deemed ineligible to enroll 
in the study will be returned no later than 6 weeks after eligibility determination.
4.5.7.2
Optional Tumor Samples at the Time of Radiographic 
Progression
Patients in all treatment arms can undergo an optional tumor biopsy to obtain a tumor 
sample at the time of radiographic disease progression (preferably within 40 days of 
radiographic progression or prior to start of the next anti-cancer treatment, whichever is 
sooner) if they have provided consent for Optional Biopsy.


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The preferred sample types include resections, core needle, excisional, incisional, punch, 
or forceps biopsies.  If such specimens are not available, any type of specimens 
including fine-needle aspiration, cell pellet specimens (e.g., from pleural effusion and 
lavage samples) can also be submitted.
The status of immune-related, tumor typerelated and other exploratory biomarkers 
(including but not limited to T-cell markers and non-inherited biomarkers identified 
through NGS on extracted DNA and RNA) in tumor tissue samples may be evaluated.
NGS may be performed by Foundation Medicine. If it is performed by Foundation 
Medicine, the investigator can obtain results from the samples collected at the time of 
disease progression in the form of an NGS report, which is available upon request 
directly from Foundation Medicine. The investigator may share and discuss the results 
with the patient, unless the patient chooses otherwise. The Foundation Medicine NGS 
assay has not been cleared or approved by the FDA; results from these investigational 
tests should not be used to guide future treatment decisions.
4.5.7.3
Tumor Samples at Other Timepoints
If a patient undergoes a medically indicated procedure (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) any time during the course of the study 
that has the likelihood of yielding tumor tissue, any remaining samples or a portion of the 
sample not necessary for medical diagnosis (leftover tumor tissue) may be obtained 
for exploratory analysis.
Patients with additional tissue samples from procedures performed at different times 
during the course of their study participation (during treatment and during survival 
follow-up) who have signed the RCR optional consent will be requested (but not required) 
to also submit these optional fresh biopsy samples for central testing.  Tumor tissue 
samples collected at the time of clinical events (e.g., clinical response, etc.) are 
preferred.  Tissue samples obtained at multiple times for individual patients will greatly 
contribute to an improved understanding of the dynamics of PD-L1 expression and 
relationship with intervening anti-cancer therapy.
4.5.7.4
Use and Storage of Remaining Samples from 
Study-Related Procedures
The remainder of samples obtained for study-related procedures will be destroyed no 
later than 5 years after the end of the study or earlier depending on local regulations.  
If the patient provides optional consent for storing samples in the RCR for future 
research (see Section 4.5.11), the samples will be destroyed no later than 15 years after 
the date of final closure of the clinical database.
4.5.8
Anti-Therapeutic Antibody Testing
Treatment with atezolizumab may elicit an immune response.  Patients with signs of any 
potential immune response to atezolizumab will be closely monitored.  Validated 


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screening and confirmatory assays will be employed to detect ATAs at multiple 
timepoints before, during, and after treatment with atezolizumab (see Appendix 1 and 
Appendix 2 for the schedule).  The immunogenicity evaluation will use a risk-based 
immunogenicity strategy (Rosenberg and Worobec 2004; Koren et al. 2008) to
characterize ATA responses to atezolizumab in support of the clinical development 
program.  This tiered strategy will include an assessment of whether ATA responses 
detected correlate with relevant clinical endpoints.  Implementation of ATA 
characterization assays will depend on the safety profile and clinical 
immunogenicity data.
4.5.9
Electrocardiograms
A 12-lead ECG is required at screening and as clinically indicated.  ECGs should be 
obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.10
Patient-Reported Outcomes
PRO data will be collected via the EORTC QLQ-C30, EORTC QLQ-LC13, SILC, and 
EQ-5D-5L to fully characterize the clinical profile of atezolizumab.
The questionnaires will be translated as required in the local language.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires scheduled for administration during a clinic visit will be completed in their 
entirety by the patient prior to the performance of non-PRO assessments and the 
administration of study treatment.
Patients will use an electronic PRO (ePRO) device to capture PRO data.  The ePRO 
device and instructions for completing the PRO questionnaires electronically will be 
provided by the investigator staff.  The data will be transmitted via a prespecified 
transmission method (e.g., Web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the internet.
The EORTC QLQ-C30 (see Appendix 7) is a validated and reliable self-report measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999) that consists of 30 questions that assess
five aspects of patient functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, pain), global health and quality of 
life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties).  Scale scores can be obtained for the multi-item scales.  


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The EORTC QLQ-C30 module takes approximately 15 minutes to complete.  
This questionnaire will be completed on the ePRO tablet at each scheduled study visit 
during study treatment and during survival follow-up at 3 months and 6 months following 
disease progression or loss of clinical benefit (for atezolizumab-treated patients who 
continue treatment after radiographic disease progression according to RECIST v1.1).
The EORTC QLQ-LC13 (see Appendix 8) module incorporates one multiple-item scale 
to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, 
dysphagia, peripheral neuropathy, alopecia, and hemoptysis.  The EORTC QLQ-LC13 
module takes approximately 15 minutes to complete.  This questionnaire will be 
completed on the ePRO tablet at each scheduled study visit during the study treatment 
period and during survival follow-up at 3 months and 6 months following disease or loss 
of clinical benefit (for atezolizumab-treated patients who continued treatment after 
disease progression according to RECIST v1.1).
The SILC scale (see Appendix 13) will be used to assess patient-reported severity of 
lung cancer symptoms (chest pain, dyspnea, and cough). The SILC scale is a 9-item 
content valid self-report measure of lung cancer symptoms. It measures severity of 
cough, dyspnea, and chest pain with a symptom severity score. This questionnaire will 
be completed using an ePRO device at the patient’s home on a weekly basis, then 
during survival follow-up every month for 6 months following disease progression or loss 
of clinical benefit (for atezolizumab-treated patients who continue treatment after disease 
progression according to RECIST v1.1).
The EQ-5D-5L is a generic, preference-based health utility measure with questions 
about mobility, self-care, usual activities, pain and discomfort, and anxiety and 
depression that is used to build a composite of the patient’s health status 
(see Appendix 9).  The EQ-5D-5L will be used in this study for economic modeling.  
This questionnaire will be completed on the ePRO tablet at each scheduled study 
visit during the study treatment period and during survival follow-up at 3 months 
and 6 months following disease progression or loss of clinical benefit (for 
atezolizumab-treated patients who continued treatment after disease progression 
according to RECIST v1.1).
Patients who discontinue study treatment for any reason other than radiographic
progressive disease or loss of clinical benefit will complete the EORTC QLQ-C30, 
EORTC QLQ-LC13, and EQ-5D-5L at each tumor assessment visit and will complete the
SILC at home on a weekly basis until radiographic disease progression per RECIST v1.1 
(or loss of clinical benefit as determined by the investigator for atezolizumab-treated 
patients who continue treatment after radiographic disease progression) (unless the 
patient withdraws consent or the Sponsor terminates the study).


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Patients whose native language is not available in the ePRO device or who are deemed 
incapable of inputting their ePRO assessment after undergoing appropriate training are 
exempt from all ePRO assessments.
4.5.11
Samples for Roche Clinical Repository
4.5.11.1
Overview of the Roche Clinical Repository
The RCR 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 and analysis of RCR 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 RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site’s IRB or EC and, if applicable, an appropriate regulatory 
body.  If a site has not been granted approval for RCR sampling, this section of the 
protocol (Section 4.5.11) will not be applicable at that site.
4.5.11.3
Sample Collection
The following samples may be collected for patients who have signed the RCR optional 
consent:

Optional fresh biopsy samples

Leftover tumor tissue samples

Remaining fluids (serum, plasma, blood cell derivatives) after study-related tests 
have been performed 

Remaining FFPE tissue (with the exception of archival FFPE blocks, which will be 
returned to sites) after study-related tests have been performed

Whole blood samples collected at screening (for screen-fail patients only)


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The following sample will be used for identification of genetic (inherited) biomarkers:

Whole blood sample for DNA extraction (6 mL) (see Appendix 1 and Appendix 2)
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database. The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens collected for the RCR will 
undergo additional processes to ensure confidentiality as described below.
4.5.11.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is “double-coded” by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A “linking key” between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche’s Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request 
by representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR 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 derived from RCR specimen analysis on individual patients will generally not 
be provided to study investigators unless a request for research use is granted.  
The aggregate results of any research conducted using RCR specimens will be available 
in accordance with the effective Roche policy on study data publication.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient’s agreement to provide optional RCR 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 by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant’s death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research.
4.5.11.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  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 RCR Subject Withdrawal Form and, if the study is ongoing, must enter the 
date of withdrawal on the RCR Research Sample Withdrawal of Informed Consent eCRF. 
If a patient wishes to withdraw consent to the testing of his or her RCR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient’s withdrawal from Study GO29438 does not, by itself, constitute withdrawal of 
specimens from the RCR.  Likewise, a patient’s withdrawal from the RCR does not 
constitute withdrawal from Study GO29438.
4.5.11.7
Monitoring and Oversight
RCR 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.  Monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RCR for the purposes of verifying 
the data provided to Roche.  The site will permit monitoring, audits, IRB/EC review, and 


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health authority inspections by providing direct access to source data and documents 
related to the RCR samples.
4.5.12
Timing of Assessments
4.5.12.1
Screening and Baseline Assessments
Screening tests and evaluations will be performed within 28 days prior to Cycle 1, Day 1.  
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 28 days prior to Cycle 1, Day 1 may be used; such tests do not need 
to be repeated for screening.
See Appendix 1 for the schedule of screening assessments and Appendix 2 for the 
schedule of PK, ATA, and biomarker sampling.
4.5.12.2
Assessments during Treatment
All visits must occur 3 days from the scheduled date unless otherwise noted 
(see Appendix 1). All assessments will be performed on the day of the specified visit 
unless a time window is specified.  Assessments scheduled on the day of study 
treatment administration (Day 1) of each cycle should be performed prior to study 
treatment infusion unless otherwise noted.
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing continuing on a 21-day schedule.  If treatment was postponed 
for fewer than 3 days, the patient can resume the original schedule.
After completion of the induction phase, one of three cycles may be delayed by 1 week 
(28 days instead of 21 days for one cycle) to allow for vacations or holidays.  Following 
the delay, the next cycle must be delivered 21 days from the previous dose 
administration:  two consecutive 28 cycles are not permitted.  If a dose modification is 
required due to toxicity, refer to Section 5.1.
Tumor assessments should occur every 6 weeks (7 days) for 48 weeks following 
Cycle 1, Day 1 and every 9 weeks (7 days) after completion of the Week 48 tumor 
assessment, regardless of treatment delays until radiographic disease progression per 
RECIST v1.1 or loss of clinical benefit for patients in Arm A who continue treatment after 
disease progression according to RECIST v1.1, withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.  Patients who discontinue treatment 
for reasons other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, 
symptomatic deterioration) and patients who start non-protocol anti-cancer therapy in the 
absence of radiographic disease progressin per RECIST v1.1 will continue scheduled 
tumor assessments until radiographic disease progression per RECIST v1.1 (or loss of 
clinical benefit for atezolizumab-treated patients who had continued treatment with 
atezolizumab after radiographic disease progression according to RECIST v1.1), 
withdrawal of consent, death, or study termination by Sponsor, whichever occurs first.


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The following assessments may be performed 96 hours before Day 1 of each cycle:

ECOG performance status

Limited physical examination

Local laboratory tests
Screening assessments performed 96 hours before Cycle 1, Day 1 are not required to 
be repeated for Cycle 1, Day 1.
See Appendix 1 for the Schedule of Assessments performed during the treatment period 
and Appendix 2 for the schedule of PK, pharmacodynamic, ATA, and biomarker 
sampling.
4.5.12.3
Assessments at Study Drug Discontinuation Visit
When a patient discontinues all study treatment, regardless of the reason for 
discontinuation, the patient will be asked to return to the clinic within 30 days after the 
treatment for a study drug discontinuation visit.  The visit at which the decision is made 
to discontinue treatment (e.g., loss of clinical benefit is confirmed [atezolizumab-treated 
patients who continued treatment after disease progression according to RECIST v1.1] 
or disease progression occurs) may be used as the study drug discontinuation visit.
See Appendix 1 and Appendix 2 for the schedule of follow-up assessments.
4.5.12.4
Follow-Up Assessments
After the study drug discontinuation visit, adverse events should be followed as outlined 
in Section 5.3.1.
For patients who discontinue study treatment for any reason other than radiographic 
progressive disease per RECIST v1.1, tumor assessments should continue at the same 
frequency as would have been followed if the patient had remained on study treatment 
until radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
patients treated with atezolizumab who continued treatment after disease progression 
according to RECIST v1.1), withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.
Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 should continue tumor assessments according to the 
protocol schedule of response assessments until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who continue
treatment after radiographic disease progression according to RECIST v1.1), withdrawal 
of consent, death, or study termination by the Sponsor, whichever occurs first.
Follow-up data collection will also include ePROs (the SILC will be completed monthly 
only for the first 6 months after disease progression or loss of clinical benefit 
(for atezolizumab-treated patients) using an ePRO device at the patient’s home.


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EORTC QLQ-C30, EORTC QLQ-LC13, and the EQ-5D-5L will be completed 3 and 
6 months after disease progression or loss of clinical benefit (for atezolizumab-treated 
patients) at the site using the ePRO tablet to record study treatmentrelated adverse 
events (including serious adverse events), subsequent anti-cancer therapies, and date 
and cause of death.
Patients who discontinue study treatment for any reason other than radiographic
progressive disease or loss of clinical benefit will complete the EORTC QLQ-C30, 
EORTC QLQ-LC13, and EQ-5D-5L at each tumor assessment visit and will complete the 
SILC at home on a weekly basis, until radiographic disease progression per RECIST
v1.1 (or loss of clinical benefit as determined by the investigator for atezolizumab-treated 
patients who continue treatment after radiographic disease progression), withdrawal of
consent ,death, loss to follow-up, termination of the study by the Sponsor, whichever 
occurs first.
Survival follow-up information will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months until death, loss to follow-up, 
or study termination by the Sponsor, whichever occurs first.  All patients will be 
periodically contacted for survival and new anti-cancer therapy information unless the 
patient requests to be withdrawn from the study (this request must be documented in the 
source documents and signed by the investigator).  If the patient withdraws from study, 
the study staff may use a public information source (e.g., county records) when 
permissible, to obtain information about survival status only.
See Appendix 1 and Appendix 2 for the schedule of follow-up assessments.
4.5.12.5
Assessments at Unplanned Visits
Assessments for unscheduled visits related to a patient’s underlying NSCLC, study drug, 
or adverse event should be performed as clinically indicated and entered on the 
Unscheduled Visit eCRFs.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include but are not limited to the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance


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Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed up for any reason after 
consent has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status

Intolerable toxicity related to atezolizumab, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Intolerable toxicity related to other components of study treatment

If one component of study treatment is discontinued permanently due to tolerability 
concerns, the patient may continue with other components of study treatment until 
disease progression or loss of clinical benefit (for atezolizumab-treated patients who 
continue treatment after disease progression according to RECIST v1.1) if agreed 
upon by the investigator and patient

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another nonprotocol-specified anti-cancer therapy (see Section 4.4.3)

Pregnancy

Radiographic disease progression per RECIST v1.1
Exception for atezolizumab treatment:  patients randomized to atezolizumab 
treatment will be permitted to continue study treatment after RECIST v1.1 for 
progressive disease are met if they meet all of the following criteria (see Figure 2 for 
schematic representation):
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
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be readily managed and stabilized by protocol-allowed 
medical interventions prior to repeat dosing
Patients must provide written consent to acknowledge deferring any standard 
treatment options that may exist in favor of continuing atezolizumab treatment 
at the time of initial progression


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A mandatory biopsy sample collection, unless not clinically feasible as 
assessed by the investigators, at the site of local or metastatic progression
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Figure 2
Criteria for Continuing Atezolizumab in Presence of Increased 
Radiographic Tumor Size (Atezolizumab Arms)
ECOG PSEastern Cooperative Oncology Group performance status; ICF Informed Consent 
Form; RECIST v1.1Response Evaluation Criteria in Solid Tumors Version 1.1.


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4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference for Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial carcinoma.  Human experience is currently limited and the entire 
safety profile is not known at this time.  The following information is based on results 
from nonclinical and clinical studies and published data on similar molecules.
5.1
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (see Sections 4.1.1
and 4.1.2) and close monitoring (as indicated below and in Section 4.5).  
See Section 5.3 (Methods and Timing for Capturing and Assessing Safety Parameters) 
for complete details regarding safety reporting for this study.
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
All serious adverse events and adverse events of special interest will be recorded during 
the study and for up to 90 days after the last dose of study treatment or initiation of new 
systemic anti-cancer therapy after the last dose of study treatment, whichever occurs 
first.  All other adverse events will be recorded during the study and for up to 30 days 
after the last dose of study treatment or initiation of new systemic anti-cancer therapy 
after the last dose of study treatment, whichever occurs first.  After the adverse event 
reporting period, all deaths should continue to be reported.  In addition, the Sponsor 
should be notified if the investigator becomes aware of any serious adverse event or 


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adverse event of special interest that is believed to be related to prior exposure to study 
treatment (see Section 5.6 for reporting instructions). These events 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 e-mailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or e-mail 
address provided to investigators. 
The potential safety issues anticipated in this study, as well as measures intended to 
avoid or minimize such toxicities, are outlined in the following sections and in
Appendix 15.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, and myositis.  Immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome (considered to be potential risks for atezolizumab).  Refer to 
Section 5.1.6.2 and Appendix 15 of the protocol and Section 6 of the Atezolizumab 
Investigator's Brochure for a detailed description of anticipated safety risks for 
atezolizumab.  
5.1.2
Risks Associated with Pemetrexed Administration
The most common side effects of pemetrexed include gastrointestinal symptoms 
(nausea, vomiting, diarrhea, or constipation), myelosuppression, infection, fatigue, 
stomatitis, loss of appetite, and rash.
For more details regarding the safety profile of pemetrexed, see the prescribing 
information for pemetrexed.
5.1.3
Risks Associated with Carboplatin
Carboplatin is known to cause bone marrow suppression including myelosuppression, 
anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is considered to be 
moderately emetogenic.  Patients will be monitored for carboplatin-related adverse 
events.
For more details regarding the safety profile of carboplatin, refer to the prescribing 
information for carboplatin.


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5.1.4
Risks Associated with Cisplatin Chemotherapy
Cisplatin is known to cause myelosuppression, ototoxicity, and nephrotoxicity.  
Cisplatin-based chemotherapy is considered to be moderately emetogenic.  Patients will 
be monitored for cisplatin-related adverse events.
For more details regarding the safety profile of cisplatin, see the prescribing information 
for cisplatin.
5.1.5
General Plan to Manage Safety Concerns
5.1.5.1
Monitoring
Safety will be evaluated in this study through the monitoring of all adverse events
defined and graded according to NCI CTCAE v4.0.  Patients will be assessed for safety 
(including laboratory values) according to the schedule in Appendix 1.  Laboratory 
values must be reviewed prior to each infusion.
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts 
(see Appendix 1 for the list and timing of study assessments).
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.
All serious adverse events and protocol-defined events of special interest (see 
Sections 5.2.2 and 5.2.3) will be reported in an expedited fashion (see Section 5.4.2).  
In addition, the iDMC and Medical Monitor will review and evaluate observed adverse 
events on a regular basis.
Patients will be followed for adverse events (including deaths, serious adverse events, 
and adverse events of special interest) during and after the adverse event reporting 
period as described in Sections 5.3.1, 5.3.5.7, 5.5, and 5.6.
5.1.6
Dose Modification
5.1.6.1
General Notes Regarding Dose Modification
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient’s chart and recorded on the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v4.0 grading 
system.

For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator 
feels it is appropriate.  For example, if a patient has Grade 1 asthenia at baseline 
that increases to Grade 2 during treatment, this will be considered a shift of one 
grade and treated as Grade 1 toxicity for dose-modification purposes.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.


