Clinical trial NCT02409342
Conditions: Non-Squamous Non-Small Cell Lung Cancer, Squamous Non-Small Cell Lung Cancer
Sponsor: Hoffmann-La Roche
Start date: 2015-07-20; Completion date: 2022-03-08
Enrollment: 572 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, open-label study will evaluate the efficacy and safety of atezolizumab compared with chemotherapy consisting of a platinum agent (cisplatin or carboplatin per investigator discretion) combined with either pemetrexed (non-squamous disease) or gemcitabine (squamous disease) in programmed death-ligand 1 (PD-L1)-selected, chemotherapy-naive participants with Stage IV Non-Squamous or Squamous NSCLC.

Detailed description:

Arms: arm 1: Participants with non-squamous NSCLC will receive chemotherapy with pemetrexed in combination with either cisplatin or carboplatin (per investigator discretion) on Day 1 of each 21-day cycle for 4 or 6 cycles as per local standard of care, followed by maintenance therapy with pemetrexed alone as per local standard of care until disease progression (per RECIST v1.1), unacceptable toxicity, or death (maximum up to approximately 58 months). Participants with squamous NSCLC will receive chemotherapy with gemcitabine on Days 1 and 8 of each 21-day cycle in combination with either cisplatin or carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles as per local standard of care, followed by best supportive care as per local standard of care until disease progression, unacceptable toxicity, or death (maximum up to approximately 58 months). arm 2: Participants with squamous or non-squamous NSCLC will receive atezolizumab on Day 1 of each 21-day cycle until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity, or death (maximum up to approximately 58 months).
Interventions: intervention 1: Atezolizumab (MPDL3280A) [TECENTRIQ], an engineered anti-PDL1 antibody intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: Gemcitabine intervention 5: Pemetrexed
Intervention descriptions: intervention 1: Atezolizumab 1200 milligram (mg) will be administered as intravenous infusion every 21 days until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity, or death (maximum up to approximately 58 months). intervention 2: Carboplatin will be administered as intravenous infusion at a dose of area under the concentration-time curve (AUC) 6 when given in combination with pemetrexed or at a dose of AUC 5 when given in combination with gemcitabine, every 21 days for 4 or 6 cycles as per local standard of care. intervention 3: Cisplatin will be administered as intravenous infusion at a dose of 75 mg per meter squared (mg/m\^2) every 21 days for 4 or 6 cycles as per local standard of care. intervention 4: Gemcitabine will be administered as intravenous infusion at a dose of 1250 mg/m\^2 (in combination with cisplatin) or 1000 mg/m\^2 (in combination with carboplatin), on Days 1 and 8 of each 21-day cycle for 4 or 6 cycles as per local standard of care. intervention 5: Pemetrexed will be administered as intravenous infusion at a dose of 500 mg/m\^2 on Day 1 of each 21-day cycle as per local standard of care until disease progression (per RECIST v1.1), unacceptable toxicity, or death (maximum up to approximately 58 months).

Protocol documents:
Prot_000.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 GO29431, Version 10
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED 
STUDY OF ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) 
COMPARED WITH A PLATINUM AGENT (CISPLATIN 
OR CARBOPLATIN) IN COMBINATION WITH 
EITHER PEMETREXED OR GEMCITABINE FOR 
PD-L1–SELECTED, CHEMOTHERAPY-NAIVE PATIENTS 
WITH STAGE IV NON-SQUAMOUS OR SQUAMOUS 
NON–SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29431
VERSION NUMBER:
10
EUDRACT NUMBER:
2014-003083-21
IND NUMBER:
117296
NCT NUMBER:
NCT02409342
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  23 December 2014
DATES AMENDED:
Version 2:  24 April 2015
Version 3:  5 October 2015
Version 4:  16 December 2015
Version 5:  29 June 2016
Version 6:  14 March 2017
Version 7:  16 April 2018
Version 8:  29 August 2018
Version 9:  14 March 2019
Version 10:  See electronic date stamp below.
 
08-Feb-2020 00:08:16
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GO29431, Version 10
PROTOCOL AMENDMENT, VERSION 10:
RATIONALE
Protocol GO29431 has been amended to update risks and management guidelines for 
atezolizumab to align with the latest Atezolizumab Investigator's Brochure (Version 15).  
Changes to the protocol, along with a rationale for each change, are summarized below:

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 (Section 5.1.1 and Appendix 14).

To address requests by the 
 
, the medical terminology of 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 
management guidelines for hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome have been added (Appendix 14).

To address a request by the 
, 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 14).

The management guidelines for infusion-related reactions associated with 
atezolizumab have been updated to include guidelines for management of 
cytokine-release syndrome (Appendix 14).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 31
1.1
Non–Small Cell Lung Cancer ................................................ 31
1.2
First-Line Treatment for NonSmall Cell Lung 
Cancer without an EGFR Mutation or ALK 
Rearrangement...................................................................... 32
1.2.1
Platinum-Based Regimen for First-Line 
NonSmall Cell Lung Cancer ................................................ 36
1.2.2
Pemetrexed plus Platinum Compounds in 
First-Line Non-Squamous NonSmall Cell Lung 
Cancer................................................................................... 36
1.2.2.1
Pemetrexed Maintenance Therapy in 
NonSquamous NonSmall Cell Lung Cancer...................... 37
1.2.3
Gemcitabine plus Platinum Compounds in 
First-Line Squamous Non-Small Cell Lung 
Cancer................................................................................... 37
1.3
First-Line Treatment for NonSmall Cell Lung 
Cancer with an EGFR Mutation or ALK 
Rearrangement...................................................................... 38
1.4
Background on Atezolizumab (MPDL3280A) ........................ 38
1.4.1
Summary of Nonclinical Studies............................................ 39
1.5
Clinical Experience with Atezolizumab .................................. 39
1.5.1
Ongoing Clinical Studies........................................................ 39
1.5.2
Clinical Safety........................................................................ 40
1.5.2.1
Single-Agent Clinical Safety in Patients with 
NonSmall Cell Lung Cancer in 
Study PCD4989g................................................................... 40
1.5.2.2
Single-Agent Clinical Safety in Patients with 
NonSmall Cell Lung Cancer in Study GO28753 
(POPLAR).............................................................................. 42
1.5.2.3
Single-Agent Clinical Safety in Patients with 
NonSmall Cell Lung Cancer in Study GO28915 
(OAK)..................................................................................... 44


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1.5.2.4
Single-Agent Clinical Safety in Patients with 
Non–Small Cell Lung Cancer in Study GO28754 
(BIRCH)................................................................................. 45
1.5.2.5
Immune-Mediated Adverse Events........................................ 45
1.5.3
Clinical Activity....................................................................... 46
1.5.3.1
Single-Agent Clinical Activity in Patients with 
Non–Small Cell Lung Cancer in 
Study PCD4989g................................................................... 46
1.5.3.2
Single-Agent Clinical Activity in Patients with 
NonSmall Cell Lung Cancer in Study GO28753 
(POPLAR).............................................................................. 48
1.5.3.3
Single-Agent Clinical Activity in Patients with 
Non–Small Cell Lung Cancer in Study GO28915 
(OAK)..................................................................................... 49
1.5.3.4
Single-Agent Clinical Activity in Patients with 
Non–Small Cell Lung Cancer in Study GO28754 
(BIRCH)................................................................................. 50
1.5.4
Clinical Pharmacokinetics and Immunogenicity..................... 51
1.5.5
Rationale for Atezolizumab Dosage ...................................... 52
1.6
Study Rationale and BenefitRisk Assessment..................... 52
2.
OBJECTIVES.............................................................................................. 54
2.1
Efficacy Objectives ................................................................ 54
2.1.1
Primary Efficacy Objective..................................................... 55
2.1.2
Secondary Efficacy Objectives .............................................. 55
2.2
Safety Objectives................................................................... 55
2.3
Pharmacokinetic Objective .................................................... 56
2.4
Exploratory Objectives........................................................... 56
3.
STUDY DESIGN......................................................................................... 56
3.1
Description of Study .............................................................. 56
3.1.1
Independent Data Monitoring Committee .............................. 59
3.2
End of Study.......................................................................... 60
3.3
Rationale for Study Design.................................................... 60
3.3.1
Rationale for Testing Atezolizumab in 
PD-L1–Selected Patients with NonSmall Cell 
Lung Cancer.......................................................................... 60
3.3.2
Rationale for Control Arm ...................................................... 61


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3.3.2.1
Rationale for Pemetrexed Combined with Either 
Cisplatin or Carboplatin for Non-Squamous 
NonSmall Cell Lung Cancer ................................................ 61
3.3.2.2
Rationale for Gemcitabine Combined with Either 
Cisplatin or Carboplatin for Squamous 
NonSmall Cell Lung Cancer ................................................ 61
3.3.3
Rationale for Overall Survival as Primary 
Endpoint ................................................................................ 62
3.3.4
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment until Loss of Clinical 
Benefit ................................................................................... 62
3.3.5
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 63
3.3.6
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens for Biomarker Evaluation ......................... 63
3.3.7
Rationale for Blood Biomarker Assessments......................... 64
3.3.8
Rationale for the Collection of Mandatory Tumor 
Specimens at Radiographic Progression............................... 65
3.4
Outcome Measures ............................................................... 65
3.4.1
Efficacy Outcome Measures.................................................. 65
3.4.1.1
Primary Efficacy Outcome Measure ...................................... 65
3.4.1.2
Secondary Efficacy Outcome Measures................................ 65
3.4.2
Safety Outcome Measures .................................................... 66
3.4.3
Pharmacokinetic Outcome Measures.................................... 66
3.4.4
Exploratory Outcome Measures ............................................ 66
4.
MATERIALS AND METHODS .................................................................... 67
4.1
Patients.................................................................................. 67
4.1.1
Inclusion Criteria.................................................................... 67
4.1.2
Exclusion Criteria................................................................... 69
4.1.2.1
Cancer-Specific Exclusions ................................................... 70
4.1.2.2
General Medical Exclusions .................................................. 70
4.1.2.3
Exclusion Criteria Related to Medications ............................. 72
4.1.2.4
Exclusion Criteria Related to Chemotherapy......................... 73
4.2
Method of Treatment Assignment and Blinding..................... 73
4.3
Study Treatment.................................................................... 74
4.3.1
Formulation, Packaging, and Handling.................................. 74


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4.3.1.1
Atezolizumab (MPDL3280A) ................................................. 74
4.3.1.2
Cisplatin, Carboplatin, Pemetrexed, and 
Gemcitabine .......................................................................... 74
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 74
4.3.2.1
Atezolizumab......................................................................... 74
4.3.2.2
Pemetrexed in Combination with Cisplatin or 
Carboplatin (Patients with Non-Squamous 
NonSmall Cell Lung Cancer Only)....................................... 76
4.3.2.3
Gemcitabine in Combination with Cisplatin or 
Carboplatin (Patients with Squamous NonSmall 
Cell Lung Cancer Only) ......................................................... 77
4.3.2.4
Cisplatin or Carboplatin Administration.................................. 78
4.3.3
Investigational Medicinal Product Accountability ................... 80
4.3.4
Post-Study Access to Atezolizumab ...................................... 80
4.4
Concomitant Therapy ............................................................ 80
4.4.1
Permitted Therapy................................................................. 80
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 81
4.4.3
Prohibited Therapy ................................................................ 82
4.5
Study Assessments ............................................................... 82
4.5.1
Informed Consent Forms and 
Prescreening/Screening Log ................................................. 83
4.5.2
Medical History and Demographic Data ................................ 83
4.5.3
Physical Examinations........................................................... 84
4.5.4
Vital Signs.............................................................................. 84
4.5.5
Tumor and Response Evaluations......................................... 84
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 86
4.5.7
Tumor Tissue Samples.......................................................... 87
4.5.7.1
Archival and Freshly Collected Tumor Tissue 
Samples for Screening .......................................................... 88
4.5.7.2
Tumor Samples at the Time of Radiographic 
Progression ........................................................................... 89
4.5.7.3
Tumor Samples at Other Timepoints..................................... 89


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4.5.8
Use and Storage of Remaining Samples from 
Study-Related Procedures..................................................... 90
4.5.9
Anti-Therapeutic Antibody Testing......................................... 90
4.5.10
Electrocardiograms................................................................ 90
4.5.11
Patient-Reported Outcomes .................................................. 90
4.5.12
Samples for Roche Clinical Repository.................................. 93
4.5.12.1
Overview of the Roche Clinical Repository............................ 93
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 93
4.5.12.3
Sample Collection.................................................................. 93
4.5.12.4
Confidentiality........................................................................ 94
4.5.12.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 95
4.5.12.6
Withdrawal from the Roche Clinical Repository..................... 95
4.5.12.7
Monitoring and Oversight....................................................... 95
4.5.13
Timing of Assessments.......................................................... 96
4.5.13.1
Screening/Baseline Assessments ......................................... 96
4.5.13.2
Assessments during Treatment............................................. 96
4.5.13.3
Assessments at Treatment Discontinuation Visit................... 97
4.5.13.4
Follow-Up Assessments ........................................................ 97
4.5.13.5
Assessments at Unscheduled Visits...................................... 98
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 99
4.6.1
Patient Discontinuation.......................................................... 99
4.6.2
Study Treatment Discontinuation........................................... 99
4.6.3
Study and Site Discontinuation............................................ 101
5.
ASSESSMENT OF SAFETY..................................................................... 101
5.1
Safety Plan .......................................................................... 101
5.1.1
Risks Associated with Atezolizumab ................................... 102
5.1.2
Risks Associated with Pemetrexed...................................... 102
5.1.3
Risks Associated with Gemcitabine..................................... 102
5.1.4
Risks Associated with Platinum-Based 
Chemotherapy..................................................................... 103
5.1.4.1
Risks Associated with Cisplatin Chemotherapy................... 103


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5.1.4.2
Risks Associated with Carboplatin Chemotherapy .............. 103
5.1.5
General Plan to Manage Safety Concerns .......................... 103
5.1.5.1
Monitoring............................................................................ 103
5.1.6
Dose Modification................................................................ 104
5.1.6.1
General Notes Regarding Dose Modification....................... 104
5.1.6.2
Atezolizumab Dose Modifications, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events ............................ 104
5.1.7
Management of Atezolizumab-Specific Adverse 
Events.................................................................................. 105
5.1.8
Pemetrexed Dose Modifications, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events ............................ 105
5.1.9
Gemcitabine Dose Modifications, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events ............................ 107
5.1.9.1
Hematologic Toxicities......................................................... 107
5.1.9.2
Non-Hematologic Toxicities................................................. 108
5.1.10
Cisplatin Dose Modifications, Treatment Delays, 
or Treatment Discontinuation and Management 
of Specific Adverse Events.................................................. 109
5.1.10.1
Hematologic Toxicities......................................................... 109
5.1.10.2
Non-Hematologic Toxicities................................................. 110
5.1.11
Carboplatin Dose Modifications, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events ............................ 111
5.1.11.1
Hematologic Toxicities......................................................... 111
5.1.11.2
Non-Hematologic Toxicities................................................. 112
5.2
Safety Parameters and Definitions ...................................... 113
5.2.1
Adverse Events ................................................................... 114
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 114
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 115
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 116
5.3.1
Adverse Event Reporting Period ......................................... 116


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5.3.2
Eliciting Adverse Event Information..................................... 116
5.3.3
Assessment of Severity of Adverse Events ......................... 116
5.3.4
Assessment of Causality of Adverse Events ....................... 117
5.3.5
Procedures for Recording Adverse Events.......................... 118
5.3.5.1
Infusion-Related Reactions.................................................. 118
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 118
5.3.5.3
Adverse Events that are Secondary to Other 
Events.................................................................................. 118
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 119
5.3.5.5
Abnormal Laboratory Values ............................................... 119
5.3.5.6
Abnormal Vital Sign Values ................................................. 120
5.3.5.7
Abnormal Liver Function Tests............................................ 121
5.3.5.8
Deaths ................................................................................. 121
5.3.5.9
Preexisting Medical Conditions............................................ 121
5.3.5.10
Worsening of NonSmall Cell Lung Cancer ........................ 122
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 122
5.3.5.12
Cases of Accidental Overdose or Medication 
Error..................................................................................... 123
5.3.5.13
Patient-Reported Outcome Data ......................................... 124
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 124
5.4.1
Emergency Medical Contacts.............................................. 125
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 125
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 125
5.4.2.2
Events That Occur after Study Drug Initiation...................... 125
5.4.3
Reporting Requirements for Pregnancies............................ 126
5.4.3.1
Pregnancies in Female Patients.......................................... 126
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 126
5.4.3.3
Abortions ............................................................................. 127
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 127
5.5
Follow-Up of Patients after Adverse Events ........................ 127
5.5.1
Investigator Follow-Up......................................................... 127
5.5.2
Sponsor Follow-Up .............................................................. 128


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5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 128
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 128
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 129
6.1
Determination of Sample Size ............................................. 129
6.2
Summaries of Conduct of Study.......................................... 130
6.3
Summaries of Treatment Group Comparability ................... 130
6.4
Efficacy Analyses ................................................................ 131
6.4.1
Primary Efficacy Endpoint.................................................... 131
6.4.2
Secondary Efficacy Endpoints............................................. 132
6.4.2.1
Progression-Free Survival ................................................... 132
6.4.2.2
Objective Response Rate.................................................... 133
6.4.2.3
Overall-Survival Analysis at 1- and 2-Year 
Landmark Timepoints .......................................................... 133
6.4.2.4
Duration of Response.......................................................... 133
6.4.2.5
Patient-Reported Outcome Analyses .................................. 134
6.4.2.6
Overall Survival and Investigator-Assessed 
Progression-Free Survival for SP263 PD-L1 and 
bTMB Subpopulation ........................................................... 134
6.5
Safety Analyses................................................................... 135
6.6
Pharmacokinetic Analyses................................................... 135
6.7
Exploratory Analyses........................................................... 136
6.7.1
Analyses of Overall Survival and Progression-
Free Survival in the 22c3 PD-L1 IHC Assay 
Subpopulation...................................................................... 136
6.7.2
PFS Analysis at 6-Month and 1-Year Landmark 
Timepoints........................................................................... 136
6.7.3
Overall Survival Analysis at 3-Year Landmark 
Timepoint............................................................................. 136
6.7.4
Impact of Demographic and Baseline 
Characteristics on Overall Survival and 
Progression-Free Survival ................................................... 136
6.7.5
Exploratory Biomarker Analysis........................................... 137
6.7.6
EQ-5D-3L Health Status Data ............................................. 137


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6.7.7
Patient-Reported Outcome Analyses .................................. 137
6.8
Sensitivity Analyses............................................................. 137
6.8.1
Impact of NonProtocol-Specified Anti-Cancer 
Therapy ............................................................................... 137
6.8.2
Impact of Proportional Hazards Assumption........................ 137
6.9
Handling of Missing Data..................................................... 138
6.10
Interim Analyses .................................................................. 138
6.10.1
Planned Interim Analysis ..................................................... 139
6.10.2
Optional Interim Analysis..................................................... 140
7.
DATA COLLECTION AND MANAGEMENT ............................................. 141
7.1
Data Quality Assurance....................................................... 141
7.2
Electronic Case Report Forms............................................. 141
7.3
Electronic Patient-Reported Outcome Data......................... 141
7.4
Source Data Documentation................................................ 142
7.5
Use of Computerized Systems ............................................ 142
7.6
Retention of Records........................................................... 143
8.
ETHICAL CONSIDERATIONS.................................................................. 143
8.1
Compliance with Laws and Regulations .............................. 143
8.2
Informed Consent................................................................ 143
8.3
Institutional Review Board or Ethics Committee.................. 145
8.4
Confidentiality...................................................................... 145
8.5
Financial Disclosure ............................................................ 146
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 146
9.1
Study Documentation .......................................................... 146
9.2
Protocol Deviations.............................................................. 146
9.3
Site Inspections ................................................................... 146
9.4
Administrative Structure....................................................... 146
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 147
9.6
Protocol Amendments ......................................................... 148
10. REFERENCES ......................................................................................... 149


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LIST OF TABLES
Table 1
Randomized Phase III Trials in Patients with Previously 
Untreated NonSmall Cell Lung Cancer ..................................... 34
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades................................................................ 41
Table 3
Adverse Events Reported in at Least 10% of Patients in 
Study GO28753 (POPLAR) ........................................................ 43
Table 4
Adverse Events in Study GO28915 (OAK) with a 
Between-Arm Difference in Frequency of at Least 
5 Percentage Points.................................................................... 44
Table 5
Adverse Events Reported in Study GO28754 (BIRCH) .............. 45
Table 6
Patients with Non–Small Cell Lung Cancer 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 v1.1) ...................................................................... 47
Table 7
Efficacy Results in Study GO28753 (POPLAR):  Intent-to-
Treat Population.......................................................................... 48
Table 8
Study GO28753 (POPLAR) Efficacy Results by Combination  
PD-L1 Diagnostic Subgroups with Complementary 
Comparison Subgroupings:  Intent-to-Treat Population.............. 49
Table 9
Study GO28754 (BIRCH) Independent Review Facility-
Assessed Objective Response Rate:  Treated Population.......... 50
Table 10
Study GO28754 (BIRCH) Efficacy Results for First-Line 
Treatment of PD-L1–Selected Patients with NSCLC .................. 51
Table 11
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 75
Table 12
Premedication for Pemetrexed plus Platinum-Based 
Chemotherapy ............................................................................ 76
Table 13
Treatment Regimen for Pemetrexed plus Platinum-Based 
Chemotherapy ............................................................................ 77
Table 14
Treatment Regimens for Gemcitabine plus Platinum-Based 
Chemotherapy ............................................................................ 78
Table 15
Vital Sign Measurements at Cycle 1 and All Subsequent 
Cycles ......................................................................................... 84
Table 16
Pemetrexed Dose Modifications for Hematologic Toxicities...... 105
Table 17
Pemetrexed Dose Modifications for Non-Hematologic 
Toxicities................................................................................... 106
Table 18
Gemcitabine Dose Modifications or Treatment Delays for 
Hematologic Toxicities on Day 1............................................... 107
Table 19
Gemcitabine Dose Modifications or Treatment Delays for 
Hematologic Toxicities on Day 8............................................... 108
Table 20
Gemcitabine Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Patient Management for 
Grade 2, 3, or 4 Non-Hematologic Toxicities ............................ 109
Table 21
Cisplatin Dose Modifications for Hematologic Toxicities ........... 110


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Table 22
Cisplatin Dose Modifications for Non-Hematologic Toxicities 
(Excluding Neurotoxicity) .......................................................... 110
Table 23
Cisplatin Dose Modifications or Treatment Discontinuation 
for Associated Neurotoxicity...................................................... 111
Table 24
Carboplatin Dose Modifications for Hematologic Toxicities ...... 112
Table 25
Carboplatin Dose Modifications or Treatment Discontinuation 
for Non-Hematologic Toxicities ................................................. 113
Table 26
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ....................................... 117
Table 27
Analysis Timing and Stopping Boundaries for Interim and 
Final Analysis for Overall Survival............................................. 140
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 57
Figure 2
Criteria for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size (Atezolizumab 
Arm Only).................................................................................. 100
Figure 3
Type I Error Control Plan .......................................................... 129
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................ 157
Appendix 2
Schedule of Pharmacokinetic, Biomarker, and Anti-
Therapeutic Antibody Assessments.......................................... 164
Appendix 3
American Joint Committee on Cancer NonSmall Cell Lung 
Cancer Staging, 7th Edition ...................................................... 165
Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication ............................... 167
Appendix 5
Modified Response Evaluation Criteria in Solid Tumors .......... 179
Appendix 6
AntiPD-L1 Immunohistochemistry.......................................... 186
Appendix 7
EORTC QLQ-C30.................................................................... 187
Appendix 8
EORTC QLQ-LC13.................................................................. 189
Appendix 9
Symptoms in Lung Cancer Scale............................................. 190
Appendix 10
EuroQoL 5 Dimension, 3 Level Questionnaire......................... 193
Appendix 11
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 196
Appendix 12
Anaphylaxis Precautions.......................................................... 197
Appendix 13
Preexisting Autoimmune Diseases .......................................... 198
Appendix 14
  Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 199


Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol GO29431, Version 10
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) 
COMPARED WITH A PLATINUM AGENT (CISPLATIN 
OR CARBOPLATIN) IN COMBINATION WITH 
EITHER PEMETREXED OR GEMCITABINE FOR 
PD-L1–SELECTED, CHEMOTHERAPY-NAIVE PATIENTS 
WITH STAGE IV NON-SQUAMOUS OR SQUAMOUS 
NON–SMALL CELL LUNG CANCER 
PROTOCOL NUMBER:
GO29431
VERSION NUMBER:
10
EUDRACT NUMBER:
2014-003083-21
IND NUMBER:
117296
NCT NUMBER:
NCT02409342
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please 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 GO29431, Version 10
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB (ANTI–PD-L1 ANTIBODY) COMPARED WITH A 
PLATINUM AGENT (CISPLATIN OR CARBOPLATIN) IN 
COMBINATION WITH EITHER PEMETREXED OR GEMCITABINE 
FOR PD-L1–SELECTED, CHEMOTHERAPY-NAIVE PATIENTS 
WITH STAGE IV NON-SQUAMOUS OR SQUAMOUS NON–SMALL 
CELL LUNG CANCER 
PROTOCOL NUMBER:
GO29431
VERSION NUMBER:
10
EUDRACT NUMBER:
2014-003083-21
IND NUMBER:
117296
NCT NUMBER:
NCT02409342
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
PHASE:
III
INDICATION:
NonSmall Cell Lung Cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
For the primary and secondary efficacy objectives, a comparison of the treatment arms will be 
performed in randomized patients who are selected on the basis of a minimum level of PD-L1 
expression on tumor cells (TCs) and/or immune cells (ICs) (TC1/2/3 or IC1/2/3; corresponding 
to 1% PD-L1 expressing TCs and 1% of tumor area occupied by PD-L1 expressing ICs) 
using a centrally performed immunohistochemistry (IHC) test, with populations excluding 
patients with a sensitizing EGFR mutation or ALK translocation (i.e., wild type [WT]).
Efficacy Objectives
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
compared with platinum-based chemotherapy consisting of a platinum agent (carboplatin or 
cisplatin) in combination with either pemetrexed (non-squamous disease) or gemcitabine 
(squamous disease) in chemotherapy-naive patients with Stage IV nonsmall cell lung cancer 
(NSCLC), as measured by overall survival (OS).
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy as 
measured by investigator-assessed progression-free survival (PFS) according to Response 
Evaluation Criteria in Solid Tumors Version 1.1, Version 1.1 (RECIST v1.1)

To evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy as 
measured by objective response rate (ORR) according to RECIST v1.1 assessed by 
investigator

To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response (DOR) according to RECIST v1.1

To evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy as 
measured by OS and investigator-assessed PFS according to RECIST v1.1 in patients with 
PD-L1 expression defined by the SP263 IHC assay


Atezolizumab—F. Hoffmann-La Roche Ltd
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
To evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy as 
measured by OS and investigator-assessed PFS according to RECIST v1.1 in patients with 
blood tumor mutational burden (bTMB)

To evaluate the OS rate at 1- and 2- year landmark timepoints in each treatment arm

To determine the impact of atezolizumab compared with platinum-based chemotherapy as 
measured by time to deterioration (TTD) and change from baseline (i.e., improvement or 
deterioration based on presenting symptomatology) in each of the patient-reported lung 
cancer symptom (cough, dyspnea, chest pain) score as assessed by the Symptoms in Lung 
Cancer (SILC) scale

To determine the impact of atezolizumab compared with platinum-based chemotherapy as
measured by TTD in patient-reported lung cancer symptoms of cough, dyspnea (multi-item 
subscale), and chest pain as measured by the European Organisation for the Research and 
Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core (QLQ-C30) and 
supplementary Quality-of-Life Questionnaire Lung Cancer Module (QLQ-LC13)
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab compared with platinum-based 
chemotherapy

To evaluate the incidence and titers of anti-therapeutic antibodies (ATAs) against 
atezolizumab and to explore the potential relationship of the immunogenicity response with 
pharmacokinetics, pharmacodynamics, safety, and efficacy
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of 
atezolizumab in chemotherapy-naive patients with Stage IV NSCLC.
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the efficacy of atezolizumab compared with platinum-based chemotherapy as 
measured by OS and investigator-assessed PFS according to RECIST v1.1 in patients with 
PD-L1 expression measured using the 22c3 PD-L1 IHC assay, but excluding patients with a 
sensitizing EGFR mutation or ALK translocation

To evaluate the efficacy of atezolizumab as measured by PFS rates at 6-month and 1-year 
landmark timepoints

To evaluate the efficacy of atezolizumab as measured by OS rate at 3-year landmark 
timepoint 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 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 atezolizumab

To evaluate the utility of biopsy at the time of apparent disease progression to distinguish 
apparent increases in tumor volume related to the immunomodulatory activity of 
atezolizumab (i.e., pseudoprogression/tumor immune infiltration) from true disease 
progression

To evaluate and compare patient’s health status as assessed by the EuroQoL 5 Dimension, 
3 Level (EQ-5D-3L) questionnaire to generate utility scores for use in economic models for 
reimbursement.

To determine the impact of atezolizumab compared with platinum-based chemotherapy as 
measured by change from baseline in patient-reported outcomes (PROs) of health-related 
quality of life, lung cancer related symptoms, and functioning as assessed by the 
EORTC QLQ-C30 and QLQ-LC13.