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
If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
component of the study treatment (i.e., atezolizumab, carboplatin, or cisplatin and/or 
pemetrexed if applicable) and the dose of that component is delayed or modified in 
accordance with the guidelines below, other components may be administered 
if there is no contraindication.

When treatment is temporarily interrupted because of toxicity caused by 
atezolizumab, carboplatin or cisplatin and/or pemetrexed (if applicable), 
the treatment cycles will be restarted such that the atezolizumab (if applicable) 
infusions remain synchronized and aligned with the chemotherapy schedule.

If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one chemotherapy drug, the dose of the other chemotherapy drug does not 
require modification.

The investigator may use discretion in modifying or accelerating the 
dose modification guidelines described below depending on the severity of toxicity 
and an assessment of the risk versus benefit for the patient, with the goal of 
maximizing patient compliance and access to supportive care.
5.1.6.2
Atezolizumab Dose Modification and Management of 
Specific Adverse Events
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 105 days beyond the last dose if they experience an 
adverse event that requires a dose to be withheld.  If atezolizumab is withheld because 
of adverse events for more than 105 days beyond the last dose, then the patient will be 
discontinued from atezolizumab treatment and will be followed up for safety and efficacy 
as specified in Section 5.2.1.
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
atezolizumab after a hold beyond 105 days, study drug may be restarted with the 
approval of the Medical Monitor.
If a patient must be tapered off steroids used to treat adverse events, atezolizumab may 
be withheld for additional time beyond 105 days from the last dose until steroids are 
discontinued or reduced to prednisone dose (or dose equivalent) 10 mg/day.  The 
acceptable length of interruption will depend on agreement between the investigator and 
the Medical Monitor.
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Medical Monitor approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor.
Refer to Appendix 15 for details on management of infusion-related reactions, 
gastrointestinal, dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, pancreatic
toxicity, neurologic toxicity, or potential eye toxicity, and other immune-mediated
adverse events.


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Refer to Appendix 11 for precautions for anaphylaxis.
5.1.7
Pemetrexed Dose Modification and Management of 
Specific Adverse Events
The dose modification guidelines are applicable for pemetrexed used as a single agent 
or in combination with cisplatin or carboplatin.
Treatment with pemetrexed should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or 4 toxicity after two dose reductions or if 
treatment is delayed for more than 63 days due to toxicities (see Table 13).
Hematologic Toxicity
At the start of each cycle, the ANC must be 1500/Land the platelet count must 
be 100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time 
for recovery.  Growth factors may be used in accordance with American Society of 
Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) 
guidelines (Smith et al. 2006; NCCN 2012).  Upon recovery, dose adjustments at the 
start of a subsequent cycle will be made on the basis of the lowest (nadir) platelet and 
neutrophil values from the previous cycle (see Table 12).
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.
Table 12 Pemetrexed Dose Modification for Hematologic Toxicities
Toxicity a
Pemetrexed Dose 
ANC 500 cells/L and platelets 50,000/L
75% of previous dose
Platelets 50,000/L, regardless of ANC
75% of previous dose
Platelets 50,000/L with Grade 2 bleeding, regardless of 
ANC
50% of previous dose
a Nadir of prior cycle.
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity.
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment then can be resumed.
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines.


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Non-Hematologic Toxicity
At the start of each cycle, the CRCL must be 45 mL/min. For enrollment and dosing 
decisions, CRCL will be estimated using the original, weight-based Cockcroft and 
Gault formula or measured using the appropriate radiolabeled method (51-CrEDTA or 
Tc99m-DTPA) to determine the GFR.  The method of CRCL assessment used at 
baseline should be used throughout the study
If a patient develops a non-hematologic toxicity (Table 13), pemetrexed should be 
withheld for up to 63 days until resolution to equal or less than the patient’s baseline 
(or Grade 1 if patient did not have that toxicity at baseline).  Treatment should be 
resumed according to the guidelines in Table 13.  For a Grade 3 or 4 neurotoxicity, 
pemetrexed should be resumed at 50% of the previous dose upon improvement, or 
discontinued immediately (based on investigator’s clinical judgment).
Table 13 Pemetrexed Dose Modification for Non-Hematologic Toxicities
Toxicity
Pemetrexed Dose
Any diarrhea requiring hospitalization (irrespective of 
grade) or Grade 3 or 4 diarrhea that occurs on 
adequate anti-diarrhea medication
75% of previous dose
Neurotoxicity
Grade 2
75% of previous dose
Grade 3 or 4
50% of previous dose or 
permanent discontinuation
Any other Grade 3 or 4 toxicities
75% of previous dose
Treatment Delays Caused by Insufficient Folic Acid or Vitamin B12 
Supplementation
Cycle 1 should not be started until both of the following requirements are met:

The patient has taken folic acid for at least 5 days immediately preceding the first 
dose of pemetrexed, and

The patient has received a vitamin B12 injection (which can be given on Cycle 1, 
Day 1)
Delay subsequent cycles until the patient has taken folic acid for at least 14 of the 
21 days before Day 1 of the subsequent cycle.
For more details regarding pemetrexed dose modification, see the prescribing 
information for pemetrexed.


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5.1.8
Platinum Chemotherapy Dose Modification and Management of 
Specific Adverse Events
5.1.8.1
Cisplatin
Treatment with cisplatin should be discontinued if a patient experiences any hematologic 
or non-hematologic Grade 3 or 4 toxicity after two dose reductions or if treatment is 
delayed for more than 63 days due to toxicities.
Hematologic Toxicity
At the start of each cycle, the ANC must be 1500/L and the platelet count must 
be 100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time 
for recovery.  Growth factors may be used in accordance with ASCO and NCCN 
guidelines (Smith et al. 2006; NCCN 2012).  Upon recovery, dose adjustments at the 
start of a subsequent cycle will be made on the basis of the lowest platelet and 
neutrophil values from the previous cycle (see Table 14).
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.
Table 14 Cisplatin Dose Modification for Hematologic Toxicities
Toxicity a
Cisplatin Dose
ANC 500 cells/L and platelets 50,000/L
75% of previous dose
Platelets 50,000/L, regardless of ANC
75% of previous dose
Platelets 50,000/L with Grade 2 bleeding, regardless of ANC
50% of previous dose
ANC 1000/L plus fever of 38.5°C
75% of previous dose
a Nadir of prior cycle.
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity.
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment then can be resumed.
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines.


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Non-Hematologic Toxicity
If a patient develops a non-hematologic toxicity (see Table 15) cisplatin should be 
withheld for up to 63 days until resolution to equal or less than the patient’s baseline
(or Grade ≤1 if patient did not have that toxicity at baseline).  Treatment should be 
resumed according to the guidelines in Table 15.
Diarrhea should be controlled with adequate anti-diarrhea medication. Nausea and/or 
vomiting should be controlled with adequate anti-emetics.
Table 15 Cisplatin Dose Modification for Non-Hematologic Toxicities 
(Excluding Neurotoxicity)
Toxicity
Cisplatin Dose
Any diarrhea requiring hospitalization (irrespective of 
grade) or Grade 3 or 4 diarrhea that occurs on adequate 
anti-diarrhea medication
75% of previous dose
Grade 3 or 4 nausea/vomiting a
75% of previous dose
Any other Grade 3 or 4 toxicity
75% of previous dose
a Despite the use of anti-emetics.
Nephrotoxicity
CRCL must be 60 mL/min prior to the start of any cycle.  If there is a decrease in CRCL 
between cycles, but the CRCL is still above 60 mL/min at time of next cycle, the treating 
physician should use his or her clinical judgment regarding continuing cisplatin, dose 
reduction, or delaying the cycle.  If a patient’s CRCL value has not returned to 
60 mL/min within 63 days following last cisplatin administration, the patient must be 
discontinued from cisplatin.
Neurotoxicity
In the event of neurotoxicity, the recommended dose adjustment for cisplatin 
is documented in Table 16.  For a Grade 3 or 4 neurotoxicity, cisplatin should be 
resumed at 50% of the previous dose upon improvement or discontinued immediately 
(based on investigator’s clinical judgment).
Table 16 Cisplatin Dose Modification for Associated Neurotoxicity
Toxicity
Cisplatin Dose
Grade 0–1 neurotoxicity
100% of previous dose
Grade 2 neurotoxicity
75% of previous dose
Grade 3 or 4 neurotoxicity
50% of previous dose or 
permanent discontinuation


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If the patient develops ototoxicity, subsequent doses of cisplatin should not be given until 
an audiometric analysis indicates that auditory acuity is within normal limits 
(http://www.drugs.com/pro/platinol.html). Refer to Table 16 for dose modification.
5.1.8.2
Carboplatin
Treatment with carboplatin should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or Grade 4 toxicity after two dose reductions or 
treatment is delayed for more than 63 days due to toxicities.
Additional guidance has been provided regarding recommended dose reductions, holds, 
and discontinuations of study treatment for toxicities and/or to comply with the 
prescribing information (see Section 4.3.2).
Hematologic Toxicity
At the start of each cycle, the ANC must be 1500/L and the platelet count must 
be 100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time 
for recovery.  Growth factors may be used in accordance with ASCO and NCCN
guidelines (Smith et al. 2006; NCCN 2012). Upon recovery, dose adjustments at the
start of a subsequent cycle will be made on the basis of the lowest platelet and 
neutrophil values from the previous cycle (see Table 17).
Table 17 Carboplatin Dose Modification for Hematologic Toxicities
Toxicity a
Carboplatin Dose 
ANC 500 cells/L and platelets 50,000/L
75% of previous dose
Platelets 50,000/L, regardless of ANC
75% of previous dose
Platelets 50,000/L with Grade 2 bleeding, regardless of ANC
50% of previous dose
ANC 1000/L plus fever of 38.5°C
75% of previous dose
a Nadir prior cycle.
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity.
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment will then be resumed.


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No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines.
Non-Hematologic Toxicity
For a non-hematologic toxicity (see Table 18), treatment should be delayed for up to 
63 days until resolution to less than or equal to the patient’s baseline value (or Grade 1 
if patient did not have that toxicity at baseline).  Dose reductions at the start of the 
subsequent cycle will be made on the basis of non-hematologic toxicities from the dose 
administered in the preceding cycle.  Table 18 provides the relevant dose adjustments 
for non-hematologic toxicities.
Table 18 Carboplatin Dose Modification on the Basis of Non-Hematologic 
Toxicities in the Preceding Cycle
Toxicity
Adjusted Carboplatin Dose as % of 
Previous Dose a
Diarrhea
Grade 3 or 4 b
75%
Nausea/vomiting
Grade 3 or 4 c
75%
Neurotoxicity
Grade 2
75%
Grade 3 or 4
50% or permanent discontinuation
Transaminase elevation
Grade 3
75%
Grade 4
Discontinue
Other
Grade 3 or 4
75%
AUCarea under the concentrationtime curve.
a If deemed appropriate by the treating physician, adjust carboplatin dose to the 
specified percentage of the previous AUC.
b Grade 3 or 4 diarrhea that occurs on adequate anti-diarrhea medication or 
any grade of diarrhea requiring hospitalization.
c Despite the use of anti-emetics.
Diarrhea should be controlled with adequate anti-diarrhea medication.  Nausea and/or 
vomiting should be controlled with adequate anti-emetics.  For a Grade 3 or 4 
neurotoxicity, carboplatin should be resumed at 50% of the previous dose upon 
improvement, or discontinued immediately (based on investigator’s clinical judgment).
5.1.9
Potential Overlapping Toxicities
To date, on the basis of safety data from Study GP28328, the risk of overlapping 
toxicities between atezolizumab, carboplatin or cisplatin, and pemetrexed is thought to 
be minimal.  Nevertheless, the attribution and management of certain adverse events 
that have been associated with each agent separately (e.g., hepatotoxicity, skin, and 
gastrointestinal toxicity) may not be unambiguous when the agents are administered 
together.  It is theoretically possible that allergic or inflammatory adverse events 


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associated with these chemotherapeutic agents (e.g., hepatotoxicity) could be 
exacerbated by the immunostimulatory activity of atezolizumab.
Toxicities should initially be managed according to the recommendations in 
Section 5.1.6.2, Section 5.1.8, and Section 5.1.9 with dose holds and modifications 
(if applicable) applied to the component of the study drug judged to be the primary cause.  
For severe (Grade 3) or persistent Grade 1 or 2 diarrhea, an endoscopic evaluation 
should be considered.  Additional tests, such as autoimmune serology or biopsies, may 
be used to determine a possible immunogenic etiology for adverse events listed above.  
If, in the opinion of the investigator, atezolizumab is a potential inciting factor, the dose of 
atezolizumab may be withheld for a maximum of 105 days beyond when the next dose 
should have been given (see Section 5.1.6.2).  Prompt symptomatic management is 
appropriate for mild immune-mediated adverse events.  In severe cases, 
immune-mediated toxicities may be acutely managed with systemic corticosteroids 
or TNF-inhibitors.  These cases should be discussed with the Medical Monitor.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
all adverse events and adverse events of special interest; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

Recurrence of an intermittent medical condition (e.g., headache) not present at
baseline

Any deterioration in a laboratory value or other clinical test result (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


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
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 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Results in a congenital anomaly and/or birth defect in a neonate or 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 
reporting instructions).


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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).  Adverse events of special interest for this study 
include the following:

Confirmed treatment-emergent autoimmune conditions:
Pneumonitis
Colitis
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, and 
hyperthyroidism
Hepatitis
Transaminitis: Grade 2 (AST or ALT3ULN and bilirubin 2ULN) or 
AST/ALT 10ULN
Systemic lupus erythematosus
Neurologic disorders: Guillain-Barré syndrome, myasthenia gravis, and 
meningoencephalitis
Nephritis

Events suggestive of hypersensitivity, cytokine release syndrome, influenza-like 
illness, systemic inflammatory response syndrome, and infusion-reaction syndromes

Cases of potential drug-induced liver injury that include an elevated ALT or AST
level in combination with either an elevated bilirubin level or clinical jaundice, as 
defined by Hy’s law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained, but prior to initiation of study 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 serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of nonprotocol-specified systemic anti-cancer 
therapy after the last dose of study treatment, whichever occurs first.  All other adverse 
events, regardless of relationship to study drug, will be reported until 30 days after the 
last dose of study drug or initiation of new anti-cancer therapy after the last dose of study 
treatment, whichever occurs first.  Instructions for reporting adverse events that occur 
after the safety 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 19 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 19 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 or 
not an adverse event is considered to be related to the study drug, indicating “yes” or “no”
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event


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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
Diagnosis versus Signs and Symptoms
For all adverse events, a diagnosis (if known) rather than individual signs and symptoms 
should be recorded on the Adverse Event eCRF (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminase levels).  However, if 
a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
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.


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5.3.5.3
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) 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 intensity should also be recorded on the Adverse Event eCRF.  If the 
event becomes serious, it should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning that the event became serious; see Section 5.4.2 for 
reporting instructions).  The Adverse Event eCRF should be updated by changing the 
event from “non-serious” to “serious,” providing the date that the event became serious, 
and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
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 is a change from baseline and 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
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.”


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.5
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 is a change from baseline and meets any of the 
following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal 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.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice


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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 5.3.5.1) 
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).
5.3.5.7
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 only on the 
Death Attributed to Progressive Disease eCRF.  All other deaths occurring 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 iDMC 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, “Death due to Unknown Cause” should be recorded on the Adverse Event 
eCRF.  If the cause of death later becomes available (e.g., after autopsy), the event 
should be replaced by the established cause of death.  The term "sudden death" should 
not be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches” or “worsened headache”).


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5.3.5.9
Worsening of NSCLC
Events that are clearly consistent with the expected pattern of progression of the NSCLC 
should not be recorded as adverse events.  These data will be captured as efficacy 
assessment data only.  In most cases, the expected pattern of progression will be based 
on RECIST.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration or 
to perform an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse
event instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Adverse Events Associated with an Overdose or Error in Drug 
Administration
Study overdose is the accidental or intentional use of a drug in an amount higher than 
the dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Study Drug Administration eCRF.


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All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
5.3.5.12
Patient-Reported Outcome Data
Adverse events 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

Adverse events of special interest

Pregnancies
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor:
, M.D.
E-Mail:
Mobile Telephone No.:


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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained, but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to Roche or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment or initiation of 
new systemic anti-cancer therapy after the last dose of study treatment, whichever 
occurs first.  All other adverse events, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study treatment or initiation of new 
anti-cancer therapy after the last dose of study treatment, whichever occurs first.
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche 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 with use of 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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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, within 5 months after the last dose 
of atezolizumab, or within 6 months after the last dose of cisplatin.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form with use of the fax number or 
email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the 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 or 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
Atezolizumab is not expected to be genotoxic. In addition, the anticipated 
concentrations of atezolizumab in seminal fluid as well as the potential risk to the 
developing conceptus is low after seminal transfer of atezolizumab to a female partner.
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the chemotherapy 
treatment period or within 6 months after the last dose of chemotherapy (i.e., carboplatin, 
cisplatin, or pemetrexed).  A Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form with use of the fax number or email address provided to investigators.  Attempts 
should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  When permitted by 
the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus to support an informed decision in cooperation with the 
treating physician and/or obstetrician.


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5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies and Birth Defects
Any congenital anomaly or birth defect in a child born to a female patient exposed to 
study drug or the female partner of a male patient exposed to study drug should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow up 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 
up all serious adverse events considered to be related to study drug 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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed up until pregnancy 
outcome.  If the EDC system is not available at the time of pregnancy outcome, follow 
reporting instructions provided in Section 5.4.3.1.


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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (as defined in Section 5.3.1), 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 or adverse 
event of special interest that is believed to be related to prior exposure to study 
treatment, the event should be reported through use of the Adverse Event eCRF.  
However, if the EDC system is not available, the investigator should report these events 
directly to the Sponsor or its designee, either by faxing or by scanning and emailing the 
paper Clinical Trial 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:

Atezolizumab Investigator’s Brochure

Prescribing information for each chemotherapy agent (cisplatin, carboplatin,
and pemetrexed)
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.


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An iDMC 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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a randomized, Phase III, global, multicenter, open-label study designed to 
evaluate the safety and efficacy of atezolizumab in combination with carboplatin or 
cisplatinpemetrexed compared with treatment with carboplatin or 
cisplatinpemetrexed in patients who are chemotherapy-naive and have Stage IV 
non-squamous NSCLC.
Approximately 568 patients will be randomized in the global enrollment phase of this 
study.  If at least 1 patient is enrolled in China during the global enrollment phase, 
additional patients will be enrolled in a China extension phase to ensure a total 
enrollment of approximately 164 patients in the China subpopulation. 
The primary analyses of Study GO29438 will include patients enrolled during the global 
enrollment phase.  The China subpopulation will include patients enrolled at sites in 
China receiving cisplatin and pemetrexed, with or without atezolizumab, during both the 
global enrollment phase and the China extension phase, which will be analyzed
separately from the analyses of patients enrolled during the global enrollment phase.
The efficacy analyses will be performed on all randomized patients (ITT) with patients 
grouped according to the treatment assigned at randomization, regardless of whether 
they received any assigned study drug.  
Safety analyses will be performed on data for all randomized patients who received any 
amount of study drug, with patients grouped according to whether any amount of 
atezolizumab was received, including cases when atezolizumab was received in error.
6.1
DETERMINATION OF SAMPLE SIZE
Determination of sample size is based on patients enrolled in the global enrollment 
phase.  This study will randomize approximately 568 patients during the global 
enrollment phase. Additional patients may be randomized during the China extension 
phase if at least one patient is enrolled in China during the global enrollment phase.
To control the overall type I error rate using the group sequential Holm procedure 
(Ye et al. 2012) for the one-sided test at 0.025 in the analyses of patients enrolled during 
the global enrollment phase, PFS in the ITT population will be tested at a one-sided 
-level of 0.002 and OS in the ITT population will be tested at a one-sided -level of 
0.023. If only PFS is statistically significant, OS in the ITT population will be tested at a 
one-sided -level of 0.025. Otherwise, OS in the ITT population will be tested at a 
one-sided -level of 0.023. If only OS is statistically significant, PFS in the ITT 


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population will be tested at a one-sided -level of 0.025 at the time of the final analysis 
of PFS.  Otherwise, PFS in the ITT population will be tested at a one-sided -level of 
0.002 at the time of PFS final analysis. The overview of the control strategy is shown 
in Figure 3.
Figure 3
Overview of the Alpha Control Strategy
ITTintent to treat; PFSprogression-free survival; OSoverall survival.
The sample size of this study is determined on the basis of the number of events 
required to demonstrate efficacy with regard to both PFS and OS (as defined in 
Section 6.4).
The estimates of the number of events required to demonstrate efficacy in the ITT 
population with regard to PFS and OS are based on the following assumptions:

1:1 randomization ratio

One-sided significance level of 0.002 for PFS and 0.023 for OS

96.0 % power to detect an HR of 0.65, corresponding to an improvement in median 
PFS from 6 months to 9.2 months

No interim analysis for PFS

81% power to detect an HR of 0.75, corresponding to an improvement in median 
OS from 14 months to 18.7 months

One interim OS analyses will be performed at the time of the PFS final analysis with 
an information fraction of approximately 78% (i.e., 78% of the required OS events 
have occurred). To adjust for the multiplicity due to the interim analyses, the 
Lan-DeMets approximation to the O’Brien-Fleming boundary will be used.