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Study Design
Description of Study
This is a randomized, Phase III, global, multicenter, open-label study designed to evaluate the 
safety and efficacy of atezolizumab compared with chemotherapy consisting of a platinum agent 
(carboplatin or cisplatin per investigator discretion) combined with either pemetrexed 
(non-squamous disease) or gemcitabine (squamous disease) in PD-L1selected,
chemotherapy-naive patients with Stage IV NSCLC.
At screening, tumor specimens from each potentially eligible patient will be tested for PD-L1 
expression by a central laboratory using an IHC assay.  Only patients who are PD-L1selected
(tumor cell [TC]1/2/3 or tumor-infiltrating immune cell [IC]1/2/3; corresponding to 1% PD-L1 
expressing TCs and 1% of tumor area occupied by PD-L1 expressing ICs) will be enrolled.  
Patients with non-squamous disease will be randomized 1:1 to receive either atezolizumab 
alone or pemetrexed in combination with cisplatin or carboplatin.  Patients with squamous 
disease will be randomized 1:1 to receive either atezolizumab alone or gemcitabine in 
combination with cisplatin or carboplatin.  Randomization will be stratified by sex (male vs. 
female), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), 
histology (non-squamous vs. squamous), and PD-L1 tumor expression by IHC (TC1/2/3 and 
any IC vs. TC0 and IC1/2/3).
Given the toxicities associated with platinum-based chemotherapies (e.g., neutropenia, anemia) 
and the requirement for pre-medications, this will be an open-label study.  No crossover will be 
allowed from the control arm (platinum-based chemotherapy) to the experimental arm 
(atezolizumab).
Atezolizumab (fixed dose of 1200 mg) will be administered intravenously on Day 1 of each 
21-day cycle.  Atezolizumab treatment may continue as long as patients are experiencing 
clinical benefit as assessed by the investigator (i.e., in the absence of unacceptable toxicity or 
symptomatic deterioration attributed to disease progression as determined by the investigator 
after an integrated assessment of radiographic data, biopsy results [if available], and clinical 
status) or until unacceptable toxicity or death.
During treatment, patients who are treated with atezolizumab and who show evidence of clinical 
benefit will be permitted to continue atezolizumab treatment after RECIST v1.1 criteria 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 radiographic progression per 
RECIST v1.1
All patients will undergo a mandatory tumor biopsy sample collection, unless not clinically 
feasible as assessed and documented by investigators, at the first evidence of radiographic 
disease progression (within 40 days of radiographic progression or prior to the start of the next 
anti-cancer treatment, whichever is sooner).  These data will be used to explore if the 
radiographic findings are consistent with the presence of tumor or if the appearance of 
progression was caused by pseudoprogression.  In addition, these data will be analyzed for the 
association between changes in tumor tissue and clinical outcome and to understand further the
potential mechanisms of resistance and progression to atezolizumab when compared to such 
mechanisms after treatment with chemotherapy.  This exploratory biomarker evaluation will not 
be used for any treatment-related decisions.  Patients who are unable to undergo biopsy 
sample collection but otherwise meet criteria listed above may continue to receive atezolizumab.
Patients randomized to receive pemetrexed in combination with either cisplatin or carboplatin 
(non-squamous disease) will receive chemotherapy intravenously on Day 1 of each 21-day 


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18/Protocol GO29431, Version 10
cycle for four or six cycles, followed by maintenance therapy with pemetrexed.  Patients 
randomized to receive gemcitabine in combination with either cisplatin or carboplatin 
(squamous disease) will receive cisplatin or carboplatin intravenously on Day 1 and gemcitabine 
intravenously on Days 1 and 8 of each 21-day cycle for four or six cycles, followed by best 
supportive care.  The intended number of cycles planned for the platinum-based induction 
chemotherapy (i.e., four or six cycles) will be specified by the investigator prior to study 
randomization.  Treatment will continue until disease progression, unacceptable toxicity, 
or death.
All patients will undergo tumor assessment at baseline and every 6 weeks (7 days) for 
48 weeks following Cycle 1, Day 1 regardless of treatment delays.  After the completion of the 
Week 48 tumor assessment, tumor assessment will be required every 9 weeks (7 days) 
regardless of treatment delays, 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 
discontinue treatment for reasons other than radiographic disease progression per 
RECIST v1.1 (e.g., toxicity, symptomatic deterioration) 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 after disease progression according to RECIST v1.1), withdrawal of consent, death, 
or study termination by Sponsor, whichever occurs first.  In the absence of radiographic disease 
progression per RECIST v1.1, tumor assessments should continue regardless of whether 
patients start a new anti-cancer therapy.
Number of Patients
Approximately 150 sites globally will participate in the study, and approximately 
555 PD-L1selected chemotherapy-naive patients with Stage IV NSCLC will be enrolled.
Target Population
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Age 18 years

ECOG Performance Status of 0 or 1

Histologically or cytologically confirmed, Stage IV non-squamous or squamous NSCLC 
(per the Union Internationale contre le Cancer/American Joint Committee on Cancer 
staging system)
Patients with tumors of mixed histology must be classified as non-squamous or 
squamous based on the major histological component.

No prior treatment for Stage IV non-squamous or squamous NSCLC
Patients known to have a sensitizing mutation in the EGFR gene or an ALK fusion 
oncogene are excluded from the study.
Patients with non-squamous NSCLC who have an unknown EGFR or ALK status will 
be required to be tested at prescreening/screening.  Patients with squamous NSCLC 
who have an unknown EGFR or ALK status will not be required to be tested at 
prescreening/screening.
EGFR and/or ALK may be assessed locally or at a central lab. Additional tissue will be 
required for central testing of EGFR and/or ALK.

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 chemotherapy, 
radiotherapy, or chemoradiotherapy cycle. 


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
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.

Tumor PD-L1 expression (TC1/2/3 or IC1/2/3; corresponding to 1% PD-L1 expressing 
TCs and 1% of tumor area occupied by PD-L1 expressing ICs), as determined by an IHC 
assay performed by a central laboratory on previously obtained archival tumor tissue or 
tissue obtained from a biopsy at screening. 
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in paraffin 
block (preferred) or 15 or more unstained, freshly cut, serial sections (on slides) from 
an FFPE tumor specimen is required for participation in this study.  This specimen 
must be accompanied by the associated pathology report.
If fewer than 15 slides are available at baseline (but no fewer than 10), the patient 
may still be eligible, upon discussion with the Medical Monitor.
For freshly collected specimens, resections, core needle biopsies, excisional, incisional, 
punch, or forceps biopsies are acceptable.
Fine-needle aspiration (defined as samples that do not preserve tissue architecture 
and yield cell suspension and/or cell smears), brushing, cell pellet from pleural effusion, 
and lavage samples are not acceptable.  
Tumor tissue from bone metastases that have been decalcified is not acceptable.
For core needle biopsy specimens, preferably, at least three cores embedded in a 
single paraffin block, should be submitted for evaluation.
For patients whose initial archival tumor tissue sample is PD-L1 negative, a biopsy can 
be performed at screening to submit fresh tissue for the purposes of testing PD-L1 
status.  A positive test result in any tumor tissue sample will satisfy this eligibility 
criterion. 

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can only be considered 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 measureable disease

Adequate hematologic and end-organ function, defined by the following laboratory test 
results obtained within 14 days prior to randomization:
ANC 1500 cells/L without granulocyte colony-stimulating factor support
Lymphocyte count 500 cells/L
Platelet count 100,000 cells/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 must have an INR or aPTT within 
therapeutic limits for at least 1 week prior to randomization.


Atezolizumab—F. Hoffmann-La Roche Ltd
20/Protocol GO29431, Version 10
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 1.5 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 60 mL/min

For female patients of childbearing potential and male patients with partners of childbearing 
potential, agreement to use a highly effective form(s) of contraception during study 
treatment that results in a low failure rate of <1% per year when used consistently and 
correctly.  Female patients should continue contraception use for 5 months after the last 
dose of atezolizumab and for 6 months after the last dose of cisplatin.  Women must refrain 
from donating eggs during this same period.  Male patients treated with chemotherapy 
(cisplatin or carboplatin plus pemetrexed or gemcitabine) should continue contraception use 
for 6 months after the last dose of chemotherapy.  Men must refrain from donating sperm 
during this same period.  Such methods include combined (estrogen and progestogen 
containing) hormonal contraception, progestogen-only hormonal contraception associated 
with inhibition of ovulation together with another additional barrier method always containing 
a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 
bilateral tubal occlusion or vasectomized partner (on the understanding that this is the only 
one partner during the entire study duration), and sexual abstinence.

Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drug.  The same rules are valid for male 
patients involved in this study if they have a partner of childbearing potential.  Male patients 
must always use a condom.

Women who are not postmenopausal (12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-Specific Exclusions

Known sensitizing mutation in the EGFR gene or 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 on 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 enrollment.


Atezolizumab—F. Hoffmann-La Roche Ltd
21/Protocol GO29431, Version 10

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)
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 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’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on thyroid-replacement 
therapy are eligible for this study.
Patients with controlled Type I diabetes mellitus on an insulin regimen are eligible for 
this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or 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 requiring 
treatment with either 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 HIV test
All patients must be tested for HIV; patients who test positive for HIV will be excluded.

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.  HBV DNA test 
must be performed in these patients prior to randomization.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA.


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
Active tuberculosis

Severe infections within 4 weeks prior to randomization, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia

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 on 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 transplantation

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

Patients with illnesses or conditions that interfere with their capacity to understand, follow 
and/or comply with study procedures
Exclusion Criteria Related to Medications

Treatment with any approved anti-cancer therapy, including hormonal therapy, within 
3 weeks prior to initiation of study treatment

Treatment with any other investigational agent with therapeutic intent within 28 days prior to 
randomization

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.

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

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-related adverse effects from antiCTLA-4 
(CTCAE Grade 3 or 4)

Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to 
randomization
Prior treatment with cancer vaccines is allowed.

Treatment with systemic corticosteroids or other 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.


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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 National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 criteria (cisplatin)

CrCl < 60 mL/min (cisplatin)

Known hypersensitivity to gemcitabine

History of radiation therapy within 7 days prior to initiating gemcitabine
Length of Study
The length of the study, from enrollment of the first patient to final analysis, is expected to be 
approximately 55 months.
End of Study
The end of the study will occur when all of the following criteria have been met:

The required number of deaths for the final analysis of OS has been observed.

The last patient, last visit has occurred. 
In addition, the Sponsor may decide to terminate the study at any time.  If the Sponsor decides 
to terminate the study, patients who are still receiving study treatment or undergoing survival 
follow-up may be enrolled in an extension study or a non-interventional study.
Outcome Measures
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is OS, defined as the time from 
randomization to death from any cause.
The secondary efficacy outcome measures for this study are as follows:

PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by the investigator with use of RECIST v1.1, or death from any cause, 
whichever occurs first

Objective response (partial response plus complete response) as determined by the 
investigator according to RECIST v1.1

DOR, defined as the time from the first occurrence of a documented objective response to 
the time of disease progression, as determined by the investigator with use of RECIST v1.1, 
or death from any cause, whichever occurs first

OS at 1- and 2-year landmark timepoints

TTD and change from baseline (i.e., improvement or deterioration based on presenting 
symptomatology) in each of the patient-reported lung cancer symptoms (cough, dyspnea, or 
chest pain) with use of the SILC scale.

TTD in patient-reported lung cancer symptoms, defined as time from randomization to 
deterioration (10-point change) in any of the following symptom subscales (cough, dyspnea 
[multi-item scale], and chest pain), whichever occurs first, as measured by the 
EORTC QLQ-LC13

OS and investigator-assessed PFS according to RECIST v1.1 in the PD-L1 (defined with 
SP263 IHC assay) and bTMB subpopulations


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Safety Outcome Measures
The safety outcome measures for this study are as follows:

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 
atezolizumab administration

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Maximum serum atezolizumab concentration observed (Cmax) after infusion on Day 1 of 
Cycle 1

Minimum serum atezolizumab concentration observed (Cmin) prior to infusion 
on Day 1 of Cycles 2, 3, 4, 8, 16, and every eighth cycle thereafter, at treatment 
discontinuation, and at 120 (30) days after the last dose of atezolizumab
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

OS and investigator-assessed PFS according to RECIST v1.1 in the PD-L1 (defined with 
22c3 assay) subpopulation

PFS at 6-month and at 1-year landmark timepoints

OS at 3-year landmark timepoint

OS and investigator-assessed PFS according to RECIST v1.1 in subgroups based on 
demographic and baseline characteristics

Status of immune cell infiltrate and other exploratory biomarkers in mandatory biopsy 
specimens collected at progression

Status of PD-L1, immune-, and NSCLC-related and other exploratory biomarkers in 
archival and/or freshly obtained 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

Utility scores of the EQ-5D-3L questionnaire

Change from baseline in PROs of health-related quality of life, lung cancer-related 
symptoms, and functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13
Investigational Medicinal Products
Test Product (Investigational Drug)
Atezolizumab, at a dose of 1200 mg, will be administered by IV infusion every 21 days.
Comparator
Non-squamous
The comparator arm includes pemetrexedcisplatin or carboplatin to be administered 
every 21 days for four or six cycles at the doses and the suggested infusion times indicated in 
the table below.  Pemetrexed will continue to be administered as maintenance regimen every 
21 days.


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Pemetrexed plus cisplatin or carboplatin regimen
Study Drug
Dose/Route
Induction Period 
(Four or Six Cycles)
Maintenance Period 
(Until PD)
Pemetrexed
500 mg/m2 IV
Over ~10 minutes on Day 1 q21d
Over approximately 
10 minutes on Day 1 q21d
Carboplatin
AUC 6 IV
Over ~3060 minutes on Day 1 
q21d
Not applicable
OR
Cisplatin
75 mg/m²
Over 1–2 hours on Day 1 q21d
Not applicable
AUCarea under the concentrationtime curve; IVintravenous; PDprogressive disease; 
q21devery 21 days.
Squamous
The comparator arm includes gemcitabine plus cisplatin or carboplatin to be administered every 
21 days for four or six cycles at the doses and the suggested infusion times indicated in the 
table below.
Gemcitabine plus Cisplatin or Carboplatin Regimen
Chemotherapy
Dose/Route
Treatment
(Four or Six Cycles)
Gemcitabine
1250 mg/m2 IV
Over 30 minutes on Days 1 & 8 q21d
Cisplatin
75 mg/ m2 IV 
Over 12 hours on Day 1 q21d
Gemcitabine
1000 mg/m2 IV
Over 30 minutes on Days 1 & 8 q21d
Carboplatin
AUC 5 IV
Over ~30–60 minutes on Day 1 q21d
AUCarea under the concentration curve; IVintravenous; q21devery 21 days.
Statistical Methods
Primary Analysis
The primary efficacy analysis is the comparison of OS between the two treatment arms 
(atezolizumab arm and chemotherapy control arm).
OS is defined as the time from randomization to death from any cause.  Data for patients who 
are not reported as having died at the time of the 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 primary efficacy analysis will be performed for the TC3 or IC3-WT subpopulation, the 
TC2/3 or IC2/3-WT subpopulation, and the TC1/2/3 or IC1/2/3-WT population.
The null and alternative hypotheses for the OS analysis can be phrased in terms of the survival 
functions SA(t) and SB(t) in the atezolizumab arm (Arm A) and the control arm (Arm B), 
respectively:
H0:  SA(t) SB(t) versus H1:  SA(t) ≠SB(t)
The stratification factors will be:  sex (male vs. female), ECOG Performance Status (0 vs. 1), 
histology (non-squamous vs. squamous), and PD-L1 tumor expression status (TC1/2/3 and any 
IC vs. TC0 and IC1/2/3).  Both stratified and unstratified analysis will be performed.  Due to the 
potential risk of over-stratification, if at least 1 stratum (i.e., for the TC1/2/3 or IC1/2/3 population, 
a combination of stratification factor levels across sex, ECOG performance status, histology, 
and PD-L1 tumor expression status per IxRS; for the TC3 or IC3 population and the TC2/3 or 
IC2/3 population, a combination of stratification factor levels across sex, ECOG performance 
status, and histology per IxRS) has less than 10 OS events, the stratification factor 




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Interim Analyses
Because of a lack of the final PD-L1 prevalence, an interim analysis of OS in the TC3 or 
IC3-WT population will be conducted when both of the following criteria have been met:

An approximately 45% eventpatient ratio has been observed in the TC3 or IC3-WT
subpopulation

Approximately 96 deaths have occurred in the TC3 or IC3-WT subpopulation
At this timepoint, it is expected that approximately 154 OS events will have occurred in the
TC2/3 or IC2/3-WT population.  If the OS interim analysis in the TC3 or IC3-WT population 
is claimed as statistically significant, the OS analysis in the TC2/3 or IC2/3 WT population 
will be conducted with the stopping boundaries for the interim and final analyses calculated 
using the Lan-DeMets approximation to the Pocock boundaries.  If there are significantly 
fewer than 154 OS events (i.e., <135 events) at the TC3 or IC3 WT interim analysis, a 
nominal two-sided alpha of 0.0001 (negligible impact on overall type I error rate) will 
be spent on the OS analysis in the TC2/3 or IC2/3-WT population at the time of the TC3 or 
IC3-WT interim analysis.  The next interim and final OS analysis in the TC2/3 or IC2/3-WT 
population will be conducted when approximately 154 and 216 events are observed, 
respectively, with the stopping boundaries calculated in the same manner as above.  
The interim and final analyses of OS in the TC1/2/3 or IC1/2/3-WT population would be 
conducted at the same time as those for the TC2/3 or IC2/3-WT population.
The interim analysis is expected to occur approximately 40 months after the first patient is 
enrolled in the study. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
anti-HBc
antibody to hepatitis B core antigen
ASCO
American Society of Clinical Oncology
ATA
anti-therapeutic antibody
AUC
area under the concentrationtime curve
BSC
best supportive care
bTMB
blood tumor mutational burden
Cmax
maximum serum concentration observed
Cmin
minimum serum concentration observed
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form
CT
computed tomography
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T lymphocyteassociated antigen 4
Ctrough
trough concentration
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
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
electronic PRO
EQ-5D-3L
EuroQoL 5 Dimension, 3 Level 
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


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Abbreviation
Definition
IC
tumor-infiltrating immune cell
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug application
IRB
Institutional Review Board
IRF
Independent Review Facility
ITT
intent to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IxRS
interactive Web/voice response system
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
PCR
polymerase chain reaction
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
PUVA
psoralen plus ultraviolet A radiation
q21d
every 21 days
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
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
Statistical Analysis Plan
SILC
Symptoms in Lung Cancer


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Abbreviation
Definition
TC
tumor cell
TMB
tumor mutational burden
TNF
tumor necrosis factor
TSH
thyroid-stimulating hormone
TTD
time to deterioration
TTF-1
thyroid transcription factor1
ULN
upper limit of normal
WT
wild type


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1.
BACKGROUND
1.1
NON–SMALL CELL 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. 2014).  
NSCLC can be divided into two major histologic types:  adenocarcinoma and squamous 
cell carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for more than 
half of all NSCLC, while squamous cell histology accounts for approximately 
25% (Langer et al. 2010) of NSCLC.  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 biomarkers may support the histologic diagnosis.  Thyroid 
transcription factor1 (TTF-1) is infrequently expressed in squamous cells and strongly 
expressed in adenocarcinoma.  In contrast, p63, CK5/6, and 34E12 are strongly 
expressed in squamous cell carcinoma and less frequently in adenocarcinoma 
(Travis et al. 2011).
Genetic changes that have prognostic and/or predictive significance in NSCLC include 
mutations in the EGFR gene, the rearrangement in the ALK gene, and mutations in the 
KRAS gene.  The rates of these mutations differ between squamous cell carcinoma and 
adenocarcinoma.  For example, EGFR kinase domain mutations have been reported in 


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10%–40% of patients with adenocarcinoma NSCLC but are infrequently observed in 
squamous NSCLC (Herbst et al. 2008).  The ALK fusion oncogene, recognized as a driver 
of lung tumorigenesis, is very rare in the squamous histology but observed in 
approximately 7% of patients with adenocarcinoma (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).
1.2
FIRST-LINE TREATMENT FOR NONSMALL CELL LUNG 
CANCER WITHOUT AN EGFR MUTATION OR ALK
REARRANGEMENT 
Patients with previously untreated NSCLC that does not harbor a driver mutation that 
confers sensitivity to a targeted agent are typically treated with chemotherapy.  The first 
evidence that chemotherapy produced a significant survival benefit in patients with 
advanced NSCLC came in 1995; a meta-analysis showed that platinum-based doublet 
chemotherapy conferred a 2-month improvement in median survival over best supportive 
care (BSC) (NSCLC Collaborative Group 1995).  More recently, the European Big Lung 
Trial demonstrated the potential benefits of chemotherapy.  In this trial, 725 patients with 
advanced NSCLC were randomly assigned to BSC plus cisplatin-based chemotherapy 
or BSC alone (Spiro et al. 2004).  Patients allocated to chemotherapy had a significantly 
longer median survival than did those managed with BSC (8 vs. 5.7 months). 
The benefit conferred by platinum-based chemotherapy regimens appears to have 
reached a plateau in objective response rate (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).
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 not harboring an activating EGFR mutation or ALK gene 
rearrangement.  In particular, for newly diagnosed advanced-stage non-squamous 
NSCLC, standard of care is a platinum doublet with either cisplatin or carboplatin and a 
taxane or pemetrexed, with or without bevacizumab.  However, well-designed clinical 
trials conducted over the last decade have demonstrated that pemetrexed and 
bevacizumab are not appropriate agents for the treatment of patients with squamous-cell 
carcinoma of the lung (Johnson et al. 2004; Scagliotti et al. 2008; Sandler et al. 2009). 
The combination of gemcitabine and a platinum analog (either cisplatin or carboplatin) 
has demonstrated efficacy as first-line treatment for squamous NSCLC and, as a result, 
is often a reference arm in clinical trials to evaluate new therapeutics (Schiller et al. 2002; 
Treat et al. 2010).


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Overall, 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 NSCLC.
Recently, immune checkpoint inhibitors, including PD-L1/PD-1 blocking antibodies, have
emerged as a new therapeutic option for first-line treatment of metastatic NSCLC. 
Study KEYNOTE-024 was a Phase III, randomized, open-label study evaluating 
pembrolizumab given as monotherapy compared with platinum-based chemotherapy in 
patients who had previously untreated advanced NSCLC with PD-L1 expression on at 
least 50% of tumor cells.  In this study, median progression-free survival (PFS) was 
10.3 months in the pembrolizumab group versus 6.0 months in the chemotherapy group 
(hazard ratio [HR]0.50; 95% CI: 0.37, 0.68; p0.001).  The estimated rate of OS at 
6 months was 80.2% (95% CI: 72.9%, 85.7%) in the pembrolizumab group versus 
72.4% (95% CI: 64.5%, 78.9%) in the chemotherapy group; median OS was not reached 
in either group.  Although the median OS was not reached in either group, OS benefit 
was observed with the treatment of pembrolizumab (HR0.60; 95% CI: 0.41, 0.89; 
p0.005) (Reck et al. 2016).  On the basis of this study, pembrolizumab was approved
as a single agent for the first-line treatment of patients with metastatic NSCLC whose 
tumors have high PD-L1 expression (tumor proportion score 50%) with no EGFR or 
ALK genomic tumor aberrations.


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


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


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1.2.1
Platinum-Based Regimen for First-Line NonSmall Cell Lung 
Cancer
Several meta-analyses have compared the use of cisplatin and carboplatin as 
treatments for NSCLC.  In general, although the objective response rate (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, 
but overall benefit was quite marginal (Hotta et al. 2004; Ardizzoni et al. 2007), and 
subgroup analyses including additional, more recent trials indicate that there may be 
no difference between the two agents (Azzoli et al. 2009; Jiang et al. 2007).
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.  Currently, the standard of care for newly diagnosed 
advancedstage squamous NSCLC includes gemcitabine in combination with a 
platinum agent.
1.2.2
Pemetrexed plus Platinum Compounds in First-Line 
Non-Squamous NonSmall Cell Lung Cancer
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 
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 plus carboplatin combination appears to be more 
favorable than that seen with other standard regimens in first-line NSCLC.
A Phase III non-inferiority study compared 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]) 
(Scagliotti et al. 2008). Therefore, in this study, patients with non-squamous NSCLC 


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randomized to the control arm will receive pemetrexed in combination with a 
platinum agent.
1.2.2.1
Pemetrexed Maintenance Therapy in NonSquamous 
NonSmall Cell Lung Cancer
A Phase III randomized, double-blind, placebo-controlled study 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, 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 who received 
placebo (unadjusted HR0.70; 95% CI: 0.56, 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 plus BSC or placebo plus BSC.  The median PFS in 
patients who received pemetrexed was 4.1 months (range 3.2–4.6 months) compared 
with a 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 trial are pending (Paz-Ares et al. 2012).
1.2.3
Gemcitabine plus Platinum Compounds in First-Line 
Squamous Non-Small Cell Lung Cancer
Although median OS, PFS, and time to progression were comparable between 
the cisplatin/pemetrexed versus cisplatin/gemcitabine treatment groups in the Phase III 
non-inferiority study referenced above (Scagliotti et al. 2008) in patients with incurable 
Stage IIIB or IV NSCLC who had received no prior chemotherapy, there was an 
improvement in survival with cisplatin/gemcitabine compared with cisplatin/pemetrexed 
in patients with squamous-cell carcinoma (10.8 vs. 9.4 months; HR1.23; 95% CI: 1.00, 


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1.51; p0.05).  Therefore, in this study, patients with squamous NSCLC randomized to 
the control arm will receive gemcitabine in combination with a platinum agent. 
1.3
FIRST-LINE TREATMENT FOR 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 (mainly non-squamous histology) 
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 
trials 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; respectively).  
Similarly, the ALK inhibitor crizotinib has 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U.S. Package Insert).  
In the Phase III GO28915 (OAK) study evaluating the efficacy and safety of 
atezolizumab versus docetaxel in patients with previously treated locally advanced or 
metastatic NSCLC, OS was similar between the atezolizumab and docetaxel arms in 
patients with an EGFR mutation (HR1.24; 95% CI: 0.71, 2.18) (Rittmeyer et al. 2017). 
Consistent results were observed with the PD-1 inhibitors nivolumab and pembrolizumab 
(Borghaei et al. 2015; Herbst et al. 2016).  
1.4
BACKGROUND ON ATEZOLIZUMAB (MPDL3280A)
Atezolizumab (MPDL3280A) is a humanized IgG1 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 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 PD-L1 and inhibits its interaction with its receptors, PD-1
and B7.1 (CD80, B7-1).  Both of these interactions are reported to provide inhibitory 
signals to T cells.
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.  Atezolizumab is approved for the treatment of 
patients with metastatic NSCLC after prior chemotherapy and for the treatment of 
patients with locally advanced or metastatic urothelial cancer after prior chemotherapy or 
who are considered cisplatin ineligible.


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1.4.1
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 trials in patients.
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.5
CLINICAL EXPERIENCE WITH ATEZOLIZUMAB
Refer to the Atezolizumab Investigator’s Brochure for details on all clinical studies 
conducted to date.
1.5.1
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).  The single-agent safety 
and efficacy data include, but are not limited to, data from the following studies:

Study PCD4989g:  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 21 days (q21d) to patients with locally advanced or metastatic solid 
malignancies or hematologic malignancies

Study GO28753 (POPLAR):  A randomized, Phase II, open-label study assessing 
the clinical benefit 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


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
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

Study GO28754 (BIRCH):  A Phase II, open-label study assessing the clinical 
benefit of atezolizumab as a single agent in patients with PD-L1selected 
(i.e., selected on the basis of a predefined level of PD-L1) locally advanced or 
metastatic NSCLC representing all lines of therapy (previously untreated to heavily 
pretreated patients with exposure to multiple prior regimens) level
1.5.2
Clinical Safety
Study PCD4989g is a Phase Ia dose escalation and expansion study, in which 
atezolizumab is being used as a single agent in patients with locally advanced or 
metastatic solid tumors or hematologic malignancies, and provides data (with 558 safety 
evaluable patients as of the data cutoff 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, 
urinary bladder cancer, melanoma, and renal cell carcinoma.  Safety data for NSCLC 
are also derived from Studies GO28753 (POPLAR), GO28915 (OAK), and GO28754 
(BIRCH).
1.5.2.1
Single-Agent Clinical Safety in Patients with NonSmall Cell 
Lung Cancer in Study PCD4989g
Of the 558 patients in Study PCD4989g, 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
Adverse Event
All Grades
n (%)
All Grades 
Related
n (%)
Grade 34
n (%)
Grade 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 or 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%), with 66 patients (11.8%) experiencing treatment-related adverse 
events.  Grade 3 or 4 adverse events considered related by the investigator included 
dyspnea, pneumonitis, increased ALT, increased AST, increased -glutamyl transferase 
(GGT), lymphocyte count decreased, cardiac tamponade, asthenia, autoimmune 
hepatitis, pneumonia, influenza, and hypoxia.
Refer to the Atezolizumab Investigator’s Brochure for details on the adverse events 
observed in patients treated with atezolizumab.


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1.5.2.2
Single-Agent Clinical Safety in Patients with NonSmall Cell 
Lung Cancer in Study GO28753 (POPLAR)
As of the 1 December 2015 data cutoff date, the Phase II POPLAR study (GO28753) 
included data from 277 safety-evaluable patients treated with either atezolizumab as a 
fixed dose of 1200 mg IV every 3 weeks (Q3W) (n142) or docetaxel 75 mg/m2 IV Q3W
(n135).  The frequency of patients in Study GO28753 who reported an adverse event 
regardless of attribution was 95.8% for the atezolizumab arm and 96.3% for the 
docetaxel arm.  A higher frequency of Grade 3 or 4 adverse events was observed 
among patients in the docetaxel arm (52.6% vs. 40.8%), explained primarily by the 
difference in adverse events due to bone marrow suppression.  The frequency of
patients who discontinued treatment because of adverse events was higher in the 
docetaxel arm than in the atezolizumab arm (22.2% vs. 8.5%). 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 
Study GO28753 (POPLAR)
No. of Patients (%)
Adverse Event
Atezolizumab
(n142)
Docetaxel
(n135)
Fatigue
55 (38.7)
54 (40.0)
Decreased appetite
49 (34.5)
28 (20.7)
Nausea
32 (22.5)
45 (33.3)
Cough
40 (28.2)
33 (24.4)
Dyspnea
39 (27.5)
27 (20.0)
Constipation
31 (21.8)
32 (23.7)
Diarrhea
25 (17.6)
38 (28.1)
Alopecia
3 (2.1)
52 (38.5)
Anemia
25 (17.6)
27 (20.0)
Pyrexia
24 (16.9)
16 (11.9)
Vomiting
20 (14.1)
18 (13.3)
Asthenia
15 (10.6)
22 (16.3)
Arthralgia
22 (15.5)
12 (8.9)
Insomnia
22 (15.5)
11 (8.1)
Rash
16 (11.3)
16 (11.9)
Back pain
16 (11.3)
11 (8.1)
Myalgia
9 (6.3)
18 (13.3)
Musculoskeletal pain
19 (13.4)
7 (5.2)
Weight decreased
16 (11.3)
9 (6.7)
Hemoptysis
15 (10.6)
8 (5.9)
Pneumonia
17 (12.0)
4 (3.0)
Neuropathy peripheral
3 (2.1)
16 (11.9)
Neutropenia
2 (1.4)
17 (12.6)
For additional information, refer to the Atezolizumab Investigator’s Brochure.