Dropout rate of 10% per 24 months assumed for all treatment arms 

Event times exponentially distributed


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With these assumptions, the PFS final analysis will be conducted after 
approximately 458 PFS events have occurred in the ITT population, and at least 
10 months after the last patient is enrolled during the global enrollment phase, whichever 
occurs later.  This is expected to occur approximately 30 months after the first patient is 
randomized.  This number of events corresponds to a minimum detectable difference in 
HR of approximately 0.764 for a one-sided -level of 0.002.  Based on the group 
sequential Holm procedure (Ye et al. 2012), if only OS is statistically significant, then 
PFS in the ITT population will be tested at a one-sided -level of 0.025 at the time of 
PFS final analysis.  In this case, the number of events corresponds to a minimum 
detectable difference of approximately 0.833 in HR.
The interim OS analysis is planned to be performed at the time of the PFS final analysis. 
However, if there are significantly fewer than the expected 312 OS events at the time of 
the final PFS analysis, a nominal of 0.01% (negligible impact on overall type I error 
rate) will be spent on the OS analysis at the time of the final PFS analysis and a second 
interim OS analysis will then be conducted after approximately 312 OS events have 
occurred (see Section 6.8.1).
Given the sample size of 568, this will result in approximately 398 OS events in the ITT 
population for the final analysis of OS, which is expected at approximately 42 months
after the first patient is randomized.
6.2
SUMMARIES OF CONDUCT OF STUDY
Study enrollment, study drug administration, reasons for discontinuation from the study 
drug, and reasons for study termination will be summarized by treatment arm. Major 
protocol deviations, including major deviations of inclusion/exclusion criteria, will be 
reported and summarized by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG performance status), will be summarized by treatment arms.  
Descriptive statistics (mean, median, SD, and range) will be presented for continuous 
data, and frequencies and percentages will be presented for categorical data.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of study drug.
6.4
EFFICACY ANALYSES
6.4.1
Co-Primary Efficacy Endpoints
The co-primary efficacy endpoints are PFS as assessed by the investigator using 
RECIST v1.1, and OS.  The primary efficacy analyses for PFS and OS will be analyzed
in the ITT population.  


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PFS is defined as the time between the date of randomization and the date of first 
documented disease progression or death, whichever occurs first.  Patients who have 
not experienced disease progression or death at the time of analysis will be censored 
at the time of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored at the date of randomization plus 1 day.
OS is defined as the time between the date of randomization and death from any cause.  
Patients who are not reported as having died at the date of analysis will be censored at 
the date when they were last known to be alive.  Patients who do not have post-baseline 
information will be censored at the date of randomization plus 1 day.
The type I error control plan for PFS and OS is presented in Section 6.1.  A group 
sequential design will be used for testing OS to account for the conduct of the interim 
analysis, which is expected to occur approximately 30 months after the first patient is 
enrolled in the study.  Details about the timing of the OS interim analysis and stopping 
boundaries are provided in Section 6.8.1.  Details about the hypothesis testing will be 
provided in the SAP.  On the basis of emerging external data, the testing strategy may 
be modified to improve the efficiency of the design.  Should this occur, modifications to 
the testing strategy will be documented in the SAP prior to the unblinding of the study.
The null and alternative hypotheses regarding PFS and OS can be phrased in terms of 
the survival functions SPFS_A (t), SOS_A (t) in the atezolizumab-containing treatment arm
(Arm A) and SPFS_B (t), SOS_B (t) in the control arm (Arm B), respectively:
H0: SPFS_A (t)SPFS_B (t) versus H1: SPFS_A (t) SPFS_B (t)
H0: SOS_A (t)SOS_B (t) versus H1: SOS_A (t) SOS_B (t)
Comparisons with respect to PFS and OS between the treatment and control arms will 
be tested based on a stratified log-rank test.  The stratification factors will be sex (male 
vs. female), ECOG performance status (0 vs. 1), type of chemotherary (carboplatin vs. 
cisplatin), and smoking status (never vs. current and/or former).  The stratification factors 
will be those used during randomization, as recorded in IxRS.  Results from an 
unstratified analysis will also be presented.  The HR will be estimated using a stratified 
Cox regression model.  Kaplan-Meier methodology will be used to estimate median PFS 
and OS for each treatment arm and to construct survival curves for visual descriptions of 
the difference between the treatment and control arms.
The Brookmeyer-Crowley methodology will be used to construct the 95% CI for the 
median PFS and OS for each treatment arm (Brookmeyer and Crowley 1982).


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6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Objective Response Rate
An objective response is defined as either an unconfirmed CR or a PR, as determined 
by the investigator using RECIST v1.1.  Patients not meeting these criteria, including
patients without any post-baseline tumor assessment, will be considered 
non-responders.
ORR is defined as the proportion of patients who had an objective response.  
The analysis population for ORR will be all randomized patients.  The confirmation of 
response in accordance with RECIST v.1.1 is not required, but ORR with confirmation 
may be evaluated as an exploratory endpoint.  An estimate of ORR and its 95% CI will 
be calculated using the Clopper Pearson method for each treatment arm. CIs for the 
difference in ORRs between the two treatment arms will be determined using the normal 
approximation to the binomial distribution.  The ORR will be compared between the two 
arms using the stratified Cochran-Mantel-Haenszel test, stratified by the same factors 
used in the primary PFS and OS analysis (see Section 6.4.1).
6.4.2.2
Duration of Response
DOR will be assessed in patients who had an objective response as determined by the 
investigator using RECIST v1.1.  DOR is defined as the time interval from the date of the 
first occurrence of a CR or PR (whichever status is recorded first) until the first date that 
progressive disease or death is documented, whichever occurs first.  Patients who have 
not progressed and who have not died at the time of analysis will be censored at the 
time of last tumor assessment date.  If no tumor assessments were performed after the 
date of the first occurrence of a CR or PR, DOR will be censored at the date of the 
first occurrence of a CR or PR plus 1 day.  DOR is based on a non-randomized subset 
of patients (specifically, patients who achieved an objective response); therefore, formal 
hypothesis testing will not be performed for this endpoint.  Comparisons between 
treatment arms will be made for descriptive purposes.  The methodologies detailed for 
the PFS analysis will be used for the DOR analysis.
6.4.2.3
Overall Survival Rate at Landmark Timepoints
The OS rates at 1 and 2 years will be estimated using Kaplan-Meier methodology for 
each treatment arm, along with 95% CIs calculated using the standard error derived 
from Greenwood’s formula.  The 95% CI for the difference in OS rates between the 
two treatment arms will be estimated using the normal approximation method.
6.4.2.4
Patient-Reported Outcomes
The change from baseline per SILC scale will be analyzed for each of the lung cancer 
symptom scores (chest pain, cough, dyspnea).  The analysis will be performed for 
patients in the ITT population with a non-missing baseline and at least a post-baseline 
PRO assessment (i.e., PRO evaluable population).  
Further details regarding all SILC analyses will be described in the SAP.


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TTD in lung-related symptoms is defined as the time from baseline to the time the 
patient’s score on the EORTC QLQ C30 or LC13 shows a 10-point increase above 
baseline in each of the following EORTC-transformed scores for cough, dyspnea 
(single item), dyspnea (multi-item subscale) and chest pain.  A 10-point change in 
score is perceived by patients to be clinically significant (Osoba et al. 1998).  If no 
baseline or post-baseline assessment is performed, data for patients will be censored at 
the date of randomization plus 1 day.  TTD in symptoms will be analyzed in the ITT 
population through use of the same methods described for the PFS and OS analyses 
(see Section 6.4.1).  Additional details regarding the analysis for the EORTC measures 
will be described in the SAP.
6.4.3
Handling of Missing Data
For PFS, data for patients without a date of disease progression will be analyzed as 
censored observations on the date of the last tumor assessment.  If no post-baseline 
tumor assessment is available, PFS will be censored at the date of randomization plus 
1 day.  Data for patients with a PFS event who missed two or more scheduled 
assessments immediately prior to the PFS event will be handled as described in the 
sensitivity analysis in Section 6.7.1.4.
For OS, data for patients who are not reported as having died will be analyzed as 
censored observations on the date they were last known to be alive.  If no post-baseline 
data are available, OS will be censored at the date of randomization plus 1 day.
For objective response, patients without any post-baseline assessment will be 
considered non-responders.
For DOR, data for patients who have not progressed and who have not died at the time 
of analysis will be censored at the time of the last tumor assessment date.  If no tumor 
assessments were performed after the date of the first occurrence of a CR or PR, DOR 
will be censored at the date of the first occurrence of a CR or PR plus 1 day.
For TTD with use of the EORTC, data for patients who have not deteriorated at the time 
of analysis will be censored at the last time they completed an assessment.  If no 
post-baseline assessment is performed, patients will be censored at the randomization 
date plus 1 day.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety-evaluable population, which is defined 
as all randomized patients who receive any amount of any component of protocol 
treatment.  Patients will be allocated according to whether any full or partial dose of 
atezolizumab was received, including when atezolizumab was received in error.
Study drug exposure, including treatment duration, number of doses, and dose intensity,
will be summarized for each treatment arm using descriptive statistics.


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Verbatim description of adverse events will be mapped to MedDRA thesaurus terms and 
graded according to NCI CTCAE v4.0.  All adverse events occurring during or after the 
first study drug dose will be summarized by treatment arm and NCI CTCAE grade.  In 
addition, serious adverse events, severe adverse events (Grade 3), adverse events of 
special interest, and adverse events leading to study drug discontinuation or interruption 
will be summarized accordingly.  Multiple occurrences of the same event will be counted 
once at the maximum severity.  The proportion of patients experiencing at least one 
adverse event will be reported by toxicity term and treatment arm.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized by treatment arm and grade.
Changes in vital signs will be summarized by treatment arm.
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion/discontinuation will be summarized by 
treatment arm.
6.6
PHARMACOKINETIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 2.  Atezolizumab 
serum concentration data (Cmin and Cmax) will be tabulated and summarized.  Descriptive 
statistics will include means, medians, ranges, and SDs, as appropriate.
Plasma concentrations of carboplatin, cisplatin, and pemetrexed will be collected in this 
study as outlined in Appendix 2.  The concentrations of carboplatin, cisplatin, and 
pemetrexed will be summarized using descriptive statistics as described above.
Additional PK analyses will be conducted, as appropriate, based on the availability of 
data.
6.7
EXPLORATORY ANALYSES
6.7.1
Exploratory Analyses of Progression-Free Survival
6.7.1.1
Progression-Free Survival Rate at Landmark Timepoints
The PFS rate, defined as the probability that a patient will be alive without disease 
progression after randomization (e.g., at 6 months and at 1 year), will be estimated using 
Kaplan-Meier methodology for each treatment arm, along with 95% CIs calculated using 
Greenwood’s formula.  The 95% CIs for the difference in PFS rates between the 
treatment arms will be estimated using the normal approximation method, and standard 
errors will be computed through use of the Greenwood method.
6.7.1.2
NonProtocol-Specified Anti-Cancer Therapy
The impact of nonprotocol-specified anti-cancer therapy on PFS will be assessed 
depending on the number of patients who receive nonprotocol-specified anti-cancer
therapy before a PFS event.  If 5% of patients received nonprotocol-specified 


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anti-cancer therapy before a PFS event in any treatment arm, a sensitivity analysis will 
be performed for the comparisons between treatment arms in which patients who 
receive nonprotocol-specified anti-cancer therapy before a PFS event will be censored 
at the last tumor assessment date before receipt of nonprotocol-specified anti-cancer 
therapy.
6.7.1.3
Subgroup Analysis
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG 
performance status, smoking status, and type of chemotherapy), the duration of PFS in 
these subgroups will be examined.  Summaries of PFS, including unstratified HRs 
estimated from Cox proportional hazards models and Kaplan-Meier estimates of median 
PFS, will be produced separately for each level of the categorical variables for the 
comparisons between treatment arms.
6.7.1.4
Sensitivity Analyses
Sensitivity analyses will be performed to evaluate the potential impact of missing 
scheduled tumor assessments on the primary analysis of PFS, as determined by the 
investigator using a PFS event imputation rule. The following two imputation rules will 
be considered:

If a patient missed two or more scheduled tumor assessments immediately prior to 
the date of the PFS event according to RECIST v1.1, the patient will be censored at 
the last tumor assessment prior to the first of these missed visits.

If a patient missed two or more tumor assessments scheduled immediately prior to 
the date of the PFS event according to RECIST v1.1, the patient will be counted as 
having progressed on the date of the first of these missing assessments.
The imputation rule will be applied to patients in both treatment arms.  Statistical 
methodologies that are analogous to those used in the primary analysis of PFS as 
specified in Section 6.4.1 will be used for this sensitivity analysis.
6.7.2
Exploratory Analyses of Overall Survival
6.7.2.1
Loss to Follow-Up
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  If 5% of patients are lost to follow-up for OS in either 
treatment arm, a sensitivity analysis will be performed for the comparisons between 
treatment arms in which patients who are lost to follow-up will be considered as having 
died at the last date they were known to be alive.
6.7.2.2
Subgroup Analysis
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG 
performance status, smoking status, type of chemotherapy, presence of liver metastases 
at baseline), the duration of OS in these subgroups will be examined.  Summaries of 


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survival, including unstratified HRs estimated from Cox proportional hazards models and 
Kaplan-Meier estimates of median survival time, will be produced separately for each 
level of the categorical variables for the comparisons between treatment arms.
6.7.2.3
Overall Survival Rate at 3-Year Landmark
The OS rates at 3 years will be estimated using Kaplan-Meier methodology for each 
treatment arm, along with 95% CIs calculated using the standard error derived from 
Greenwood’s formula.  The 95% CI for the difference in OS rates between the 
two treatment arms will be estimated using the normal approximation method.
6.7.2.4
Milestone Overall Survival Analysis
To assess the effect of long-term survival and delayed clinical effects, a milestone OS 
analysis will be conducted (Chen 2015).  The milestone OS is an OS endpoint with 
cross-sectional assessment at a pre-specified timepoint.  The milestone OS analysis will 
be performed using the same methods as those specified for the primary OS analysis, 
and the specific definition of milestone will be documented in the Statistical Analysis 
Plan (SAP).
6.7.2.5
NonProtocol-Specified Anti-Cancer Therapy
The impact of nonprotocol-specified anti-cancer therapy on OS may be assessed, 
depending on the number of patients who receive such therapy.  For example, the 
duration from initiation of nonprotocol-specified anti-cancer therapy to death or 
censoring date could be discounted in accordance with a range of possible effects on 
OS of subsequent nonprotocol-specified anti-cancer therapy (e.g., 10%, 20%, 30%).  
Further details regarding these sensitivity analyses will be described in the SAP.
6.7.3
Exploratory Biomarker Analysis
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with study drug response, including efficacy and/or adverse 
events.  The tumor biomarkers include but are not limited to PD-L1 and CD8, as defined 
by IHC, qRT-PCR, or other methods.  Additional pharmacodynamic analyses will be 
conducted as appropriate.  Results from these exploratory analyses will not be included 
in the Clinical Study Report. 
6.7.4
EQ-5D-5L Health Status Data
EQ-5D-5L health status data will be used for obtaining utility measures for economic 
modeling.  These analyses will not be included in the Clinical Study Report.


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6.7.5
Exploratory Patient-Reported Outcome Analyses
Compliance rates for each questionnaire will be summarized in the ITT population as 
detailed in the SAP.
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) and the 
mean change from baseline at each timepoint will be reported for each score of the PRO 
questionnaires.  
Change from baseline with use of the EORTC will be analyzed for patients in the 
exploratory efficacy analysis populations with a baseline and a post-baseline PRO 
assessment. 
6.8
INTERIM ANALYSES
6.8.1
Planned Interim Analyses
There are no interim analyses planned for PFS in this study.  An external iDMC will be 
set up to evaluate safety data on an ongoing basis.  All summaries and analyses by 
treatment arm for the iDMC’s review will be prepared by an iDCC.  Members of the 
iDMC will be external to the Sponsor and will follow a charter that outlines their roles and 
responsibilities.  Any outcomes of these safety reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the IRBs/ECs.  
A detailed plan will be included in the iDMC Charter.
The interim efficacy analysis of OS will be conducted by the Sponsor at the time of the 
final PFS analysis.  
The interim OS analysis will be conducted when approximately 312 OS events in the ITT 
population have been observed.  This is expected to occur approximately 30 months 
after the first patient is randomized, but the exact timing of this analysis will depend on 
the actual number and timing of OS events.  If there are significantly fewer than the 
expected 312 OS events at the time of the final PFS analysis, a nominal two-sided of
0.01% (negligible impact on overall type I error rate) will be spent on the OS analysis at 
the time of the final PFS analysis and a second interim OS analysis will then be 
conducted after approximately 312 OS events have occurred.
The final OS analysis will be conducted when approximately 398 OS events in the ITT 
population have been observed.  This is expected to occur approximately 42 months
after the first patient is randomized, but the exact timing of this analysis will depend on 
the actual number and timing of OS events.
To control type I error for OS, the stopping boundaries for the OS interims and 
final analysis are to be computed with use of the Lan-DeMets approximation to the 
O’Brien-Fleming boundary as shown in Table 20.