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1.5.2.3
Single-Agent Clinical Safety in Patients with NonSmall Cell 
Lung Cancer in Study GO28915 (OAK)
As of the 7 July 2016 data cutoff date for the primary analysis, Phase III Study GO28915
(OAK) included data from 609 patients treated with atezolizumab as a fixed dose of 
1200 mg IV Q3W and 578 patients treated with docetaxel 75 mg/m2 IV Q3W.  The 
frequency of patients who reported any adverse event regardless of attribution was 
94.1% for the atezolizumab arm and 96.0% for the docetaxel arm.  A higher frequency of 
Grade 3 or 4 adverse events was observed among patients in the docetaxel arm 
(53.6% vs. 37.3%).  The frequency of patients who discontinued treatment because 
of adverse events was higher in the docetaxel arm than in the atezolizumab arm 
(18.7% vs. 7.6%).  Table 4 lists adverse events with a between-arm difference in 
frequency of at least 5 percentage points.
Table 4
Adverse Events in Study GO28915 (OAK) with a Between-Arm 
Difference in Frequency of at Least 5 Percentage Points
Adverse Event
Atezolizumab
Docetaxel
Fatigue
26.8%
35.5%
Alopecia
0.5%
34.9%
Diarrhea
15.4%
24.4%
Anemia
11.5%
23.5%
Nausea
17.7%
22.7%
Myalgia
6.4%
15.7%
Neutropenia
1.6%
15.6%
Peripheral edema
8.9%
14.2%
Peripheral neuropathy
Stomatitis
3.9%
3.1%
11.2%
10.9%
Febrile neutropenia
0.2%
10.7%
Dysgeusia
3.0%
10.0%
Musculoskeletal pain
10.5%
4.3%
Pruritus
8.2%
3.1%
Source:  Rittmeyer et al. 2017. 


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1.5.2.4
Single-Agent Clinical Safety in Patients with Non–Small Cell 
Lung Cancer in Study GO28754 (BIRCH)
As of the 28 May 2015 data cutoff date for the primary analysis, 659 patients were 
evaluable for safety.  Table 5 shows the overall safety findings in Study GO28754. 
Table 5
Adverse Events Reported in Study GO28754 (BIRCH)
No. of Patients (%)
Parameter
Cohort 1
1L
(n139)
Cohort 2
2L
(n267)
Cohort 3
3L+
(n253)
All Patients
(n659)
All-cause AEs
91%
92%
96%
94%
All-cause Grade 34 AEs 
40%
37%
39%
38%
Related adverse event
57%
63%
69%
64%
Related Grade 34 AEs
9%
12%
11%
11%
AE leading to withdrawal 
from treatment
6%
6%
4%
5%
Related Grade 5 (fatal) AE
0
0
0.4%a
0.2%
1Lfirst line; 2Lsecond line; 3Lthird line; AEadverse event.
a One Grade 5 treatment-related event (pneumonia).
Adapted from Besse et al. 2015.
The most commonly reported adverse events (all grade) were fatigue, diarrhea, and 
nausea.  The adverse event profile observed in Study GO28754 is consistent with that 
observed in Study PCD4989g (overall and NSCLC populations), as well as with the 
atezolizumab arm in Studies GO28753 (POPLAR) and GO28915 (OAK).
For additional information, refer to the Atezolizumab Investigator’s Brochure.
1.5.2.5
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 regarding 
immune-mediated adverse events observed in patients treated with atezolizumab.


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1.5.3
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.
1.5.3.1
Single-Agent Clinical Activity in Patients with Non–Small Cell 
Lung Cancer in Study PCD4989g
As of the clinical data cutoff date of 2 December 2014, the safety and efficacy 
evaluable population included 88 patients with locally advanced or metastatic NSCLC.  
The median age was 60.5 years (range from 24 to 84 years) and represented a heavily 
pretreated patient population in that 97.7% of the patients had received ≥2 prior 
systemic therapies and 77.3% of the patients had received ≥4 prior systemic therapies.  
Overall, responses were observed in 20 of 88 patients (22.7%) with NSCLC and 
included responses in patients with non-squamous and squamous NSCLC 
(16 in 67 patients and 4 in 21 patients, respectively).  A total of 8 of the 20 responding 
patients had continued to respond at the time of the clinical data cutoff.  
Table 6 displays the confirmed ORR, 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 tumor cells (TCs) and tumor-infiltrating 
immune cells (ICs) for PD-L1 expression on baseline tumor tissue from NSCLC patients 
have been performed.  Higher ORRs were associated with higher PD-L1 expression.
Refer to the Atezolizumab Investigator’s Brochure for details on the clinical activity of 
atezolizumab in patients with NSCLC treated to date.


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Table 6
Patients with Non–Small Cell Lung Cancer 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 v1.1)
PD-L1 IHC 
Expression 
Category
ORR by RECIST, v1.1
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; SDstable disease; PDprogressive disease; RECIST Response Evaluation Criteria 
in Solid Tumors; 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.


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1.5.3.2
Single-Agent Clinical Activity in Patients with NonSmall Cell 
Lung Cancer in Study GO28753 (POPLAR)
The primary OS analysis in Study GO28753 (POPLAR) was conducted when 
173 deaths had occurred (clinical cutoff, 8 May 2015).  Key efficacy results for the ITT 
population are shown in Table 7.  Atezolizumab showed significant improvement in 
OS compared with docetaxel in patients with advanced, previously treated NSCLC 
unselected for PD-L1 expression.  OS was 12.6 months (95% CI: 9.7, 16.4 months) for 
atezolizumab versus 9.7 months (95% CI: 8.6, 12.0 months) 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) (see Table 7). Objective responses with 
atezolizumab were durable, with a median duration of 14.3 months 
(95% CI: 11.6 months, not estimable) compared with 7.2 months (95% CI: 5.6, 
12.5 months) for docetaxel (Fehrenbacher et al. 2016).
Table 7
Efficacy Results in Study GO28753 (POPLAR):  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%


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At the time of an updated analysis representing an additional 7 months of follow-up 
(1 December 2015 data cutoff date), 200 of 287 randomized patients (70%) had died.  
Improvement in OS benefit was observed for atezolizumab compared with docetaxel in 
the ITT population (stratified HR0.69; 95% CI: 0.52, 0.92) (see Table 8).  The median 
OS in the ITT population was 12.6 months (95% CI: 9.7, 16.0 months) in the 
atezolizumab arm and 9.7 months (95% CI: 8.6, 12.0 months) in the docetaxel arm.  
PFS was similar between groups (2.7 months with atezolizumab vs. 3.4 months with 
docetaxel) (Smith et al. 2016).  
The updated OS and PFS analyses for the ITT population and by PD-L1 expression 
levels are shown in Table 8.  Improvement in OS numerically increased with increasing 
PD-L1 expression, whereas patients with the lowest PD-L1 expression levels 
experienced OS similar to that in the docetaxel group (see Table 8). 
Table 8
Study GO28753 (POPLAR) Efficacy Results by Combination 
PD-L1 Diagnostic Subgroups with Complementary Comparison 
Subgroupings:  Intent-to-Treat Population
Population
HR (95% CI)
Total No. of Patients
(Atezolizumab/
Docetaxel)
OS
PFS
ITT
0.69 (0.52, 0.92)
0.92 (0.71, 1.20)
287 (144/143)
TC3 or IC3
0.45 (0.22, 1.95)
0.60 (0.32, 1.13)
47 (24/23)
TC2/3 or IC2/3
0.50 (0.31, 0.80)
0.71 (0.47, 1.08)
105 (50/55)
TC1/2/3 or IC1/2/3
0.59 (0.41, 0.83)
0.86 (0.63, 1.16)
195 (93/102)
TC0 and IC0
0.88 (0.55, 1.42)
1.06 (0.68, 1.67)
92 (51/41)
HRhazard ratio; ICtumor-infiltrating immune cell; ITTintent to treat; OSoverall 
survival; PFSprogression-free survival; TCtumor cell.
Notes:  The data cutoff date is 1 December 2015.
The HRs are stratified for the ITT population and unstratified for the PD-L1 
expression subgroups.
In summary, the data from Study GO28753 (POPLAR) show that atezolizumab provides 
survival benefit compared with docetaxel in previously treated patients with NCSLC.
1.5.3.3
Single-Agent Clinical Activity in Patients with Non–Small Cell 
Lung Cancer in Study GO28915 (OAK)
The co-primary endpoints of Study GO28915 (OAK) were OS in all randomized patients 
(ITT population) and OS in a PD-L1selected subgroup in the primary analysis 
population (TC1/2/3 or IC1/2/3).  
At the time of the primary analysis (7 July 2016 data cutoff date), which included data 
from the first 850 randomized patients (425 in the atezolizumab arm and 425 in the 
docetaxel arm), the median duration of survival follow-up was 21 months and 


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569 patients had died.  In the ITT population, OS was significantly improved with 
atezolizumab compared with docetaxel (median OS, 13.8 vs. 9.6 months; HR0.73;
95% CI: 0.62, 0.87; p0.0003).  For the TC1/2/3 or IC1/2/3 subgroup, OS was also 
significantly improved with atezolizumab compared with docetaxel (median OS, 
15.7 vs. 10.3 months; HR0.74; 95% CI: 0.58, 0.93; p0.0102).  
PFS was similar between the atezolizumab and docetaxel arms (median PFS,
2.8 vs. 4 months; HR0.95; 95% CI: 0.82, 1.10).  Fifty-eight patients (14%) in the 
atezolizumab arm and 57 patients (13%) in the docetaxel arm achieved a confirmed
objective response per RECIST v1.1.  Objective responses with atezolizumab were 
durable, with a median duration of 16.3 months (95% CI: 10.0 months, not estimable) in 
the atezolizumab arm compared with 6.2 months (95% CI: 4.9, 7.6 months) in the 
docetaxel arm (Rittmeyer et al. 2017).
1.5.3.4
Single-Agent Clinical Activity in Patients with Non–Small Cell 
Lung Cancer in Study GO28754 (BIRCH)
Primary Efficacy Analysis
The primary analysis of Study GO28754 (BIRCH) was performed approximately 
6 months after the last patient was enrolled (clinical cutoff 28 May 2015; 
Besse et al. 2015).  Independent Review Facility (IRF)-assessed ORR by line of therapy 
is shown in Table 9. 
Table 9
Study GO28754 (BIRCH) Independent Review Facility-Assessed 
Objective Response Rate:  Treated Population
Primary Efficacy 
Endpoint
IRF-ORR per RECIST 
v1.1
Cohort 1 (1L) 
N139
Cohort 2 (2L)
N267
Cohort 3 (3L)
N253
All treated patients
(TC2/3 or IC2/3)
n139
n267
n253
Responders (%)
27 (19.4%)
46 (17.2%)
44 (17.4%)
95% CI
13.2, 27.0
12.9, 22.3
12.9, 22.6
TC3 or IC3 patients
n65
n122
n115
Responders (%)
17 (26.2%)
29 (23.8%)
31 (27.0%)
95% CI
16.0, 38.5
16.5, 32.3
19.1, 36.0
1Lfirst line; 2Lsecond line; 3Lthird line; ICtumorinfiltrating immune cell; 
IRFindependent review facility; ORRobjective response rate; RECIST Response 
Evaluation Criteria in Solid Tumors; TCtumor cell.
Source: Besse et al. 2015.
The study met its primary objective of demonstrating a statistically significant and 
clinically meaningful ORR assessed by IRF per RECIST v1.1 compared with historical 
control groups (ORR range, 5%15%) in the seven pre-specified subpopulations
(p0.0001).  At the clinical cutoff, more than 58% of responders assessed by IRF per 


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RECIST v1.1 had an ongoing response in each line of therapy and each PD-L1 
expression level.  The estimated median DOR was 8.4 months in the TC2/3 or IC2/3
patients although follow-up is limited.  At the time of the primary analysis, OS data were 
not yet mature.
Updated Efficacy Analysis for Patients Receiving First-Line Treatment 
(Cohort 1)
An updated efficacy analysis (1 August 2016 data cutoff date) conducted for 
138 patients receiving first-line treatment (Cohort 1) with a minimum follow-up of 
22.5 months, provided evidence of a clinically meaningful benefit of atezolizumab as 
first-line treatment for patients with NSCLC, as demonstrated by a median OS of 
23.5 months for all patients (TC2/3 or IC2/3).  As shown in Table 10, ORR was 25% 
(95% CI: 18%, 33%) and median PFS was 7.3 months (95% CI: 5.7, 9.7 months) for all 
patients (TC2/3 or IC2/3) (Garassino et al. 2016). 
Table 10 Study GO28754 (BIRCH) Efficacy Results for First-Line Treatment 
of PD-L1–Selected Patients with NSCLC
No. of 
Patients
ORR, %
(95% CI)
Median DOR, 
months
(95% CI)
Median PFS, 
months
(95% CI)
Median OS, 
months
(95% CI)
All treated patients 
(TC2/3 or IC2/3)
138
25
(18, 33)
16.5
(9.9, NE)
7.3
(5.7, 9.7)
23.5
(18.1, NE)
TC3 or IC3 patients
65
34
(23, 47)
NE
(8.5, NE)
7.3
(4.9, 12,0)
26.9
(12.0, NE)
CIconfidence interval; DORduration of response; IC tumor-infiltrating immune cell; NEnot
estimable; ORRobjective response rate; OSoverall survival; PFSprogression-free survival; 
TCtumor cell. 
Notes:  The data cutoff date is 1 August 2016.
ORR, DOR, and PFS data are based on investigator assessment.
1.5.4
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 at 
steady state had a range of 3.114.14 mL/kg and 48.1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 dosed at the 10-, 15-, and 20-mg/kg dose levels have maintained the expected 
target trough levels of drug despite the detection of ATAs.  To date, no clear relationship 


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between the detection of ATAs and adverse events or infusion reactions has been 
observed.
1.5.5
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.
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 mg/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, 
pharmacokinetics, 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 q21d 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 q21d regimen (or fixed-dose equivalent).  From inspection 
of available observed Ctrough data, moving further to the 20-mg/kg atezolizumab 
q21d regimen does not appear to be warranted to maintain targeted Ctrough levels relative 
to the proposed 15-mg/kg atezolizumab q21d 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.
1.6
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).


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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 
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 tumor cells (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.  
In Study PCD4989g, a Phase Ia dose-escalation and expansion study, objective 
responses with atezolizumab monotherapy were observed in a broad range of 
malignancies. In Studies GO28753 (POPLAR) and GO28915 (OAK), there was 
significant improvement in OS with atezolizumab compared with docetaxel in patients 
with previously treated advanced NSCLC. Additionally, there was a clinically meaningful 
benefit observed with atezolizumab given as first-line treatment for PD-L1selected 
patients (TC2/3 or IC2/3) with NSCLC in Study GO28754 (BIRCH).
On the basis of these observations, Study GO29431 (IMpower110) is designed to 
evaluate whether the anti-tumor effect seen in atezolizumab-treated patients would 
translate into prolonged OS and PFS compared with platinum-based chemotherapy in 
patients with NSCLC who are selected on the basis of a minimum level of PD-L1 tumor 
expression on TCs and/or ICs (TC1/2/3 or IC1/2/3; corresponding to 1% PD-L1 
expressing TCs and 1% of tumor area occupied by PD-L1 expressing ICs).  A PD-L1 
immunohistochemistry (IHC) assay will be used to identify patients by their tumor PD-L1 
expression (see Appendix 6).
Study GO29431 will enroll patients with Stage IV NSCLC who are naive to 
chemotherapy treatment and for whom the experimental arm can represent a valuable 
treatment option and can offer a reasonable benefit-risk balance.
In order to account for the possibility of pseudoprogression/tumor-immune infiltration 
(i.e., radiographic increase in tumor volume caused by the influx of immune cells; 


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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 3.3.4 and Section 4.6) with use of modified 
RECIST criteria (in addition to RECIST v1.1) to evaluate clinical benefit.  As it is not yet 
possible to reliably differentiate pseudoprogression/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.  Investigators 
should make a careful assessment of the potential benefit of continuing treatment with 
atezolizumab, considering radiographic data and the clinical status of the patient.  
If, after an integrated assessment of radiographic data and clinical status, the decision is 
made to continue treatment with atezolizumab following apparent radiographic 
progression, patients must provide written consent at that time to acknowledge deferring 
other treatment options in favor of continuing study treatment.
Atezolizumab has been generally well tolerated (see Section 1.5.2).  Adverse events 
with potentially immune-mediated causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis 
have been observed.  To date, these events have been manageable with treatment.
In summary, treatment with atezolizumab offers the potential for clinical benefit in 
patients with NSCLC, in particular among those having tumor tissue with PD-L1 
expression.  Because most atezolizumab-related toxicities observed to date have been 
mild and transient in nature and do not overlap with the adverse effects of chemotherapy, 
patients who do not respond to study treatment with atezolizumab are considered likely 
to be able to subsequently receive standard therapies for which they would otherwise 
have been eligible.  Patients will be fully informed of the risk of continuing study 
treatment with atezolizumab 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 [if available], and the clinical status of 
the patient.
2.
OBJECTIVES
2.1
EFFICACY OBJECTIVES
For the primary and secondary efficacy objectives, a comparison of the treatment arms 
will be performed in randomized patients who are selected on the basis of a minimum 
level of PD-L1 expression on TCs and/or ICs (TC1/2/3 or IC1/2/3; corresponding to 
1% PD-L1 expressing TCs and 1% of tumor area occupied by PD-L1 expressing ICs) 
using a centrally performed IHC test (see Appendix 6), with populations excluding 
patients with a sensitizing EGFR mutation or ALK translocation.


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2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
compared with platinum-based chemotherapy consisting of a platinum agent (cisplatin or 
carboplatin) in combination with either pemetrexed (non-squamous disease) or 
gemcitabine (squamous disease) in chemotherapy-naive patients with Stage IV NSCLC, 
as measured by OS.
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of atezolizumab compared with platinum-based 
chemotherapy as measured by investigator-assessed PFS according to RECIST 
v1.1 (see Appendix 4)

To evaluate the efficacy of atezolizumab compared with platinum-based 
chemotherapy as measured by ORR according to RECIST v1.1 assessed by 
investigator

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
DOR according to RECIST v1.1

To evaluate the efficacy of atezolizumab compared with platinum-based 
chemotherapy as measured by OS and investigator-assessed PFS according to 
RECIST v1.1 in patients with PD-L1 expression defined by the SP263 IHC assay

To evaluate the efficacy of atezolizumab compared with platinum-based 
chemotherapy as measured by OS and investigator-assessed PFS according to 
RECIST v1.1 in patients with blood tumor mutational burden (bTMB)

To evaluate the OS rate at 1- and 2- year landmark timepoints in each treatment 
arm

To determine the impact of atezolizumab compared with platinum-based 
chemotherapy as measured by time to deterioration (TTD) and change from 
baseline (i.e., improvement or deterioration based on presenting symptomatology) in 
each of the patient-reported lung cancer symptom (cough, dyspnea, chest pain) 
score as assessed by the Symptoms in Lung Cancer (SILC) scale (Appendix 9)

To determine the impact of atezolizumab compared with platinum-based 
chemotherapy as measured by TTD in patient-reported lung cancer symptoms of 
cough, dyspnea (multi-item subscale), and chest pain as measured by the European 
Organisation for the Research and Treatment of Cancer (EORTC) Quality-of-Life 
Questionnaire Core (QLQ-C30; see Appendix 7) and supplementary Quality-of-Life 
Questionnaire Lung Cancer Module (QLQ-LC13; see Appendix 8)
2.2
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab compared with 
platinum-based chemotherapy


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
To evaluate the incidence and titers of ATAs against atezolizumab and to explore 
the potential relationship of the immunogenicity response with pharmacokinetics, 
pharmacodynamics, safety, and efficacy
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the pharmacokinetics of atezolizumab 
in chemotherapy-naive patients with Stage IV NSCLC.
2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To evaluate the efficacy of atezolizumab compared with platinum-based 
chemotherapy as measured by OS and investigator-assessed PFS according to 
RECIST v1.1 in patients with PD-L1 expression measured using the 22c3 PD-L1 
IHC assay, but excluding patients with a sensitizing EGFR mutation or ALK 
translocation

To evaluate the efficacy of atezolizumab as measured by PFS rates at 6-month and 
1-year landmark timepoints

To evaluate the efficacy of atezolizumab as measured by OS rate at 3-year
landmark timepoint 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 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 atezolizumab

To evaluate the utility of biopsy at the time of apparent disease progression to 
distinguish apparent increases in tumor volume related to the immunomodulatory 
activity of atezolizumab (i.e., pseudoprogression/tumor immune infiltration) from true 
disease progression

To evaluate and compare patient’s health status as assessed by the 
EuroQoL 5 Dimension, 3 Level (EQ-5D-3L) questionnaire to generate utility scores 
for use in economic models for reimbursement

To determine the impact of atezolizumab compared with platinum-based 
chemotherapy as measured by change from baseline in patient-reported outcomes 
(PROs) of health-related quality of life, lung cancer related symptoms, and 
functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a randomized, Phase III, global, multicenter, open-label study designed to 
evaluate the safety and efficacy of atezolizumab compared with chemotherapy 
consisting of a platinum agent (cisplatin or carboplatin per investigator discretion) 


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combined with either pemetrexed (non-squamous disease) or gemcitabine (squamous 
disease) in PD-L1selected, chemotherapy-naive patients with Stage IV NSCLC.
Figure 1 illustrates the study design.  A schedule of assessments is provided in 
Appendix 1.
Figure 1
Study Schema
AUCarea under the concentrationtime curve; ECOG PSEastern Cooperative Oncology 
Group Performance Status; IVintravenous; NSCLCnonsmall cell lung cancer;
PD-L1programmed deathligand 1; q21devery 21 days; RECIST Response Evaluation 
Criteria in Solid Tumors.
Note:  Gemcitabine is given on Days 1 and 8.
At screening, tumor specimens from each potentially eligible patient will be tested for 
PD-L1 expression by a central laboratory using an IHC assay (see Appendix 6).  
Only patients who are PD-L1 selected (TC1/2/3 or IC1/2/3; corresponding to 1% PD-L1 
expressing TCs and 1% of tumor area occupied by PD-L1 expressing ICs) will be 
enrolled.  Patients with non-squamous disease will be randomized 1:1 to receive either 
atezolizumab alone or pemetrexed in combination with cisplatin or carboplatin.  Patients 


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with squamous disease will be randomized 1:1 to receive either atezolizumab alone or 
gemcitabine in combination with cisplatin or carboplatin.  Randomization will be stratified 
by sex (male vs. female), ECOG Performance Status (0 vs. 1), histology (non-squamous 
vs. squamous), and PD-L1 tumor expression by IHC (TC1/2/3 and any IC vs. TC0 and 
IC1/2/3).
Given the toxicities associated with platinum-based chemotherapies (e.g., neutropenia, 
anemia) and the requirement for pre-medications, this will be an open-label study.  
No crossover will be allowed from the control arm (platinum-based chemotherapy) to the 
experimental arm (atezolizumab).
Atezolizumab (fixed dose of 1200 mg) will be administered intravenously on Day 1 of 
each 21-day cycle.  Atezolizumab treatment may continue as long as patients are 
experiencing clinical benefit as assessed by the investigator (i.e., in the absence of 
unacceptable toxicity or symptomatic deterioration attributed to disease progression as 
determined by the investigator after an integrated assessment of radiographic data, 
biopsy results [if available], and clinical status) or until unacceptable toxicity or death.
During treatment, patients who are treated with atezolizumab and who show evidence of 
clinical benefit will be permitted to continue atezolizumab treatment after RECIST v1.1 
criteria 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 radiographic 
progression per RECIST v1.1
All patients will undergo a mandatory tumor biopsy sample collection, unless not 
clinically feasible as assessed and documented by investigators, at the first evidence of 
radiographic disease progression (within 40 days of radiographic progression or prior to 
the start of the next anti-cancer treatment, whichever is sooner).  These data will be 
used to explore if the radiographic findings are consistent with the presence of tumor or 
if the appearance of progression was caused by pseudoprogression.  In addition, these 
data will be analyzed for the association between changes in tumor tissue and clinical 
outcome and to understand further the potential mechanisms of resistance and 
progression to atezolizumab when compared to such mechanisms after treatment with 
chemotherapy.  This exploratory biomarker evaluation will not be used for any 


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treatment-related decisions.  Patients who are unable to undergo biopsy sample 
collection but otherwise meet criteria listed above may continue to receive atezolizumab.
Patients randomized to receive pemetrexed in combination with either cisplatin or 
carboplatin (non-squamous disease) will receive chemotherapy intravenously on Day 1 
of each 21-day cycle for four or six cycles, followed by maintenance therapy with 
pemetrexed.  Patients randomized to receive gemcitabine in combination with either 
cisplatin or carboplatin (squamous disease) will receive cisplatin or carboplatin 
intravenously on Day 1 and gemcitabine intravenously on Days 1 and 8 of each 21-day 
cycle for four or six cycles, followed by best supportive care.  The intended number of 
cycles planned for the platinum-based induction chemotherapy (i.e., four or six cycles) 
will be specified by the investigator prior to study randomization.  Treatment will continue 
until disease progression, unacceptable toxicity, or death.  Refer to 
Sections 4.3.2.24.3.2.4 for treatment administration details.
All patients will undergo tumor assessment at baseline and every 6 weeks (7 days) for 
48 weeks following Cycle 1, Day 1 regardless of treatment delays.  After the completion 
of the Week 48 tumor assessment, tumor assessment will be required every 9 weeks
(7 days) regardless of treatment delays, 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 discontinue treatment for reasons other than 
radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration) 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 after disease 
progression according to RECIST v1.1), withdrawal of consent, death, or study 
termination by Sponsor, whichever occurs first.  In the absence of radiographic disease 
progression per RECIST v1.1, tumor assessments should continue regardless of 
whether patients start a new anti-cancer therapy.
3.1.1
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will be used to evaluate safety data 
when approximately 50 and 150 patients have received at least two 21-day cycles of 
study therapy, and then every 6 months thereafter until the study data are unblinded or 
the study is terminated by the Sponsor.  Members of the iDMC will be external to the 
Sponsor and will follow a charter that outlines their roles and responsibilities.
All summaries and analyses by treatment arm for the iDMC review will be prepared by 
an independent Data Coordinating Center (iDCC).  The safety data will include 
demographic data, adverse event data (including 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.


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Following the safety data reviews, the iDMC will provide a recommendation to the 
Sponsor as to whether the study may continue, whether amendments to the protocol 
should be implemented, or whether the study should be stopped.  The final decision will 
rest with the Sponsor.
The iDMC will also be responsible for evaluating efficacy data at the pre-specified OS 
interim analysis.  The interim analysis of efficacy data will be conducted in accordance 
with the methods that are specified in the Statistical Analysis Plan (SAP).  The iDMC 
recommendations to stop the study because of substantial evidence of efficacy of the 
study drug or to continue to the final analysis must be based on the specified interim 
analysis stopping guidelines as specified in the iDMC charter. 
Any outcomes of these safety and efficacy reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the Institutional 
Review Boards/Ethics Committees (IRBs/ECs).
3.2
END OF STUDY
The end of the study will occur when all of the following criteria have been met:

The required number of deaths for the final analysis of OS has been observed 
(see Section 6.10.1).

The last patient, last visit has occurred. 
In addition, the Sponsor may decide to terminate the study at any time.  If the Sponsor 
decides to terminate the study, patients who are still receiving study treatment or 
undergoing survival follow-up may be enrolled in an extension study or a 
non-interventional study. 
3.3
RATIONALE FOR STUDY DESIGN
This Phase III study design is based on the assumption that in patients with Stage IV 
NSCLC who are chemotherapy-naive and whose tumors are selected for PD-L1 
expression, treatment with atezolizumab may prolong OS compared with treatment with 
platinum-based chemotherapy.
3.3.1
Rationale for Testing Atezolizumab in PD-L1–Selected Patients 
with NonSmall Cell Lung Cancer
Despite recent improvements in treatment, the prognosis for patients with advanced 
NSCLC remains dismal, with a median OS of approximately 12.5 months 
(Sandler et al. 2006).  Patients who receive second-line treatment for their disease 
have an even more limited prognosis, with 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 impact quality of life.  Therefore, there is a continuing need 
for more efficacious, better tolerated treatments.


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Inhibition of PD-L1/PD-1 signaling has been shown to produce durable responses in 
some patients, and expression of PD-L1 by TCs and/or ICs in several tumor types 
(including NSCLC) correlates with response to therapy (Topalian et al. 2012;
Fehrenbacher et al. 2016).
Data from the Phase Ia Study PCD4989g suggest that tumor PD-L1 status as 
determined by IHC in patients with NSCLC correlates with response to atezolizumab 
(see Section 1.5.3).  In Study GO28753 (POPLAR) and Study GO28915 (OAK), 
improvement in OS was observed with atezolizumab compared with docetaxel in 
previously treatment patients with NSCLC, including patients in the TC1/2/3 or IC1/2/3 
subgroup (Fehrenbacher et al. 2016; Rittmeyer et al. 2017).  In addition, data from 
Study GO28754 (BIRCH) demonstrated a clinically meaningful benefit of atezolizumab 
as first-line treatment for PD-L1selected patients (TC2/3 or IC2/3) with NSCLC, as 
demonstrated by a median OS of 23.5 months (Garassino et al. 2016).  These data 
provide a rationale for evaluating the efficacy of atezolizumab in patients with Stage IV 
NSCLC selected on the basis of tumor PD-L1 expression.
3.3.2
Rationale for Control Arm
3.3.2.1
Rationale for Pemetrexed Combined with Either Cisplatin or 
Carboplatin for Non-Squamous NonSmall Cell Lung Cancer
In the first-line treatment setting for non-squamous NSCLC that does not harbor a driver 
mutation, standard of care is a platinum doublet with either cisplatin or carboplatin and a 
taxane or pemetrexed, with or without bevacizumab.  Furthermore, in the Phase III 
clinical study evaluating pemetrexed maintenance therapy following four cycles of 
platinum-based doublet chemotherapy, pemetrexed significantly improved PFS 
(4.3 vs. 2.6 months) (HR0.50; 95% CI: 0.420.61; p0.0001) and OS 
(13.4 vs. 10.6 months) (HR0.79; 95% CI: 0.650.95; p0.012) when compared with 
placebo (Ciuleanu et al. 2009). This Phase III trial resulted in regulatory approval for 
pemetrexed in non-squamous NSCLC as maintenance therapy of patients with locally 
advanced or metastatic NSCLC whose disease has not progressed after four cycles of 
platinum-based first-line chemotherapy.
On the basis of these results, patients with non-squamous NSCLC in the control group 
will receive the combination of a platinum-based chemotherapy (cisplatin or carboplatin) 
and pemetrexed, which is a standard-of-care regimen for patients with non-squamous 
NSCLC.  This control group will be instrumental in assessing the relative benefit and 
safety of atezolizumab compared with chemotherapy in the front-line treatment setting.
3.3.2.2
Rationale for Gemcitabine Combined with Either Cisplatin or 
Carboplatin for Squamous NonSmall Cell Lung Cancer
In the first-line treatment setting for non-squamous NSCLC that does not harbor a driver 
mutation, standard of care is a platinum doublet with either cisplatin or carboplatin and 
a taxane or pemetrexed, with or without bevacizumab.  However, well-designed 
clinical studies conducted over the last decade have clearly demonstrated that 


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bevacizumab and pemetrexed are not appropriate agents for the treatment of patients 
with squamous-cell carcinoma of the lung (Johnson et al. 2004; Scagliotti et al. 2008; 
Sandler et al. 2009).  The combination of gemcitabine and a platinum agent (either 
cisplatin or carboplatin) has demonstrated efficacy as first-line treatment for squamous 
NSCLC and, as a result, is often a reference arm in clinical trials evaluating new 
therapeutics (see Table 1 in Section 1.2; Schiller et al. 2002; Scagliotti et al. 2008; 
Treat et al. 2010).  Patients with squamous NSCLC in the control group will receive 
gemcitabine combined with either cisplatin or carboplatin, which is a standard-of-care 
regimen for patients with squamous NSCLC.
3.3.3
Rationale for Overall Survival as Primary Endpoint
Recent data suggest that OS may be a more sensitive endpoint for cancer 
immunotherapy than PFS.  For example, in Studies GO28753 (POPLAR) and GO28915
(OAK), an OS benefit was observed in the atezolizumab arm compared with the 
docetaxel arm in the TC1/2/3 or IC1/2/3 subgroup, whereas PFS was similar in the two
treatment arms (Barlesi et al. 2016; Smith et al. 2016).  In Study GO28754 (BIRCH) 
study, the median OS observed in PD-L1selected patients (TC2/3 or IC2/3) with 
advanced NSCLC who received first-line treatment with atezolizumab (Cohort 1) was
favorable compared with data from platinum-based chemotherapy regimens, whereas 
PFS was consistent with data from platinum-based chemotherapy regimens (Garassino 
et al. 2016).  In addition, improvement in OS is generally accepted as the most objective 
and best measure of clinical benefit for patients with advanced lung cancer.  Therefore, 
OS has been selected as the primary endpoint for this study.
3.3.4
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 disease progression (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure (see Section 1.6).  Because of 
the potential for pseudoprogression/tumor immune infiltration, this study will allow 
patients randomized to receive atezolizumab to continue to receive study treatment after 
apparent radiographic progression per RECIST v1.1, 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, biopsy results 
[if available], and clinical status (see Section 3.1).
Although tumor response will be evaluated according to RECIST v1.1 for the efficacy 
endpoints (i.e., PFS, objective response, and DOR), tumor response will also be 
evaluated according to modified RECIST, which allows the incorporation of new lesions 
into the calculation of total tumor burden after baseline and takes into account the 
potential for pseudoprogression/tumor immune infiltration (see Appendix 5).  Tumor 
assessments will be performed according to RECIST v1.1 and modified RECIST for 


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patients in the atezolizumab arm, and only according to RECIST v1.1 for patients in the 
chemotherapy arm.
3.3.5
Rationale for Patient-Reported Outcome Assessments
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on health-related quality 
of life (HRQoL) (Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).
Chest pain, dyspnea, and cough have been regarded as the most frequent and clinically 
relevant disease-related symptoms experienced by patients with NSCLC.  In this study, 
the SILC scale will be used to assess the effect of atezolizumab and platinum-based 
chemotherapy on TTD and change from baseline of specific lung cancer symptoms 
(cough, dyspnea, and chest pain) in patients with Stage IV NSCLC in the first-line setting.
In addition, 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 QLQ-LC13 was consistent with superior PFS, OS, and 
quality-of-life benefits in the erlotinib arm compared with the placebo arm 
(Aaronson et al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  In addition, patients in 
the afatinib LUX-Lung first-line study reported significant delay of TTD in lung cancer 
symptoms (cough, pain, dyspnea) as measured by the EORTC QLQ-C30 and 
QLQ-LC13 (Yang et al. 2013).  In order to assess the HRQoL and symptom severity of 
patients in this study, PRO data will be collected from patients enrolled in this study 
using the validated questionnaires EORTC QLQ-C30 and QLQ-LC13.
Patients will also complete the EQ-5D-3L PRO instrument (see Appendix 10) to 
generate utility scores for use in economic models for reimbursement.
3.3.6
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens for Biomarker Evaluation
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 Studies PCD4989g (Herbst et al. 2014; Horn et al. 2015), 
GO28754 (BIRCH) (Besse et al. 2015), GO28753 (POPLAR) (Fehrenbacher et al. 2016),
GO28625 (FIR) (Spigel et al. 2015), and GO28915 (OAK) (Rittmeyer et al. 2017).  
In this study, archival and/or fresh tumor specimens from patients will be prospectively 
tested for PD-L1 expression by a central laboratory during the prescreening/screening 
period.  Only patients with PD-L1selected tumors (defined by expression of PD-L1 on 
TCs or ICs, corresponding to 1% PD-L1 expressing TCs and 1% of tumor area 
occupied by PD-L1 expressing ICs) will be enrolled.
In addition to the assessment of PD-L1 status, this study will assess a correlation 
between other tumor-based biomarkers and atezolizumab efficacy.  This evaluation of 


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biomarkers may provide evidence for biologic activity of atezolizumab in patients with 
NSCLC, help to identify which patients may benefit most from atezolizumab and help 
future development of alternative diagnostic options.
Other exploratory biomarkers, such as potential predictive and prognostic biomarkers 
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 NGS and to evaluate expression of genes to 
assess their association with efficacy and to identify somatic mutations to increase 
understanding of disease pathobiology.  Methods for the biomarkers analysis may also 
include, but are not limited to, digital polymerase chain reaction (PCR), qRTPCR, and 
proteomics-based approaches.
3.3.7
Rationale for Blood Biomarker Assessments
Exploratory analyses of the POPLAR and OAK studies demonstrated that TMB 
measured by a novel blood-based assay (bTMB) is associated with improved efficacy of 
atezolizumab in 2L+ NSCLC (Gandara et al. 2018).  Importantly, bTMB did not correlate 
with the PD-L1 status by IHC, suggesting that bTMB may represent an additional 
biomarker to identify patients who may derive clinical benefit from single-agent 
atezolizumab.  Based on these findings, OS and PFS will be analyzed in patients with 
defined levels on bTMB (including bTMB 10, bTMB 16, and bTMB 20) as part of the 
secondary analysis. 
Other blood-based biomarkers (including, but not limited to circulating tumor DNA 
[ctDNA]) may be also evaluated and correlated with atezolizumab efficacy, including
evaluation of various predictive cutoffs for novel blood-based assays. This evaluation of 
blood-based markers may provide evidence for biologic activity of atezolizumab in 
patients with NSCLC, help to identify patients who may benefit most from atezolizumab,
and help future development of tissue-free diagnostic options for patients who have 
inadequate quality or insufficient quantity of tumor tissue for biomarker testing. 
Blood samples will be collected at screening and/or baseline, during therapy, and at first 
evidence of radiographic disease progression or loss of clinical benefit in order to better 
understand the changes in blood-based biomarker profiles and potential mechanisms of 
resistance upon progression.  Blood samples may also be evaluated for additional 
exploratory biomarkers that may be associated with the therapeutic effects of 
atezolizumab or the pathogenesis of NSCLC.  Methods for exploratory analysis include, 
but are not limited to, digital PCR, qRTPCR, NGS, immunoassays, and 
proteomics-based approaches.
In addition, potential correlations of these biomarkers with the safety and activity of 
atezolizumab may be explored.  


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3.3.8
Rationale for the Collection of Mandatory Tumor Specimens at 
Radiographic Progression
Anti-tumor immune responses such as those associated with atezolizumab may result in 
objective responses that are delayed and can be preceded by initial apparent 
radiographic progression.  This initial apparent progression may occur as a result of 
either delayed anti-tumor activity and/or robust tumor immune infiltration with a 
concomitant increase in tumor size.  In addition, lesions that would otherwise be 
undetectable with conventional imaging (i.e., micrometastatic disease) may increase in 
size as a result of these processes and be recorded as new lesions (Hales et al. 2010).
A mandatory tumor biopsy will be performed in all patients, if clinically feasible, at the 
time of first radiographic progression, to evaluate the utility of the tissue biopsy in 
distinguishing pseudoprogression/tumor-immune infiltration from true progression.  
In addition, mechanisms relating to progression, resistance, predictive, prognostic, and 
pharmacodynamic relationships in tumor biomarkers (including, but not limited to, PD-L1, 
CD8, mutation status, and others) and efficacy will be evaluated.  DNA and/or RNA 
extraction may be performed to enable NGS to identify somatic mutations that are 
associated with disease progression or acquired resistance to atezolizumab and to 
increase understanding of disease pathobiology.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
3.4.1.1
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is 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 as follows:

PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by the investigator with use of RECIST v1.1, or death 
from any cause, whichever occurs first

Objective response (PR plus CR) as determined by the investigator according to 
RECIST v1.1

DOR, defined as the time from the first occurrence of a documented objective 
response to the time of disease progression, as determined by the investigator with 
use of RECIST v1.1, or death from any cause, whichever occurs first

OS at 1- and 2-year landmark timepoints

TTD and change from baseline (i.e., improvement or deterioration based on 
presenting symptomatology) in each of the patient-reported lung cancer symptoms 
(cough, dyspnea, or chest pain) with use of the SILC scale


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
TTD in patient-reported lung cancer symptoms, defined as time from randomization 
to deterioration (10-point change) in any of the following symptom subscales 
(cough, dyspnea [multi-item scale], and chest pain), whichever occurs first, as 
measured by the EORTC QLQ-LC13

OS and investigator-assessed PFS according to RECIST v1.1 in the PD-L1 (defined 
with SP263 IHC assay) and bTMB subpopulations
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events graded according to the 
NCI CTCAE v4.0

Changes in vital signs, physical findings, and clinical laboratory test results during 
and following atezolizumab 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 as follows:

Maximum serum atezolizumab concentration observed (Cmax) after infusion on 
Day 1 of Cycle 1

Minimum serum atezolizumab concentration observed (Cmin) prior to infusion on 
Day 1 of Cycles 2, 3, 4, 8, 16, and every eighth cycle thereafter, at treatment 
discontinuation, and at 120 (30) days after the last dose of atezolizumab
3.4.4
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

OS and investigator-assessed PFS according to RECIST v1.1 in the PD-L1 
(defined with 22c3 assay) subpopulation

PFS at 6-month and at 1-year landmark timepoints

OS at 3-year landmark timepoint

OS and investigator-assessed PFS according to RECIST v1.1 in subgroups based 
on demographic and baseline characteristics

Status of immune cell infiltrate and other exploratory biomarkers in mandatory 
biopsy specimens collected at progression

Status of PD-L1, immune-, and NSCLC-related and other exploratory biomarkers 
in archival and/or freshly obtained 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

Utility scores of the EQ-5D-3L questionnaire

Change from baseline in PROs of health-related quality of life, lung cancer-related 
symptoms, and functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 150 sites globally will participate in the study, and approximately 
555 PD-L1selected chemotherapy-naive patients with Stage IV NSCLC will be enrolled.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Age 18 years

ECOG Performance Status of 0 or 1 (see Appendix 11)

Histologically or cytologically confirmed, Stage IV non-squamous or 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 histology must be classified as non-squamous or 
squamous based on the major histological component.

No prior treatment for Stage IV non-squamous or squamous NSCLC
Patients known to have a sensitizing mutation in the EGFR gene or an ALK 
fusion oncogene are excluded from the study. 
Patients with non-squamous NSCLC who have an unknown EGFR or ALK 
status will be required to be tested at prescreening/screening.  Patients with 
squamous NSCLC who have an unknown EGFR or ALK status will not be 
required to be tested at prescreening/screening.
EGFR and/or ALK may be assessed locally or at a central lab. Additional tissue 
will be required for central testing of EGFR and/or ALK.

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 chemotherapy, radiotherapy, or chemoradiotherapy 
cycle.

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


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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.

Tumor PD-L1 expression (TC1/2/3 or IC1/2/3; corresponding to 1% PD-L1 
expressing TCs and 1% of tumor area occupied by PD-L1 expressing ICs), as 
determined by an IHC assay performed by a central laboratory on previously 
obtained archival tumor tissue or tissue obtained from a biopsy at screening. 
See Section 4.5.7.1.
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in 
paraffin block (preferred) or 15 or more unstained, freshly cut, serial sections 
(on slides) from an FFPE tumor specimen is required for participation in this 
study.  This specimen must be accompanied by the associated pathology report.
If fewer than 15 slides are available at baseline (but no fewer than 10), the 
patient may still be eligible, upon discussion with the Medical Monitor.
For freshly collected specimens, resections, core needle biopsies, excisional, 
incisional, punch, or forceps biopsies are acceptable.
Fine-needle aspiration (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or cell smears), brushing, cell pellet 
from pleural effusion, and lavage samples are not acceptable.  
Tumor tissue from bone metastases that have been decalcified is not 
acceptable.
For core needle biopsy specimens, preferably, at least three cores embedded 
in a single paraffin block, should be submitted for evaluation.
For patients whose initial archival tumor tissue sample is PD-L1 negative, a 
biopsy can be performed at screening to submit fresh tissue for the purposes of 
testing PD-L1 status.  A positive test result in any tumor tissue sample will 
satisfy this eligibility criterion. 

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can only be considered 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 measureable 
disease

Adequate hematologic and end-organ function, defined by the following laboratory 
test results obtained within 14 days prior to randomization:
ANC 1500 cells/L without granulocyte colony-stimulating factor support
Lymphocyte count 500 cells/L
Platelet count 100,000 cells/L without transfusion


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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 must have 
an INR or aPTT within therapeutic limits for at least 1 week prior to 
randomization.
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 1.5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 60 mL/min

For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement to use a highly effective form(s) of contraception 
during study treatment that results in a low failure rate of <1% per year when used 
consistently and correctly.  Female patients should continue contraception use for 
5 months after the last dose of atezolizumab and for 6 months after the last dose of 
cisplatin.  Women must refrain from donating eggs during this same period.  
Male patients treated with chemotherapy (cisplatin or carboplatin plus pemetrexed 
or gemcitabine) should continue contraception use for 6 months after the last dose
of chemotherapy. Men must refrain from donating sperm during this same period.  
Such methods include combined (estrogen and progestogen containing) hormonal 
contraception, progestogen-only hormonal contraception associated with inhibition 
of ovulation together with another additional barrier method always containing a 
spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 
bilateral tubal occlusion or vasectomized partner (on the understanding that this is 
the only one partner during the entire study duration), and sexual abstinence.
Oral contraception should always be combined with an additional contraceptive 
method because of a potential interaction with the study drug.  The same rules are 
valid for male patients involved in this study if they have a partner of childbearing 
potential.  Male patients must always use a condom.

Women who are not postmenopausal (12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug.
4.1.2
Exclusion Criteria
Patients who meet any of the criteria in the following sections will be excluded from 
study entry.


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4.1.2.1
Cancer-Specific Exclusions

Known sensitizing mutation in the EGFR gene or 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 on 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 enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled or symptomatic hypercalcemia (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)
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 to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation


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
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’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 13 for 
a more comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-related hypothyroidism on 
thyroid-replacement therapy are eligible for this study.
Patients with controlled Type I diabetes mellitus on an insulin regimen are 
eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (i.e., 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 
requiring treatment with either 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 HIV test
All patients must be tested for HIV; patients who test positive for HIV will be 
excluded.

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 [HBc Ab] and absence of 
HBsAg) are eligible.  HBV DNA test must be performed in these patients prior 
to randomization.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction 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


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
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 on 
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 transplantation

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

Patients with illnesses or conditions that interfere with their capacity to understand, 
follow and/or comply with study procedures
4.1.2.3
Exclusion Criteria Related to Medications

Treatment with any approved anti-cancer therapy, including hormonal therapy, 
within 3 weeks prior to initiation of study treatment

Treatment with any other investigational agent with therapeutic intent within 28 days 
prior to randomization

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.

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

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-related adverse effects from antiCTLA-4 
(CTCAE Grade 3 or 4)


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
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is 
longer, prior to randomization
Prior treatment with cancer vaccines is allowed.

Treatment with systemic corticosteroids or other 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 criteria (cisplatin)

CrCl 60 mL/min (cisplatin)

Known hypersensitivity to gemcitabine

History of radiation therapy within 7 days prior to initiating gemcitabine
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 
(including determination of tumor PD-L1 status by central testing), personnel at the study 
site will enter demographic and baseline characteristics in the interactive voice or 
Web-based 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.  Randomization to one of two treatment arms will occur in a 1:1 ratio.
Permuted-block randomization will be applied to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified by the following criteria:

Sex (male vs. female)

ECOG Performance Status (0 vs. 1)

Histology (non-squamous vs. squamous)

Tumor tissue PD-L1 expression by IHC TC1/2/3 and any IC vs. TC0 and IC1/2/3)


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Patients should receive their first dose of study treatment on the day of randomization if 
possible.  If this is not possible, the first dose should occur within 5 days after 
randomization.
4.3
STUDY TREATMENT
Patients with non-squamous disease will receive either atezolizumab alone or 
pemetrexed in combination with cisplatin or carboplatin.  Patients with squamous 
disease will receive either atezolizumab alone or gemcitabine in combination with 
cisplatin or carboplatin.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab (MPDL3280A)
The atezolizumab (MPDL3280A) drug product is provided by the Sponsor as a sterile 
liquid in a single-use, 20-mL glass vial.  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
Cisplatin, Carboplatin, Pemetrexed, and Gemcitabine
Cisplatin, carboplatin, pemetrexed, and gemcitabine will be used in commercially 
available formulations.  For information on the formulation, packaging, and handling of 
cisplatin, carboplatin, pemetrexed, and gemcitabine, see the local prescribing 
information for each drug.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in Section 5.3.5.12.
Guidelines for atezolizumab treatment interruption or discontinuation for patients who 
experience adverse events are provided in Section 5.1.6 and Appendix 14.
4.3.2.1
Atezolizumab
Patients who are randomized to be treated with atezolizumab will receive 1200 mg 
atezolizumab administered by IV infusion q21d in a monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.
Atezolizumab infusions will be administered per the instructions outlined in Table 11.


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Table 11 Administration of First and Subsequent Infusions 
of Atezolizumab
First Infusion
Subsequent Infusions

No pre-medication is allowed.

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 intravenous infusion 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, 
pre-medication 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, continue 
subsequent infusions 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) during the infusion if 
clinically indicated or if 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 if 
patient experienced symptoms during 
previous infusion.
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 and Section 5.1.7, and Appendix 14.
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, 
and administration.


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4.3.2.2
Pemetrexed in Combination with Cisplatin or Carboplatin
(Patients with Non-Squamous NonSmall Cell Lung Cancer
Only)
Each study site will administer pemetrexed (non-squamous NSCLC) in combination 
with platinum-based chemotherapy (cisplatin or carboplatin) for four or six cycles.  
The intended number of chemotherapy induction cycles (four or six cycles) will be 
specified by the investigator prior to randomization.  The selected platinum 
chemotherapy agent should remain the same for all cycles (e.g., patients who start on 
pemetrexed plus cisplatin should remain on this combination and not switch to 
pemetrexed pluscarboplatin or vice versa).  However, for patients who experience
unacceptable toxicity with the selected platinum chemotherapy, a switch may be 
considered after discussion with and approval by the Medical Monitor.
Patients should receive steroid, folic acid, and vitamin B12 premedication for 
pemetrexed. The choice of steroid and timing of premedication can be administered 
according to the local standard of care and prescribing information (see Table 12 and 
Section 5.1.8). Folic acid supplementation may be started before randomization in all 
patients at the discretion of the investigator to meet the local standard of care in 
anticipation for pemetrexed-based treatment and then discontinued in patients assigned 
to the atezolizumab arm after randomization.  In addition, patients should receive 
anti-emetic and IV hydration for platinum-based treatments according to the local 
standard of care and prescribing information.  
Table 12 lists the suggested premedication for pemetrexed plus platinum-based 
chemotherapy and Table 13 lists the doses that will be used and the suggested infusion 
times for pemetrexed plus platinum-based chemotherapy. Chemotherapy infusion times 
may be adapted in accordance with local standard of care.
Table 12 Premedication for Pemetrexed plus Platinum-Based 
Chemotherapy
Premedication
Dose/Route
Timing
Folic acid
350–1000 g PO
Once daily beginning 5–7 days before Cycle 1, Day 1, and 
continuing until 3 weeks after discontinuation of 
pemetrexed or as per local standard of care.
Vitamin B12
1000 g IM
q9w beginning Cycle 1, Day 1, and continuing until 
3 weeks after discontinuation of pemetrexed or as per 
local standard of care. 
Dexamethasone
(suggested)
4 mg PO
Twice daily the day prior to, the day of, and the day after 
each infusion of pemetrexed or as per local standard of 
care.
IMintramuscular; PO oral; q9wevery 9 weeks.
Note:  Prophylactic anti-emetics per local practice.


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Table 13 Treatment Regimen for Pemetrexed plus Platinum-Based 
Chemotherapy
Study Drug
Dose/Route
Induction Period 
(Four or Six Cycles)
Maintenance Period 
(Until PD)
Pemetrexed
500 mg/m2 IV
Over ~10 minutes on Day 1 q21d
Over approximately 
10 minutes on Day 1 q21d
Carboplatin
AUC 6 a IV
Over ~3060 minutes on Day 1 q21d
Not applicable
OR
Cisplatin
75 mg/m²
Over 1–2 hours on Day 1 q21d
Not applicable
AUCarea under the concentration-time curve; IVintravenous; PDprogressive disease; 
q21devery 21 days.
a See Section 4.3.2.4 for details on dose calculation of carboplatin.
Pemetrexed will be administered by IV infusion at a dose of 500 mg/m2 on Day 1 of each 
21-day cycle, followed by carboplatin or cisplatin at approximately 30 minutes after the 
completion of pemetrexed.  Patients who do not experience disease progression per 
RECIST v1.1 after completing (four or six cycles of) induction treatment, will continue 
maintenance treatment with pemetrexed, given on Day 1 of each 21-day cycle until 
disease progression per RECIST v1.1. All patients eligible for pemetrexed therapy 
should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) for at least 2 days 
prior to pemetrexed administration if the NSAID has a short elimination half-life, for 
at least 5 days prior to pemetrexed administration if the NSAID has a long elimination 
half-life, on the day of pemetrexed administration, and at least 2 days following 
pemetrexed administration.
Guidelines for dose modification and treatment interruption or discontinuation are
provided in Section 5.1.8 for pemetrexed, Section 5.1.10 for cisplatin, and Section 5.1.11
for carboplatin.  
4.3.2.3
Gemcitabine in Combination with Cisplatin or Carboplatin
(Patients with Squamous NonSmall Cell Lung Cancer Only)
Each study site will administer gemcitabine (squamous NSCLC) in combination 
with platinum-based chemotherapy (cisplatin or carboplatin) for four or six cycles.  
The intended number of chemotherapy induction cycles (four or six cycles) will be 
specified by the investigator prior to randomization.  The selected platinum 
chemotherapy agent should remain the same for all cycles (e.g., patients who start on 
gemcitabine plus cisplatin should remain on this combination and not switch to 
gemcitabine pluscarboplatin or vice versa).  However, for patients who experience 
unacceptable toxicity with the selected platinum chemotherapy, a switch may be 
considered after discussion with and approval by the Medical Monitor.


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Patients should receive anti-emetic therapy and IV hydration for platinum-based 
treatments according to the local standard of care and prescribing information.  Table 14
lists the doses that will be used and the suggested infusion times for gemcitabine plus 
platinum-based treatments. Chemotherapy infusion times may be adapted in 
accordance with local standard of care. 
Table 14 Treatment Regimens for Gemcitabine plus Platinum-Based 
Chemotherapy
Chemotherapy
Dose/Route
Treatment
(Four or Six Cycles)
Gemcitabine
1250 mg/m2 IV
Over 30 minutes on Days 1 and 8 q21d
Cisplatin
75 mg/m2 IV 
Over 12 hours on Day 1 q21d
Gemcitabine
1000 mg/m2 IV
Over 30 minutes on Days 1 and 8 q21d
Carboplatin
AUC 5 IV
Over approximately 30–60 minutes on Day 1 
q21d
AUCarea under the concentration curve; IVintravenous; q21devery 21 days.
Gemcitabine will be administered by IV infusion at a dose of 1250 mg/m2 (in combination 
with cisplatin) or 1000 mg/m2 (in combination with carboplatin) over 30 minutes on Days 1 
and 8 of each 21-day cycle followed by cisplatin or carboplatin at approximately 30 minutes 
after the completion of gemcitabine infusion on Day 1 only.
Gemcitabine injection must be diluted prior to infusion.  The recommended diluent for 
reconstitution of gemcitabine is 0.9% sodium chloride injection without preservatives. 
The administration of gemcitabine should be done in accordance with local practice and 
the prescribing information; sites should follow their institutional standard of care for 
determining the gemcitabine dose for obese patients and for dose adjustment in the 
event of patient weight changes.
Guidelines for dose modification and treatment interruption or discontinuation are
provided in Section 5.1.9 for gemcitabine, Section 5.1.10 for cisplatin, and 
Section 5.1.11 for carboplatin. 
4.3.2.4
Cisplatin or Carboplatin Administration
Each site will choose to treat a given patient with either cisplatin or carboplatin according 
to local practice.
Cisplatin
Cisplatin should be administered by IV infusion approximately 30 minutes after 
completion of the pemetrexed or gemcitabine infusion at a dose of 75 mg/m² over 
12 hours as per Table 13 or Table 14, respectively.  Patients must receive adequate 
anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin.


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Refer to local clinical practice guidelines for further details.
Carboplatin
Carboplatin should be administered by IV infusion at a dose of AUC 6 when given in 
combination with pemetrexed (see Table 13) or at a dose of AUC 5 when given in 
combination with gemcitabine (see Table 14), after completion of the pemetrexed or 
gemcitabine infusion, with standard anti-emetics per local practice guidelines.
The carboplatin dose 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 
NOTE:  For patients with an abnormally low serum creatinine level, estimate GFR using 
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 on the basis of 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 caused by overdosing.  On the basis of 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 125 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.


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Refer to the FDA’s communication regarding carboplatin dosing for more details at 
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm.
4.3.3
Investigational Medicinal Product Accountability
The IMPs for this study are atezolizumab, pemetrexed, gemcitabine, carboplatin, and 
cisplatin.  IMPs required for completion of this study will be provided by the Sponsor or 
appointed designee if required by local health authority regulations.  The study site will 
acknowledge receipt of atezolizumab with use of the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or 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
Patients may continue to receive atezolizumab as part of an extension study.  
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 
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, herbal or homeopathic remedies, nutritional supplements) used by a patient in 
addition to protocolspecified study treatment 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.


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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 or symptomatic 
relief of pain) provided it does not interfere with the assessment of tumor target 
lesions (e.g., the lesion to be 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 

Corticosteroids (10 mg oral prednisone or equivalent) 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, as 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 as per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local practice).  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 12).
All concomitant medications must be recorded on the appropriate Concomitant 
Medications electronic Case Report Form (eCRF).  Protocol-specified study treatments, 
including maintenance treatment with pemetrexed, should not be recorded as 
concomitant medications.
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 


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whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance; see 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.
Refer to Appendix 14 for additional information on the management of adverse events 
associated with atezolizumab.
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 the patient has 
discontinued study treatment.  This includes but is not limited to chemotherapy, 
hormonal therapy, immunotherapy, radiotherapy, non-approved experimental agents, or 
herbal therapy (unless otherwise noted). 
The following medications are prohibited during the study, unless otherwise noted:

Denosumab; patients who are receiving denosumab prior to enrollment must be 
willing and eligible to receive a bisphosphonate instead while in the study. 

Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to randomization, 
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 of the chest and non-contrast CT or MRI scans of 
the abdomen and pelvis should be performed. 
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
The Schedules of 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.


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If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits rescheduled accordingly.
4.5.1
Informed Consent Forms and Prescreening/Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations and may be obtained more 
than 28 days before initiation of study treatment.
Prior to signing the main consent form for the study, patients may specifically allow for 
the collection and testing of archival or fresh tumor tissue by signing the prescreening 
consent form.  Patients may also allow for central evaluation of their tissue for EGFR
and/or ALK status. 
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 
prescreening/screening log to record details of all patients prescreened/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 per RECIST v1.1 at a tumor response evaluation and are eligible and willing 
to continue treatment with atezolizumab must sign consent at that time to acknowledge 
deferring other treatment options in favor of continuing treatment with atezolizumab.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, non-NSCLC cancer 
history (including prior cancer therapies and procedures), reproductive status, smoking 
history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, 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 with non-squamous disease who were 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
prescreening or screening period.  If EGFR mutations or ALK status testing is performed 
locally, additional tumor sections may be required for central evaluation of the mutational 
status of these genes.  Please review tissue requirements for central evaluation in the 
central laboratory instruction manual. 