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Table 20 Analysis Timing and Stopping Boundary of Overall Survival
Analysis Timing
Planned 
Information 
Fraction
Stopping Boundary for Rejection of H0
ITT Population
One-sided alpha0.023
One-sided alpha0.025
Interim analysis
78%
HR 0.769
(p0.0102)
HR .773
(p0.0114)
Final analysis
100%
HR 0.814
(p0.0200)
HR 0.817
(p0.0217)
HRhazard ratio; ITTintent-to-treat; pone-sided p-value.
6.8.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis for the primary endpoint of PFS 
and/or OS beyond what is specified in Section 6.8.1.  Below are the specifications in 
place to ensure the study continues to meet the highest standards of integrity when an 
optional interim analysis is executed.
The interim analysis will be conducted by an external statistical group and reviewed by 
the iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified 
in the iDMC Charter.
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC Charter will document potential recommendations the iDMC 
can make to the Sponsor as a result of the analysis (e.g., stop the study for positive 
efficacy, stop the study for futility), and the iDMC Charter will also be made available to 
relevant health authorities.
6.9
CHINA SUBPOPULATION ANALYSIS
Approximately 568 patients will be randomized in the global enrollment phase of this 
study.  If at least 1 patient is enrolled in China during the global enrollment phase, 
additional patients in China will be enrolled in a subsequent China extension phase as 
needed to ensure a total enrollment of approximately 164 patients in the China 
subpopulation. The China subpopulation will include patients enrolled at sites in China 
receiving cisplatin and pemetrexed with or without atezolizumab, during both the global 
enrollment phase and the China extension phase, whose data will be analyzed 
separately from data of patients enrolled during the global enrollment phase. 
The objective of the China extension phase and the China subpopulation analyses is to 
assess the treatment effects of atezolizumab in the population of patients in China and 


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to investigate the consistency in treatment effects between the China subpopulation and 
the global population for the purpose of registration in China.
The final analysis of PFS in the China subpopulation will be conducted after 
approximately 115 PFS events in the China subpopulation have occurred.  The 
proposed 115 PFS events will provide 89% probability of observing at least 50% of the 
risk reduction in PFS expected to be observed in the global population.
The final analysis of OS in the China subpopulation will be conducted after 
approximately 120 OS events in the China subpopulation have occurred.  The proposed 
120 OS events will provide 79% probability of observing at least 50% of the risk 
reduction in OS expected to be observed in the global population. The timing for OS 
anlaysis in the China subpopulation will be revised according to the observed HR and 
data maturity from the global analysis. Methods for analyzing data from the China 
subpopulation will be provided in the SAP.  Results from these analyses will be 
summarized in a separate report.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, which includes
quality checking of the data.  Data entered manually will be collected via EDC through 
use of eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event 
of discrepant data, the Sponsor will request data clarification from the sites, which the 
sites will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected electronically through use of electronic devices 
provided by an ePRO vendor.  The electronic device is designed for entry of data in a 
way that is attributable, secure, and accurate, in compliance with the FDA regulations for 
electronic records (21 Code of Federal Regulations, Part 11).  The data will be 
transmitted to a centralized database at the ePRO vendor.  The data from the ePRO 
devices are available for view access only via secure access to a Web portal provided 
by the ePRO vendor.  Only identified and trained users may view the data, and their 
actions become part of the audit trail.  The Sponsor will have view access only.  Regular 
data transfers will occur from the centralized database at the vendor to the database at 
the Sponsor.
Once the study is complete, the ePRO data, audit trail, and study and system 
documentation will be archived.  The Sponsor will receive all data entered by patients on 
the e-diary and tablet device and all study documentation.
Details regarding patient-reported data and the electronic device is available in the 
Study Reference Manual.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by 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.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, the name of the 
person making the change, and the date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 


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U.S. Investigational New Drug (IND) Application will comply with the FDA regulations 
and applicable local, state, and federal laws.  Studies conducted in the European Union 
(E.U.) or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC) and applicable local, regional, and national laws.
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.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining samples for optional exploratory research.  The investigator or authorized 
designee will explain to each patient the objectives of the exploratory research.  Patients 
will be told that they are free to refuse to participate and may withdraw their specimens 
at any time and for any reason during the storage period.  A separate, specific signature 
will be required to document a patient’s agreement to allow any remaining specimens to 
be used for exploratory research.  Patients who decline to participate will not provide a 
separate signature.
The Informed Consent Form will also contain the following additional signature pages:

A signature page for patients receiving atezolizumab who wish, if approved by the 
treating physician, to continue treatment beyond initial radiographic disease
progression and meet criteria specified in Section 4.6.2.  This separate consent is to 
be signed after initial radiographic disease progression has occurred and patients 
have discussed other available treatment options and the potential risks of 
continuing treatment.

A signature page for patients that consent to an optional biopsy at the time of 
radiographic disease progression (see Section 4.5.7.2)
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.


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


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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other 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.
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.


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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 and managed by F. Hoffmann-La Roche Ltd.  
Approximately 225 sites globally will participate in the study and approximately 
568 patients will be randomized.  Additional patients will be enrolled in China to ensure a 
total of approximately 164 patients in the China cisplatin subpopulation, including those 
enrolled in China in the global enrollment phase and those enrolled in the China 
extension phase.
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.
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:
http://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 Sponsor will comply with the requirements for publication of study results.  
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.


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
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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Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Assessments
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation Visit
Survival Follow-Up
Days 28
to 1
Induction Phase
(Cycles 14 or 6)
Maintenance
Phase
30 Days after Last 
Dose of Study 
Treatment
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit
Every 21 Days
(3 Days) b
Every 21 Days
(3 Days)
Informed consent
x
Tumor tissue specimen (blocks or 10 or more FFPE slides 
preferred, if available). c
Fresh or archival tissue can be used.
x
Demographic data
x
Medical history and baseline conditions
x
NSCLC cancer history
x
Vital signs d
x
x
x
x
Weight
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examination e
x
x
x
ECOG performance status
x
x
x
x
12-Lead ECG
x
x f
x f
x f
Hematology g
x
x
x
x
Serum chemistry h
x
x
x
x
Coagulation test (aPTT or INR)
x
x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol GO29438, Version 7
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation Visit
Survival Follow-Up
Days 28
to 1
Induction Phase
(Cycles 14 or 6)
Maintenance
Phase
30 Days after Last 
Dose of Study 
Treatment
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit
Every 21 Days
(3 Days) b
Every 21 Days
(3 Days)
Pregnancy test (women of childbearing-potential ONLY)
x i
x j
x j
x j
TSH, free T3, free T4 k
x
x
x
x
ALK and/or EGFR assessment if status is unknown (may 
be done locally or centrally)
x
HIV, HBV, HCV serology l
x
Urinalysis m
x
Determination of duration of induction treatment
x
Induction treatment administration
Arm A:  atezolizumabcarboplatin or 
cisplatinpemetrexed
Arm B:  carboplatin or cisplatinpemetrexed
x n
Maintenance treatment administration
Arm A:  atezolizumabpemetrexed
Arm B:  pemetrexed
x n
Tumor response assessment
x o
x p
x p
x q
Serum sample for atezolizumab ATA assessment 
(atezolizumab-treated patients only) r
x
x
x
120 (30) days after 
last dose of 
atezolizumab


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol GO29438, Version 7
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation Visit
Survival Follow-Up
Days 28
to 1
Induction Phase
(Cycles 14 or 6)
Maintenance
Phase
30 Days after Last 
Dose of Study 
Treatment
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit
Every 21 Days
(3 Days) b
Every 21 Days
(3 Days)
Serum sample for PK sampling (atezolizumab-treated 
patients only) r
x
x
x
120 (30) days after 
last dose of 
atezolizumab
Carboplatin, cisplatin, and pemetrexed PK sampling 
(20 patients in Arm A) r
x
Optional tumor biopsy s
Optional at time of radiographic 
progression
Blood samples for biomarkers r
x
x
x
x
120 (30) days after 
last dose of 
atezolizumab
Optional blood for DNA extraction (RCR only) r, t
x
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab-treated patients)
At time of radiographic progression
Optional tumor biopsy at other timepoints (RCR only)
Any time during study treatment or during survival follow-up
Adverse events
x
x
x
x u
x u
Concomitant medications
x v
x
x
x
Patient-reported outcomes (EORTC QLQ-C30, EORTC 
QLQ-LC13, SILC, and EQ-5D-5L) v
x w
x w
x w
Survival and anti-cancer therapy follow-up
x
x
x x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol GO29438, Version 7
ATAanti-therapeutic antibody; CTcomputed tomography; ECOGEastern Cooperative Oncology Group; EORTCEuropean Organization for Research and 
Treatment of Cancer; ePROelectronic Patient-Reported Outcome; EQ-5D-5LEuroQoL 5 Dimensions 5-Level Version; FFPEformalin-fixed paraffin-embedded; 
HBcAbhepatitis B core antibody; HBVhepatitis B virus; HCVhepatitis C virus; IVintravenous; MRImagnetic resonance imaging; NSCLCnonsmall cell 
lung cancer; PCRpolymerase chain reaction; PDpharmacodynamic; PD-L1programmed deathligand 1; PKpharmacokinetic; PROPatient-Reported 
Outcome; QLQ-C30Quality-of-Life QuestionnaireCore 30; QLQ-LC13Quality-of-Life Questionnaire Lung Cancer module; RCRRoche Clinical Repository; 
RECISTResponse Evaluation Criteria in Solid Tumors; SILCSymptoms in Lung Cancer; TSHthyroid-stimulating hormone.
a
Assessments should be performed before study drug infusion unless otherwise noted.
b
Cycle 1, Day 1 must be performed within 5 days after the patient is randomized. Screening assessments performed 96 hours before Cycle 1, Day 1 are not 
required to be repeated for Cycle 1, Day 1. In addition, ECOG performance status, limited physical examination, and local laboratory tests may be performed 
96 hours before Day 1 of each cycle as specified in Section 4.5.12.2.
c
Any available tumor tissue sample can be submitted before or within 4 weeks after enrollment. It is strongly encouraged that the sites submit representative 
tumor specimens preferably in paraffin blocks or as 10 (or more) serial, freshly cut, unstained slides for biomarker analysis.  See Section 4.1.1, Inclusion Criteria, 
and Section 4.5.7.1.
d
Vital signs include pulse rate, respiratory rate, blood pressures, and temperature. Vital signs should be recorded as described in Section 4.5.4.
e
Symptom-directed physical examinations; see Section 4.5.3 for details.
f
ECG recordings will be obtained when clinically indicated.
g
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, 
basophils, and other cells), and platelet count.
h
Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.
i
Serum pregnancy test within 14 days before Cycle 1, Day 1.
j
Urine pregnancy tests; if a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test.
k
Thyroid function testing (TSH, free T3, free T4) collected at Cycle 1, Day 1 and every fourth cycle thereafter.  Note:  Total T3 will be tested only at sites where 
free T3 testing cannot be performed.
l
All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study.  HBV DNA must be 
collected prior to randomization in patients who have negative serology for hepatitis B surface antigen and positive serology for HBcAb.
m Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood) should be obtained at screening and when clinically indicated throughout the 
study.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol GO29438, Version 7
n
For atezolizumab, the initial dose will be delivered over 60 (15) minutes.  If the first infusion is well tolerated, all subsequent infusions may be delivered over 
30 (10) minutes until disease progression per RECIST v1.1 or loss of clinical benefit.  For carboplatin or cisplatin and pemetrexed, study drug will be 
administered according to the local prescribing information, including premedication with steroids (see Section 4.3.2).
o
CT scans (with oral/IV contrast unless contraindicated) or MRI scans of the chest and abdomen.  A CT scan of the pelvis is required at screening and as 
clinically indicated or as per local standard of care at subsequent response evaluations.  A CT (with contrast) or MRI scan of the head must be done at screening 
to evaluate CNS metastasis in all patients.  See Section 4.5.5 for details.
p
Perform every 6 weeks (7 days) (approximately every two cycles) for 12 months following Cycle 1, Day 1, and then every 9 weeks (7 days) thereafter after 
completion of the Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression (loss of clinical benefit for patients 
assigned to atezolizumab who continue treatment with atezolizumab after disease progression according to RECIST v1.1), withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first.  See Section 4.5.5 for details.
q
If a patient discontinues study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration), 
tumor assessments will continue at the same frequency as would have been followed if the patient had remained on study treatment until radiographic disease 
progression (loss of clinical benefit for patients treated with atezolizumab who continue treatment after disease progression according to RECIST v1.1), 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if patient starts another anti-cancer therapy after study treatment 
discontinuation, unless consent is withdrawn.
r
See Appendix 2 for detailed schedule.
s
Optional tumor biopsy at radiographic disease progression, if clinically feasible, preferably within 40 days of radiographic progression or prior to start of the next 
anti-cancer therapy, whichever occurs is sooner.
t
The optional RCR whole blood sample requires an additional informed consent and the sample can be collected at any time during the course of the study.
u
All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the last dose of 
study treatment or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of relationship to study drug, will be reported
until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths should continue to be 
reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that is 
believed to be related to prior exposure to study treatment (see Section 5.6).
v
From 7 days before screening.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol GO29438, Version 7
w EORTC QLQ-C30, EORTC QLQ-LC13, and the EQ-5D-5L questionnaires will be completed by the patients on the ePRO tablet at each scheduled study visit 
prior to administration of study drug and prior to any other study assessment(s).  SILC will be completed using an ePRO device at the patient’s home on a 
weekly basis.  During survival follow-up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D- 5L questionnaires will be completed at 3 and 6 months 
following disease progression.  The SILC will be completed monthly during survival follow-up for 6 months following disease progression or loss of clinical benefit 
(for atezolizumab-treated patients who continue after disease progression according to RECIST v1.1).  Patients who discontinue study treatment for any reason 
other than radiographic progressive disease or loss of clinical benefit will complete the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L at each tumor 
assessment visit and will complete the SILC at home on a weekly basis, until radiographic disease progression per RECIST v1.1 (or for atezolizumab-treated 
patients who continue treatment after radiographic disease progression) or loss of clinical benefit as determined by the investigator (unless the patient withdraws 
consent or the Sponsor terminates the study).  Study personnel should review all questionnaires for completeness before the patient leaves the investigational 
site.
x
Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death, loss to 
follow-up, or study termination by the Sponsor, whichever occurs first.  All patients will be periodically contacted for survival and new anti-cancer therapy 
information unless the patient requests to be withdrawn from follow-up (this request must be documented in the source documents and signed by the 
investigator).  If the patient withdraws from the study, study staff may use a public information source (e.g., county records), when permissible, to obtain 
information about survival status only.


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Appendix 2
Schedule of Pharmacokinetic, Biomarker, and Anti-Therapeutic 
Antibody Assessments
Study Visit
Time
Arm A
(Atezolizumab
Carboplatin or Cisplatin 
Pemetrexed)
Arm B
(Carboplatin or 
Cisplatin 
Pemetrexed)
Screening
N/A
Biomarkers a
Biomarkers a
Cycle 1, Day 1
Pre-dose (same day as 
treatment administration) 
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
Carboplatin or cisplatin 
pharmacokinetics c
Pemetrexed 
pharmacokinetics c
Biomarkers b
30 (10) minutes after 
end of atezolizumab 
infusion
Atezolizumab 
pharmacokinetics
NA
510 minutes before the 
end of carboplatin or 
cisplatin infusion b
Carboplatin or cisplatin 
pharmacokinetics c
NA
1 hour after end of 
carboplatin or cisplatin 
infusion b
Carboplatin or cisplatin 
pharmacokinetics c
NA
510 minutes before the 
end of pemetrexed 
infusion b
Pemetrexed 
pharmacokinetics c
NA
1 hour after end of 
pemetrexed infusion b
Pemetrexed 
pharmacokinetics c
NA
Cycle 2, Day 1
Pre-dose (same day as 
treatment administration)
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
Biomarkers b
Cycle 3, Day 1
Pre-dose (same day as 
treatment administration)

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers b

Carboplatin or cisplatin 
pharmacokinetics c

Pemetrexed 
pharmacokinetics c
Biomarkers b


Appendix 2
Schedule of Pharmacokinetic, Biomarker, and Anti-Therapeutic 
Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol GO29438, Version 7
Study Visit
Time
Arm A
(Atezolizumab
Carboplatin or 
Cisplatin 
Pemetrexed)
Arm B
(Carboplatin or 
Cisplatin 
Pemetrexed)
510 minutes before the 
end of carboplatin or 
cisplatin infusion b
Carboplatin or 
cisplatin 
pharmacokinetics c
NA
1 hour after end of 
carboplatin or cisplatin 
infusion b
Carboplatin or 
cisplatin 
pharmacokinetics c
NA
510 minutes before the 
end of pemetrexed 
infusion b
Pemetrexed 
pharmacokinetics c
NA
1 hour after end of 
pemetrexed infusion b
Pemetrexed 
pharmacokinetics c
NA
Cycles 4, 8, and 
16, Day 1
Pre-dose (same day as 
treatment administration)

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers b

Biomarkers b
After Cycle 16, 
every eighth cycle, 
Day 1 (3 days)
Pre-dose (same day as 
treatment administration)

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers b

Biomarkers b
At time of fresh 
biopsy 
(on-treatment or at 
progression, 
including during 
follow-up)
At visit
Biomarkers b

Biomarkers b
Treatment 
discontinuation 
visit
At visit

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers b

Biomarkers b
120 (30 days) 
after last dose of 
atezolizumab
At visit

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers b

Biomarkers b


Appendix 2
Schedule of Pharmacokinetic, Biomarker, and Anti-Therapeutic 
Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol GO29438, Version 7
Study Visit
Time
Arm A
(Atezolizumab
Carboplatin or Cisplatin 
Pemetrexed)
Arm B
(Carboplatin or 
Cisplatin 
Pemetrexed)
At any time during 
the study (RCR 
consent required)
At visit
Optional RCR blood 
(DNA extraction) d
Optional RCR blood 
(DNA extraction) d
ATAanti-therapeutic antibody; NAnot applicable; PKpharmacokinetic; RCRRoche Clinical 
Repository.
Note:  Serum PK samples for atezolizumab; plasma PK samples for carboplatin or cisplatin and 
pemetrexed.
a Whole blood for biomarkers.
b Plasma and serum for biomarkers.
c At selected centers, 20 patients in Arm A will undergo the additional PK assessments for 
carboplatin or cisplatin and pemetrexed where applicable.
d The optional RCR blood sample (for DNA extraction) requires an additional informed consent 
and can be collected at any time during the course of the study.


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Appendix 3
American Joint Committee on Cancer
NonSmall Cell Lung Cancer Staging, 7th Edition


Appendix 3
American Joint Committee on Cancer 
NonSmall Cell Lung Cancer Staging, 7th Edition (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol GO29438, Version 7
Reference:  Lung. In: Edge S, Byrd DR, Compton CC, et al, editors. AJCC Cancer Staging 
Manual, Seventh Edition. Chicago: Springer, 2010:267–70.


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows.
a.
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resolution imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
b.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1 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.
2
For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol GO29438, Version 7
c.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such 
as CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS
a.
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
b.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol GO29438, Version 7
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
Chest X-Ray.  Chest CT scan is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, particularly 
in identifying new lesions.  However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT scan or MRI scan (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 a baseline contrast CT scan is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) scan will be performed 
should also be based on the tumor type and the anatomic location of the disease 
and should be optimized to allow for comparison with the prior studies if possible.  
Each case should be discussed with the radiologist to determine if substitution of these 
other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward.  Care must be taken in measurement of target lesions on a 
different modality and interpretation of non-target disease or new lesions since the same 
lesion may appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol GO29438, Version 7
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or two 
organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will be 
recorded as non-target lesions (even if the size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI scan the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis 
10 mm are considered non-pathological and should not be recorded or followed.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol GO29438, Version 7
Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target 
lesions.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, 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”).
RESPONSE CRITERIA
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b.
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol GO29438, Version 7
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
10 mm.
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked.)
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol GO29438, Version 7
c.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although 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 protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level)
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
d.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III studies when it is not a criterion of study entry to have measurable 
disease.  The same general concepts apply here as noted above; however, in this 
instance, there is no measurable disease assessment to factor into the interpretation of 
an increase in non-measurable disease burden.  Because worsening in non-target 
disease cannot be easily quantified (by definition:  if all lesions are truly non-measurable), 
a useful test that can be applied when assessing patients for unequivocal progression 
is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease; that is, an increase in tumor burden 
representing an additional 73% increase in volume (which is equivalent to a 
20% increase in diameter in a measurable lesion).  Examples include an increase in 
a pleural effusion from “trace” to “large” or an increase in lymphangitic disease from 
localized to widespread or may be described in protocols as “sufficient to require a 


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol GO29438, Version 7
change in therapy.”  If unequivocal progression is seen, the patient should be considered 
to have had overall PD at that point.  Although it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible 
to do so; therefore, the increase must be substantial.
e.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol GO29438, Version 7
Table 1  Timepoint Response:  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 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.
Table 2  Timepoint Response: Patients with Non-Target 
Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
b.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol GO29438, Version 7
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen 
in the case of PD.  For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and, during the study, only two lesions were assessed, but those gave 
a sum of 80 mm; the patient will have achieved PD status, regardless of the contribution 
of the missing lesion.
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol GO29438, Version 7
Table 3  Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
PR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
c.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol GO29438, Version 7
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 disease as shown in Tables 13.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.


Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol GO29438, Version 7
Appendix 5
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment.
Modified Response Evaluation Criteria in Solid Tumors (RECIST) is derived from 
RECIST, Version 1.1 (v1.1) conventions1 and immune-related response criteria2 (irRC).  
When not otherwise specified, RECIST v1.1 conventions will apply.
Modified RECIST and RECIST v1.1:  Summary of Changes
RECIST v1.1
Modified RECIST
New lesions after baseline
Define progression
New measurable lesions are 
added into the total tumor burden 
and followed.
Non-target lesions
May contribute to the 
designation of overall 
progression
Contribute only in the assessment 
of a complete response
Radiographic progression
First instance of 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease
Determined only on the basis of 
measurable disease
RECIST Response Evaluation Criteria in Solid Tumors.
A. DEFINITIONS OF MEASURABLE/NON-MEASURABLE LESIONS
All measurable and non-measurable lesions should be assessed at Screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
performed, as clinically indicated for suspicion of progression.  
1 Eisenhauer et al. Eur J Cancer 2009;45: 22847; Topalian et al. N Engl J Med
2012;366:244354; and Wolchok et al. Clin Can Res 2009;15:741220.
2 Wolchok et al. Clin Can Res 2009;15:741220; Nishino et al. J Immunother Can 2014;2:17; 
Nishino et al. Clin Can Res 2013;19:393643.


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol GO29438, Version 7
A.1
MEASURABLE LESIONS
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.
A.2
NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
A.3
SPECIAL CONSIDERATIONS REGARDING LESION 
MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions.
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
Blastic bone lesions are non-measurable.


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol GO29438, Version 7
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.
B. TUMOR RESPONSE EVALUATION
B.1 DEFINITIONS OF TARGET/NON-TARGET LESIONS
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one 
or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-target lesions (even if the size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance, the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol GO29438, Version 7
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm but 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of 10 mm are considered non-pathological and should not be 
recorded or followed.
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions.
Non-Target Lesions
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required.
It is possible to record multiple non-target lesions involving the same organ as a single 
item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).
After baseline, changes in non-target lesions will contribute only in the assessment 
of CR (i.e., a CR is attained only with the complete disappearance of all tumor lesions, 
including non-target lesions) and will not be used to assess progressive disease.
New Lesions
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will also be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST, (e.g., nonlymph node lesions must be 10 mm; see note for new 
lymph node lesions below).  Up to a maximum of five new lesions total (and a maximum 
of two lesions per organ), all with measurements at all timepoints, can be included in the 
tumor response evaluation.  New lesion types that would not qualify as target lesions per 
RECIST cannot be included in the tumor response evaluation.
New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent timepoint will be measured from that point on and contribute to the sum 
of longest diameters (SLD), if the maximum number of 5 measurable new lesions being 
followed has not been reached. 


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol GO29438, Version 7
B.2 CALCULATION OF SUM OF THE DIAMETERS
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden.
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses.
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1.
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions selected at 
baseline and up to five new measurable lesions (with a maximum of two new lesions per 
organ) that have emerged after baseline will contribute to the sum of the diameters at 
tumor assessment.  Hence, each net percentage change in tumor burden per 
assessment with use of modified RECIST accounts for the size and growth kinetics of 
both old and new lesions as they appear.
Note:  In the case of new lymph nodes, RECIST v1.1 criteria for measurability 
(equivalent to baseline target lesion selection) will be followed.  That is, if at first 
appearance the short axis of a new lymph node lesion 15 mm, it will be considered a 
measureable new lesion and will be tracked and included in the SLD.  Thereafter, the 
lymph node lesion will be measured at subsequent timepoints and measurements will be 
included in the SLD, even if the short axis diameter decreases to 15 mm (or even 
10 mm).  However, if it subsequently decreases to 10 mm, and all other lesions are 
no longer detectable (or have also decreased to a short axis diameter of 10 mm if 
lymph nodes), then a response assessment of CR may be assigned.
If at first appearance the short axis of a new lymph node is 10 mm and 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion. It 
will not be included in the SLD unless it subsequently becomes measurable (short axis 
diameter 15 mm).
The appearance of new lymph nodes with diameter 10 mm should not be considered 
pathological and not considered a new lesion.


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol GO29438, Version 7
B.3 RESPONSE CRITERIA
Timepoint Response
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
Complete Response (CR):  Disappearance of all target and non-target lesions.  Lymph 
nodes that shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
Note: the appearance of new measurable lesions is factored into the overall tumor 
burden, but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and selected new measurable lesions, taking as reference the smallest sum on 
study (nadir SLD; this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution to 
total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response.
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is
considered not evaluable (NE) at that timepoint.  If only a subset of lesion 
measurements are made at an assessment, usually the case is also considered NE at 
that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This 
would only happen in the case of PD.  For example, if a patient had a baseline sum of 
50 mm with three measured lesions and at follow-up only two lesions were assessed but 


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol GO29438, Version 7
those gave a sum of 80 mm, the patient will be assigned PD status, regardless of the 
contribution of the missing lesion.
Table 1  Modified RECIST Timepoint Response Definitions
% Change in Sum of the Diameters a
Non-Target Lesion 
Response 
Assessment
Overall Modified RECIST 
Timepoint Response
100% from baseline b
CR
CR
100% from baseline b
Non-CR or not all 
evaluated
PR
30% from baseline
Any
PR
30% to 20%
Any
SD
Not all evaluated
Any
NE
20%from nadir SLD
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
RECIST Response Evaluation Criteria in Solid Tumors; SD stable disease; SLDsum of the 
longest diameter.
a Percent change in sum of the diameters (including measurable new lesions when present).
b When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if CR criteria are met, since a normal lymph node is 
defined as having a short axis of 10 mm.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 10 mm in order to meet the definition of 
CR.


Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol GO29438, Version 7
Appendix 6
AntiPD-L1 Immunohistochemistry
OVERVIEW
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody 
immunohistochemistry (IHC) assay will be used to determine 
programmed deathligand 1 (PD-L1) IHC status.  The antiPD-L1 (SP142) rabbit 
monoclonal antibody IHC assay is currently being developed by Ventana Medical 
Systems as a companion diagnostic to atezolizumab.  For Study GO29438, the 
antiPD-L1 (SP142) IHC assay will be used for investigational purposes only.
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody is intended for 
laboratory use in the semi-quantitative immunohistochemical assessment of the PD-L1 
protein in formalin-fixed paraffin-embedded nonsmall cell lung carcinoma (NSCLC) 
tissue stained on a Ventana BenchMark ULTRA automated slide stainer.  It is indicated 
as an aid in the selection of NSCLC patients with locally advanced or metastatic disease 
who might benefit from treatment with atezolizumab.
This assay is for investigational use only.  The performance characteristics of this 
product have not been established.
DEVICE DESCRIPTION
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody is a pre-dilute, 
ready-to-use antibody product optimized for use with the Ventana Medical Systems 
OptiView DAB IHC Detection Kit and the OptiView Amplification Kit on Ventana Medical 
Systems automated BenchMark ULTRA platforms.  One 5-mL dispenser of antiPD-L1 
(SP142) rabbit monoclonal primary antibody contains approximately 36 g of rabbit 
monoclonal antibody directed against the PD-L1 protein and contains sufficient reagent 
for 50 tests.  The reagents and the IHC procedure are optimized for use on the 
BenchMark ULTRA automated slide stainer, utilizing Ventana System Software (VSS). 
SCORING SYSTEM
PD-L1 staining with antiPD-L1 (SP142) rabbit monoclonal primary antibody in NSCLC 
can be observed in both tumor cells and tumor-infiltrating immune cells.
Details of the criteria for PD-L1 diagnostic assessment are described in the IDI 
document.


Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol GO29438, Version 7
Appendix 7
EORTC QLQ-C30


Appendix 7
EORTC QLQ-C30 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol GO29438, Version 7


Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol GO29438, Version 7
Appendix 8
EORTC QLQ-LC13


Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol GO29438, Version 7
Appendix 9
EQ-5D-5L


Appendix 9
EQ-5D-5L (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol GO29438, Version 7


Appendix 9
EQ-5D-5L (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol GO29438, Version 7


Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol GO29438, Version 7
Appendix 10
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


Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol GO29438, Version 7
Appendix 11
Anaphylaxis Precautions
EQUIPMENT NEEDED

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.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.


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182/Protocol GO29438, Version 7
Appendix 12
Preexisting Autoimmune Diseases
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias for whom the 
clinical suspicion of autoimmune disease is low.  Patients with a history of autoimmune-
related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible 
for this study.  In addition, transient autoimmune manifestations of an acute infectious 
disease that resolved upon treatment of the infectious agent are not excluded 
(e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any uncertainty about
autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune thrombocytopenic 
purpura
Behcet’s disease
Bullous pemphigold
Chronic fatigue syndrome
Chronic inflammatory demyelinating
    polyneuropathy
Chung-Strauss syndrome
Crohn’s disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada disease
Wegener’s granulomatosis


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 13
Symptoms in Lung Cancer


Appendix 13
Symptoms in Lung Cancer (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol GO29438, Version 7


Appendix 13
Symptoms in Lung Cancer (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol GO29438, Version 7




Appendix 14
Additional Guidance on Chemotherapy Administration (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol GO29438, Version 7
Within a 4-cycle induction regimen, chemotherapy may be paused for a total of two 
consecutive or non-consecutive cycles before chemotherapy should be permanently 
discontinued.  Within a 6-cycle induction regimen, chemotherapy may be paused for a
total of three non-consecutive cycles before chemotherapy should be permanently 
discontinued.
The recommended time window for administration of all study treatment components 
within a cycle is 3 days.  If atezolizumab was given but chemotherapy could not be 
administered on the same day, and the delay between the first and last component of 
study treatment would be more than 3 days, the remaining components should be 
delayed until the next cycle and the chemotherapy induction cycle considered not done.
If it is anticipated that a component of study treatment cannot be administered, it is 
recommended to delay all study treatment for up to 2 weeks.  However, if it is anticipated 
that chemotherapy will be delayed by more than 2 weeks, then atezolizumab should be 
a given without chemotherapy, which will be delayed until the next cycle, provided there 
is no contraindication.
eCRF Data Entry for Recording Interruption and Re-Introduction 
of Chemotherapy
Because of the complex nature and possible permutations of such dosage interruptions 
and reintroductions, site personnel should contact the Monitor, and the Monitor will 
instruct the site on how to open the appropriate visits and electronic Case Report Form 
(eCRF) so that the site can then record the interruption and reintroduction accordingly on 
the eCRF.


Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol GO29438, Version 7
Appendix 15
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The 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 
may be considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every 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.  Management guidelines for pulmonary events are provided in Table 1.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
189/Protocol GO29438, Version 7
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol GO29438, Version 7
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
191/Protocol GO29438, Version 7
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol GO29438, Version 7
Table 3
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol GO29438, Version 7
Table 3
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
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 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
194/Protocol GO29438, Version 7
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
195/Protocol GO29438, Version 7
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
196/Protocol GO29438, Version 7
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
197/Protocol GO29438, Version 7
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
198/Protocol GO29438, Version 7
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, 
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.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
199/Protocol GO29438, Version 7
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-mediated
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.a

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated
myocarditis, Grade 3-4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. a, b

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
200/Protocol GO29438, Version 7
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE 
SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
201/Protocol GO29438, Version 7
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of 
IV fluids for hydration.

In case of rapid decline or prolonged CRS (2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
202/Protocol GO29438, Version 7
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 2 a
Fever b with 
hypotension not 
requiring 
vasopressors
and/or
Hypoxia requiring 
low-flow oxygen d
by nasal cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated, and 
manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor.

If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  

For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol GO29438, Version 7
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ toxicities as 
per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e  For patients who are refractory to 
anti-cytokine therapy, experimental treatments g may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
204/Protocol GO29438, Version 7
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive airway 
pressure; CRS cytokine-release syndrome; CTCAE Common Terminology Criteria for 
Adverse Events; eCRF electronic Case Report Form; HLH hemophagocytic 
lymphohistiocytosis; ICU intensive care unit; IRRinfusion-related reaction; 
MAS macrophage activation syndrome; NCCN National Cancer Comprehensive Network; 
NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e
There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not 
been established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be considered 
after consulting the Medical Monitor and considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
205/Protocol GO29438, Version 7
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
206/Protocol GO29438, Version 7
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
207/Protocol GO29438, Version 7
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority 
of 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.  Management guidelines for dermatologic 
events are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
208/Protocol GO29438, Version 7
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Immune-mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia gravis 
and Guillain-Barré 
syndrome 
(any grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
209/Protocol GO29438, Version 7
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function. Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
210/Protocol GO29438, Version 7
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
211/Protocol GO29438, Version 7
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among 
the most common disorders.  Initial diagnosis is based on clinical (muscle weakness, 
muscle pain, skin rash in dermatomyositis), biochemical (serum creatine kinase 
increase), and imaging (electromyography/MRI) features, and is confirmed with a 
muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
212/Protocol GO29438, Version 7
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
213/Protocol GO29438, Version 7
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS), which are considered to be potential risks for atezolizumab.  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of 
the following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100 109/L (100,000/L)
–
ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should 
be classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181 109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


Appendix 15
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
214/Protocol GO29438, Version 7
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
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Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther 
Clin Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.

SAP_001.pdf: 
 
Official Title: 
 
A Phase III, Open-Label, Randomized Study of  
Atezolizumab (MPDL3280A, ANTI−PD-L1 Antibody) in 
Combination with Carboplatin or Cisplatin+Pemetrexed 
Compared with Carboplatin or Cisplatin+Pemetrexed in 
Patients who are Chemotherapy-Naive and have Stage IV 
Non-SQUAMOUS Non−Small Cell Lung Cancer  
 
 
 
 
NCT Number: NCT02657434 
Document Date: SAP Version 3: 07-May-18 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO29438 
  
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (MPDL3280A, 
ANTI−PD-L1 ANTIBODY) IN COMBINATION WITH 
CARBOPLATIN OR CISPLATIN+PEMETREXED 
COMPARED WITH CARBOPLATIN OR 
CISPLATIN+PEMETREXED IN PATIENTS WHO ARE 
CHEMOTHERAPY-NAIVE AND HAVE STAGE IV 
NON-SQUAMOUS NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: GO29438 
STUDY DRUG: 
Atezolizumab  
VERSION NUMBER: 
3 
IND NUMBER: 
117296 
EUDRACT NUMBER: 
2015-003605-42 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Ph.D. 
DATE FINAL: 
7 May 2018 
DATE AMENDED: 
 
Name                                                             Reason for Signing                              Date and Time
07-May-2018 20:35:09
(UTC)
Company Signatory
See electronic date stamp below. 






Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan GO29438 
4.4.2 
Secondary Efficacy Endpoints 
............................................... 17 
4.4.2.1 
Objective Response Rate 
...................................................... 17 
4.4.2.2 
Duration of Response 
............................................................ 17 
4.4.2.3 
Overall Survival Rates at 1- and 2-Year 
Landmark Timepoints ............................................................ 18 
4.4.2.4 
Patient-Reported Outcomes 
.................................................. 18 
4.4.3 
Exploratory Efficacy Endpoints 
.............................................. 19 
4.4.3.1 
Exploratory Analyses of Progression-Free 
Survival 
.................................................................................. 19 
4.4.3.1.1 
PFS at 6-Months and 1-Year Landmark 
Timepoints 
............................................................................. 19 
4.4.3.1.2 
Impact of Non−Protocol-Specified Anti-Cancer 
Therapy ................................................................................. 19 
4.4.3.1.3 
Subgroup Analyses ............................................................... 20 
4.4.3.1.4 
Impact of Missing Scheduled Tumor 
Assessments ......................................................................... 20 
4.4.3.2 
Exploratory Analyses of Overall Survival 
............................... 20 
4.4.3.2.1 
Overall Survival at 3-Year Landmark Timepoint .................... 20 
4.4.3.2.2 
Impact of Loss to Follow-Up 
.................................................. 20 
4.4.3.2.3 
Subgroup Analyses ............................................................... 21 
4.4.3.2.4 
Milestone Overall Survival Analysis 
....................................... 21 
4.4.3.2.5 
Impact of Non−Protocol-Specified Anti-Cancer 
Therapy ................................................................................. 21 
4.4.3.3 
Biomarker Analysis 
................................................................ 22 
4.4.3.4 
Utility Scores of the EuroQoL 5 Dimensions 5-
Level Version 
......................................................................... 22 
4.4.3.5 
Patient-Reported Outcomes of Health-Related 
Quality of Life 
......................................................................... 22 
4.4.4 
Sensitivity Analysis 
................................................................ 23 
4.4.4.1 
Delayed Clinical Effect 
........................................................... 23 
4.4.4.2 
Progression-Free Survival by Independent 
Review Facility 
....................................................................... 23 
4.5 
Pharmacokinetic Analyses 
..................................................... 24 
4.6 
Safety Analyses 
..................................................................... 24 
4.6.1 
Exposure of Study Medication 
............................................... 24 
4.6.2 
Adverse Events ..................................................................... 24 


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5/Statistical Analysis Plan GO29438 
4.6.3 
Laboratory Data 
..................................................................... 24 
4.6.4 
Vital Signs 
.............................................................................. 25 
4.6.5 
Anti-Drug Antibody Against Atezolizumab 
............................. 25 
4.7 
Missing Data 
.......................................................................... 25 
5. 
 
................................................................. 25 
6. REFERENCES ........................................................................................... 27 
 
LIST OF TABLES 
Table 1 
Study GO29438 Treatment Arms 
.................................................. 8 
Table 2 
Analysis Timing and Stopping Boundaries of 
Progression-Free Survival........................................................... 14 
Table 3 
Analysis Timing and Stopping Boundaries of Overall Survival 
.... 14 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema 
............................................................................... 7 
Figure 2 
Overview of the Alpha Control Strategy 
...................................... 12 
 
LIST OF APPENDICES 
Appendix 1 Protocol Synopsis for Study GO29438 ....................................... 28 
Appendix 2 Schedule of Assessments for Study GO29438 
........................... 38 


Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan GO29438 
1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study GO29438 (IMpower132), a Phase III, open-label, 
randomized study of atezolizumab (anti−programmed death−ligand 1 [PD-L1] antibody) 
in combination with carboplatin or cisplatin
 +
 pemetrexed compared with carboplatin or 
cisplatin
 +
 pemetrexed in patients who are chemotherapy naive and have Stage IV 
non−squamous non−small cell lung cancer (NSCLC).  The background for the study can 
be found in the study protocol. 
2. 
STUDY DESIGN 
This is a randomized, Phase III, multicenter, open-label study designed to 
evaluate the safety and efficacy of atezolizumab in combination with cisplatin or 
carboplatin
 +
 pemetrexed compared with treatment with cisplatin or 
carboplatin
 +
 pemetrexed in patients who are chemotherapy naive and have 
Stage IV non-squamous NSCLC.  Figure 1 illustrates the study design. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Statistical Analysis Plan GO29438 
Figure 1 Study Schema 
 
ECOG PS=Eastern Cooperative Oncology Group performance status; NSCLC=non−small cell 
lung cancer; RECIST v1.1=Response Evaluation Criteria in Solid Tumors, Version 1.1. 
 