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Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination, according to local practice, should be performed at 
screening.  Any abnormality identified at screening should be recorded on the General 
Medical History and Baseline Conditions eCRF.
At subsequent visits, 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 pulse rate, respiratory rate, systolic and 
diastolic blood pressures, and temperature.  Vital signs will be measured and recorded
at screening and as described in Table 15.
Table 15 Vital Sign Measurements at Cycle 1 and All Subsequent Cycles
Cycle 1
Treatment Arm
Timepoints
Atezolizumab
Within 60 minutes prior to atezolizumab infusion
During the infusion (every 15 [5] minutes) and within 30 (10) minutes after 
atezolizumab infusion, if clinically indicated
Chemotherapy
Within 60 minutes prior to pemetrexed or gemcitabine infusion
As clinically indicated prior to, during, or after cisplatin or carboplatin infusion
Subsequent Cycles
Treatment Arm
Timepoints
Atezolizumab 
or 
chemotherapy
Within 60 minutes prior to infusion
During the infusion if clinically indicated or if symptoms occurred during the prior 
infusion 
Within 30 (10) minutes after infusion if clinically indicated or if symptoms 
occurred during the prior infusion
For patients in the atezolizumab arm, refer to Table 11.
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.


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A CT (with contrast) or MRI scan of the head must be done at screening to evaluate 
CNS metastasis in all patients.  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 this study 
(see Section 4.1.2.1 for CNS-related exclusions).
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for 
a full-contrast diagnostic CT scan.
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 a history of irradiated brain metastases at
screening are not required to undergo 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 through use of 
RECIST v1.1 (see Appendix 4) and modified RECIST (see Appendix 5).  Tumor 
assessments will be performed according to RECIST v1.1 and modified RECIST for 
patients in the atezolizumab arm, and only according to RECIST v1.1 for patients in the 
chemotherapy arm.  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 will be performed every 6 weeks (7 days) for 48 weeks following 
Cycle 1, Day 1, and then every 9 weeks (7 days) after the 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 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.  At the investigator’s discretion, CT scans should be 
repeated at any time if progressive disease is suspected.
Patients who discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) 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), 


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withdrawal of consent, death, or study termination by Sponsor, whichever occurs first.  
In the absence of radiographic disease progression per RECIST v1.1, tumor 
assessments will continue regardless of whether patients start a new anti-cancer therapy.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (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 (if considered standard of care for 
the region), calcium, phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, 
LDH, total protein, and albumin)

Coagulation (INR or aPTT)

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed on Day 1 of each 
cycle during treatment prior to administration of study treatment.  A serum 
pregnancy test must be performed if the urine pregnancy test result is positive. 
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/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 [TSH], free T3, free T4)
Total T3 will be tested only at sites where free T3 is not performed.

HBV serology:  HBsAg, antibodies against HBsAg, total hepatitis B core antibody 
(HBcAb)
HBV DNA test must be performed prior to randomization if patient has a 
negative serology for HBsAg and a positive serology for HBcAb.

HCV serology:  hepatitis C virus antibody (anti-HCV)
HCV RNA test results must be obtained prior to randomization if patient tests 
positive for anti-HCV.

HIV testing
All patients will be tested for HIV prior to the inclusion into the study and 
patients who are HIV-positive will be excluded from the clinical study.


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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 (patients assigned to atezolizumab only)
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 assay (patients assigned to atezolizumab only)
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.

Biomarker assays
Blood samples will be obtained for biomarker evaluation (including, but not 
limited to PD-L1, PD-1, mutational load, and other 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 plasma 
and serum for the determination of changes in blood-based biomarkers 
(e.g., ctDNA).  Whole blood samples may be processed to obtain their 
derivatives (e.g., RNA and DNA) and may be evaluated for immune-related, 
tumor typerelated, and other exploratory biomarkers (e.g., alterations in gene 
expression or single nucleotide polymorphisms).

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 4.5.12.  
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 4.5.12.
Refer to the laboratory manual for additional details on laboratory assessments and 
sample handling.
4.5.7
Tumor Tissue Samples
A central laboratory will coordinate the sample collection of tissue 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.
Refer to the laboratory manual for additional details on tissue sample handling.


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4.5.7.1
Archival and Freshly Collected Tumor Tissue Samples for 
Screening
Representative tumor specimens in paraffin blocks (preferred) or 15 (or more) freshly cut, 
serial unstained sections (on slides) with an associated pathology report must be 
submitted for determination of PD-L1 status to ensure patient meets eligibility criteria 
prior to randomization.  If fewer than 15 slides are available at baseline (but no fewer 
than 10), the patient may still be eligible, upon discussion with the Medical Monitor.
In addition, expression of PD-L1 defined by the SP263 IHC assay will be evaluated.  
Exploratory biomarkers (including, but not limited to PD-L1, PD-1, mutational load, and 
other biomarkers related to immune or NSCLC biology, such as T-cell biomarkers or 
non-inherited biomarkers identified through NGS on extracted DNA and/or RNA) may
also be evaluated. For patients with non-squamous NSCLC, EGFR and/or ALK status if 
unknown may be assessed locally or at a central lab.  Additional tissue will be required 
for central testing of EGFR and/or ALK. 
Tumor tissue should be of good quality based on total and viable tumor content 
(sites will be informed if the quality of the submitted specimen is inadequate to determine 
tumor PD-L1 status).
An archival tumor specimen should be submitted if available.  If an archival specimen is 
not available, the patient may still be eligible, with the assumption that the patient is 
willing to consent to and undergo a pre-treatment biopsy or resection of the tumor.  
For freshly collected biopsy specimens, acceptable samples include those outlined 
below, provided there is a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method:

Core needle biopsy sample collection for deep tumor tissue; at least three cores, 
embedded into a single paraffin block, should be submitted for evaluation

Excisional, incisional, punch, or forceps biopsy sample collection for cutaneous, 
subcutaneous, or mucosal lesions

Tumor tissue resections
Fine-needle aspiration (defined as samples that do not preserve tissue architecture and 
yield cell suspension and/or cell smears), brushing, cell pellets from pleural effusion, and 
lavage samples are not acceptable.
Tumor tissue from bone metastases that have been decalcified is not acceptable.
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.


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4.5.7.2
Tumor Samples at the Time of Radiographic Progression
Patients in all treatment arms will undergo a mandatory tumor biopsy to obtain a tumor 
sample, unless not clinically feasible, at the time of radiographic disease progression 
(within 40 days of radiographic progression or prior to the start of the next anti-cancer 
treatment, whichever is sooner).
Acceptable samples include those outlined below: 

Core needle biopsy sample collection for deep tumor tissue; at least three cores, 
embedded into a single paraffin block, should be submitted for evaluation

Excisional, incisional, punch, or forceps biopsy 

Tumor tissue resection
The status of immune-related, tumor typerelated and other exploratory biomarkers 
(including, but not limited to, T-cell biomarkers and non-inherited biomarkers identified 
through NGS on extracted DNA and/or RNA) in tumor tissue samples may be evaluated.
NGS may be performed by Foundation Medicine. If performed by Foundation Medicine, 
the investigator can obtain results from the samples collected at the time of disease 
progression in the form of an 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) are preferred.  
Tissue samples obtained at multiple times from individual patients will greatly contribute 
to an improved understanding of the dynamics of PD-L1 expression and relationship 
with intervening anti-cancer therapy.


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4.5.8
Use and Storage of Remaining Samples from Study-Related 
Procedures
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and PK and immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed, or earlier 
depending on local regulations.

Blood and tumor tissue samples collected for biomarker research will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed, or 
earlier depending on local regulations.
4.5.9
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 
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 utilize 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 may include an assessment of whether detected 
ATA responses correlate with relevant clinical endpoints.  Implementation of 
ATA characterization assays will depend on the safety profile and clinical 
immunogenicity data.
4.5.10
Electrocardiograms
A twelve-lead ECG is required at screening and when clinically indicated.  ECGs for 
each patient should be obtained from the same machine wherever possible.  Lead 
placement should be as consistent as possible.  ECG recordings must be performed 
after the patient has been resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.11
Patient-Reported Outcomes
PRO data will be collected via the SILC, EORTC QLQ-C30, QLQ-LC13, and EQ-5D-3L 
questionnaires to more fully characterize the clinical profile of atezolizumab.


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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/or instructions for completing the PRO questionnaires electronically will be 
provided by the investigator staff.  The data will be transmitted via a pre-specified 
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 SILC scale (see Appendix 9) will be used to assess patient-reported severity of lung 
cancer symptoms (cough, dyspnea, and chest pain).  The SILC scale is a nine-item 
content valid self-report measure of lung cancer symptoms.  It measures severity of 
cough, dyspnea, and chest pain with a total symptom severity score.  This questionnaire 
will be completed using an ePRO device at the patient’s home on a weekly basis, then 
monthly during survival follow-up for 6 months following 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).  
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/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.  
The EORTC QLQ-C30 module takes approximately 10 minutes to complete.  This 
questionnaire will be completed on the ePRO tablet at the site according to the tumor 
assessment schedule during the study treatment period (i.e., every 6 weeks (7 days) 
for 48 weeks following Cycle 1, Day 1, and every 9 weeks (7 days) thereafter after the 
completion of the Week 48 tumor assessment 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). During survival follow-up, the questionnaire will be completed at 3 and 
6 months following 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) if the patient returns
to the clinic. 
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, 


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dysphagia, peripheral neuropathy, alopecia, and hemoptysis.  The QLQ-LC13 module 
takes approximately 5 minutes to complete.  This questionnaire will be completed on the 
ePRO tablet at the site according to the tumor assessment schedule during the study 
treatment period (i.e., every 6 weeks (7 days) for 48 weeks following Cycle 1, Day 1, 
and every 9 weeks (7 days) thereafter after the completion of the Week 48 tumor 
assessment 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). During survival 
follow-up the questionnaire will be completed at 3 and 6 months following 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) if the patient returns to the clinic.
The EQ-5D-3L is a generic, preference-based health utility measure with questions 
about mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that is 
used to build a composite of the patient’s health status (see Appendix 10).  The 
EQ-5D-3L will be utilized in this study for economic modeling.  This questionnaire will be 
completed on the ePRO tablet at the site according to the tumor assessment schedule
during the study treatment period (i.e., every 6 weeks (7 days) for 48 weeks following 
Cycle 1, Day 1, and every 9 weeks (7 days) thereafter after the completion of the 
Week 48 tumor assessment 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). 
During survival follow-up, the questionnaire will be completed at 3 and 6 months 
following 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) if the patient returns to 
the clinic.  
Patients who discontinue study treatment for any reason other than 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) will complete the EORTC QLQ-C30, EORTC QLQ-LC13, and 
EQ-5D-3L at each tumor assessment visit and will complete the SILC at home on a 
weekly basis, until 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), unless the patient 
withdraws consent or the Sponsor terminates the study, whichever occurs first.
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported as outlined in Section 5.3.5.12.


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Patients whose native language is not available on the ePRO device or who are deemed 
by the investigator incapable of inputting their ePRO assessment after undergoing 
appropriate training are exempted from completing all ePRO assessments.
4.5.12
Samples for Roche Clinical Repository
4.5.12.1
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
4.5.12.2
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/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 4.5.12) will not be applicable at that site.
4.5.12.3
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 and specimen collection 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 will undergo additional 
processes to ensure confidentiality, as described below.
4.5.12.4
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.
4.5.12.5
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.
4.5.12.6
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.  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 trial 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 specimens 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 GO29431 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 GO29431.
4.5.12.7
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.
4.5.13
Timing of Assessments
4.5.13.1
Screening/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.
4.5.13.2
Assessments during Treatment
All treatment visits must occur within 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 and visits 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 four or six cycles of pemetrexed or gemcitabine combined with a 
platinum agent (for patients in the control arm) or after five cycles (for patients in the 
atezolizumab arm), one of three cycles may be delayed by 1 week (28 days instead 
of 21 days for one cycle) to allow for vacations/holidays.  Following the delay, the 
next cycle must be delivered 21 days from the previous dose administration.  
Two consecutive 28-day cycles are not permitted.
If a dose modification is required due to toxicity, refer to Section 5.1.
Tumor assessments will occur every 6 weeks (7 days) for 48 weeks following Cycle 1, 
Day 1, and 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 (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 discontinue treatment for reasons other 
than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration) will continue scheduled tumor assessments until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients 


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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.  In the absence of radiographic disease progression per 
RECIST v1.1, tumor assessments will continue regardless of whether patients start a 
new anti-cancer therapy.
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. 
Local hematology tests must also be performed prior to gemcitabine infusions on Day 8. 
See Appendix 1 for the schedule of assessments performed during the treatment period 
and Appendix 2 for the schedule of PK, ATA, and biomarker sampling.
4.5.13.3
Assessments at Treatment Discontinuation Visit
Patients who discontinue study treatment will return to the clinic for a treatment 
discontinuation visit within 30 days after the last dose of study treatment.  The visit at 
which a response assessment shows radiographic disease progression according to 
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) may be used as the treatment discontinuation visit.
See Appendix 1 and Appendix 2 for assessments to be performed at the treatment 
discontinuation visit.
Patients who discontinue study treatment must be followed according to the follow-up 
visit schedule for progression and/or survival until death, loss to follow-up, or withdrawal 
of consent, which will be defined as study discontinuation.
4.5.13.4
Follow-Up Assessments
After the Treatment 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 
disease progression per RECIST v1.1, tumor assessments will continue at the same 
frequency as would have been followed if the patient had continued study treatment until 
radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who had continued treatment with atezolizumab after 


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radiographic 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 will 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 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.
Follow-up data collection will also include ePROs (only for the first 6 months after 
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); SILC will be completed monthly for 6 months 
using an ePRO device at the patient’s home and EORTC QLQ-C30, EORTC QLQ-LC13, 
and EQ-5D-3L will be completed at the site on the ePRO tablet at 3 and 6 months after 
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) if the patient returns to the clinic. Patients who 
discontinue study treatment for any reason other than disease progression per 
RECIST v1.1 will complete the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L at 
each tumor assessment visit and will complete the SILC at home on a weekly basis, until 
radiographic disease progression per RECIST v1.1 as determined by the investigator,
unless the patient withdraws consent or the Sponsor terminates the study.
Adverse events will be followed as described in Section 5.5.
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 the 
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 assessments to be performed during Follow-Up 
visits.
4.5.13.5
Assessments at Unscheduled Visits
Assessments for unscheduled visits related to a patient’s underlying NSCLC, study 
treatment, or adverse events should be performed as clinically indicated and entered 
into Unscheduled Visit eCRFs.


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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
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results
[if available], 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 study treatments

Any medical condition that may jeopardize the patient’s safety if he or she continues 
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-treated patients only:  patients will be permitted to 
continue atezolizumab treatment after RECIST v1.1 criteria for disease progression 
are met if they meet all of the following criteria (see Figure 2
below 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 that can be attributed to disease 
progression


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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 other treatment 
options in favor of continuing atezolizumab treatment at the time of initial 
progression
Availability of 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 drug discontinuation should be documented on the 
appropriate eCRF.
Figure 2
Criteria for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size (Atezolizumab Arm Only)
ECOG PSEastern Cooperative Oncology Group Performance Status; RECIST Response 
Evaluation Criteria in Solid Tumors.


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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 Council 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
The following information is based on results from nonclinical and clinical studies for 
atezolizumab 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 monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.  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 until the 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 


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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).  The potential safety issues 
anticipated in this trial, as well as measures intended to avoid or minimize such toxicities, 
are outlined in the following sections.
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 
Appendix 14 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
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, refer to the pemetrexed 
prescribing information.
5.1.3
Risks Associated with Gemcitabine
Gemcitabine infusion times that are longer than 60 minutes or gemcitabine 
administration that occurs more frequently than once a week have been shown to 
increase toxicity. Pulmonary toxicity has been reported with the use of gemcitabine.  
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia has been 
reported with gemcitabine as a single agent or in combination with other cytotoxic drugs.  
Hemolytic-uremic syndrome and/or renal failure have been reported following one or 
more doses of gemcitabine.  Renal failure leading to death or requiring dialysis, despite 
discontinuation of therapy, has been rarely reported.  Serious hepatotoxicity, including 
liver failure and death, has been reported very rarely in patients receiving gemcitabine 
alone or in combination with other potentially hepatotoxic drugs.
Patients will be monitored for gemcitabine-related adverse events. For more details 
regarding the safety profile of gemcitabine, refer to the gemcitabine prescribing 
information.


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5.1.4
Risks Associated with Platinum-Based Chemotherapy
5.1.4.1
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, refer to the cisplatin prescribing 
information.
5.1.4.2
Risks Associated with Carboplatin Chemotherapy
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 carboplatin 
prescribing information.
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 and Appendix 2 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, 5.3.5.8, 5.5, and 5.6.


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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 
considers it is appropriate.  For example, if a patient has Grade 1 asthenia at 
baseline that increases to Grade 2 during study treatment, this will be considered a 
shift of one grade and treated as Grade 1 toxicity for dose-modification purposes.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.

If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one component of chemotherapy, the dose of the other chemotherapy component
does not require modification and the other chemotherapy component(s) may be 
administered if there is no contraindication.  

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 Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment with atezolizumab 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 105 days beyond the last dose, then the 
patient will be discontinued from atezolizumab treatment and will be followed for safety 
and efficacy as specified in Section 5.2.1.  Exceptions require Medical Monitor approval.
If a patient must be tapered off steroids used to treat adverse events, atezolizumab may 
be withheld for additional time 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 reasons other than toxicity, such as surgical procedures, may be 
allowed with Medical Monitor approval.  The acceptable length of interruption will depend 
on agreement between the investigator and the Medical Monitor.


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5.1.7
Management of Atezolizumab-Specific Adverse Events
Refer to Appendix 14 for details on management of atezolizumab-specific adverse 
events.  Refer to Appendix 12 for precautions for anaphylaxis.
5.1.8
Pemetrexed Dose Modifications, Treatment Delays, or 
Treatment Discontinuation 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.
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 American Society of 
Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) 
guidelines (Smith et al. 2006; LitRef_National_Comprehensive_Cancer_Ne2NCCN 
2014).  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 16).
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.  
Table 16 Pemetrexed Dose Modifications for Hematologic Toxicities
Toxicity a
Pemetrexed Dose 
ANC 500/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.


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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 can then be resumed.
No dose reductions are recommended for anemia.  Patients should be supported per 
institutional guidelines.
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 (1976) 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 17), 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 17.  For 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 17 Pemetrexed Dose Modifications 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 
Grade 3 or 4
75% of previous dose
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 5 to 7 days preceding the first dose of 
pemetrexed or as per local standard of care, but not later than Cycle 1, Day 1.

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.


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For more details regarding pemetrexed dose modification, refer to the pemetrexed 
prescribing information.
5.1.9
Gemcitabine Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events
The dose modification guidelines for gemcitabine are provided below.  
Treatment with gemcitabine 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.
5.1.9.1
Hematologic Toxicities
Gemcitabine dose modifications for hematologic toxicity should be based on the 
granulocyte and platelet counts taken on Days 1 and 8 of treatment (Table 18 and 
Table 19).  Patients receiving gemcitabine should be monitored prior to each dose with a 
full blood count, including differential and platelet counts. 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; 
LitRef_National_Comprehensive_Cancer_Ne2NCCN 2014).  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 16).
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.  
Table 18 Gemcitabine Dose Modifications or Treatment Delays for 
Hematologic Toxicities on Day 1
Absolute Granulocyte Count
(106/L)
Platelet Count
(106/L)
Gemcitabine
% of Full Dose
1500
and
100,000
100%
1500
or
100,000
Withhold


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Table 19 Gemcitabine Dose Modifications or Treatment Delays for 
Hematologic Toxicities on Day 8
Absolute Granulocyte Count
Platelet Count
Gemcitabine
% of Full Dose
1000/L
and
100,000/L
100%
500999/L
or
50,00099,999/L
75%
500/L
or
50,000/L
Withhold
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 can then be resumed.
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines.
5.1.9.2
Non-Hematologic Toxicities
In general, for Grade 3 or 4 non-hematologic toxicities, gemcitabine should be withheld 
or dose reduced by 50%, according to investigator’s clinical judgment.
Permanent discontinuation should be considered for any of the following events:

Unexplained dyspnea or other evidence of severe pulmonary toxicity

Severe hepatic toxicity

Hemolytic-uremic syndrome

Capillary-leak syndrome

Posterior reversible encephalopathy syndrome
Table 20 provides dose modification guidelines for non-hematologic toxicities.


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Table 20 Gemcitabine Dose Modifications, Treatment Delays, or Treatment 
Discontinuation and Patient Management for Grade 2, 3, or 4 
Non-Hematologic Toxicities
Grade 2
Grade 3
Grade 4
First appearance 
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
same dose with 
prophylaxis where 
possible. 
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
75% of original dose 
with prophylaxis where 
possible.
Discontinue treatment 
unless considered it to be 
in the best interest of the 
patient to continue at 50% 
of original dose, once 
toxicity has resolved to 
Grade 1 or better.
Second 
appearance of 
same toxicity 
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
75% of original dose.
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
50% of original dose.
Third appearance 
of same toxicity 
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
50% of original dose.
Discontinue treatment 
permanently.
Fourth 
appearance of 
same toxicity
Discontinue treatment 
permanently.
5.1.10
Cisplatin Dose Modifications, Treatment Delays, or Treatment 
Discontinuation and Management of Specific Adverse Events
The dose modification guidelines for cisplatin are provided below.  
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 treatment is 
delayed for more than 63 days due to toxicities.
5.1.10.1
Hematologic Toxicities
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 American Society of 
Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) 
guidelines (Smith et al. 2006; NCCN 2014).  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 21).
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.


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Table 21 Cisplatin Dose Modifications for Hematologic Toxicities
Toxicity a
Cisplatin Dose 
ANC 500/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 can then be resumed.
No dose reductions are recommended for anemia. Patients should be supported per 
institutional guidelines.
5.1.10.2
Non-Hematologic Toxicities
If a patient develops a non-hematologic toxicity (see Table 22), cisplatin should be 
withheld for up to 63 days until resolution to less than or equal to 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 22.
Diarrhea should be controlled with adequate anti-diarrhea medication. Nausea and/or 
vomiting should be controlled with adequate anti-emetics.  
Table 22 Cisplatin Dose Modifications 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 antiemetics.


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Nephrotoxicity
CrCl must be 60 mL/min prior to the start of any cycle of cisplatin.  If there is a 
decrease in CrCl between cycles, but the CrCl is still 60 mL/min at the time of the next 
cycle, the investigator should use 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 should be discontinued 
from cisplatin.
Neurotoxicity
In the event of neurotoxicity, the recommended dose adjustment for cisplatin is 
documented in Table 23.  For 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 23 Cisplatin Dose Modifications or Treatment Discontinuation for 
Associated Neurotoxicity
Toxicity
Cisplatin Dose 
Grade 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
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). See Table 23 for dose modifications.
5.1.11
Carboplatin Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events
The dose modification guidelines for carboplatin are provided below.  
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.
5.1.11.1
Hematologic Toxicities
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 American Society of Clinical 
Oncology (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 24).


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In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.
Table 24 Carboplatin Dose Modifications for Hematologic Toxicities
Toxicity a
Carboplatin Dose 
ANC 500/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 can then be resumed.
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines.
5.1.11.2
Non-Hematologic Toxicities
For a non-hematologic toxicity (see Table 25), 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 25 provides the dose modifications for 
non-hematologic toxicities.


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Table 25 Carboplatin Dose Modifications or Treatment Discontinuation for
Non-Hematologic Toxicities
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 curve.
a If deemed appropriate by the investigator, 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 antiemetics.
Diarrhea should be controlled with adequate anti-diarrhea medication.  Nausea and/or 
vomiting should be controlled with adequate anti-emetics.  For 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).
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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


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criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported immediately by the 
investigator to the Sponsor (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:

The following confirmed treatment-emergent autoimmune conditions:
Pneumonitis
Hypoxia or dyspnea Grade 3
Colitis
Endocrinopathies:  diabetes mellitus, pancreatitis, or adrenal insufficiency
Vasculitis
Hepatitis
Transaminitis:  Grade 2 (AST or ALT 3ULN and bilirubin 2ULN) OR 
AST/ALT 10ULN
Systemic lupus erythematosus
Guillain-Barré syndrome
Skin reactions:  vitiligo, pemphigoid

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response system, or infusion-reaction syndromes

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study 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.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 to 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).  
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 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.  Instructions for reporting adverse events that occur after the 
adverse event reporting period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 26 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 26 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the 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; colloquialisms and abbreviations should be avoided.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events that are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.


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
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme 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.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.


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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."
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 (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should 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 (see Section 5.3.5.4 for 
details on recording persistent adverse events).


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5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

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
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of NSCLC should be recorded only on the Study 
Discontinuation 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, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
During survival follow-up, deaths attributed to progression of NSCLC should be recorded 
on the Study Discontinuation eCRF. 
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.


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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”).
5.3.5.10
Worsening of NonSmall Cell Lung Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 criteria.  In rare cases, the determination of 
clinical progression will be on the basis of 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 caused by disease progression, it should be 
reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or 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 caused solely by 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


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5.3.5.12
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with study treatment, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF as 
described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
For the study drugs (atezolizumab, cisplatin, carboplatin, pemetrexed, gemcitabine), 
each adverse event associated with a special situation should be recorded separately on 
the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).  Adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.


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As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data and safety analyses will not be 
performed using PRO data.  However, if any PRO responses suggestive of a possible 
adverse event are identified during site review of the PRO data, the investigator will 
determine whether the criteria for an adverse event have been met and, if so, will report 
the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
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 (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality on the basis of 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.


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5.4.1
Emergency Medical Contacts
Medical Monitor (Roche Medical Responsible) Contact Information
Medical Monitor:
, M.D., Ph.D. (Primary)
E-Mail:
Telephone No.:
  
Mobile Telephone No.:
  
Medical Monitor:
, M.D. (Secondary)
Email:
Mobile Telephone No: 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
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 and 
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 with use of 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 anti-cancer therapy after the last dose of study drug, whichever occurs first.  
All other adverse events, regardless of relationship to study treatment, will be reported 
until 30 days after the last dose of study drug or initiation of new anti-cancer therapy
after the last dose of study drug, 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.


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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.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of 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 
e-mail address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study treatment and counsel 
the patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until the conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the Adverse Event eCRF.  In addition, the investigator 
will submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during study treatment with 
chemotherapy or within 6 months after the last dose of chemotherapy.  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 
e-mail address provided to investigators.  Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient 
exposed to study treatment.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 


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information on the risks of the pregnancy and the possible effects on the fetus to support 
an informed decision in cooperation with the treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as 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/Birth Defects
Any congenital anomaly/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 each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered related to study drug or trial-related procedures until 
a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  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 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 should be reported through use of the Study Discontinuation 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

E.U. Summary of Product Characteristics for each chemotherapy agent
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor safety data during the study.  An aggregate report of any clinically 
relevant imbalances that do not favor the test product will be submitted to health 
authorities.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a randomized, Phase III, open-label study designed to evaluate the safety and 
efficacy of atezolizumab compared with treatment with chemotherapy consisting of a 
platinum agent (cisplatin or carboplatin per investigator discretion) combined with either 
pemetrexed (non-squamous NSCLC) or gemcitabine (squamous NSCLC).
For the efficacy analyses, patients will be grouped according to the treatment assigned 
at randomization.  For the safety analyses, patients will be grouped according to whether 
any amount of atezolizumab was received, including the case when atezolizumab was 
received in error.
6.1
DETERMINATION OF SAMPLE SIZE
A total enrollment of approximately 555 patients was planned for this study such that 
approximately 64% of those enrolled would be PD-L1 TC2/3 or IC2/3 patients. A recent 
prevalence report shows an increase in the prevalence of TC3 or IC3, which could lead 
to a fully powered study of OS evaluation in the TC3 or IC3 subpopulation.  Data from 
the atezolizumab first-line NSCLC Phase III Studies GO29436 (IMpower150; Socinski
2018) and GO29437 (IMpower131; Jotte 2018) as well as the atezolizumab second-line 
NSCLC Phase III Study GO28915 (OAK; Rittmeyer et al. 2017) have shown the greatest
treatment benefit of OS in the TC3 or IC3 subpopulation. The OS analysis of this study 
will therefore first be conducted in the TC3 or IC3 subpopulation excluding patients with 
a sensitizing EGFR mutation or ALK translocation (i.e., TC3 or IC3-wild type [WT]). 
The overall type I error rate will be controlled at a two-sided alpha-level of 0.05.  
Comparisons with respect to the primary endpoint of OS between treatment arms will be 
tested in a hierarchical fashion for the following populations: TC3 or IC3-WT, TC2/3 or 
IC2/3-WT, and TC1/2/3 or IC1/2/3-WT.  The updated type I error control plan is shown in 
Figure 3.
Figure 3
Type I Error Control Plan
ICtumor-infiltrating immune cells; OSoverall survival; TCtumor cell; WT=wild type.


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Estimates of the number of events required to demonstrate efficacy in terms of OS are 
based on the following assumptions:

1:1 randomization ratio

One interim analysis of OS in the TC3 or IC3-WT, TC2/3 or IC2/3-WT, and TC1/2/3 
or IC1/2/3-WT populations, with stopping boundaries determined by the Lan-DeMets 
approximation to the Pocock boundaries

Two-sided significance level of 0.05 (see Figure 3)

99% power to detect a HR of 0.45 for OS in the TC3 or IC3-WT subpopulation,
85% power to detect a HR of 0.65 for OS in the TC2/3 or IC2/3-WT subpopulation,
and 77% power to detect a HR of 0.75 for OS in the TC1/2/3 or IC1/2/3-WT
population

Median survival of 14 months in the control arm (platinum-based chemotherapy)

Event times exponentially distributed

Dropout rate assumed for all treatment arms of 5% per 24 months

 
With these assumptions, the final OS analysis will be conducted when approximately 
135 deaths have occurred in the TC3 or IC3-WT subpopulation.  Details on the timing of 
the interim analysis and stopping boundaries are provided in Section 6.10.1.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, study drug administration, and discontinuation from the study will be 
summarized by treatment arm.  The incidence of study drug discontinuation will similarly 
be tabulated.  Protocol deviations, including major deviations of inclusion/exclusion
criteria, will be summarized in a similar manner by treatment arm.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics, such as age, sex, race/ethnicity, and 
baseline disease characteristics, such as ECOG Performance Status and histology, will 
be summarized by treatment arm.  Baseline measurements are the last available data 
obtained prior to patients receiving the first dose of study drug, unless otherwise noted.
Descriptive statistics (mean, median, SD, and range) will be presented for continuous 
data and frequencies and percentages will be presented for categorical data.


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6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy analysis is the comparison of OS between the two treatment arms 
(atezolizumab arm and chemotherapy control arm).
OS is defined as the time from randomization to death from any cause.  Data for patients 
who are not reported as having died at the time of the 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 primary efficacy analysis will be performed for the TC3 or IC3 subpopulation, the 
TC2/3 or IC2/3 subpopulation, and the TC1/2/3 or IC1/2/3 population, with all 
populations excluding patients with a sensitizing EGFR mutation or ALK translocation.
The null and alternative hypotheses for the OS analysis can be phrased in terms of the 
survival functions SA(t) and SB(t) in the atezolizumab arm (Arm A) and the control arm 
(Arm B), respectively:
H0:  SA(t)SB(t) versus H1:  SA(t) ≠SB(t)
The stratification factors will be:  sex (male vs. female), ECOG Performance Status 
(0 vs. 1), histology (non-squamous vs. squamous), and PD-L1 tumor expression status 
(TC1/2/3 and any IC vs. TC0 and IC1/2/3).  Both stratified and unstratified analysis will 
be performed.  Due to the potential risk of over-stratification (Akazawa et al. 1997), if at 
least 1 stratum (i.e., for the TC1/2/3 or IC1/2/3 population, a combination of stratification 
factor levels across sex, ECOG performance status, histology, and PD-L1 tumor 
expression status per IxRS; for the TC3 or IC3 population and the TC2/3 or IC2/3 
population, a combination of stratification factor levels across sex, ECOG performance 
status, and histology per IxRS) has less than 10 OS events, the stratification factor 
(1 of 4 stratification factors for the TC1/2/3 or IC1/2/3 population: sex, ECOG 
performance status, histology, and PD-L1 tumor expression by IHC per IxRS; 1 of 3 
stratification factors for the TC3 or IC3 population and the TC2/3 or IC2/3 population: 
sex, ECOG performance status, and histology 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 less 
than 10 OS events in the analysis population. The final set of stratification factors used 
in the stratified analyses of OS for a specific analysis population (e.g., TC2/3 or IC2/3)
will be applied to all other efficacy endpoints where stratified analyses are planned for 
the same analysis population.
The HR will be estimated using a stratified Cox regression model at the time of both the 
interim and final analyses.


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The unstratified HR will also be presented. Kaplan-Meier methodology will be used 
to estimate the median OS for each treatment arm and to construct survival 
curves for the visual description of the difference between the treatment arms.  
The Brookmeyer-Crowley methodology will be used to construct a 95% CI for the 
median OS for each treatment arm (Brookmeyer and Crowley 1982).
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 40 months after the first 
patient is enrolled in the study.  The type I error control plan is presented in Section 6.1, 
and details on the timing of the interim analysis and stopping boundaries are provided in 
Section 6.10.1.  Details on 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 any unblinding of the data.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints, except for OS and PFS in the SP263 PD-L1 and 
bTMB subpopulations (Section 6.4.2.6), will be analyzed in the TC3 or IC3 
subpopulation, the TC2/3 or IC2/3 subpopulation, and/or the TC1/2/3 or IC1/2/3 
population (depending on the results of the primary endpoint analyses), with all 
populations excluding patients with a sensitizing EGFR mutation or ALK translocation
(referred to as the "secondary efficacy analysis populations" throughout Section 6.4.2).
6.4.2.1
Progression-Free Survival
PFS is defined as the time (in months) from randomization to the first occurrence of
disease progression, as determined by the investigator with use of RECIST v1.1, 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 last tumor assessment.  
Patients with no post-baseline tumor assessment will be censored at the date of 
randomization plus 1 day.  Final PFS analyses will occur at the time of OS interim 
analyses (as defined in Section 6.10.1).  If the primary OS analyses are significant for 
the TC3 or IC3 subpopulation, the TC2/3 or IC2/3 subpopulation, and the TC1/2/3 or 
IC1/2/3 population, with all populations excluding patients with a sensitizing EGFR 
mutation or ALK translocation, the final PFS analyses will be performed in a fixed order 
to control the overall type I error rate at 0.05.  Specifically, PFS for the TC3 or IC3 
subpopulation, the TC2/3 or IC2/3 subpopulation, and TC1/2/3 or IC1/2/3 population will 
be tested in this fixed order at a significance level of 0.05 respectively, with populations 
excluding patients with a sensitizing EGFR mutation or ALK translocation. PFS will 
be analyzed through use of the same methods described for the OS analysis (see 
Section 6.4.1).  Further details regarding the PFS analyses will be described in the SAP.


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6.4.2.2
Objective Response Rate
An objective response is defined as either an unconfirmed 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.
ORR is defined as the proportion of patients who had an objective response.  ORR will 
be analyzed in the secondary efficacy analysis populations.  Patients must have 
measurable disease at baseline to be included in the analysis.  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 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 OS analysis (see Section 6.4.1).
6.4.2.3
Overall-Survival Analysis at 1- and 2-Year Landmark
Timepoints
The 1-year and 2-year survival rate is defined as the probability that a patient will be 
alive at 1 year or 2 years, respectively, after randomization.  The analysis population for 
the 1-year and 2-year survival rate will be the secondary efficacy analysis populations.  
The Kaplan-Meier method will be used to estimate the 1-year and 2-year survival rate for 
each treatment arm.  The 95% CI for the difference in OS rates between the two 
treatment arms will be estimated through use of the normal approximation method, and 
standard errors will be computed through use of the Greenwood method.
6.4.2.4
Duration of Response
DOR is defined as the period measured 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.  Disease progression will be determined on 
the basis of investigator assessment with use of RECIST v1.1.  DOR will be assessed in 
patients who had an objective response during the study as determined by the 
investigator with use of RECIST v1.1.  Patients who have not progressed and who have 
not died by the date of data cutoff for 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 analysis will be performed on the basis of a non-randomized subset of patients 
who achieve an objective response in the secondary efficacy analysis populations; 
therefore, formal hypothesis testing will not be performed for this endpoint.  DOR will be 


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estimated using Kaplan-Meier methodology.  Comparisons between treatment arms will 
be made for descriptive purposes only.
6.4.2.5
Patient-Reported Outcome Analyses
TTD with use of the SILC scale is defined as the time from randomization to the first 
documented deterioration of disease symptom in each of the SILC symptom scores
(cough, dyspnea, or chest pain).  Data for patients who have not deteriorated will be 
censored at the last time when they completed an assessment for cough, dyspnea, or 
chest pain.  If no baseline or post-baseline assessment is performed, data for patients 
will be censored at the date of randomization plus 1 day.  TTD with use of the SILC 
scale will be analyzed in the secondary efficacy analysis populations through use of the 
same methods described for the OS analysis (see Section 6.4.1).
Change from baseline per SILC scale will also be analyzed.  The analysis will be 
performed for patients in the secondary efficacy analysis populations with a baseline and
a post-baseline PRO assessment. The SILC scale comprises three individual symptoms 
(dyspnea cough, chest pain) and will be scored at the individual symptom level, thus will 
have a dyspnea score, cough score, and chest pain score. Each symptom score will be 
calculated as the average of responses for the symptom items. An increase in score is 
suggestive of a worsening in symptomatology (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.
Further details regarding all SILC analyses will be described in the SAP.
TTD will be documented for a 3-symptom composite endpoint using the following 
EORTC QLQ-LC13 symptom scores (cough, chest pain, and dyspnea [multi-item scale]).  
TTD is defined as the time from baseline to the time the patient’s score shows a 
10-point increase above baseline in any of the listed symptom scores, whichever 
occurs first.  A 10-point change in the score is perceived by patients as 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 with use 
of the EORTC will be analyzed in the secondary efficacy analysis populations through 
use of the same methods described for the OS analysis (see Section 6.4.1).  Further 
details regarding the TTD analysis for the EORTC measures will be described in 
the SAP.
6.4.2.6
Overall Survival and Investigator-Assessed Progression-Free 
Survival for SP263 PD-L1 and bTMB Subpopulation
OS and investigator-assessed PFS in patients with PD-L1 expression defined by the 
SP263 IHC assay (including populations of patients with PD-L1 expression on 1%, 
25%, and 50% of tumor cells) and in patients with bTMB (including bTMB10, bTMB 


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16, and bTMB 20) will be analyzed (pending data availability). This will be analyzed 
through use of the same methods described for the OS analysis (see Section 6.4.1).
6.5
SAFETY ANALYSES
Safety analyses will include all treated patients, defined as randomized patients who 
received any amount of study treatment.  For the safety analyses, patients will be 
grouped according to whether any amount 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.
Verbatim description of adverse events will be mapped to 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, 4, or 5), 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.
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.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data and changes in vital signs will be summarized by treatment arm. 
Serum levels and incidence of ATA against atezolizumab will be summarized to explore 
the potential relationship of the immunogenicity response with pharmacokinetics, safety, 
and efficacy.
6.6
PHARMACOKINETIC ANALYSES
PK and pharmacodynamic 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.
Additional PK and pharmacodynamic analysis will be conducted based on the availability 
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6.7
EXPLORATORY ANALYSES
Unless otherwise indicated, the exploratory efficacy endpoints will be analyzed in the 
TC3 or IC3 subpopulation, the TC2/3 or IC2/3 subpopulation, and/or the TC1/2/3 or 
IC1/2/3 population (depending on the results of the primary endpoint analyses), 
excluding patients with a sensitizing EGFR mutation or ALK translocation (referred to as 
the "exploratory efficacy analysis populations" throughout Section 6.7).
6.7.1
Analyses of Overall Survival and Progression-Free Survival in
the 22c3 PD-L1 IHC Assay Subpopulation
OS and investigator-assessed PFS according to RECIST v1.1 will be analyzed for the 
subpopulation of patients with PD-L1 expression using the 22c3 PD-L1 IHC assay,
excluding patients with a sensitizing EGFR mutation or ALK translocation.  Details 
regarding these analyses will be described in the SAP or the Biomarker Analysis Plan.  
Results from these analyses may not be included in the Clinical Study Report but may 
instead be presented in a separate biomarker report.
6.7.2
PFS Analysis at 6-Month and 1-Year Landmark Timepoints
The 6-month and 1-year PFS rate, defined as the probability that a patient will be alive 
without disease progression at 6 months or 1 year, respectively, after randomization, will 
be analyzed in the exploratory efficacy analysis populations. The Kaplan-Meier method 
will be used to estimate the 6-month and 1-year PFS rate for each treatment arm.  
The 95% CI for the difference in 6-month and 1-year PFS rates between the two 
treatment arms will be estimated through use of the normal approximation method, and 
standard errors will be computed through use of the Greenwood method.
6.7.3
Overall Survival Analysis at 3-Year Landmark Timepoint
The 3-year survival rate is defined as the probability that a patient will be alive at 3 years 
after randomization.  The analysis population for the 3-year survival rate will be the 
exploratory efficacy analysis populations.  The methodologies for OS analysis at 
landmark timepoint outlined in Section 6.4.2.3 will be used.
6.7.4
Impact of Demographic and Baseline Characteristics on 
Overall Survival and Progression-Free Survival
To assess the consistency of the study results in subgroups defined by demographic 
(e.g., age, sex, and race/ethnicity) and baseline characteristics (e.g., PD-L1 tumor 
expression status, histology, ECOG Performance Status, smoking history, number of 
metastatic sites, location of metastases, size of primary tumor, etc.), OS and 
investigator-assessed PFS according to RECIST v1.1 will be examined in these 
subgroups within the exploratory efficacy analysis populations.  Summaries of OS and 
PFS, including unstratified HRs estimated from Cox proportional hazards models and 
Kaplan-Meier estimates of median OS and PFS, will be produced separately for each 
level of the categorical variables.


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6.7.5
Exploratory Biomarker Analysis
Exploratory biomarker analyses will be performed in all randomized patients in an effort 
to understand the association of these biomarkers 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.
6.7.6
EQ-5D-3L Health Status Data
The EQ-5D-3L health status data will be used for obtaining utility measures for 
economic modeling.  These analyses will not be analyzed as an endpoint for the Clinical 
Study Report.
6.7.7
Patient-Reported Outcome Analyses
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.
Compliance rates will be summarized by listing the numbers and proportions of patients 
who completed the PRO assessments at each timepoint by treatment arm.  Reasons for 
non-completion will be summarized if available. 
6.8
SENSITIVITY ANALYSES
6.8.1
Impact of 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 nonprotocol-specified anti-cancer 
therapy (i.e., >10% of patients). 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%).
This sensitivity analysis will be conducted in the TC3 or IC3 subpopulation, the TC2/3 or 
IC2/3 subpopulation, and/or the TC1/2/3 or IC1/2/3 population (depending on the results 
of the primary endpoint analyses), with all populations excluding patients with a 
sensitizing EGFR mutation or ALK translocation. Further details regarding these 
sensitivity analyses will be described in the SAP.
6.8.2
Impact of Proportional Hazards Assumption
If the proportional hazards assumption is equivocal, restricted mean survival time may
be assessed and the difference between treatment arms will be evaluated for several 
timepoints.  The weighted log-rank test (Fleming and Harrington 1991) of OS may also 
be performed for treatment comparison for exploratory purposes.  No multiplicity 
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will be conducted in the TC3 or IC3 subpopulation, the TC2/3 or IC2/3 subpopulation,
and/or the TC1/2/3 or IC1/2/3 population (depending on the results of the primary 
endpoint analyses), with all populations excluding patients with a sensitizing EGFR 
mutation or ALK translocation. Further details regarding these sensitivity analyses will 
be described in the SAP.
6.9
HANDLING OF MISSING DATA
For OS, data for patients who are not reported as having died will be analyzed as 
censored observations on the date when 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 PFS, patients without a date of disease progression and death 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.
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 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 complete or partial response 
plus 1 day.
For TTD with use of SILC scale analysis, data for patients who have not deteriorated will 
be censored at the last time when they were known to have not deteriorated (i.e., the 
last assessment).  If no baseline or post-baseline assessment is performed, data for 
patients will be censored at the date of randomization plus 1 day.
6.10
INTERIM ANALYSES
An iDMC will be used to evaluate interim safety data on a regular basis and interim 
efficacy data at a pre-specified timepoint.  All summaries/analyses by treatment arm for 
the iDMC’s review will be prepared by an external iDCC.  Members of the iDMC will be 
external to the Sponsor and will follow a charter that outlines their roles and 
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6.10.1
Planned Interim Analysis
Because of a lack of the final PD-L1 prevalence, an interim analysis of OS in the TC3 or 
IC3-WT population will be conducted when both of the following criteria have been met:

An approximately 45% eventpatient ratio has been observed in the TC3 or IC3 
subpopulation, excluding patients with a sensitizing EGFR mutation or ALK 
translocation

Approximately 96 deaths have occurred in the TC3 or IC3 subpopulation, excluding 
patients with a sensitizing EGFR mutation or ALK translocation
At this timepoint, it is expected that approximately 154 OS events will have occurred in 
the TC2/3 or IC2/3-WT population. If the OS interim analysis in the TC3 or IC3-WT 
population is claimed as statistically significant, the OS analysis in the TC2/3 or 
IC2/3-WT population will be conducted with the stopping boundaries for the interim and 
final analyses calculated using the Lan-DeMets approximation to the Pocock boundaries. 
If there are significantly fewer than 154 OS events (i.e., <135 events) at the TC3 or 
IC3-WT interim analysis, a nominal two-sided alpha of 0.0001 (negligible impact on 
overall type I error rate) will be spent on the OS analysis in the TC2/3 or IC2/3-WT 
population at the time of the TC3 or IC3-WT interim analysis.  The next interim and final 
OS analysis in the TC2/3 or IC2/3-WT population will be conducted when approximately 
154 and 216 events are observed, respectively, with the stopping boundaries calculated 
in the same manner as above. The interim and final analyses of OS in the TC1/2/3 or 
IC1/2/3-WT population would be conducted at the same time as those for the TC2/3 or 
IC2/3-WT population.
If the OS interim analysis in the TC3 or IC3-WT population is not claimed as statistically 
significant, the final analysis will be conducted when approximately 135 OS events have 
occurred in this population, and the OS in the TC2/3 or TC2/3-WT and TC1/2/3 or 
IC1/2/3-WT populations will be tested at the planned interim and final analyses 
accordingly.  
The interim and final analyses are expected to occur approximately 40 and 55 months, 
respectively, after the first patient is enrolled in the study, but the exact timing of these 
analyses will depend on the occurrence of OS events.  The stopping boundaries for the 
interim and final analyses are shown in Table 27.


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Table 27 Analysis Timing and Stopping Boundaries for Interim and Final 
Analysis for Overall Survival
Interim and Final Analysis for OS
Analysis 
Population
Analysis Timing
Approximate Time from First Patient in (months)
40
55
TC3 or IC3-WT
Information Fraction
(No. of events)
71% (96)
100% (135)
Stopping Boundary
HR (p-value a)
HR 0.657 (p 0.0399)
HR 0.678 (p 0.0242)
TC2/3 or IC2/3-
WT
Information Fraction
(No. of events)
71% (154)
100% (216)
Stopping Boundary
HR (p-value a)
HR 0.718 (p 0.0400)
HR 0.736 (p 0.0242)
TC1/2/3 or 
IC1/2/3-WT
Information Fraction
(No. of events)
72% (281)
100% (390)
Stopping Boundary
HR (p-value a)
HR 0.783 (p 0.0403)
HR 0.796 (p 0.0241)
HRhazard ratio; ICtumor-infiltrating immune cell; OSoverall survival; TCtumor cell; 
WT=wild type.
a Two-sided p-value.
6.10.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one additional interim efficacy analysis for the primary endpoint 
of OS beyond what is specified in Section 6.10.1.  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 efficacy and safety analysis will be conducted by an iDCC 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 
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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC with 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.
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 with 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.


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Once the study is complete, the ePRO data, audit trail, and trial 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 trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational 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 


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trail that shows the original data, as well as the reason for the change, name of the 
person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, 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 Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug application (IND) 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 


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designee will explain to each patient the objectives, methods, and potential risks 
associated with each optional procedure.  Patients will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason.  
A separate, specific signature will be required to document a patient's agreement to 
allow the collection of optional samples and 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 
investigator, to continue treatment beyond initial radiographic disease progression 
per RECIST v1.1 and meet criteria specified in Section 4.6.2.  This separate 
consent is to be signed after initial radiographic disease progression per RECIST 
v1.1 has occurred and patients have discussed other available treatment options 
and the potential risks of continuing treatment.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA).  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, 


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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.
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.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 150 sites globally will participate in the study, and approximately 
555 patients will be randomized.
Randomization will occur through an IxRS.  Central facilities will be used for certain 
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.


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9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  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 trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol GO29431, Version 10
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).


Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol GO29431, Version 10
10.
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Appendix 1
Schedule of Assessments
Procedure
Screening
All Treatment 
Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up b
Days –28
to –1
Every 21 days
(3 Days) c
30 Days after 
Last Dose
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Informed consent 
Prescreening for PD-L1 testing d
Main ICF for study participation
x
Tumor tissue specimen for PD-L1 testing 
(15 FFPE slides required; blocks preferred) e, f
Fresh or archival tissue can be used.
x
EGFR and/or ALK assessment if status 
unknown (required for patients with 
non-squamous disease) g 
x
Demographic data
x
Medical history and baseline conditions
x
NSCLC cancer history
x
Vital signs h
x
x i
x i
Weight
x
x
x
Height
x
Complete physical examination
x
Limited physical examination j
x
x
ECOG Performance Status
x
x
x
12-lead ECG
x
x k
x k


Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol GO29431, Version 9
Appendix 1
Schedule of Assessments (cont.)
Procedure
Screening
All Treatment 
Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up b
Days –28
to –1
Every 21 days
(3 Days) c
30 Days after 
Last Dose
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Hematology l
x m
x
x
Serum chemistry n
x m
x
x
Coagulation test (INR or aPTT)
x m
x
Pregnancy test (women of childbearing 
potential ONLY)
x o
x p
x p
TSH, free T3, free T4 q
x
x r
x r
HIV, HBV, HCV serology s
x
Urinalysis t
x
Study treatment administration
x u
Tumor response assessment
x v
x w
x x
Serum sample for ATA assessment 
(atezolizumab-treated patients only) y
x
x
120 (30) days after 
last dose 
Serum sample for PK sampling
(atezolizumab-treated patients only) y
x
x
120 (30) days after 
last dose
Blood samples for PD biomarkers y
x
x
x
120 (30) days after 
last dose
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab-treated
patients only)
At time of radiographic progression 


Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol GO29431, Version 9
Appendix 1
Schedule of Assessments (cont.)
Procedure
Screening
All Treatment 
Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up b
Days –28
to –1
Every 21 days
(3 Days) c
30 Days after 
Last Dose
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Tumor biopsy
At time of radiographic progression z
Adverse events
x aa
x
x bb
Concomitant medications
From 7 days 
before 
screening
x
x
Patient-reported outcomes cc
x
x dd
Survival and anti-cancer therapy follow-up b
x
anti-HBc antibody against hepatitis B core antigen; ATAanti-therapeutic antibody; CT computerized tomography; 
ECOGEastern Cooperative Oncology Group; EORTCEuropean Organisation for Research and Treatment of Cancer; 
ePROelectronic patient-reported outcome; EQ-5D-3LEuroQoL5 Dimension, 3 Level; FFPEformalin-fixed paraffin-embedded; 
HBVhepatitis B virus; HCVhepatitis C virus; ICFInformed Consent Form; IVintravenous; QLQ-LC13Lung Cancer module; 
MRImagnetic resonance imaging; NSCLCnonsmall cell lung cancer; PDpharmacodynamic; PD-L1programmed 
deathligand 1; PKpharmacokinetic; QLQ-C30Quality-of-Life Questionnaire Core 30; SILCSymptoms in Lung Cancer; 
TSHthyroid-stimulating hormone.
a Assessments should be performed before study drug infusion unless otherwise noted.
b 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 1
Schedule of Assessments (cont.)
c Cycle 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 4.5.13.2.
d Patients have the option to sign the Prescreening ICF to consent to PD-L1 tissue testing during prescreening, prior to signing 
the main ICF for study participation.  Consent may be obtained more than 28 days before initiation of study treatment.  For 
patients with non-squamous NSCLC, EGFR and/or ALK status if unknown may be assessed locally or at a central lab.  
Additional tissue will be required for central testing of EGFR and/or ALK. 
e  If a representative FFPE tumor specimen in paraffin block (preferred) or 15 (or more), freshly cut, unstained serial sections (on 
slides) from an FFPE tumor specimen are not available for PD-L1 testing, contact the Medical Monitor to discuss to determine if 
the patient may participate in the study.  Fine-needle aspiration (defined as samples that do not preserve tissue architecture and 
yield cell suspension and/or cell smears), brushing, cell pellets from pleural effusion, and lavage samples are NOT acceptable.  
For core needle biopsy specimens, at least three cores should be submitted for evaluation.  Retrieval of archival tumor sample 
can occur more than 28 days prior to randomization.  See Section 4.5.7.1 and Section 4.1.1 for details.
f
For patients whose initial archival tumor tissue sample is PD-L1 negative, a biopsy can be performed at screening to submit 
fresh tissue for the purposes of testing PD-L1 status.  A positive result in any tumor tissue sample will satisfy this eligibility 
criterion.
g  Patients with non-squamous NSCLC who have an unknown EGFR and/or ALK status will be required to be tested at 
prescreening/screening.  Patients with squamous NSCLC who have an unknown status will not be required to be tested at 
prescreening/screening. EGFR and/or ALK may be assessed locally or at a central lab. Additional tissue will be required for 
central testing of EGFR and/or ALK.  See Section 4.1.1 Inclusion criteria for details.
h Vital signs include pulse rate, respiratory rate, blood pressures, and temperature. 
i
For both study treatment arms, the patient’s vital signs should be recorded within 60 minutes before infusion, and during and
after the infusion if clinically indicated.  For the atezolizumab arm, vital signs should also be collected during the first infusion 
every 15 (5) minutes and within 30 (10) minutes after the first infusion if clinically indicated.  For subsequent infusions in 
both arms, vital signs will be collected within 60 minutes prior to the infusion and should be collected during the infusion and 
within 30 (10) minutes after the infusion, if clinically indicated or if symptoms occurred in the prior infusion.  See Section 4.5.4
for details.
j
Symptom-directed physical examinations; see Section 4.5.3 for details. 
k ECG recordings will be obtained when clinically indicated.


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Appendix 1
Schedule of Assessments (cont.)
l
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, 
lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet count.  Hematology tests must be performed 
prior to Day 1 infusions, and for gemcitabine administration, also prior to Day 8 infusions.
m At screening, the patient must have adequate hematologic and end-organ function defined by laboratory results obtained within 
14 days prior to randomization, as described in Section 4.1.1.
n Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2 (if considered 
standard of care for the region), calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total 
protein, and albumin.  
o Serum pregnancy test within 14 days before Cycle 1, Day 1.
p Urine pregnancy tests; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
q Total T3 will be tested only at sites where free T3 is not performed.
r
Thyroid function testing (TSH, free T3, free T4) collected at Cycle 1, Day 1, and every fourth cycle thereafter. 
s 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 HBsAg test result at screening) will be 
excluded from the study.  Patients with past or resolved HBV infection (defined as the presence of HBcAb and absence of 
HBsAg) are eligible; HBV DNA must be performed prior to randomization in these patients.  Patients with HCV will be excluded 
from the study; patients who test positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV 
RNA.
t
Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood). Urinalysis is required at screening and will be 
obtained during study treatment when clinically indicated.
u For atezolizumab, the initial dose will be delivered over 60 (10) 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 
chemotherapy, study drug will be administered according to the doses and suggested infusion times, including premedication, 
as described in Section 4.3.2.24.3.2.4.
v CT scans (with oral/IV contrast unless contraindicated) or MRI 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 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.


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Appendix 1
Schedule of Assessments (cont.)
w Perform every 6 weeks (7 days; approximately every two cycles) for 48 weeks 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 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.  CT scans may be repeated at any time if 
progressive disease is suspected. Tumor assessments will be performed according to RECIST v1.1 (see Appendix 4) and 
modified RECIST (see Appendix 5) for patients in the atezolizumab arm, and only according to RECIST v1.1 for patients in the 
chemotherapy arm. See Section 4.5.5 for details.
x
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 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, even if 
patient starts another anti-cancer therapy after study treatment discontinuation.
y
See Appendix 2 for detailed schedule.
z
Mandatory tumor biopsy at radiographic disease progression, if clinically feasible, within 40 days of radiographic progression or 
prior to the start of the next anti-cancer therapy, whichever is sooner (see Section 4.5.7.2).
aa Only serious adverse events caused by protocol-mandated intervention should be reported.
bb 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 new systemic anti-cancer therapy after last dose of study treatment.  
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 systemic anti-cancer therapy after last dose of study treatment.  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).


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Appendix 1
Schedule of Assessments (cont.)
cc EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L questionnaires will be completed by the patients on the ePRO tablet 
according to the tumor assessment schedule (i.e., every 6 weeks (7 days) for 48 weeks following Cycle 1, Day 1, and every 
9 weeks (7 days) thereafter after the completion of the Week 48 tumor assessment 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)prior to administration of study drug and prior to any other study 
assessments.  The SILC scale will be completed using an electronic device at the patient’s home on a weekly basis.  Patients 
who discontinue study treatment for any reason other than 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) will complete the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L at each tumor assessment visit and 
will complete the SILC at home on a weekly basis, until radiographic disease progression per RECIST v1.1, 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.  Patients whose native language is not available in the ePRO device or who 
are deemed by the investigator incapable of inputting their ePRO assessment after undergoing appropriate training are exempt 
from all ePRO assessments.
dd During survival follow-up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L will be completed at 3 and 6 months 
following disease progression (or loss of clinical benefit for atezolizumab-treated patients who had continued treatment with 
atezolizumab after radiographic disease progression according to RECIST v1.1) if the patient returns to the clinic.  The SILC 
scale will be completed monthly during survival follow-up for 6 months following disease progression (or loss of clinical benefit 
for atezolizumab-treated patients who had continued treatment with atezolizumab after radiographic disease progression 
according to RECIST v1.1).  


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Appendix 2
Schedule of Pharmacokinetic, Biomarker, and Anti-Therapeutic 
Antibody Assessments
Study Visit
Time
Patients Randomized 
to Chemotherapy
Patients 
Randomized to 
Atezolizumab
Screening

Biomarkers a
Biomarkers a
Cycle 1, Day 1
Prior to dosing 
(same day as 
treatment 
administration)
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
30 (10) minutes 
after end of 
atezolizumab
infusion

Atezolizumab 
pharmacokinetics
Cycles 2, 3, 4, 8 and 
16, Day 1
Prior to dosing 
(same day as 
treatment 
administration)
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
After Cycle 16, every 
eighth cycle, Day 1
Prior to dosing 
(same day as 
treatment 
administration)
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
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
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
12030 days after 
last dose of 
atezolizumab
At visit

ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
Any timepoint during 
the study (RCR 
consent required)
Optional RCR blood 
(DNA extraction) b
Optional RCR blood 
(DNA extraction) b
ATAanti-therapeutic antibody; RCRRoche Clinical Repository.
a Whole blood for biomarkers.
b Plasma and serum for biomarkers.


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


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Appendix 3
American Joint Committee on Cancer
NonSmall Cell Lung Cancer Staging, 7th Edition (cont.)
Reference:  Lung. In: Edge S, Byrd DR, Compton CC, et al, editors. AJCC Cancer Staging 
Manual, Seventh Edition. Chicago: Springer, 2010:267–70.


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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 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)

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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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). 
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, 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 or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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, additionally, 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 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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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 during the 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 during the 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 


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
baseline examination), even if the nodes regress to 10 mm during the 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 in the 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.
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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)

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 trials 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 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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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 trials; 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 
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 


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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 


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.)
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.


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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) conventions3 and immune-related response criteria4 (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.  
                                                
3
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.
4
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.


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
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.