Eligible patients were stratified by sex (male vs. female), smoking status (never vs. 
current and/or former), Eastern Cooperative Oncology Group (ECOG) performance 
status (0 vs. 1), and chemotherapy regimen (carboplatin vs. cisplatin) and randomized 
by a 1:1 ratio to receive one of the treatment regimens shown in Table 1. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Statistical Analysis Plan GO29438 
Table 1 Study GO29438 Treatment Arms 
Treatment Arm 
Induction 
(Four or Six 21-Day Cycles) 
Maintenance 
(21-Day Cycles) 
A 
Atezolizumab +
 carboplatin or 
cisplatin
 +
 pemetrexed 
Atezolizumab +
 pemetrexed 
B 
Carboplatin or cisplatin +
 pemetrexed 
Pemetrexed 
 
Patients randomized to Arm A receive 1200 mg of atezolizumab.  Atezolizumab 
infusions are administered per the instructions outlined in the protocol. 
Institutions should follow their standard administration procedures for pemetrexed.  The 
premedication doses administered should be in compliance with the prescribing 
information. 
Cisplatin by intravenous (IV) infusion should be administered approximately 30 minutes 
after completion of the pemetrexed infusion at a dose of 75 mg/m² over 1−2 hours or per 
standard of care at the institution. 
Carboplatin should be administered 30 minutes after completion of pemetrexed 
administration by IV infusion over 30−60 minutes to achieve an initial target area under 
the concentration−time curve of 6 mg/mL/min (Calvert formula dosing) with standard 
anti-emetics per local practice guidelines. 
The number of cycles of induction treatment (four or six) is at the discretion of the 
investigator and will be determined and documented prior to randomization.  Induction 
treatment is administered on a 21-day cycle until the following occurs (whichever occurs 
first):  1) administration of four or six cycles, 2) unacceptable toxicity, or 3) documented 
disease progression. 
Following the induction phase, patients who have not experienced disease progression 
or unacceptable toxicity continue treatment with maintenance therapy as shown in 
Table 1.  Patients randomized to either Arm A or B continue treatment with pemetrexed 
maintenance until progressive disease, unacceptable toxicity, or death.  During induction 
or maintenance treatment, patients randomized to Arm A may continue treatment with 
atezolizumab beyond progressive disease by Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST v1.1), provided they are experiencing clinical benefit as 
assessed by the investigator. 
Treatment with chemotherapy (both in Arm A and B) is discontinued for all patients who 
exhibit evidence of progressive disease by RECIST v1.1. 
Patients undergo tumor assessments at baseline and every 6 weeks for the 
first 48 weeks following Cycle 1, Day 1, regardless of dose delays.  After the completion 


Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Statistical Analysis Plan GO29438 
of the Week 48 tumor assessment, tumor assessment are required every 9 weeks.  
Patients undergo tumor assessments until radiographic disease progression per 
RECIST v1.1 or loss of clinical benefit (for atezolizumab-treated only patients who 
continue treatment after radiographic disease progression according to RECIST v1.1), 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  
Patients who discontinue treatment for reasons other than radiographic disease 
progression (e.g., toxicity) continue scheduled tumor assessments until radiographic 
disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab-treated 
patients who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever 
occurs first, regardless of whether patients start a new anti-cancer therapy. 
An independent Data Monitoring Committee (iDMC) monitors safety data. 
This study had planned to enroll approximately 568 patients across all sites in the global 
enrollment phase. 
 
 
 
 
 
  
2.1 
PROTOCOL SYNOPSIS 
The protocol synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Co-Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are: 
• Progression free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression as determined by the investigator using 
RECIST v1.1 or death from any cause, whichever occurs first 
• Overall survival (OS), defined as the time from randomization to death from any 
cause 
 
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are: 
• Objective response, defined as partial response (PR) or complete response (CR) as 
determined by the investigator according to RECIST v1.1 
• Duration of response (DOR), defined as the time interval from first occurrence of a 
documented objective response to the time of disease progression as determined 


Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Statistical Analysis Plan GO29438 
by the investigator using RECIST v1.1 or death from any cause, whichever comes 
first 
• OS rates at 1-year and 2-year landmark timepoints 
• Time to deterioration (TTD) in patient-reported lung cancer symptoms, defined as 
time from randomization to deterioration (10-point change) on each of the European 
Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life 
Questionnaire−Core 30 (QLQ-C30) and supplemental lung cancer module 
(QLQ-LC13) symptom subscales 
• Change from baseline in patient-reported lung cancer symptoms with use of the 
Symptoms in Lung Cancer (SILC) scale symptom score 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
The exploratory efficacy outcome measures for this study are: 
•  PFS rates at 6-month and at 1-year landmark timepoints 
• OS rate at 3-year landmark timepoint 
• Milestone survival 
• OS and investigator-assessed PFS according to RECIST v1.1 in subgroups based 
on demographic and baseline characteristics 
• Status of PD-L1−, immune- and NSCLC-related, and other exploratory biomarkers 
in archival and/or fresh tumor tissues, and blood (or blood derivatives) collected 
before, during, or after treatment with atezolizumab or at progression and 
association with disease status and/or response to atezolizumab in combination with 
chemotherapy 
• Utility scores of the EuroQoL 5 Dimensions 5-Level Version (EQ-5D-5L) for use in 
medical economic modeling 
• Change from baseline in patient-reported outcomes (PROs) of health-related quality 
of life, lung cancer−related symptoms, and health status as assessed by the 
EORTC QLQ-C30 and QLQ-LC13 
 
2.2.4 
Pharmacokinetic Outcome Measures 
The pharmacokinetic (PK) outcome measures for this study are: 
• Maximum observed serum atezolizumab concentration (C
max) after infusion (Arm A) 
• Minimum observed serum atezolizumab concentration (C
min) prior to infusion 
at selected cycles, at treatment discontinuation, and at 120 (
 ±
 30) days after the 
last dose of atezolizumab (Arm A) 
• Plasma concentrations for carboplatin or cisplatin (Arm A) 
• Plasma concentrations for pemetrexed (Arm A) 


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11/Statistical Analysis Plan GO29438 
2.2.5 
Safety Outcome Measures 
The safety outcome measures for this study are: 
• Incidence, nature, and severity of adverse events graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 (NCI CTCAE v4.0) 
• Changes in vital signs, physical findings, and clinical laboratory test results during 
and following study treatment administration 
• Incidence of anti-drug antibody (ADA) response to atezolizumab and potential 
correlation with PK, safety, and efficacy parameters 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
2.3.1 
Determination of Sample Size in the Global Enrollment Phase 
Determination of sample size is based on patients enrolled in the global enrollment 
phase.  This study will randomize approximately 568 patients during the global 
enrollment phase. 
 
 
To control the overall type I error rate using the group sequential Holm procedure 
(Ye et al. 2013) for the one-sided test at 0.025 in the analyses of patients enrolled during 
the global enrollment phase, PFS in the ITT (intent-to-treat) population will be tested at a 
one-sided α-level of 0.002 and OS in the ITT population will be tested at a one-sided 
α-level of 0.023.  If only PFS is statistically significant, OS in the ITT population will be 
tested at a one-sided α-level of 0.025.  Otherwise, OS in the ITT population will be 
tested at the initially assigned a one-sided α-level of 0.023.  If only OS is statistically 
significant, PFS in the ITT population will be tested at a one-sided α-level of 0.025 at the 
time of the primary analysis of PFS.  Otherwise, PFS in the ITT population will be tested 
at the initially assigned one-sided α-level of 0.002 at the time of PFS primary analysis.  
The overview of the α control strategy is shown in Figure 2. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Statistical Analysis Plan GO29438 
Figure 2 Overview of the Alpha Control Strategy 
 
ITT=intent to treat; PFS=progression-free survival; OS=overall survival. 
 
The sample size of this study is determined on the basis of the number of events 
required to demonstrate efficacy with regard to both PFS and OS. 
The estimates of the number of events required to demonstrate efficacy in the ITT 
population with regard to PFS are based on the following assumptions: 
• 1:1 randomization ratio 
• One-sided significance level of 0.002 for PFS and 0.023 for OS 
• Log-rank test 
• 96.0% power to detect a hazard ratio (HR) of 0.65, corresponding to an 
improvement in median PFS from 6 months to 9.2 months 
• No interim analysis for PFS 
• 81% power to detect an HR of 0.75, corresponding to an improvement in median 
OS from 14 months to 18.7 months 
• One interim OS analyses will be performed at the time of the PFS primary analysis 
with an information fraction of approximately 78% (i.e., 78% of the required OS 
events have occurred).  To adjust for the multiplicity due to the interim analyses, the 
Lan-DeMets approximation to the O’Brien-Fleming boundary will be used. 
• Dropout rate of 10% per 24 months assumed for all treatment arms 
• Event times exponentially distributed 
 
2.3.2 
 
 
 
 
 


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13/Statistical Analysis Plan GO29438 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4 
ANALYSES TIMING 
There are no interim analyses planned for the co-primary endpoint of PFS in this study. 
The PFS primary analysis will be conducted when approximately 458 PFS events have 
occurred in the ITT population and at least 10 months after the last patient is enrolled 
during the global enrollment phase, whichever occurs later.  This is expected to occur 
approximately 30 months after the first patient is randomized.  This number of events 
corresponds to a minimum detectable difference in HR of approximately 0.764 for a 
one-sided α-level of 0.002.  Based on the group sequential Holm procedure 
(Ye et al. 2013), if only OS is statistically significant, then PFS in the ITT population will 
be tested at a one-sided α-level of 0.025 at the time of PFS primary analysis.  In this 
case, the number of events corresponds to a minimum detectable difference of 
approximately 0.833 in HR as shown in Table 2. 
The interim efficacy analysis of OS will be conducted by the Sponsor at the time of the 
primary PFS analysis.  It is estimated that approximately 312 OS events in the 
ITT population will have been observed at this timepoint and it is expected to occur 
approximately 30 months after the first patient is randomized. 
The final OS analysis will be conducted when approximately 398 OS events in the 
ITT population have been observed.  This is expected to occur approximately 42 months 
after the first patient is randomized, but the exact timing of this analysis will depend on 
the actual number and timing of OS events. 


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14/Statistical Analysis Plan GO29438 
To control type I error for OS, the stopping boundaries for the OS interims and final 
analysis are to be computed with use of the Lan-DeMets approximation to the Pocock 
boundary as shown in Table 3. The stopping boundary for the OS interim will be 
adjusted according to the observed number of OS events at the time of primary PFS 
analysis.  
Table 2 Analysis Timing and Stopping Boundaries of Progression-Free 
Survival 
Analysis Timing 
Stopping Boundary for Rejection of H0 
ITT Population 
One-Sided alpha=0.002 
One-Sided alpha=0.025 
Final analysis 
HR<0.764 
HR<0.833 
HR=hazard ratio; ITT=intent-to-treat 
 
Table 3 Analysis Timing and Stopping Boundaries of Overall Survival 
Analysis Timing 
Planned 
Information 
Fraction 
Stopping Boundary for Rejection of H0 
ITT Population 
One-sided alpha=0.023 One-sided alpha=0.025 
Interim analysis 
78% 
HR <
 0.792 
(p
 ≤
 0.0196) 
HR <
 0.795 
(p
 ≤
 0.0213) 
Final analysis 
100% 
HR<0.794 
(p
 ≤
 0.0108) 
HR <
 0.797 
(p
 ≤
 0.0119) 
HR=hazard ratio; ITT=intent-to-treat. 
Note: p=one-sided p-value. 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Eligible patients will be randomized in a 1:1 ratio to receive either carboplatin/ 
cisplatin
 +
 pemetrexed
 +
 atezolizumab or carboplatin/cisplatin
 +
 pemetrexed with the 
use of a stratified permuted-block randomization.  The randomization will be stratified 
for the following factors: 
• Sex (male vs. female) 
• Smoking status (never vs. current or former) 
• ECOG performance status (0 vs. 1) 
• Chemotherapy (cisplatin vs. carboplatin) 
 
Under Versions 1 and 2 of Protocol GO29438, PD-L1 expression by 
immunohistochemistry (IHC) (tumor cell [TC] 2/3 and any tumor-infiltrating immune cell 
[IC] vs. TC0/1 and IC2/3 vs. TC0/1 and IC0/1) was used as one of the stratification 


Atezolizumab—F. Hoffmann-La Roche Ltd 
15/Statistical Analysis Plan GO29438 
factors instead of chemotherapy.  Distribution of stratification factors between treatment 
arms will be assessed to evaluate potential imbalances. 
3.2 
DATA MONITORING 
An iDMC has been used to evaluate safety during the study on a regular basis.  All 
summaries and analyses by treatment arm for the iDMC review are prepared by an 
external independent Data Coordinating Center.  Members of the iDMC are external 
to the Sponsor and follow a separate iDMC Charter that outlines their roles and 
responsibilities, as well as a detailed monitoring plan.  Refer to the iDMC Charter 
for further detail. 
4. 
STATISTICAL METHODS FOR PATIENTS ENROLLED IN THE 
GLOBAL ENROLLMENT PHASE 
The analyses described in this SAP will supersede those specified in Protocol GO29438 
for the purposes of a regulatory filing.  The analyses throughout Section 4 are based 
only on those patients who are enrolled in the global enrollment phase, 
 
 
 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The ITT population is defined as all randomized patients, whether or not the patients 
received the assigned treatment.  
 
  The ITT patients will be analyzed 
according to the treatment assigned at randomization by the interactive voice/Web 
response system (IxRS). 
4.1.2 
Pharmacokinetic-Evaluable Population 
PK analyses will be based on PK observations from all patients who received 
atezolizumab, carboplatin, cisplatin or pemetrexed treatment and who provided at least 
one evaluable PK sample. 
 
. 
4.1.3 
Safety Population 
The safety population is defined as patients who received any amount of study treatment.  
 
  Patients who received any amount of atezolizumab will be analyzed as part 
of the Arm A even if atezolizumab was given in error.  Patients who were randomized to 
the study but did not receive any study drug will not be included in the safety population. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Enrollment, major protocol deviations (including major deviations of inclusion and/or 
exclusion criteria), and reasons for discontinuation from the study will be summarized 


Atezolizumab—F. Hoffmann-La Roche Ltd 
16/Statistical Analysis Plan GO29438 
by treatment arm for the ITT population.  Study treatment administration and reasons 
for discontinuation from study treatment will be summarized by treatment arm for the 
safety population. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics, such as age and race/ethnicity, and baseline disease 
characteristics, such as histology subtype, current disease status, and stratification 
factors (sex, smoking status, ECOG performance status, chemotherapy), will be 
summarized by treatment arm for the ITT population. 
Baseline values are the last available data obtained prior to the patient receiving the 
first dose of any study treatments on Cycle 1, Day 1 visits unless otherwise noted.  
Descriptive statistics (mean, median, SD, range) will be presented for continuous 
variables, and frequencies and percentages will be presented for categorical variables. 
4.4 
EFFICACY ANALYSIS 
All efficacy endpoints will be analyzed on the ITT population. The stratification factors 
will be those used for randomization and will be obtained from the IxRS (sex, smoking 
status, ECOG performance status, and chemotherapy type).  
 
if at least one stratum (i.e., a combination of 
stratification factor levels across sex, smoking status, ECOG performance status, and 
chemotherapy type per IxRS) has fewer than 10 events (PFS or OS events), the 
stratification factor (one of 4 stratification factors: sex, smoking status, ECOG 
performance status, and chemotherapy type per IxRS) which contains the level with the 
smallest number of patients will be removed from the stratified analyses.  The removal of 
the stratification factor will continue until there is no stratum with fewer than 10 events 
(PFS or OS events).  The final set of stratification factors used in stratified analyses will 
be applied to all endpoints where stratified analyses are planned. 
4.4.1 
Co-Primary Efficacy Endpoints 
4.4.1.1 
Progression-Free Survival 
PFS is defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator using RECIST v1.1 or death from any 
cause, whichever occurs first.  Patients who have not experienced disease progression 
or death at the time of analysis will be censored at the time of the last tumor assessment.  
Patients with no post-baseline tumor assessment will be censored at the date of 
randomization plus 1 day. 
Treatment comparisons will be based on the stratified log-rank test in the ITT population.  
The null and alternative hypotheses can be phrased in terms of the survival functions 
SPFS_A (t) and SPFS_B (t) in Arm A and Arm B, respectively: 
H0:  S
PFS_A (t)=SPFS_B (t) versus H
1:  S
PFS_A (t)>SPFS_B (t) 
 


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17/Statistical Analysis Plan GO29438 
Kaplan-Meier methodology will be used to estimate median PFS for each treatment arm 
and construct survival curves for the visual description of the difference between the 
treatment arms.  The Brookmeyer-Crowley methodology will be used to construct the 
95% CI for the median PFS for each treatment arm (Brookmeyer and Crowley 1982). 
The HR, λPFS_A/λPFS_B, where λPFS_A and λPFS_B represent the hazard of PFS in Arm A and 
Arm B, respectively, will be estimated with a stratified Cox regression model and the 
same stratification variables used for the stratified log-rank test. 
Results from an unstratified analysis will also be provided. 
4.4.1.2 
Overall Survival 
OS is defined as the time from randomization to death from any cause.  Patients who 
are not reported as having died at the date of analysis will be censored at the date when 
they were last known to be alive.  Patients who do not have post-baseline information 
will be censored at the date of randomization plus 1 day. 
OS will be analyzed with the same methodologies as PFS.  Treatment comparisons will 
be based on the stratified log-rank test in the ITT population.  The null and alternative 
hypotheses can be phrased in terms of the survival functions SOS_A (t) and SOS_B (t) in 
Arm A and Arm B, respectively: 
H0:  S
OS_A (t)=SOS_B (t) versus H
1:  S
OS_A (t)>SOS_B (t) 
 
4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients who had an 
objective response (confirmation not required).  An objective response is defined as 
either CR or PR, as determined by the investigator with use of RECIST v1.1.  Patients 
not meeting these criteria, including patients without any post-baseline tumor 
assessments, will be considered non-responders. 
The analysis population for ORR will be the ITT population.  An estimate of ORR and its 
95% CI will be calculated with the Clopper-Pearson method for each treatment arm.  The 
95% CIs for the difference in ORRs between the two treatment arms will be computed 
using the normal approximation to the binomial distribution.  The ORR will be compared 
between the two arms using the stratified Cochran-Mantel-Haenszel test, stratified by 
the same factors used in the primary PFS and OS analyses (see Section 4.4.1). 
Confirmation of response according to RECIST v1.1 is not required, but for the 
exploratory purposes, ORR with confirmation may be reported. 
4.4.2.2 
Duration of Response 
DOR is defined for patients with an objective response as the time from the first 
documented objective response to documented disease progression as determined by 
the investigator with use of RECIST v1.1 or death from any cause, whichever occurs first.  


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18/Statistical Analysis Plan GO29438 
Data for patients who are alive and who have not experienced disease progression at 
the time of the analysis will be censored at the date of the last tumor assessment.  If no 
tumor assessments were performed after the date of the first occurrence of the objective 
response (CR or PR), DOR will be censored at the date of the first occurrence of the 
objective response.  Because the determination of DOR is based on a non-randomized 
subset of patients, formal hypothesis testing will not be performed.  DOR will be 
estimated using KM methodology. Comparisons between treatment arms will be made 
using the stratified and unstratified log-rank test for descriptive purposes only. 
Confirmation of response in accordance with RECIST v1.1 will not be required, but for 
exploratory purposes, DOR for patients with confirmed response may be reported. 
4.4.2.3  
Overall Survival Rates at 1- and 2-Year Landmark Timepoints 
The OS rates at the 1-and 2-year landmark time points are defined as the probabilities 
that patients are alive 1-and 2-years after randomization, respectively.  The OS rate at 
the 1-and 2-year landmark timepoints after randomization within the ITT population will 
be estimated for each treatment arm using KM methodology, along with 95% CI 
calculated with the standard error derived from the Greenwood formula.  The 95% CI for 
the difference in OS rates between the two treatment arms will be estimated with the 
normal approximation method, with standard errors computed using the Greenwood 
method. 
4.4.2.4 
Patient-Reported Outcomes 
The EORTC QLQ-C30 and EORTC QLQ-LC13 will be scored according to the EORTC 
scoring manual (Fayers et al. 2001). All EORTC scales and single-item measures will be 
linearly transformed so that each score has a range of 0-100. A high score for a 
functional/global health status scale represents a high or healthy level of 
functioning/HRQoL; however a high score for a symptom scale or item represents a high 
level of symptomatology or problems. A ≥10-point change in the symptoms subscale 
score is perceived by patients as clinically significant (Osoba et al. 1998).   
The SILC questionnaire comprises three individual symptoms (dyspnea, cough, chest 
pain) and will be scored at the individual symptom level, thus will have a dyspnea score, 
chest pain score, and cough score. Each individual symptom score will be calculated as 
the average of responses for the symptom items [e.g. Chest Pain Score=mean (item 1; 
item 2)]. An increase in score is suggestive of a worsening in symptomology (i.e. 
frequency or severity). A score change of ≥0.3 points for the dyspnea and cough 
symptom scores is considered to be clinically significant; whereas a score change of 
≥0.5 points for the chest pain score is considered to be clinically significant. 
The ITT population will be used for TTD analysis.  Patients whose symptoms have not 
deteriorated before the last PRO assessment is completed will be censored at the date 
of last PRO assessment.  Patients with no baseline assessment or post-baseline 
assessments will be censored at the date of randomization plus 1 day. 