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
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 


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
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 complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including non-target lesions) and will not be used 
to assess progressive disease.
New Lesions
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will also be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST, (e.g., nonlymph node lesions must be 10mm; see note for new 
lymph node lesions below).  Up to a maximum of five new lesions total (and a maximum 
of two lesions per organ), all 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 


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Modified Response Evaluation Criteria in Solid Tumors (cont.)
of longest diameters (SLD), if the maximum number of 5 measurable new lesions being 
followed has not been reached. 
B.2 CALCULATION OF SUM OF THE DIAMETERS
A sum of the diameters (longest 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.


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
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 in 
the 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 
during the study (nadir SLD; this includes the baseline sum if that is the smallest during 
the 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 


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
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 complete response criteria are met, since a normal 
lymph node is defined as having a short axis of 10 mm.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 10 mm in order to meet 
the definition of CR.


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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 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 GO29431, the antiPD-L1 (SP142) IHC assay will be used for investigational 
purposes only.
The Ventana PD-L1 (SP142) rabbit monoclonal primary antibody is intended for the 
qualitative immunohistochemical assessment of the PD-L1 protein in formalin-fixed, 
paraffin-embedded nonsmall cell lung carcinoma (NSCLC) tissue stained with a 
BenchMark ULTRA automated staining instrument.  It is indicated as an aid in identifying 
patients who are eligible for treatment with atezolizumab. 
The clinical interpretation of any staining, or the absence of staining, must be 
complemented by histological studies and evaluation of proper controls. Evaluation 
must be made by a qualified pathologist within the context of the patient’s clinical history 
and other diagnostic tests.
CAUTION—Investigational device.  Limited by Federal (or United States) law to 
investigational use.
DEVICE DESCRIPTION
The Ventana 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. 
SCORING SYSTEM
PD-L1 staining with PD-L1 (SP142) rabbit monoclonal primary antibody in NSCLC can 
be observed in both tumor cells and tumor-infiltrating immune cells.


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Appendix 7
EORTC QLQ-C30


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Appendix 7
EORTC QLQ-C30 (cont.)


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Appendix 8
EORTC QLQ-LC13


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Appendix 9
Symptoms in Lung Cancer Scale


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Appendix 9
Symptoms in Lung Cancer Scale (cont.)


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Appendix 9
Symptoms in Lung Cancer Scale (cont.)


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Appendix 10
EuroQoL 5 Dimension, 3 Level Questionnaire


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Appendix 10
EuroQoL 5 Dimension, 3 Level Questionnaire (cont.)


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Appendix 10
EuroQoL 5 Dimension, 3 Level Questionnaire (cont.)


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Appendix 11
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead


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Appendix 12
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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Appendix 13
Preexisting Autoimmune Diseases
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be subjects with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
will 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 over 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 nodosa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter 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
199/Protocol GO29431, Version 10
Appendix 14
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. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
105 days after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 105 days to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 105 days if the Medical Monitor agrees that the patient is likely to derive 
clinical benefit.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.
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 


Appendix 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
200/Protocol GO29431, Version 10
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.
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
201/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
202/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
204/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
205/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
206/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
207/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
208/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
209/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
210/Protocol GO29431, Version 10
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.

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.

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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
211/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
212/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
213/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
214/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
215/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
216/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
217/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
218/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
219/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
220/Protocol GO29431, Version 10
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 


Appendix 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
221/Protocol GO29431, Version 10
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as non-
steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
222/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
223/Protocol GO29431, Version 10
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Event
Management
Immune-mediated
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact 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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
224/Protocol GO29431, Version 10
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 14
Risks Associated with Atezolizumab
and Guidelines for Management of Adverse Events
Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
225/Protocol GO29431, Version 10
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.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
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 (ANTI−PD−L1 ANTIBODY) COMPARED WITH A 
PLATINUM AGENT (CISPLATIN OR CARBOPLATIN) IN 
COMBINATION WITH EITHER PEMETREXED OR GEMCITABINE 
FOR PD-L1−SELECTED, CHEMOTHERAPY-NAIVE PATIENTS 
WITH STAGE IV NON-SQUAMOUS OR SQUAMOUS NON−SMALL 
CELL LUNG CANCER 
NCT Number: NCT02409342 
Document Date: SAP Version 3: 02-April-2019 
 
 


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 GO29431
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (ANTIPDL1 ANTIBODY) 
COMPARED WITH A PLATINUM AGENT (CISPLATIN OR 
CARBOPLATIN) IN COMBINATION WITH EITHER 
PEMETREXED OR GEMCITABINE FOR 
PD-L1SELECTED, CHEMOTHERAPY-NAIVE PATIENTS 
WITH STAGE IV NON-SQUAMOUS OR SQUAMOUS
NONSMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29431
STUDY DRUG:
Atezolizumab (MPDL3280A)
VERSION NUMBER:
3
IND NUMBER:
117296
EUDRACT NUMBER:
2014-003083-21
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, M.Sc.
DATE FINAL:
Version 1:  18 April 2017
Version 2: 19 December 2018
DATE(S) AMENDED
See electronic date stamp below.
Name                                                             Reason for Signing                              Date and Time
(UTC)
02-Apr-2019 19:04:42
Company Signatory


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GO29431
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
The Statistical Analysis Plan (SAP) for Study GO29431 has been amended to reflect 
changes made in the protocol which consists of the following main changes in Statistical 
Analysis Plan:

The tumor cell (TC)3 or tumor infiltrating immune cell (IC)3 population excluding 
patients with a sensitizing epidermal growth factor receptor (EGFR) mutation or 
anaplastic lymphoma kinase (ALK) translocation (i.e., TC3 or IC3-wild type [WT]) 
has been added as the first test in the hierarchy (see Sections 2.3 and 2.4)

The timing of the efficacy analysis has been updated to be when the prespecified 
criteria are met for the TC3 or IC3-WT population (see Sections 2.3 and 2.4)
In addition, the cutoffs have been clarified to include 1%, 25%, and 50% of tumor 
cells for the programmed deathligand 1 (PD-L1) SP263 immunohistochemistry (IHC) 
assay and include 10, 16, and 20 mutations for the blood tumor mutation burden
(bTMB) assay (see Section 4.4.2.6).
This amendment represents cumulative changes to the original analysis plan.  Additional 
minor changes have been made to improve clarity and consistency.


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan GO29431
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 8
2.2
Outcome Measures ................................................................. 8
2.2.1
Primary Efficacy Outcome Measure ........................................ 8
2.2.2
Secondary Efficacy Outcome Measures.................................. 9
2.2.3
Exploratory Efficacy Outcome Measures................................. 9
2.2.4
Pharmacokinetic Efficacy Outcome Measures ...................... 10
2.2.5
Safety Outcome Measures .................................................... 10
2.3
Determination of Sample Size ............................................... 10
2.3.1
Determination of Sample Size in the Global 
Enrollment Phase .................................................................. 10
2.4
Interim Analysis Timing.......................................................... 11
3.
STUDY CONDUCT..................................................................................... 14
3.1
Randomization Issues ........................................................... 14
3.2
Data Monitoring ..................................................................... 15
4.
STATISTICAL METHODS .......................................................................... 15
4.1
Analysis Populations ............................................................. 15
4.1.1
Efficacy Analysis Populations................................................ 15
4.1.2
Pharmacokinetic–Evaluable Population................................. 16
4.1.3
Safety Population .................................................................. 16
4.2
Analysis of Study Conduct..................................................... 16
4.3
Analysis of Treatment Group Comparability .......................... 16
4.4
Efficacy Analysis.................................................................... 16
4.4.1
Primary Efficacy Endpoint...................................................... 16
4.4.2
Secondary Efficacy Endpoints............................................... 18
4.4.2.1
Progression-Free Survival ..................................................... 18
4.4.2.2
Objective Response Rate...................................................... 18
4.4.2.3
Overall Survival at 1- and 2-Year Landmark 
Timepoints............................................................................. 19


Atezolizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan GO29431
4.4.2.4
Duration of Response............................................................ 19
4.4.2.5
Patient-Reported Outcomes .................................................. 19
4.4.2.6
Overall Survival and Investigator-Assessed 
Progression-Free Survival for SP263 PD-L1 and 
bTMB Subpopulation ............................................................. 21
4.4.3
Exploratory Efficacy Endpoints.............................................. 21
4.4.3.1
Analyses of Overall Survival and 
Progression-Free Survival in the 22c3 PD-L1 IHC 
Assay Subpopulation............................................................. 21
4.4.3.2
PFS Analysis at 6-Month and 1-Year Landmark 
Timepoints............................................................................. 22
4.4.3.3
Overall Survival Analysis at 3-Year Landmark 
Timepoint............................................................................... 22
4.4.3.4
Impact of Demographic and Baseline 
Characteristics on Overall Survival and 
Progression-Free Survival ..................................................... 22
4.4.3.5
Exploratory Biomarker Analysis............................................. 22
4.4.3.6
EQ-5D-3L Health Status Data ............................................... 23
4.4.3.7
Additional Patient-Reported Outcome Analyses.................... 23
4.4.4
Sensitivity Analyses............................................................... 23
4.4.4.1
Censoring for NonProtocol-Specified 
Anti-Cancer Therapy ............................................................. 23
4.4.4.2
Impact of Proportional Hazards Assumption.......................... 24
4.4.4.3
Impact of Potential Imbalance between 
Treatment Arms..................................................................... 24
4.4.4.4
Impact of Expansion of PD-L1 Selection Criteria 
for Patient Eligibility ............................................................... 24
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 24
4.6
Safety Analyses..................................................................... 24
4.6.1
Exposure of Study Medication............................................... 25
4.6.2
Adverse Events ..................................................................... 25
4.6.3
Laboratory Test Result Data.................................................. 25
4.6.4
Vital Signs.............................................................................. 25
4.6.5
Anti-Therapeutic Antibody ..................................................... 25
4.7
Missing Data.......................................................................... 25


Atezolizumab—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan GO29431
5.
REFERENCES ........................................................................................... 26
LIST OF TABLES
Table 1
Analysis Timing and Stopping Boundary for Interim and Final 
Analysis for Overall Survival ....................................................... 13
LIST OF FIGURES
Figure 1 
Study Schema for Study IMpower110........................................... 7
Figure 2 
Type I Error Control Plan ............................................................ 11
LIST OF APPENDICES
27
Appendix 2
Schedule of Assessments........................................................... 40
48


Atezolizumab—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan GO29431
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study GO29431 (IMpower110), “A Phase III, Open-Label, 
Randomized Study of TECENTRIQ(Atezolizumab, MPDL3280A, AntiPD-L1 Antibody) 
Compared with a Platinum Agent (Cisplatin or Carboplatin) in Combination with Either 
Pemetrexed or Gemcitabine for PD-L1Selected, Chemotherapy-Naive Patients with 
Stage IV Non-Squamous or Squamous Non-Small Cell Lung Cancer”.  The background 
for the study can be found in the study Protocol.
2.
STUDY DESIGN
This is a randomized, Phase III, global, multicenter, open-label study designed to 
evaluate the safety and efficacy of atezolizumab compared with chemotherapy 
consisting of a platinum agent (cisplatin or carboplatin per investigator discretion) 
combined with either pemetrexed (non-squamous disease) or gemcitabine (squamous 
disease) in programmed deathligand 1 (PD-L1)selected patients, chemotherapy-naive 
patients with Stage IV nonsmall cell lung cancer (NSCLC).
Figure 1 illustrates the Study GO29431 study design.  Eligible patients will be stratified 
by sex (male vs. female), Eastern Cooperative Oncology Group (ECOG) performance 
status (0 vs. 1), histology (non-squamous vs. squamous), and PD-L1 tumor expression 
status (tumor cell [TC]1/2/3 and any tumor-infiltrating immune cell [IC] vs. TC0 and 
IC1/2/3).  Patients with non-squamous disease will be randomized in 1:1 ratio to receive 
either atezolizumab alone or pemetrexed in combination with cisplatin or carboplatin.  
Patients with squamous disease will be randomized in 1:1 ratio to receive either 
atezolizumab alone or gemcitabine in combination with cisplatin or carboplatin.


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan GO29431
Figure 1
Study Schema for Study IMpower110
AUCarea under the concentrationtime curve; ECOG PSEastern Cooperative Oncology 
Group performance status; IVintravenous; NSCLCnonsmall cell lung cancer;
PDprogressive disease; PD-L1programmed deathligand 1; q21devery 21 days; 
RECIST Response Evaluation Criteria in Solid Tumors.
Note:  Gemcitabine is administered on Days 1 and 8.
Atezolizumab (fixed dose of 1200 mg) will be administered intravenously on Day 1 of 
each 21-day cycle.  Atezolizumab treatment may continue as long as patients 
experience a clinical benefit as assessed by the investigator (i.e., in the absence of 
unacceptable toxicity or symptomatic deterioration attributed to disease progression as 
determined by the investigator after an integrated assessment of radiographic data, 
biopsy results [if available], and clinical status) or until unacceptable toxicity or death.
Patients randomized to receive pemetrexed in combination with either cisplatin or 
carboplatin (to treat non-squamous disease) will receive chemotherapy intravenously on 
Day 1 of each 21-day cycle for four or six cycles, followed by maintenance therapy with 
pemetrexed.  Patients who are randomized to receive gemcitabine in combination with 
either cisplatin or carboplatin (squamous disease) will receive cisplatin or carboplatin 
intravenously on Day 1 and gemcitabine intravenously on Days 1 and 8 of each 21-day 
cycle for four or six cycles, followed by best supportive care.  The intended number of 


Atezolizumab—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan GO29431
cycles planned for the platinum-based induction chemotherapy (i.e., four or six cycles) 
will be specified by the investigator prior to study randomization.  Treatment will continue 
until disease progression, unacceptable toxicity, or death.
All patients will undergo tumor assessment at baseline and every 6 weeks (7 days) for 
48 weeks following Cycle 1, Day 1 regardless of treatment delays.  After the completion 
of the Week 48 tumor assessment, tumor assessment will be required every 9 weeks 
(7 days) regardless of treatment delays, until radiographic disease progression per 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (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 discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) 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.  
In the absence of radiographic disease progression per RECIST v1.1, tumor 
assessments should continue regardless of whether patients start a new anti-cancer 
therapy.
The primary efficacy endpoint is overall survival (OS).  The secondary endpoints include 
investigator-assessed progression-free survival (PFS), objective response rate (ORR), 
duration of response (DOR) per RECIST v1.1, time to deterioration (TTD) and change 
from baseline per the Symptoms in Lung Cancer (SILC) scale, and TTD per European 
Organisation for Research and Treatment of Cancer (EORTC) scale.  Other endpoints 
include safety, pharmacokinetics, and exploratory outcome measures (see Section 2.2).
An independent Data Monitoring Committee (iDMC) has been monitoring both safety 
and efficacy data (see Section 3.2).
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
Primary Efficacy Outcome Measure
The primary efficacy outcome measure for this study is OS, defined as the time from 
randomization to death from any cause.  


Atezolizumab—F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan GO29431
2.2.2
Secondary Efficacy Outcome Measures
The secondary 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 with use of RECIST v1.1 or death 
from any cause, whichever occurs first.  

Objective response (partial response [PR] plus complete response [CR]) as 
determined by the investigator according to RECIST v1.1

DOR, defined as the time from the first occurrence of a documented objective 
response to the time of disease progression as determined by the investigator with 
use of RECIST v1.1 or death from any cause, whichever occurs first

OS and Investigator-assessed PFS according to RECIST v1.1 in patients with 
PD-L1 expression defined by the SP263 immunohistochemistry (IHC) assay

OS and investigator-assessed PFS according to RECIST v1.1 in patients with blood 
tumor mutational burden (bTMB)

OS at 1-year and 2-year landmark timepoints

TTD and change from baseline (i.e., improvement or deterioration based on 
presenting symptomatology) in each of the patient-reported lung cancer symptoms 
(cough, dyspnea, or chest pain) score as assessed by the SILC

TTD in patient-reported lung cancer symptoms of cough, dyspnea (multi-item 
subscale), and chest pain, defined as time from randomization to deterioration 
(10-point change) as assessed respectively by the EORTC Quality-of-Life 
Questionnaire Core 30 (QLQ-C30) and supplementary EORTC Quality-of-Life 
Questionnaire Lung Cancer Module (QLQ-LC13) scale
2.2.3
Exploratory Efficacy Outcome Measures
The exploratory outcome measures for this study are:

OS and investigator-assessed PFS according to RECIST v1.1 in patients with 
PD-L1 expression measured using the 22c3 PD-L1 IHC assay

PFS at 6-month and at 1-year landmark timepoints

OS at 3-year landmark timepoint

OS and investigator-assessed PFS according to RECIST v1.1 in subgroups based 
on demographic and baseline characteristics 

Status of immune-cell infiltrate and other exploratory biomarkers in mandatory 
biopsy specimens collected at progression

Status of PD-L1, immune-, and NSCLC-related and other exploratory biomarkers 
in archival and/or freshly obtained 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

Utility scores of the EuroQoL 5 Dimension, 3 Level (EQ-5D-3L) questionnaire


Atezolizumab—F. Hoffmann-La Roche Ltd
10/Statistical Analysis Plan GO29431

Change from baseline in patient-reported outcomes (PROs) of health-related quality 
of life (HRQoL), lung cancer-related symptoms, and functioning as assessed by the 
EORTC QLQ-C30 and QLQ-LC13 
2.2.4
Pharmacokinetic Efficacy Outcome Measures
The pharmacokinetic (PK) outcome measures for this study are:

Maximum serum atezolizumab concentration observed (Cmax) after infusion on 
Day 1 of Cycle 1

Minimum serum atezolizumab concentration observed (Cmin) prior to infusion on 
Day 1 of Cycles 2, 3, 4, 8, 16, and every eighth cycle thereafter, at treatment 
discontinuation, and at 120 (30) days after the last dose of atezolizumab
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 atezolizumab administration

Incidence of anti-therapeutic antibody (ATA), also known as anti-drug antibody 
(ADA), response to atezolizumab and potential correlation with PK, 
pharmacodynamics (PD), safety, and efficacy parameters
2.3
DETERMINATION OF SAMPLE SIZE
2.3.1
Determination of Sample Size in the Global Enrollment Phase
Approximately 150 sites globally will participate in the study, and approximately 
555 PD-L1selected, chemotherapy-naive patients with Stage IV NSCLC are planned to
be enrolled.  For the primary comparison of OS, the Sponsor will control the overall 
type I error rate for the two-sided tests at 0.05 for the TC3 or IC3 subpopulation, the 
TC2/3 or IC2/3 subpopulation and the TC1/2/3 or IC1/2/3 population, with all populations 
excluding patients with a sensitizing EGFR mutation or ALK translocation.  The hierarchy 
of spending is specified in Figure 2.


Atezolizumab—F. Hoffmann-La Roche Ltd
11/Statistical Analysis Plan GO29431
Figure 2
Type I Error Control Plan
ICtumor-infiltrating immune cell; OSoverall survival; TCtumor cell; WT=wild type (i.e., 
excluding patients with a sensitizing epidermal growth factor receptor [EGFR] mutation or 
anaplastic lymphoma kinase [ALK] translocation).
Estimates of the number of events required to demonstrate efficacy in terms of OS are 
based on the following assumptions: 

1:1 randomization ratio

One interim analysis of OS in the TC3 or IC3-wild type (WT), the TC2/3 or IC2/3-WT,
and the TC1/2/3 or IC1/2/3-WT population with stopping boundaries determined by 
the Lan-DeMets approximation to the Pocock boundary

Two-sided significance level of 5% in the TC3 or IC3-WT, the TC2/3 or IC2/3-WT,
and the TC1/2/3 or IC1/2/3-WT population

99% power to detect a hazard ratio (HR) of 0.45 for OS in the TC3 or IC3-WT 
subpopulation, 85% power to detect a HR of 0.65 for OS in the TC2/3 or IC2/3-WT
subpopulation, and 77% power to detect a HR of 0.75 for OS in the TC1/2/3 or 
IC1/2/3-WT population

Median survival of 14 months in the control arm (platinum-based chemotherapy)

Event times exponentially distributed

Dropout rate assumed for all treatment arms of 5% per 24 months

Prevalence rate of 37% for TC3 or IC3 and 59% for TC2/3 or IC2/3 within the 
TC1/2/3 or IC1/2/3 population
With these assumptions, the final OS analysis will be conducted when approximately 
135 deaths have occurred in the TC3 or IC3-WT subpopulation. 
2.4
INTERIM ANALYSIS TIMING
The Sponsor plans to conduct one interim efficacy analysis for the primary endpoint of 
OS in the TC3 or IC3-WT, the TC2/3 or IC2/3-WT, and the TC1/2/3 or IC1/2/3-WT
populations, respectively. With a lack of the final PD-L1 prevalence, to ensure the data 
maturity and have sufficient event-patient ratio for the evaluation of the OS benefit, an 


Atezolizumab—F. Hoffmann-La Roche Ltd
12/Statistical Analysis Plan GO29431
interim analysis of OS in the TC3 or IC3-WT population will be conducted when both of 
the following criteria have been met:

An approximately 45% event-patient ratio has been observed in the TC3 or IC3-WT
subpopulation

Approximately 96 deaths have occurred in the TC3 or IC3-WTsubpopulation
Based on the assumptions specified in Section 2.3.1, it is expected that approximately 
154 OS events would have occurred in the TC2/3 or IC2/3-WT population at the time of 
the interim analysis of OS in the TC3 or IC3-WT subpopulation. If the OS interim 
analysis in the TC3 or IC3-WT population is claimed as statistically significant, the OS 
analysis in the TC2/3 or IC2/3-WT population will be tested under the overall type I error 
of 0.05. If there are significantly fewer than 154 OS events (i.e., <135 events) in the 
TC2/3 or IC2/3-WT population at the time of TC3 or IC3-WT OS interim analysis, a 
nominal two-sided alpha of 0.0001 (negligible impact on overall type I error rate) will be 
spent on the OS interim analysis in the TC2/3 or IC2/3-WT population.  The next interim 
and final OS analysis in the TC2/3 or IC2/3-WT population will be conducted when 
approximately 154 and 216 events are observed, respectively.  The interim and final 
analyses of OS in TC1/2/3 or IC1/2/3-WT would be conducted at the same time as those 
for the TC2/3 or IC2/3-WT population.
If the OS interim analysis in the TC3 or IC3-WT population is not claimed as statistically 
significant, the final analysis will be conducted when approximately 135 OS events have 
occurred in this population and if this final analysis is claimed statistically significant, the 
OS in the TC2/3 or TC2/3-WT and TC1/2/3 or IC1/2/3-WT populations will be tested at 
the planned interim and final analyses accordingly.  Details are provided at the end of 
this section.
The interim and final analyses are expected to occur approximately 40 and 55 months,
respectively, after the first patient is enrolled in the study, but the exact timing of these 
analyses will depend on the occurrence of OS events.  The stopping boundaries for the 
interim and final analyses are shown in Table 1.  


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Table 1
Analysis Timing and Stopping Boundary for Interim and Final 
Analysis for Overall Survival
Interim and Final Analysis for OS
Analysis 
Population
Analysis Timing
Approximate Time from First Patient in (months)
40
55
TC3 or IC3-WT
Information Fraction
(No. of events)
71% (96)
100% (135)
Stopping Boundary b
HR (p-value a)
HR 0.657 (p 0.0399)
HR 0.678 (p 0.0242)
TC2/3 or IC2/3-
WT
Information Fraction
(No. of events)
71% (154)
100% (216)
Stopping Boundary b
HR (p-value a)
HR 0.718 (p 0.0400)
HR 0.736 (p 0.0242)
TC1/2/3 or 
IC1/2/3-WT
Information Fraction
(No. of events)
72% (281)
100% (390)
Stopping Boundary b
HR (p-value a)
HR 0.783 (p 0.0403)
HR 0.796 (p 0.0241)
HRhazard ratio; ICtumor-infiltrating immune cell; OSoverall survival; TCtumor cell; 
WTwild type.
a Two-sided p-value.
b The Lan-DeMets approximation to the Pocock boundary
Boundaries will be adjusted based on observed number of OS events by using the Lan-
DeMets approximation to the Pocock boundary. Hypothesis testing will be conducted in 
the order described below: 

Step 1:  The interim analysis will test the null hypothesis of no difference in OS 
between the two arms in the TC3 or IC3-WT subpopulation.  If the two-sided p-value 
that corresponds to the stratified log-rank test is 3.99%, the null hypothesis will be 
rejected and it will be concluded that atezolizumab prolongs the duration of OS 
relative to control treatment in the TC3 or IC3-WT subpopulation.




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


3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
A permuted-block randomization was applied to ensure a balanced assignment to each 
treatment arm for the following stratification factors:

Sex (male vs. female)

ECOG performance status (0 vs. 1)

Histology (non-squamous vs. squamous)

PD-L1 tumor expression status (TC1/2/3 and any IC vs. TC0 and IC1/2/3)


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3.2
DATA MONITORING
An iDMC will be used to evaluate safety data during the study on a regular basis and 
evaluate efficacy data at the prespecified OS interim analysis.  Members of the iDMC will 
be external to the Sponsor and will follow a charter that outlines their roles and 
responsibilities.  All summaries and analyses by treatment arm for the iDMC review will 
be prepared by an independent Data Coordinating Center (iDCC).  
The safety data will include demographic data, adverse event data (including serious 
adverse events and adverse events of special interest), study conduct data, and relevant 
laboratory data.  Following the safety data reviews, the iDMC will provide a 
recommendation to the Sponsor as to whether the study may continue, whether 
amendments to the protocol should be implemented, or whether the study should be 
stopped.  The final decision will rest with the Sponsor.
The interim analysis of efficacy data will be conducted in accordance with the methods 
that are specified in Section 2.4.  The iDMC recommendations to unblind the study 
because of substantial evidence of efficacy of the study drug or to continue to the final 
analysis must be based on the specified interim analysis guidelines as specified in the 
iDMC Charter. 
Any outcomes of these safety and efficacy reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the Institutional 
Review Boards and/or Ethics Committee.
4.
STATISTICAL METHODS
The analyses described in this SAP will supersede those specified in the protocol for 
Study GO29431 for the purposes of a regulatory filing.
4.1
ANALYSIS POPULATIONS
4.1.1
Efficacy Analysis Populations
The randomized population or intent-to-treat (ITT) population is defined as all 
randomized patients, regardless of receipt of the assigned treatment.
The primary efficacy endpoint, OS, will be analyzed in three PD-L1selected populations, 
the TC3 or IC3-WTsubpopulation, the TC2/3 or IC2/3-WT subpopulation and the 
TC1/2/3 or IC1/2/3-WT population.  
Unless otherwise indicated, the secondary efficacy endpoints will be analyzed in TC1/2/3 
or IC1/2/3-WT, TC2/3 or IC2/3-WT, and/or TC3 or IC3-WT (depending on the results of 
the primary endpoint analyses, referred to as the "secondary efficacy analysis 
populations" throughout Section 4.4.2).


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Unless otherwise indicated, the exploratory efficacy endpoints will be analyzed in 
TC1/2/3 or IC1/2/3-WT, TC2/3 or IC2/3-WT, and/or TC3 or IC3-WT (depending on the 
results of the primary endpoint analyses, referred to as the "exploratory efficacy analysis 
populations" throughout Section 4.4.3).
For efficacy analyses, patients will be grouped per the treatment that was assigned at 
the time of randomization regardless whether they received any assigned study drug.
4.1.2
Pharmacokinetic–Evaluable Population
PK analyses will be based on PK observations from all randomized patients who 
received atezolizumab and provided at least one PK sample that was evaluable. 
4.1.3
Safety Population
Safety analyses will include treated patients, defined as randomized patients who 
received any amount of study treatment. 
For the safety analyses, patients will be grouped according to whether any amount of 
atezolizumab was received, including when atezolizumab was received in error.  
Specifically for patients who were randomized to the control arm, if atezolizumab was 
received in error, patients will be grouped to the atezolizumab arm for the safety 
analyses.  
4.2
ANALYSIS OF STUDY CONDUCT
Enrollment, study drug administration, and discontinuation from the study will be 
summarized by treatment arm.  The incidence of study drug discontinuation will similarly 
be tabulated.  Protocol deviations, including major deviations of inclusion/exclusion 
criteria, will be summarized in a similar manner by treatment arm.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics, such as age, sex, race/ethnicity, and 
baseline disease characteristics, such as ECOG performance status and histology, will 
be summarized by treatment arm for the TC3 or IC3-WT subpopulation, the TC2/3 or 
IC2/3-WT subpopulation, and/or the TC1/2/3 or IC1/2/3-WT population (depending on 
the results of the primary endpoint analyses).  Baseline measurements are the last 
available data obtained prior to Cycle 1, Day 1 visits unless otherwise stated.  
Descriptive statistics (mean, median, SD, and range) will be presented for continuous 
data, and frequencies and percentages will be presented for categorical data.
4.4
EFFICACY ANALYSIS
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is OS defined as the time from randomization to death 
from any cause. Data for patients who are not reported as having died at the time of the 
analysis will be censored at the date when they were last known to be alive.  Patients 


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who do not have any post-baseline information will be censored at the date of 
randomization plus1 day.
The primary efficacy analysis is the comparison of OS between the two treatment arms 
(atezolizumab arm and chemotherapy control arm). Treatment comparisons will be 
based on the stratified log-rank test. For the TC3 or IC3-WT subpopulation and the 
TC2/3 or IC2/3-WT subpopulation, the stratification factors will be those that were used 
during randomization (i.e., sex [male vs. female], ECOG performance status [0 vs. 1], 
histology [non-squamous vs. squamous]).  For the TC1/2/3 or IC1/2/3-WT population,
the stratification factors will be those that were used during randomization (i.e., sex 
[male vs. female], ECOG performance status [0 vs. 1], histology [non-squamous vs. 
squamous], and PD-L1 tumor expression status [TC1/2/3 and any IC vs. TC0 and 
IC1/2/3]) as recorded in the interactive Web/voice response system (IxRS). Due to the 
potential risk of over-stratification (Akazawa et al. 1997), if at least 1 stratum (i.e., for the 
TC1/2/3 or IC1/2/3-WT population, a combination of stratification factor levels across sex, 
ECOG performance status, histology, and PD-L1 tumor expression status per IxRS; for 
the TC3 or IC3-WT population and the TC2/3 or IC2/3-WT population, a combination of 
stratification factor levels across sex, ECOG performance status, and histology per IxRS) 
has less than 10 OS events, the stratification factor (1 of 4 stratification factors for the 
TC1/2/3 or IC1/2/3 population:  sex, ECOG performance status, histology, and PD-L1 
tumor expression by IHC per IxRS; 1 of 3 stratification factors for the TC3 or IC3-WT
population and the TC2/3 or IC2/3-WT population:  sex, ECOG performance status, and 
histology 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 less than 10 OS events in the analysis population.  
The final set of stratification factors used in the stratified analyses of OS for a specific 
analysis population (e.g., TC2/3 or IC2/3) will be applied to all other efficacy endpoints 
where stratified analyses are planned for the same analysis population.  The analyses 
that are based on stratification factors as recorded on the electronic Case Report Form 
(eCRF) may also be provided.  Results from an unstratified analysis will also be provided.
The null and alternative hypotheses for the OS analysis can be phrased in terms of the 
survival functions SA(t) and SB(t) in the atezolizumab arm (Arm A) and the control arm 
(Arm B), respectively:
H0:  SA(t)SB(t) versus H1:  SA(t) ≠SB(t).
The Kaplan-Meier methodology will be used to estimate the median OS 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 OS for each treatment arm 
(Brookmeyer and Crowley 1982).
The HR, A/B, where A and B represent the hazard of OS in the atezolizumab arm and 
the control arm, respectively, will be estimated with a stratified Cox regression model 


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with the same stratification variables that are used in the stratified log-rank test at the 
interim and final analyses. The unstratified HR will also be presented.
4.4.2
Secondary Efficacy Endpoints
Unless otherwise indicated, the secondary efficacy endpoints will be analyzed in the TC3 
or IC3-WT subpopulation, the TC2/3 or IC2/3-WT subpopulation, and/or the TC1/2/3 or 
IC1/2/3-WT population (depending on the results of the primary endpoint analyses) 
(referred to as the “secondary efficacy analysis populations” throughout Section 4.4.2).
4.4.2.1
Progression-Free Survival
PFS is defined as the time (in months) from randomization to the first occurrence of 
disease progression, as determined by the investigator with use of RECIST v1.1, 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 last tumor assessment.  
Patients with no post-baseline tumor assessment will be censored at the date of 
randomization plus1 day.  
The PFS analyses will occur at the time of OS interim analyses (as defined in 
Section 2.4).  
 the PFS analyses will be performed 
based on the prespecified number of events in the TC3 or IC3-WT subpopulation, TC2/3 
or IC2/3-WT subpopulation, and the TC1/2/3 or IC1/2/3-WT population.  Specifically PFS 
for the TC3 or IC3-WT, TC2/3 or IC2/3-WT, and TC1/2/3 or IC1/2/3-WT populations will 
be tested in the prespecified order at a two-sided significance level of 0.05, respectively.  
,

 

 

 
PFS will be analyzed through use of the same methods described for the OS analysis 
(see Section 4.4.1).
4.4.2.2
Objective Response Rate
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.