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TTD according to the EORTC QLQ-C30 and EORTC QLQ-LC13 measures will be 
evaluated in each of the following linearly transformed symptom scores:  cough, 
dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain.   
For the symptom to be considered “deteriorated,” a score increase of ≥10 points above 
baseline must be held for at least two consecutive assessments or an initial score 
increase of ≥10 points is followed by death within 3 weeks from the last assessment. The 
methodologies outlined for the analysis of PFS will be used for the analyses of TTD of 
the prespecified symptoms of the EORTC QLQ-C30 and EORTC QLQ-LC13 measure.  
The estimated Kaplan-Meier plots will be provided for each symptom separately. 
Summary statistics (mean, SD, median, range) of the change from baseline per SILC 
scales may be provided. The analysis will be performed for patients in the PRO-
evaluable population, which is defined as all randomized patients with a non-missing 
baseline assessment and at least one non-missing post-baseline assessment until 
treatment discontinuation. Graphs of the mean changes and standard errors over time 
from the baseline assessment for the scales will be provided for each treatment arm. 
The analysis of SILC change from baseline will be performed at all on-treatment 
timepoints, as well as at the time of disease progression per RECIST v1.1 (PRO 
assessment completed within 7 days of date of radiographic disease progression), at the 
last dose of treatment received before treatment discontinuation for any cause, and at 
the survival follow-up visits through 6 months.  Repeated measures mixed-effect model 
will be used for comparing the scale scores (SILC) between treatment arms. The model 
will include a term for intercept, a term for linear time trend, a term for treatment group, 
and a term of treatment-by-time interaction.  Repeated measured over time will be 
accounted for by unstructured covariance structure. 
In addition, to interpret the evolution over time in lung-cancer disease symptoms, the 
analyses described in Section 4.4.3.5 may be documented in the PRO-evaluable 
population. 
Analyses including the SILC questionnaire may not be included within the CSR. 
4.4.3 
Exploratory Efficacy Endpoints 
4.4.3.1 
Exploratory Analyses of Progression-Free Survival 
4.4.3.1.1 
PFS at 6-Months and 1-Year Landmark Timepoints 
PFS rates at 6 months and 1 year will be estimated and analyzed using the same 
method as described in Section 4.4.2.3. 
4.4.3.1.2 
Impact of Non−Protocol-Specified Anti-Cancer Therapy 
The impact of non−protocol-specified anti-cancer therapy (NPT) on PFS as determined 
by the investigator will be assessed depending on the number of patients who receive 
NPT before a PFS event.  If >
 5% of patients received NPT before a PFS event in any 
treatment arm, a sensitivity analysis will be performed for the comparisons between two 


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20/Statistical Analysis Plan GO29438 
treatment arms in which data from patients who received NPT before a PFS event will 
be censored at the last tumor assessment date before receipt of NPT. 
The methods outlined for the primary efficacy endpoints will be used for these analyses. 
4.4.3.1.3 
Subgroup Analyses 
The consistency of PFS results in subgroups will be examined in the populations where 
PFS benefit has been demonstrated. To assess the consistency of the study results in 
subgroups defined by demographics (e.g., age, sex, and race/ethnicity), baseline 
prognostic characteristics (e.g., ECOG performance status, smoking status, and type of 
chemotherapy), the duration of PFS in these subgroups will be examined.  Summaries of 
PFS, including unstratified HRs estimated from Cox proportional hazards models and 
Kaplan-Meier estimates of median PFS, will be produced separately for each level of the 
categorical variables for the comparisons between treatment arms and displayed in a 
forest plot (Lewis and Clarke 2001). 
4.4.3.1.4 
Impact of Missing Scheduled Tumor Assessments 
The impact of missing scheduled tumor assessments on PFS will be assessed 
depending on the number of patients who missed assessments scheduled immediately 
prior to the date of disease progression per RECIST v1.1 or the data cutoff.  If
 >
 5% of 
patients missed two or more assessments scheduled immediately prior to the date of 
disease progression per RECIST v1.1 or the data cutoff in any treatment arm, the 
following two sensitivity analyses will be performed: 
• If a patient missed two or more scheduled tumor assessments immediately prior to 
the date of the PFS event according to RECIST v1.1, the patient will be censored at 
the last tumor assessment prior to the first of these missed visits. 
• If a patient missed two or more assessments scheduled immediately prior to the 
date of the PFS event, the patient will be counted as having disease progression on 
the date of the first of these missing assessments. 
 
Statistical methodologies analogous to those used in the primary analysis of PFS as 
specified in Section 4.4.1 will be used for this sensitivity analysis. 
4.4.3.2 
Exploratory Analyses of Overall Survival 
4.4.3.2.1  
Overall Survival at 3-Year Landmark Timepoint   
OS rate at 3 years will be estimated and analyzed using the same method as described 
in Section 4.4.2.3. 
4.4.3.2.2 
Impact of Loss to Follow-Up 
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  If
 >
 5% of patients are lost to follow-up for OS in either 
treatment arm, a sensitivity analysis will be performed for the comparisons between two 
treatment arms in which patients who are lost to follow-up will be considered as having 
died at the last date they were known to be alive. 


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The methods outlined for the primary efficacy endpoint analyses will be used for these 
analyses. 
4.4.3.2.3 
Subgroup Analyses 
The consistency of OS results in subgroups will be examined in the populations where 
OS benefit has been demonstrated.  To assess the consistency of the study results in 
subgroups defined by demographics (e.g., age, sex, and race/ethnicity), baseline 
prognostic characteristics (e.g., ECOG performance status, smoking status, type of 
chemotherapy, presence of liver metastases at baseline), and the duration of OS in 
these subgroups will be examined.  Summaries of survival, including unstratified HRs 
estimated from Cox proportional hazards models and Kaplan-Meier estimates of median 
survival time, will be produced separately for each level of the categorical variables for 
the comparisons between treatment arms and displayed in a forest plot (Lewis and 
Clarke 2001). 
4.4.3.2.4 
Milestone Overall Survival Analysis 
To assess the potential effect of long-term survival and delayed clinical effects, a 
milestone OS analysis may be conducted (Chen 2015).  The milestone timepoints may 
be chosen such that the patients included in the analysis will achieve a certain patient-
event ratio.  The milestone OS analysis will be conducted only when the milestone 
duration has elapsed from the time the last patient entered the study, using the same 
methods as those specified for the primary OS analysis. 
4.4.3.2.5 
Impact of Non−Protocol-Specified Anti-Cancer Therapy 
The impact of NPT on OS will be assessed depending on the number of patients who 
receive NPT.  If
 >
 10% of patients received an NPT in the control arm, the following 
analyses may be performed to compare treatment arms: 
• The discount method uses a “discounted” survival time after switching for patients 
who switch treatments based on a user-specified assumption for the effect on OS. 
OS will be discounted in accordance with a range of possible effects on OS of the 
subsequent NPT after treatment switching occurred (e.g., 10%, 20%, 30%). 
• Rank-preserving structural failure time provides an estimate of the OS time for the 
control group had NPT not occurred (Robins and Tsiatis 1991).  It estimates OS 
measured from the time of NPT by applying an estimate of the benefit of the NPT. 
The total overall survival time (sum of time to NPT and the estimated survival time 
after NPT started) will then be analyzed using the same methodology as for the 
primary analysis of OS. 
• The inverse probability of censoring weighting method censors patients at start of 
NPT and uses the control arm patients to create weights that represent how 
NPT-treated-like a non-NPT-treated patient is (Robins and Finkelstein 2000). These 
time-varying weights are included in the OS analysis to correct the effect of NPT by 
giving increased weight to non-censored patients with similar characteristics to 
censored patients. 
 


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4.4.3.3 
Biomarker Analysis 
Exploratory biomarker analyses may be performed in an effort to understand the 
association of these markers with efficacy (PFS, OS, and/or ORR, etc.).  The biomarkers 
include but are not limited to blood-based tumor mutational burden (bTMB) using the 
cut-offs of ≥10 and ≥16 separately (given data availability), and PD-L1 IHC using a 
cut-off of PD-L1 expression (e.g.at least 1% of tumor and/or tumor-infiltrating immune 
cells for TC1/2/3 or IC1/2/3 population with SP142 assay) (given data availability).  
Additional analyses of predictive, prognostic, and pharmacodynamic exploratory 
biomarkers (such as additional PD-L1 IHC assays or PD-L1 expression cut-offs) in 
archival and/or fresh tumor tissue and blood and their association with disease status, 
mechanisms of resistance, and/or response to study treatment may be conducted as 
appropriate.  These exploratory analyses may not be included in the Clinical Study 
Report (CSR). 
4.4.3.4 
Utility Scores of the EuroQoL 5 Dimensions 5-Level Version 
For the EQ-5D-5L health state profiles, descriptive statistics summarizing the proportions 
of patients who reported having “no,” “slight,” “moderate,” “severe,” or “extreme/unable” 
problems at each time point will be reported.  Patients without post-baseline 
assessments will be excluded from this analysis.  A single summary index from the 
EQ-5D-5L health states will be used in this study for economic modeling.  These results 
will not be reported in the CSR. 
4.4.3.5 
Patient-Reported Outcomes of Health-Related Quality of Life 
Additional PROs of health-related quality of life (Global Health Status), function (Physical 
and Role Function), commonly reported treatment-related symptoms (e.g., 
nausea/vomiting, diarrhea, and peripheral neuropathy), and disease-related symptoms 
(e.g., chest pain, cough, dyspnea) will be assessed according to the EORTC QLQ-C30, 
EORTC QLQ-LC13, and SILC scoring manual guidelines.  Missing PRO scores will not 
be imputed.  The following analyses may not be included in the Clinical Study Report. 
In the ITT population, summary statistics (mean, SD, median, 25th and 75th percentiles, 
and range) and the proportion of patients per response category will be reported for all 
the items and subscales of the EORTC QLQ-C30 questionnaire and the EORTC 
QLQ-LC13 according to the EORTC scoring manual guidelines and the SILC symptom 
score by visit (baseline, end of treatment, disease progression, survival follow-up) and 
by treatment arm. 
In the ITT population, completion and compliance rates will be summarized by number 
and proportion of patients among those expected to complete each questionnaire at 
each time point by treatment arm.  If collected, reasons for non-completion will be 
summarized at each time point by treatment arm. 
In addition, to interpret the evolution over time in lung-cancer disease symptoms, 
treatment-related symptoms, HRQoL, and function, the following analyses may be 


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documented in the PRO-evaluable population, which is defined as all randomized 
patients with a non-missing baseline assessment and at least one non-missing 
post-baseline assessment until treatment discontinuation. 
•  The mean change in scores from baseline at each timepoint, including end of 
treatment and disease progression.  Repeated measures mixed-effect model will be 
used for comparing the scale scores (EORTC QLQ-C30, EORTC QLQ-LC13) 
between treatment arms.  The model will include a term for intercept, a term for 
linear time trend, a term for treatment group, and a term of treatment-by-time 
interaction.  Repeated measured over time will be accounted for by unstructured 
covariance structure. 
• The number and proportion of patients with a clinically meaningful change will be 
summarized by treatment arm for each of the scale scores (EORTC QLQ-C30, 
EORTC QLQ-LC13, and SILC).  The 95% CI around the proportion will be 
calculated using the Clopper-Pearson method for each treatment arm.  The 
difference in proportions between the two treatment arms will be presented with a 
two-sided 95% CI based on a normal approximation to the binomial distribution. 
 
PRO data obtained from measures completed during the survival follow-up phase 
(EORTC QLQ-C30, EORTC QLQ-LC13, EQ-5D-5L, and SILC) will be summarized 
descriptively.   
4.4.4 
Sensitivity Analysis 
4.4.4.1 
Delayed Clinical Effect 
If a delayed separation of the KM curves is observed at the beginning of the curves and 
the delay is
 ≥
 3 months, the following analyses could be conducted to assess a potential 
delayed clinical effect for the treatment group. 
Restricted Mean Survival Time 
The restricted mean survival time (RMST) will be computed for OS using the area under 
the curve from baseline to several timepoints.  RMST will be computed for each 
treatment arm and the difference with its 95% CI will be displayed. 
Weighted Log-Rank Analysis  
Where the delayed clinical effect is
 >
 10% of the median survival time of the control 
group, an analysis of OS may be performed using the weighted log-rank test (Fleming 
and Harrington 1991) that weights more heavily on late events to account for the 
delayed clinical effect (Fine 2007). 
4.4.4.2 
Progression-Free Survival by Independent Review Facility 
PFS as assessed by the IRF is defined as the time from randomization to the first 
documented disease progression as determined by the IRF using RECIST v1.1 or death 
from any cause, whichever occurs first. PFS as assessed by the IRF will be examined as 
sensitivity analysis using the same methods that will be used for PFS as assessed by 
the investigator. 


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4.5 
PHARMACOKINETIC ANALYSES 
PK analyses will be performed for the PK-evaluable population.  Atezolizumab serum 
concentration data (Cmin and Cmax) will be tabulated and summarized.  Descriptive 
statistics will include means, medians, ranges, and SDs, as appropriate.  In addition, the 
concentrations of carboplatin, cisplatin, and pemetrexed will be summarized with these 
descriptive statistics. 
Additional PK analyses will be conducted as appropriate, on the basis of the availability 
of data.  These additional PK analyses will not be included in the CSR. 
4.6 
SAFETY ANALYSES 
Unless specified otherwise, safety analyses described in this section will be conducted 
for the safety population, with patients grouped according to whether they received any 
atezolizumab treatment (i.e., patients who received any dose of atezolizumab will be 
included in the atezolizumab arm for the safety analyses). 
4.6.1 
Exposure of Study Medication 
Study drug exposure statuses, which include treatment duration, number of cycles, and 
dose intensity, will be summarized for each treatment arm with descriptive statistics. 
4.6.2 
Adverse Events 
Verbatim description of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded by the investigator 
according to NCI CTCAE v4.0.  Treatment-emergent adverse events will be summarized 
by mapped term, appropriate thesaurus level, NCI CTCAE grade, and treatment arm.  In 
addition, serious adverse events, severe adverse events (Grade ≥
 3), adverse events of 
special interest, immune-mediated adverse events, and adverse events leading to study 
drug discontinuation or interruption will be summarized accordingly.  Multiple 
occurrences of the same event will be counted once at the maximum grade. 
For reporting purposes, “treatment emergent” is defined as adverse events occurring on 
or after the first dose of study drug is administered until the clinical cutoff date. 
All listings of adverse events will also include all adverse events with onset on or after 
the first study drug treatment until the data cutoff date. 
Deaths reported during the study treatment period and the follow-up period after 
treatment completion and/or discontinuation will be summarized by treatment arm. 
4.6.3 
Laboratory Data 
Laboratory data will be summarized by treatment arm.  Values outside the normal 
ranges will be summarized by treatment arm.  In addition, selected laboratory data will 
be summarized by treatment arm and NCI CTCAE grade. 


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4.6.4 
Vital Signs 
Changes in selected vital signs will be summarized by treatment arm and by change 
over time, which includes change from baseline.  Baseline is defined as the 
measurement obtained on Cycle 1, Day 1 before the first dose of study drug is 
administered. 
ECOG performance status will also be summarized over time. 
4.6.5 
Anti-Drug Antibody Against Atezolizumab 
Incidence of ADA against atezolizumab will be summarized.  The analyses of 
pharmacokinetics, key efficacy, and safety by ADA status will be conducted to explore 
the potential impact of immunogenicity. 
4.7 
MISSING DATA 
See Sections 4.4 and 4.6 for methods for handling missing data for the primary and 
secondary endpoints. 
5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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. 


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6.  
REFERENCES 
Akazawa K, Nakamura T, Palesch Y. Power of logrank test and Cox regression model in 
clinical trials with heterogeneous samples. Stat Med. 1997;16:583-97. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29−41. 
Chen TT. Milestone survival: a potential intermediate endpoint for immune checkpoint 
inhibitors. J Natl Cancer Inst 2015;107:djv156. 
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual. 3rd 
ed. Brussels: European Organisation for Research and Treatment of Cancer, 2001. 
Fine GD. Consequences of delayed treatment effects on analysis of time-to-event 
endpoints. Ther Innov Regul Sci 2007;41:535−9. 
Fleming TR, Harrington DP. Counting processes and survival analysis. New York: John 
Wiley & Sons, 1991. 
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479−80. 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:139−44. 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Commun Stat Theory Methods 
1991;20:2609−31. 
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in 
an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-
rank tests. Biometrics 2000;56:779−88. 
Ye Y, Li A, Liu L, et al. A group sequential Holm procedure with multiple primary 
endpoints. Stat Med 2013;32:1112−24.


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Appendix 1   
Protocol Synopsis for Study GO29438 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (MPDL3280A, ANTI−PD-L1 ANTIBODY) 
IN COMBINATION WITH CARBOPLATIN OR 
CISPLATIN +
 PEMETREXED COMPARED WITH CARBOPLATIN 
OR CISPLATIN +
 PEMETREXED IN PATIENTS WHO ARE 
CHEMOTHERAPY-NAIVE AND HAVE STAGE IV 
NON-SQUAMOUS NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: GO29438 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2015-003605-42 
IND NUMBER: 
117296 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
PHASE: 
III 
INDICATION: 
Non-squamous non−small cell lung cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab in 
combination with carboplatin or cisplatin
 +
 pemetrexed compared with carboplatin or 
cisplatin
 +
 pemetrexed in patients who are chemotherapy-naive and have Stage IV 
non-squamous non−small cell lung cancer (NSCLC).  Specific objectives and corresponding 
endpoints for the study are outlined below. 
Efficacy Objectives 
The co-primary objectives of this study are: 
• To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1) 
• To evaluate the efficacy of atezolizumab as measured by overall survival (OS) 
The secondary efficacy objectives for this study are: 
• To evaluate the efficacy of atezolizumab as measured by investigator-assessed objective 
response rate (ORR) according to RECIST v1.1 
• To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response (DOR) according to RECIST v1.1 
 


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Appendix 1   
Protocol Synopsis for Study GO29438 (cont.)  
• To evaluate the OS rate at 1 and 2 years 
• To determine the impact of atezolizumab as measured by the change from baseline in 
patient-reported lung cancer symptoms of cough, dyspnea (single-item and multi-item 
subscales), chest pain, or arm/shoulder pain, using the European Organization for the 
Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire−Core 30 (QLQ-
C30) and the supplemental lung cancer module (QLQ-LC13) 
• To determine the impact of atezolizumab as measured by the change from baseline in 
patient-reported lung cancer symptoms (chest pain, dyspnea, and cough) scores using the 
Symptoms in Lung Cancer (SILC) scale symptom severity scores 
 
Safety Objectives 
The safety objectives for this study are: 
• To evaluate the safety and tolerability of atezolizumab when given in combination with 
carboplatin or cisplatin
 +
 pemetrexed or as maintenance therapy with pemetrexed alone 
• To evaluate the incidence and titers of anti-therapeutic antibody against atezolizumab and 
to explore the potential relationship of the immunogenicity response with pharmacokinetics, 
safety, and efficacy 
 
Pharmacokinetic Objectives 
The PK objectives for this study are: 
• To characterize the pharmacokinetics of atezolizumab when given in combination with 
carboplatin or cisplatin
 +
 pemetrexed or pemetrexed alone 
• To characterize the pharmacokinetics of carboplatin when given in combination with 
atezolizumab and pemetrexed 
• To characterize the pharmacokinetics of cisplatin when given in combination with 
atezolizumab
 +
 pemetrexed 
• To characterize the pharmacokinetics of pemetrexed when given in combination with 
atezolizumab
 +
 carboplatin or cisplatin 
 
Exploratory Objectives 
The exploratory objectives for this study are: 
• To evaluate the PFS rate at 6-month and 1-year landmark timepoints 
• To evaluate the OS rate at 3 years in each treatment arm 
• To evaluate the efficacy of atezolizumab as measured by OS and investigator-assessed PFS 
according to RECIST v1.1 in subgroups based on demographic and baseline 
characteristics 
• To evaluate the efficacy of atezolizumab as measured by milestone survival 
• To evaluate the relationship between biomarkers in tumors and blood (including but not 
limited to programmed death−ligand 1 (PD-L1), programmed death−1 (PD-1), somatic 
mutations and others), as defined by immunohistochemistry (IHC), quantitative reverse 
transcriptase−polymerase chain reaction (qRT-PCR), next-generation sequencing, and/or 
other methods and measures of efficacy 
• To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease status, mechanisms 
of resistance, and/or response to study treatment 
• To evaluate and compare patient’s health status as assessed by the EuroQoL 
5 Dimensions 5-Level questionnaire to generate utility scores for use in economic models 
for reimbursement 
 




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Appendix 1   
Protocol Synopsis for Study GO29438 (cont.)  
 