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ORR is defined as the proportion of patients who had an objective response.  The 
analysis of ORR will be performed for patients in the secondary efficacy analysis 
populations who have measurable disease at baseline.  The confirmation of response in 
accordance with RECIST v.1.1 is not required, but for the exploratory purpose, rate of 
confirmed response may be reported as needed.
An estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson 
method for each treatment arm.  The 95% CIs for the difference in ORRs between the 
two 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 OS 
analysis (see Section 4.4.1).
4.4.2.3
Overall Survival at 1- and 2-Year Landmark Timepoints
The 1- and 2-year OS rates are defined as the probabilities that patients are alive 1 and 
2 years after randomization, respectively.  The KaplanMeier method will be used to 
estimate the 1- and 2-year OS rates for each treatment arm.  The 95% CI for the 
difference in OS rates between the two treatment arms will be estimated with the normal 
approximation method and standard errors computed using the Greenwood method.
4.4.2.4
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.  
Data for patients who are alive and 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.  Comparisons 
between treatment arms will be made for descriptive purposes.  The same 
methodologies detailed for the OS analysis will be used for the DOR analysis.
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.
4.4.2.5
Patient-Reported Outcomes
Patient-reported data regarding symptoms of lung cancer, symptoms commonly 
associated with cancer treatments, and disease and treatment’s impact on patients’ 
functioning and HRQoL (assessed using the SILC, EORTC QLQ-C30 and EORTC 
QLQ-LC13) will be collected.  Sensitivity analyses (e.g., missing data, in the 
PRO-evaluable population) may be conducted as appropriate.


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The EORTC QLQ-C30 and EORTC QLQ-LC13 will be scored according to the EORTC 
scoring manual 3rd edition (Fayers et al. 2001).  The QLQ-C30 and QLQ-LC13 are
composed of both multi-item scales and single-item measures including functional 
scales, symptom scales, and a global health status/quality-of-life (QoL) scale.  For 
multi-item scales, if 50% of items within the scale are missing at a given timepoint, the 
scale score will be calculated on the basis of the non-missing items.  If 50% of items in 
a multi-item scale are missing or if a single-item measure is missing, then the scale is 
considered missing.  Each of the QLQ-C30 and QLQ-LC13 scale and single-item 
measure scores will be linearly transformed so that each score will range from 0100. A
high score for a functional scale represents a high/healthy level of functioning, a high 
score for the global health status/HRQoL scale represents high HRQoL; and a high 
score for a symptom scale/item represents a high level of symptomatology/problems.  A
10-point change in the EORTC scale score is perceived by patients as clinically 
significant (Osoba et al. 1998).  
Each SILC symptom scale (dyspnea, cough, chest pain) score will be calculated as the 
average of the component items (range 0 to 4). An increase in score suggests 
worsening in symptomatology. A symptom score change of 0.3 points for the dyspnea 
and cough scores is considered to be clinically significant; whereas a symptom score 
change of 0.5 points for the chest pain score is considered to be clinically significant.
Time to Deterioration in Patient-Reported Lung Cancer-Related Symptoms
TTD in each lung cancer-related symptom (cough, dyspnea, chest pain; assessed by the 
SILC) is defined as the time from randomization to confirmed clinically meaningful 
deterioration in each SILC symptom score.  Confirmed clinically meaningful deterioration 
in lung cancer symptoms is defined as the first 0.3-point increase above baseline for 
the dyspnea and cough scores and the first 0.5-point increase above baseline for the 
chest pain score, which must be maintained for at least two consecutive assessments,
or must be followed by death from any cause within one week from the last assessment.
TTD of lung cancer-related symptoms (cough, dyspnea, chest pain; assessed by the
EORTC QLQ-LC13) as a 3-symptom composite endpoint is defined as the time from 
randomization to confirmed clinically meaningful deterioration in EORTC QLQ-LC13 
cough, dyspnea, or chest pain score, whichever occurs first.  Confirmed clinically 
meaningful deterioration in lung cancer symptoms is defined as the first 10-point 
increase above baseline in any of the three symptom scores (whichever occurs first), 
which must be held for at least two consecutive assessments; or the first 10-point 
increase above baseline must be followed by (1) death within 6 weeks from the last 
assessment through Week 48 or (2) death within 9 weeks from the last assessment from 
Week 48 thereafter.  TTD in the individual QLQ-LC13 symptom scales will also be 
evaluated.  
TTD analyses will be performed in the secondary efficacy analysis populations and will 
include all data collected through disease progression and survival follow-up.  The 


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methodologies that are outlined for the analysis of OS will be used for these TTD 
analyses.  If no baseline or post-baseline assessment is performed, patients will be 
censored at the randomization date plus1 day. Patients without deterioration at the time 
of analysis will be censored at the last time they were known to have not deteriorated, 
i.e., the last assessment.  There will be no imputation for missing baseline or 
post-baseline data for the TTD analysis.  Sensitivity analyses around event definitions 
(e.g., time to permanent deterioration) may be conducted as appropriate.
Change from Baseline in Patient-Reported Lung Cancer-Related Symptoms
Summary statistics (mean, SD, median, interquartile range [IQR], range) of the change 
from baseline per SILC will be provided.  The analysis will be performed for patients in 
the secondary efficacy analysis populations. Graphs of the mean changes and 95% CI
over time from the baseline assessment for the total scale and subscales will be 
provided. The analyses 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 progressive disease), at the last dose of treatment 
received before treatment discontinuation of any cause, and the survival follow-up visits 
through 6 months.  Longitudinal mixed models (e.g., repeated measures, linear) may be 
used to estimate least-square mean score changes from baseline by treatment arm and 
differences between treatment arms (including effect sizes). Within-patient change may
be evaluated using cumulative distribution function (CDF) analyses by treatment arm.  
4.4.2.6
Overall Survival and Investigator-Assessed Progression-Free 
Survival for SP263 PD-L1 and bTMB Subpopulation
OS and investigator-assessed PFS in patients with PD-L1 expression on tumor cells 
defined by the SP263 IHC assay (including 1%, 25%, and 50% of tumor cells) and in 
patients with bTMB (including bTMB 10, bTMB 16, and bTMB 20 mutations) will be 
analyzed and included in the Clinical Study Report (CSR; pending data availability).  
This will be analyzed through use of the same methods described for the OS analysis.
4.4.3
Exploratory Efficacy Endpoints
Unless otherwise indicated, the exploratory efficacy endpoints will be analyzed in the 
TC3 or IC3-WT subpopulation, the TC2/3 or IC2/3-WT subpopulation, and/or the 
TC1/2/3 or IC1/2/3-WT population (depending on the results of the primary endpoint 
analyses) (referred to as the “exploratory efficacy analysis populations” throughout 
Section 4.4.3).
4.4.3.1
Analyses of Overall Survival and Progression-Free Survival in 
the 22c3 PD-L1 IHC Assay Subpopulation
OS and investigator-assessed PFS, according to RECIST v1.1, will be analyzed in 
subpopulation of patients with PD-L1 expression using the 22c3 PD-L1 IHC assay, 
excluding patients with a sensitizing EGFR mutation or ALK translocation and will be 
analyzed with the same methods as described in Section 4.4.1.  The details of the 


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analysis may be described in a separate Biomarker Analysis Plan (BAP).  These 
exploratory analyses will not be included in the CSR.
4.4.3.2
PFS Analysis at 6-Month and 1-Year Landmark Timepoints
The 6-month and 1-year PFS rates are defined as the probability that patients are alive 
without disease progression at 6 months and 1 year after randomization, respectively.  
The KaplanMeier method will be used to estimate the 6-month and 1-year PFS rate for 
each treatment arm.  The 95% CI for the difference in PFS rates between the two 
treatment arms will be estimated with the normal approximation method and the 
standard errors computed with the Greenwood method.
4.4.3.3
Overall Survival Analysis at 3-Year Landmark Timepoint
The 3-year OS rate is defined as defined as the probabilities that patients are alive 
3 years after randomization.  The Kaplan-Meier method will be used to estimate the 
3-year OS rate for each treatment arm.  The 95% CI for the difference in OS rates 
between the two treatment arms will be estimated with the normal approximation method 
and standard errors computed with the Greenwood method.
4.4.3.4
Impact of Demographic and Baseline Characteristics on 
Overall Survival and Progression-Free Survival
To assess the consistency of the study results in subgroups defined by demographic 
(e.g., age, sex, and race/ethnicity) and baseline prognostic characteristics (e.g., PD-L1 
tumor expression status, histology, ECOG performance status, smoking history, number 
of metastatic sites, location of metastases, size of primary tumor, etc.), OS and 
investigator-assessed PFS according to RECIST v1.1 in these subgroups will be 
examined in the TC3 or IC3-WT, the TC2/3 or IC2/3-WT, and/or TC1/2/3 or IC1/2/3-WT 
populations, depending on the results of primary efficacy analyses.  Summaries of OS 
and PFS, including unstratified HRs estimated from Cox proportional hazards models 
and Kaplan-Meier estimates of median OS and PFS, will be produced separately for 
each level of the categorical variables and displayed on a Forest plot 
(Lewis and Clarke 2001).  Additionally, estimates of median OS, PFS, and survival 
curves will be constructed by histology and PD-L1 subgroups (TC3 or IC3-WT, TC2/3 or 
IC2/3-WT, and/or TC1/2/3 or IC1/2/3-WT, depending on the results of primary efficacy 
analyses), by the Kaplan-Meier methodology.
4.4.3.5
Exploratory Biomarker Analysis
Exploratory biomarker analyses in tumor tissue and/or blood will be performed in all 
randomized patients in an effort to understand the association of these biomarkers with 
study drug response, including efficacy and/or adverse events.  The exploratory
biomarkers may include but are not limited to PD-L1 and CD8, as defined by IHC, 
quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), or other 
methods.  Additional PD analyses may be conducted as appropriate.  Results from these 
exploratory analyses will not be included in the CSR.


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4.4.3.6
EQ-5D-3L Health Status Data
EQ-5D-3L data will be used to generate health status and utility scores for use in 
economic models.  For the EQ-5D-3L health-state profiles, descriptive statistics that 
summarize the proportions of patients who reported having “no,” “some,” or “extreme” 
problems at each timepoint will be reported.  Frequencies and percentages of missing 
data will also be reported at each timepoint.  Patients without post-baseline assessments 
will be excluded from this analysis.  A single summary index from the EQ-5D-3L health 
status will be utilized in this study for economic modeling. These results will not be 
reported in the CSR.
4.4.3.7
Additional Patient-Reported Outcome Analyses
EORTC QLQ-C30 and QLQ-LC13 scale score changes from baseline will be 
descriptively analyzed using summary statistics (mean, SD, median, IQR, range) by 
treatment arm for patients with a baseline assessment and at least one post-baseline 
assessment.  Missing post-baseline items and subscales will not be imputed and will be 
summarized as observed.  CDF analyses of global health status, physical function, and 
role function (as measured by the QLQ-C30) may be performed by treatment arm.  The 
remaining QLQ-C30 scales (e.g., appetite loss, diarrhea) and QLQ-LC13 scales 
(e.g.,arm/shoulder pain, sore mouth) may be evaluated using longitudinal mixed models.
Completion rates will be calculated as the number of patients who completed a PRO 
assessment divided by the number of patients expected to complete a PRO assessment 
at each timepoint by treatment arm. Reasons for non-completion will be summarized if 
available in the CRF.
4.4.4
Sensitivity Analyses
Unless otherwise indicated, the sensitivity analysis will be conducted in the TC3 or 
IC3-WT subpopulation, the TC2/3 or IC2/3-WT subpopulation, and/or the TC1/2/3 or 
IC1/2/3-WT population (depending on the results of the primary endpoint analyses) 
(referred to as the “sensitivity analysis populations” throughout Section 4.4.4). In addition 
to the following sensitivity analyses, OS and investigator-assessed PFS according to 
RECIST v1.1 in the ITT population will be analyzed using the same methods described 
in Section 4.4.1.
4.4.4.1
Censoring for NonProtocol-Specified Anti-Cancer Therapy
The impact of nonprotocol-specified anti-cancer therapy on OS will be assessed 
depending on the number of patients who receive nonprotocol-specified anti-cancer 
therapy.  If 10% of patients received nonprotocol-specified anti-cancer therapy before 
an OS event in any treatment arm, a “discounted” survival time will be generated based 
on a user-specified assumption for the OS effect for patients who started 
nonprotocol-specified anti-cancer therapy. The duration from initiation of 
nonprotocol-specified anti-cancer therapy to death or censoring date will 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%, etc.).  Additional 


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sensitivity analyses such as an analysis with the rank that preserves a structural failure 
time model may be used to estimate patient OS without nonprotocol-specified
anti-cancer therapy, if deemed necessary. After adjustments are made for the effect of 
subsequent nonprotocol-specified anti-cancer therapy on OS, the methods that outlined 
for the primary efficacy endpoint analyses will be used for these analyses (see 
Section 4.4.1).  
4.4.4.2
Impact of Proportional Hazards Assumption
If the proportional hazards assumption is equivocal, restricted mean survival time may 
be assessed and the difference between treatment arms will be tested for several 
timepoints.  The weighted log-rank test (Fleming and Harrington 1991) of OS may also 
be performed for treatment comparison with exploratory purpose.  No multiplicity 
adjustment will be done for these sensitivity analyses.
4.4.4.3
Impact of Potential Imbalance between Treatment Arms
Since randomization is not stratified by the PD-L1 status of TC3 or IC3 and TC2/3 or 
IC2/3 at baseline, the treatment groups may be unbalanced with respect to some 
baseline disease characteristic and demographic factors within the subgroups. If 
substantial baseline factor imbalances are observed, the stratified Cox regression 
analysis including such prognostic factors may be performed to investigate the potential 
impact of such imbalances on the treatment effect.
4.4.4.4
Impact of Expansion of PD-L1 Selection Criteria for Patient 
Eligibility
The demographics and baseline characteristics may be summarized for patients enrolled 
before and after expansion of PD-L1 selection criteria for patient eligibility.  Descriptive 
statistics (mean, median, SD, and range) may be presented for continuous data, and 
frequencies and percentages may be presented for categorical data.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC 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.
Additional PK analyses will be conducted as appropriate on the basis of the availability 
of data.
4.6
SAFETY ANALYSES
Unless specified otherwise, the safety analyses that are described below will be 
conducted for the safety population and patients will be grouped in accordance whether 
any atezolizumab treatment was received (i.e., patients who received any dose of 
atezolizumab will be included in the atezolizumab arm).  Patients who were randomized 
but did not receive any amount of any study drug will be not included in safety analyses.


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4.6.1
Exposure of Study Medication
Study drug exposure with inclusion of 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 the medical dictionary for 
regulatory activities (MedDRA) thesaurus terms.  Adverse events will be graded by the 
investigator in accordance with the NCI CTCAE v4.0.  Treatment-emergent adverse 
events will be summarized by mapped term, appropriate thesaurus level, NCI CTCAE 
grade, and treatment arm.  Multiple occurrences of the same event will be counted once 
at the maximum grade.  Adverse events, common adverse events (defined as adverse 
events that occur in at least 10% of patients), serious adverse events, treatment-related 
serious adverse events, severe adverse events (Grade 3), adverse events of special 
interest, and adverse events that lead to study drug discontinuation or interruption will be 
summarized.
Treatment-emergent is defined as all events with onset on or after the first study drug 
treatment up to the data cutoff date.  Listings of adverse events will include all adverse 
events with onset on or after the first study drug treatment up to the data cutoff date.
Deaths during the study treatment period and those reported during the follow-up period 
after treatment completion or discontinuation and causes of death will be summarized by 
treatment arm.
4.6.3
Laboratory Test Result Data
Laboratory test result data will be summarized over time with inclusion of change from 
baseline by treatment arm.  Values outside normal ranges will be summarized.  
Additionally, selected laboratory test result data will be classified according to 
NCI CTCAE and summarized by grade. The highest NCI CTCAE grade post-baseline 
will also be reported and shift tables from baseline to worst value during the study 
post-baseline will be presented.
4.6.4
Vital Signs
Changes in selected vital signs will be summarized by treatment arm.
4.6.5
Anti-Therapeutic Antibody
Serum levels and incidence of ATAs, also known as ADAs, against atezolizumab will be 
summarized.  The analyses of pharmacokinetics, key efficacy, and safety by ATA status 
will be conducted to explore the potential impact of immunogenicity.
4.7
MISSING DATA
Refer to Sections 4.4.1 and 4.4.2 for methods on how to handle missing data for the 
primary and secondary efficacy endpoints.


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5.
REFERENCES
Akazawa K, Nakamura T, Palesch Y. Power of Logrank Test and Cox Regression Model 
in Clinical Trials with Heterogeneous Samples. Statistics in Medicine 
1997;16:583-597.
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics
1982;38:2941.
Fayers PM, Aaronson NK, Bjordal K, et al. EORTC QLQ-C30 scoring manual (3rd 
edition). Brussels: EORTC, 2001.
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.


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Appendix 2
Schedule of Assessments
Procedure
Screening
All Treatment 
Cycles a
Treatment Discontinuation Visit
Survival Follow-Up b
Days –28
to –1
Every 21 days
(3 Days) c
30 Days after Last Dose
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Informed consent 
Prescreening for PD-L1 testing d
Main ICF for study participation
x
Tumor tissue specimen for PD-L1 testing (15 FFPE 
slides required; blocks preferred) e, f
Fresh or archival tissue can be used.
x
EGFR and/or ALK assessment if status unknown 
(required for patients with non-squamous disease) g 
x
Demographic data
x
Medical history and baseline conditions
x
NSCLC cancer history
x
Vital signs h
x
x i
x i
Weight
x
x
x
Height
x
Complete physical examination
x
Limited physical examination j
x
x
ECOG Performance Status
x
x
x
12-lead ECG
x
x k
x k


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Appendix 2
Schedule of Assessments (cont.)
Procedure
Screening
All Treatment 
Cycles a
Treatment Discontinuation Visit
Survival Follow-Up b
Days –28
to –1
Every 21 days
(3 Days) c
30 Days after Last Dose
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Hematology l
x m
x
x
Serum chemistry n
x m
x
x
Coagulation test (INR or aPTT)
x m
x
Pregnancy test (women of childbearing potential 
ONLY)
x o
x p
x p
TSH, free T3, free T4 q
x
x r
x r
HIV, HBV, HCV serology s
x
Urinalysis t
x
Study treatment administration
x u
Tumor response assessment
x v
x w
x x
Serum sample for ATA assessment (atezolizumab-
treated patients only) y
x
x
120 (30) days after 
last dose 
Serum sample for PK sampling
(atezolizumab-treated patients only) y
x
x
120 (30) days after 
last dose
Blood samples for PD biomarkers y
x
x
x
120 (30) days after 
last dose
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab-treated
patients only)
At time of radiographic progression 


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Appendix 2
Schedule of Assessments (cont.)
Procedure
Screening
All Treatment 
Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up b
Days –28
to –1
Every 21 days
(3 Days) c
30 Days after 
Last Dose
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Tumor biopsy
At time of radiographic progression z
Adverse events
x aa
x
x bb
Concomitant medications
From 7 days 
before 
screening
x
x
Patient-reported outcomes cc
x
x dd
Survival and anti-cancer therapy follow-up b
x
anti-HBc antibody against hepatitis B core antigen; ATAanti-therapeutic antibody; CT computerized tomography; ECOGEastern Cooperative 
Oncology Group; EORTCEuropean Organisation for Research and Treatment of Cancer; ePRO electronic patient-reported outcome; EQ-5D-
3LEuroQoL5 Dimension, 3 Level; FFPEformalin-fixed paraffin-embedded; HBVhepatitis B virus; HCVhepatitis C virus; ICF Informed 
Consent Form; IVintravenous; QLQ-LC13Lung Cancer module; MRImagnetic resonance imaging; NSCLCnonsmall cell lung cancer; 
PDpharmacodynamic; PD-L1programmed deathligand 1; PKpharmacokinetic; QLQ-C30Quality-of-Life Questionnaire Core 30; 
SILCSymptoms in Lung Cancer; TSHthyroid-stimulating hormone.
a Assessments should be performed before study drug infusion unless otherwise noted.
b 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 Assessments (cont.)
c Cycle 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 4.5.13.2.
d Patients have the option to sign the Prescreening ICF to consent to PD-L1 tissue testing during prescreening, prior to signing the main ICF for 
study participation.  Consent may be obtained more than 28 days before initiation of study treatment.  For patients with non-squamous NSCLC, 
EGFR and/or ALK status if unknown may be assessed locally or at a central lab.  Additional tissue will be required for central testing of EGFR 
and/or ALK. 
e If a representative FFPE tumor specimen in paraffin block (preferred) or 15 (or more), freshly cut, unstained serial sections (on slides) from an 
FFPE tumor specimen are not available for PD-L1 testing, contact the Medical Monitor to discuss to determine if the patient may participate in 
the study.  Fine-needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or cell smears),
brushing, cell pellets from pleural effusion, and lavage samples are NOT acceptable.  For core needle biopsy specimens, at least three cores 
should be submitted for evaluation.  Retrieval of archival tumor sample can occur more than 28 days prior to randomization.  See Section 4.5.7.1 
and Section 4.1.1 for details.
f
For patients whose initial archival tumor tissue sample is PD-L1 negative, a biopsy can be performed at screening to submit fresh tissue for the 
purposes of testing PD-L1 status.  A positive result in any tumor tissue sample will satisfy this eligibility criterion.
g Patients with non-squamous NSCLC who have an unknown EGFR and/or ALK status will be required to be tested at prescreening/screening.  
Patients with squamous NSCLC who have an unknown status will not be required to be tested at prescreening/screening. EGFR and/or ALK 
may be assessed locally or at a central lab. Additional tissue will be required for central testing of EGFR and/or ALK.  See Section 4.1.1 
Inclusion criteria for details.
h Vital signs include pulse rate, respiratory rate, blood pressures, and temperature. 
i
For both study treatment arms, the patient’s vital signs should be recorded within 60 minutes before infusion, and during and after the infusion if 
clinically indicated.  For the atezolizumab arm, vital signs should also be collected during the first infusion every 15 (5) minutes and within 30 
(10) minutes after the first infusion if clinically indicated.  For subsequent infusions in both arms, vital signs will be collected within 60 minutes 
prior to the infusion and should be collected during the infusion and within 30 (10) minutes after the infusion, if clinically indicated or if 
symptoms occurred in the prior infusion.  See Section 4.5.4 for details.
j
Symptom-directed physical examinations; see Section 4.5.3 for details. 
k ECG recordings will be obtained when clinically indicated.


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Appendix 2
Schedule of Assessments (cont.)
l
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, basophils, and other cells), and platelet count.  Hematology tests must be performed prior to Day 1 infusions, and for gemcitabine 
administration, also prior to Day 8 infusions.
m At screening, the patient must have adequate hematologic and end-organ function defined by laboratory results obtained within 14 days prior to 
randomization, as described in Section 4.1.1.
n Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2 (if considered standard of care 
for the region), calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  
o Serum pregnancy test within 14 days before Cycle 1, Day 1.
p Urine pregnancy tests; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
q  Total T3 will be tested only at sites where free T3 is not performed.
r Thyroid function testing (TSH, free T3, free T4) collected at Cycle 1, Day 1, and every fourth cycle thereafter. 
s 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 HBsAg test result at screening) will be excluded from the study.  Patients 
with past or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible; HBV DNA must be performed prior 
to randomization in these patients.  Patients with HCV will be excluded from the study; patients who test positive for HCV antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA.
t
Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood). Urinalysis is required at screening and will be obtained during 
study treatment when clinically indicated.
u For atezolizumab, the initial dose will be delivered over 60 (10) 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 chemotherapy, study drug will be 
administered according to the doses and suggested infusion times, including premedication, as described in Section 4.3.2.2-4.3.2.4.
v CT scans (with oral/IV contrast unless contraindicated) or MRI 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 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.
w Perform every 6 weeks (7 days; approximately every two cycles) for 48 weeks 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 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.  CT 
scans may be repeated at any time if progressive disease is suspected.  Tumor assessments will be performed according to RECIST v1.1 (see


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cc EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L questionnaires will be completed by the patients on the ePRO tablet according to the 
tumor assessment schedule (i.e., every 6 weeks (7 days) for 48 weeks following Cycle 1, Day 1, and every 9 weeks (7 days) thereafter after 
the completion of the Week 48 tumor assessment 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)prior to administration of study drug and prior to any other study assessments.  The SILC scale will be completed using an electronic device 
at the patient’s home on a weekly basis.  Patients who discontinue study treatment for any reason other than 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) will complete the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L at each tumor assessment visit 
and will complete the SILC at home on a weekly basis, until radiographic disease progression per RECIST v1.1, 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.  Patients whose native language is not available in the ePRO device or who are deemed by the investigator incapable of 
inputting their ePRO assessment after undergoing appropriate training are exempt from all ePRO assessments.
Appendix 2
Schedule of Assessments (cont.)
Appendix 4) and modified RECIST (see Appendix 5) for patients in the atezolizumab arm, and only according to RECIST v1.1 for patients in the 
chemotherapy arm. See Section 4.5.5 f or details.
x 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 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, even if patient starts another anti-cancer therapy after study treatment discontinuation.
y See Appendix 2 for detailed schedule.
z Mandatory tumor biopsy at radiographic disease progression, if clinically feasible, within 40 days of radiographic progression or prior to the start 
of the next anti-cancer therapy, whichever is sooner (see Section 4.5.7.2).
aa Only serious adverse events caused by protocol-mandated intervention should be reported.
bb 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 new systemic anti-cancer therapy after last dose of study treatment.  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 systemic anti-cancer therapy after 
last dose of study treatment.  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).


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Appendix 2
Schedule of Assessments (cont.)
dd During survival follow-up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L will be completed at 3 and 6 months following disease 
progression (or loss of clinical benefit for atezolizumab-treated patients who had continued treatment with atezolizumab after radiographic 
disease progression according to RECIST v1.1) if the patient returns to the clinic.  The SILC scale will be completed monthly during survival 
follow-up for 6 months following disease progression (or loss of clinical benefit for atezolizumab-treated patients who had continued treatment 
with atezolizumab after radiographic disease progression according to RECIST v1.1).  


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Appendix 2
Schedule of Assessments (cont.)
Schedule of Pharmacokinetic, Biomarker, and Anti-Therapeutic Antibody 
Assessments
Study Visit
Time
Patients 
Randomized to 
Chemotherapy
Patients Randomized to 
Atezolizumab
Screening

Biomarkers a
Biomarkers a
Cycle 1, Day 1
Prior to dosing (same 
day as treatment 
administration)
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
30 (10) minutes 
after end of 
atezolizumab infusion

Atezolizumab 
pharmacokinetics
Cycles 2, 3, 4, 8 and 
16, Day 1
Prior to dosing (same 
day as treatment 
administration)
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
After Cycle 16, every 
eighth cycle, Day 1
Prior to dosing (same 
day as treatment 
administration)
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
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
Biomarkers b
ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
120 30 days after 
last dose of 
atezolizumab
At visit

ATA
Atezolizumab 
pharmacokinetics
Biomarkers b
Any time point during 
the study (RCR 
consent required)
Optional RCR blood 
(DNA extraction) b
Optional RCR blood (DNA 
extraction) b
ATAanti-therapeutic antibody; RCRRoche Clinical Repository.
a Whole blood for biomarkers.
b Plasma and serum for biomarkers.


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