Target Population 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry: 
• Signed Informed Consent Form 
• Male or female, 18 years of age or older 
• ECOG performance status of 0 or 1 
• Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 7th 
edition; Detterbeck et al. 2009) 
Patients with tumors of mixed non-small cell histology (i.e., squamous and 
non-squamous) are eligible if the major histological component appears to be 
non-squamous. 
• No prior treatment for Stage IV non-squamous NSCLC 
Patients with a sensitizing mutation in the epidermal growth factor receptor (EGFR) 
gene are excluded given that erlotinib, gefitinib, or another EGFR tyrosine kinase 
inhibitor is the appropriate initial treatment of EGFR-mutant NSCLC. 
Patients with an anaplastic lymphoma kinase (ALK) fusion oncogene are excluded 
given that crizotinib or other ALK inhibitors is the appropriate initial treatment of 
NSCLC in patients having an ALK fusion oncogene. 
Patients with unknown EGFR and ALK status require test results at screening. ALK 
and/or EGFR may be assessed at a local or central laboratory. 
• Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy or 
chemoradiotherapy with curative intent for non-metastatic disease must have experienced a 
treatment-free interval of at least 6 months from randomization since the last dose of 
chemotherapy and/or radiotherapy. 
• Patients with a history of treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria: 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord) 
No ongoing requirement for corticosteroids as therapy for CNS disease 
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
randomization 
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study 
• Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, these 
patients may then be eligible without the need for an additional brain scan prior to 
randomization, if all other criteria are met. 
• Patients should submit a pre-treatment tumor tissue sample (if available).  If tumor tissue is 
not available (e.g., depleted for prior diagnostic testing), patients are still eligible. 
If tumor tissue is available, a representative formalin-fixed paraffin-embedded (FFPE) 
tumor specimen in paraffin block or unstained, freshly cut, serial sections (preferably at 
least 10) from an FFPE tumor specimen, are preferred.  If 10 sections are not available, 
fewer can be submitted. 
If FFPE specimens described above are not available, any type of specimens 
(including fine-needle aspiration, cell pellet specimens [e.g., from pleural effusion], and 
lavage samples) are also acceptable. 


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Appendix 1   
Protocol Synopsis for Study GO29438 (cont.)  
 
This specimen should be accompanied by the associated pathology report. 
Any available tumor tissue sample should be submitted before or within 4 weeks 
after enrollment. 
• Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease. 
• Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 14 days prior to randomization: 
ANC ≥
 1500 cells/µL without granulocyte colony-stimulating factor support 
Lymphocyte count ≥
 500/µL 
Platelet count ≥
 100,000/µL without transfusion 
Hemoglobin ≥
 9.0 g/dL 
Patients may be transfused to meet this criterion. 
INR or aPTT ≤
 1.5
 ×
 upper limit of normal (ULN) 
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose. 
AST, ALT, and alkaline phosphatase ≤
 2.5
 ×
 ULN, with the following exceptions: 
Patients with documented liver metastases:  AST and/or ALT ≤
 5
 ×
 ULN 
Patients with documented liver or bone metastases:  alkaline phosphatase 
≤
 5
 ×
 ULN. 
Serum bilirubin ≤
 1.25
 ×
 ULN 
Patients with known Gilbert disease who have serum bilirubin level ≤3× ULN may 
be enrolled. 
Calculated creatinine clearance (CRCL) ≥45 mL/min or, if using cisplatin, 
calculated CRCL must be ≥60 mL/min 
•
 
 
•  For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% 
per year during the treatment period and for at least 5 months after the last dose of 
atezolizumab or 6 months after the last dose of cisplatin. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥
 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Examples of non-hormonal contraceptive methods with a failure rate of <
 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
33/Statistical Analysis Plan GO29438 
Appendix 1   
Protocol Synopsis for Study GO29438 (cont.)  
 
• For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate 
of <
 1% per year during the chemotherapy treatment period and for at least 6 months 
after the last dose of chemotherapy. 
With pregnant female partners, men must remain abstinent or use a condom during 
the chemotherapy treatment period and for at least 6 months after the last dose of 
chemotherapy. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusions 
• Patients with a sensitizing mutation in the EGFR gene or an ALK fusion oncogene 
• Active or untreated CNS metastases as determined by CT or magnetic resonance imaging 
evaluation during screening and prior radiographic assessments 
• Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for ≥
 2 weeks prior to randomization 
• Leptomeningeal disease 
• Uncontrolled tumor-related pain 
Patients requiring pain medication must be receiving a stable regimen at study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to randomization.  
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period. 
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not currently associated 
with spinal cord compression) should be considered for loco-regional therapy, if 
appropriate, prior to randomization. 
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
• Uncontrolled or symptomatic hypercalcemia (>
 1.5 mmol/L ionized calcium or 
calcium >
 12 mg/dL or corrected serum calcium >
 ULN) 
Patients who are receiving denosumab prior to randomization must be willing and 
eligible to discontinue its use and replace it with a bisphosphonate instead while in the 
study. 
• Malignancies other than NSCLC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS >
 90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous-cell skin cancer, localized prostate cancer treated surgically with 
curative intent, ductal carcinoma in situ treated surgically with curative intent) 


Atezolizumab—F. Hoffmann-La Roche Ltd 
34/Statistical Analysis Plan GO29438 
Appendix 1   
Protocol Synopsis for Study GO29438 (cont.)  
 
• Known tumor PD-L1 expression status as determined by an IHC assay from other clinical 
studies (e.g., patients whose PD-L1 expression status was determined during screening for 
entry into a study with anti-PD-1 or anti−PD-L1 antibodies but were not eligible are excluded) 
 
General Medical Exclusions 
• Women who are pregnant, lactating, or intending to become pregnant during the study 
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
• History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study. 
Patients with controlled Type I diabetes mellitus who are receiving a stable dose of 
insulin regimen are eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions:  
Rash must cover less than 10% of body surface area 
Disease is well controlled at baseline and only requiring low potency topical 
steroids 
No acute exacerbations of underlying condition within the last 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids) 
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• Positive test for HIV 
All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the clinical study. 
• Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody and absence of HBsAg) are 
eligible only if they are negative for HBV DNA. 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA. 
• Active tuberculosis 
• Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
• Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
randomization 


Atezolizumab—F. Hoffmann-La Roche Ltd 
35/Statistical Analysis Plan GO29438 
Appendix 1   
Protocol Synopsis for Study GO29438 (cont.)  
 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
• 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 
Patients with known coronary artery disease, congestive heart failure not meeting 
the above criteria, or left ventricular ejection fraction <
 50% must be receiving a 
stable medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate. 
• Major surgical procedure other than for diagnosis within 28 days prior to randomization or 
anticipation of need for a major surgical procedure during the course of the study 
• Prior allogeneic bone marrow transplantation or solid organ transplant 
• Administration of a live attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study 
• Any other diseases, 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 or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications 
• Illness or condition that may interfere with a patient’s capacity to understand, follow, and/or 
comply with study procedures 
Exclusion Criteria Related to Medications 
• Prior treatment with EGFR inhibitors or ALK inhibitors 
• Any approved anti-cancer therapy, including hormonal therapy within 21 days prior to 
initiation of study treatment. 
• Treatment with any other investigational agent with therapeutic intent within 28 days prior to 
randomization 
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, 
and anti−PD-L1 therapeutic antibodies 
Patients who have had prior anti−cytotoxic T-lymphocyte associated antigen 4 
(CTLA-4) treatment may be enrolled, provided the following requirements are met: 
Last dose of anti-CTLA-4 at least 6 weeks prior to randomization 
No history of severe immune-mediated adverse effects from anti-CTLA-4 
(National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] Grade 3 and 4) 
• Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
interleukin [IL]-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to 
randomization 
Prior treatment with cancer vaccines is allowed. 
• Treatment with systemic immunosuppressive medications (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor 
necrosis factor agents) within 2 weeks prior to randomization 
Patients who have received acute, low-dose (≤ 10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in the 
study. 






Atezolizumab—F. Hoffmann-La Roche Ltd 
38/Modification Plan GO29537, Version 1 
Appendix 2   
Schedule of Assessments for Study GO29438 
Procedure 
Screening 
All Treatment Cycles a 
Treatment 
Discontinuation Visit 
Survival Follow-Up 
Days −28 
to −1 
Induction Phase 
(Cycles 1−4 or 6) 
Maintenance 
Phase 
≤ 30 Days after Last 
Dose of Study 
Treatment 
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit 
Every 21 Days 
(± 3 Days) b 
Every 21 Days 
(± 3 Days) 
Informed consent 
x 
 
 
 
 
Tumor tissue specimen (blocks or 10 or more FFPE slides 
preferred, if available). 
c 
Fresh or archival tissue can be used. 
x 
 
 
 
 
Demographic data 
x 
 
 
 
 
Medical history and baseline conditions 
x 
 
 
 
 
NSCLC cancer history 
x 
 
 
 
 
Vital signs d 
x 
x 
x 
x 
 
Weight 
x 
x 
x 
x 
 
Height 
x 
 
 
 
 
Complete physical examination 
x 
 
 
 
 
Limited physical examination e 
 
x 
x 
x 
 
ECOG performance status 
x 
x 
x 
x 
 
12-Lead ECG 
x 
x f 
x f 
x f 
 
Hematology g 
x 
x 
x 
x 
 
Serum chemistry h 
x 
x 
x 
x 
 
Coagulation test (aPTT or INR) 
x 
 
 
x 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
39/Modification Plan GO29537, Version 1 
Procedure 
Screening 
All Treatment Cycles a 
Treatment 
Discontinuation Visit 
Survival Follow-Up 
Days −28 
to −1 
Induction Phase 
(Cycles 1−4 or 6) 
Maintenance 
Phase 
≤ 30 Days after Last 
Dose of Study 
Treatment 
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit 
Every 21 Days 
(± 3 Days) b 
Every 21 Days 
(± 3 Days) 
Pregnancy test 
 (women of childbearing-potential ONLY) 
x i 
x j 
x j 
x j 
 
TSH, free T3, free T4 k 
x  
x 
x 
x  
 
ALK and/or EGFR assessment if status is unknown (may 
be done locally or centrally) 
x 
 
 
 
 
HIV, HBV, HCV serology 
l 
x 
 
 
 
 
Urinalysis m 
x 
 
 
 
 
Determination of duration of induction treatment 
x 
 
 
 
 
Induction treatment administration  
Arm A:  atezolizumab
 +
 carboplatin or 
cisplatin
 +
 pemetrexed 
Arm B:  carboplatin or cisplatin
 +
 pemetrexed 
 
x n 
 
 
 
Maintenance treatment administration 
Arm A:  atezolizumab +
 pemetrexed 
Arm B:  pemetrexed 
 
 
x n 
 
 
Tumor response assessment  
x o 
x p 
x p 
 
x q 
Serum sample for atezolizumab ADA assessment 
(atezolizumab-treated patients only) r 
 
x 
x 
x 
120 (± 30) days after 
last dose of 
atezolizumab 
Serum sample for PK sampling (atezolizumab-treated 
patients only) r 
 
x 
x 
x 
120 (± 30) days after 
last dose of 
atezolizumab 


Atezolizumab—F. Hoffmann-La Roche Ltd 
40/Modification Plan GO29537, Version 1 
Procedure 
Screening 
All Treatment Cycles a 
Treatment 
Discontinuation Visit 
Survival Follow-Up 
Days −28 
to −1 
Induction Phase 
(Cycles 1−4 or 6) 
Maintenance 
Phase 
≤ 30 Days after Last 
Dose of Study 
Treatment 
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit 
Every 21 Days 
(± 3 Days) b 
Every 21 Days 
(± 3 Days) 
Carboplatin, cisplatin, and pemetrexed PK sampling 
(20 patients in Arm A) 
r 
 
x 
 
 
 
Optional tumor biopsy s 
 
Optional at time of radiographic 
progression 
 
 
Blood samples for biomarkers r 
x 
x 
x 
x 
120 (± 30) days after 
last dose of 
atezolizumab 
Optional blood for DNA extraction (RCR only) r, t 
 
x 
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab-treated patients) 
 
At time of radiographic progression 
 
 
Optional tumor biopsy at other timepoints (RCR only) 
 
Any time during study treatment or during survival follow-up 
Adverse events 
x 
x 
x 
x u 
x u 
Concomitant medications 
x v 
x 
x 
x 
 
Patient-reported outcomes (EORTC QLQ-C30, EORTC 
QLQ-LC13, SILC, and EQ-5D-5L) v 
 
x w 
x w 
 
x w 
Survival and anti-cancer therapy follow-up 
 
x 
x 
 
x x 
ADA =
 anti-drug antibody; CT =
 computed tomography; ECOG
 =
 Eastern Cooperative Oncology Group; EORTC =
 European Organization for Research and 
Treatment of Cancer; ePRO =
 electronic Patient-Reported Outcome; EQ-5D-5L
 =
 EuroQoL 5 Dimensions 5-Level Version; FFPE =
 formalin-fixed paraffin-embedded; 
HBcAb =
 hepatitis B core antibody; HBV =
 hepatitis B virus; HCV
 =
 hepatitis C virus; IV =
 intravenous; MRI
 =
 magnetic resonance imaging; NSCLC =
 non−small cell 
lung cancer; PCR=polymerase chain reaction; PD =
 pharmacodynamic; PD-L1
 =
 programmed death−ligand 1; PK
 =
 pharmacokinetic; PRO =
 Patient-Reported 
Outcome; QLQ-C30 =
 Quality-of-Life Questionnaire−Core 30; QLQ-LC13
 =
 Quality-of-Life Questionnaire Lung Cancer module; RCR =
 Roche Clinical Repository; 
RECIST =
 Response Evaluation Criteria in Solid Tumors; SILC =
 Symptoms in Lung Cancer; TSH
 =
 thyroid-stimulating hormone. 
a Assessments should be performed before study drug infusion unless otherwise noted. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
41/Modification Plan GO29537, Version 1 
b Cycle 1, Day 1 must be performed within 5 days after the patient is randomized. Screening assessments performed ≤
 96 hours before Cycle 1, Day 1 are not 
required to be repeated for Cycle 1, Day 1.  In addition, ECOG performance status, limited physical examination, and local laboratory tests may be performed 
≤
 96 hours before Day 1 of each cycle as specified in Section 4.5.12.2. 
c Any available tumor tissue sample can be submitted before or within 4 weeks after enrollment. It is strongly encouraged that the sites submit representative 
tumor specimens preferably in paraffin blocks or as 10 (or more) serial, freshly cut, unstained slides for biomarker analysis.  See Section 4.1.1, Inclusion Criteria, 
and Section 4.5.7.1. 
d Vital signs include pulse rate, respiratory rate, blood pressures, and temperature.  Vital signs should be recorded as described in Section 4.5.4. 
e Symptom-directed physical examinations; see Section 4.5.3 for details. 
f ECG recordings will be obtained when clinically indicated. 
g Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, 
basophils, and other cells), and platelet count. 
h Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. 
i Serum pregnancy test within 14 days before Cycle 1, Day 1. 
j Urine pregnancy tests; if a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test. 
k Thyroid function testing (TSH, free T3, free T4) collected at Cycle 1, Day 1 and every fourth cycle thereafter.  Note:  Total T3 w
ill be tested only at sites where 
free T3 testing cannot be performed. 
l All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study.  HBV DNA must be 
collected prior to randomization in patients who have negative serology for hepatitis B surface antigen and positive serology for HBcAb. 
m Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood) should be obtained at screening and when clinically indicated throughout the 
study. 
n For atezolizumab, the initial dose will be delivered over 60 (± 15) minutes.  If the first infusion is well tolerated, all subsequent infusions may be delivered over 
30 (± 10) minutes until disease progression per RECIST v1.1 or loss of clinical benefit.  For carboplatin or cisplatin and pemetrexed, study drug will be 
administered according to the local prescribing information, including premedication with steroids (see Section 4.3.2). 
o CT scans (with oral/IV contrast unless contraindicated) or MRI scans of the chest and abdomen.  A CT scan of the pelvis is required at screening and as 
clinically indicated or as per local standard of care at subsequent response evaluations.  A CT (with contrast) or MRI scan of the head must be done at screening 
to evaluate CNS metastasis in all patients.  See Section 4.5.5 for details. 
p Perform every 6 weeks (± 7 days) (approximately every two cycles) for 12 months following Cycle 1, Day 1, and then every 9 weeks (± 7 days) thereafter after 
completion of the Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression (loss of clinical benefit for patients 
assigned to atezolizumab who continue treatment with atezolizumab after disease progression according to RECIST v1.1), withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first.  See Section 4.5.5 for details. 
q If a patient discontinues study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration), tumor assessments will continue at the same frequency as would have been followed if the patient had remained on study treatment until 


Atezolizumab—F. Hoffmann-La Roche Ltd 
42/Modification Plan GO29537, Version 1 
radiographic disease progression (loss of clinical benefit for patients treated with atezolizumab who continue treatment after disease progression according to 
RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if patient starts another anti-cancer therapy after 
study treatment discontinuation, unless consent is withdrawn. 
r See Appendix 2 for detailed schedule. 
s Optional tumor biopsy at radiographic disease progression, if clinically feasible, preferably within 40 days of radiographic progression or prior to start of the next 
anti-cancer therapy, whichever occurs is sooner. 
t The optional RCR whole blood sample requires an additional informed consent and the sample can be collected at any time during the course of the study. 
u All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the last dose of 
study treatment or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of relationship to study drug, will be reported 
until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After this period, all deaths should continue to be 
reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that 
is believed to be related to prior exposure to study treatment (see 
Section 5.6).  
v From 7 days before screening. 
w EORTC QLQ-C30, EORTC QLQ-LC13, and the EQ-5D-5L questionnaires will be completed by the patients on the ePRO tablet at each scheduled study visit 
prior to administration of study drug and prior to any other study assessment(s).  SILC will be completed using an ePRO device at the patient’s home on a 
weekly basis.  During survival follow-up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D- 5L questionnaires will be completed at 3 and 6 months 
following disease progression.  The SILC will be completed monthly during survival follow-up for 6 months following disease progression or loss of clinical benefit 
(for atezolizumab-treated patients who continue after disease progression according to RECIST v1.1).  Patients who discontinue study treatment for any reason 
other than radiographic progressive disease or loss of clinical benefit will complete the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L at each tumor 
assessment visit and will complete the SILC at home on a weekly basis, until radiographic disease progression per RECIST v1.1 (or for atezolizumab-treated 
patients who continue treatment after radiographic disease progression) or loss of clinical benefit as determined by the investigator (unless the patient withdraws 
consent or the Sponsor terminates the study).  Study personnel should review all questionnaires for completeness before the patient leaves the investigational 
site. 
x Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death, loss to 
follow-up, or study termination by the Sponsor, whichever occurs first.  All patients will be periodically contacted for survival and new anti-cancer therapy 
information unless the patient requests to be withdrawn from follow-up (this request must be documented in the source documents and signed by the 
investigator).  If the patient withdraws from the study, study staff may use a public information source (e.g., county records), when permissible, to obtain 
information about survival status only