Conditions: Carcinoma, Non-Squamous Non-Small Cell Lung
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 723
Healthy volunteers: no

Brief summary:
This randomized Phase III, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab (an engineered anti-programmed death-ligand 1 \[PD-L1\] antibody) in combination with carboplatin+nab-paclitaxel compared with treatment with carboplatin+nab-paclitaxel in chemotherapy-naive participants with Stage IV non-squamous NSCLC. Participants were randomized in a 2:1 ratio to Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) or Arm B (Nab-Paclitaxel+Carboplatin).

Detailed description:

Arms:
arm 1: Participants received intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurred first during induction treatment phase. Participants received IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit. arm 2: Participants received IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurred first during induction treatment phase. Participants received best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed was also permitted. Participants who were consented prior to approval of protocol Version 5 were given the option to cross over to receive atezolizumab as monotherapy until disease progression.

Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody intervention 2: Carboplatin intervention 3: Nab-Paclitaxel intervention 4: Pemetrexed
Intervention descriptions: intervention 1: Atezolizumab was administered as IV infusion at a dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Atezolizumab was administered to participants who were randomized to "Arm A (Atezolizumab + Nab-Paclitaxel + Carboplatin)" and to participants in "Arm B (Nab-Paclitaxel + Carboplatin)" who cross over at progression. intervention 2: Carboplatin was administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle. intervention 3: Nab-paclitaxel was administered as IV infusion at a dose of 100 milligrams per square meter (mg/m\^2) on Days 1, 8, and 15 of each 21-day cycle. intervention 4: Switch maintenance to pemetrexed can be administered within 6 weeks of Day 1 of the last induction cycle.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY EVALUATING THE EFFICACY 
AND SAFETY OF ATEZOLIZUMAB (MPDL3280A, 
ANTI-PD-L1 ANTIBODY) IN COMBINATION WITH 
CARBOPLATIN + NAB-PACLITAXEL FOR 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV 
NON-SQUAMOUS NON-SMALL CELL LUNG CANCER 
NCT Number: 
NCT02367781 
Document Dates: 
Protocol Amendment Version 7: 24 October 2018 
SAP Version 4: 4 May 2018 
 
 
 


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 GO29537, Version 7
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY EVALUATING THE EFFICACY 
AND SAFETY OF ATEZOLIZUMAB (MPDL3280A, 
ANTIPD-L1 ANTIBODY) IN COMBINATION WITH 
CARBOPLATINNAB-PACLITAXEL FOR 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV 
NON-SQUAMOUS NONSMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29537/NCT02367781
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003206-32
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267) 
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
21 November 2014
DATES AMENDED:
Version 2:  29 March 2015
Version 3:  24 August 2015
Version 4:  11 November 2015
Version 5:  15 June 2016
Version 6:  1 March 2017
Version 7:  See electronic date stamp below.
24-Oct-2018 09:26:56
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GO29537, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol GO29537 has been amended to reflect a change in the definition for the end of 
study.  Changes to the protocol, along with a rationale for each change, are summarized 
below:

The end of study definition has been corrected.  This correction ensures that the 
study continues until last patient, last visit or until the Sponsor terminates the study 
(Section 3.2).

The inclusion criterion that addresses female contraception has been modified to 
specify when women must refrain from donating eggs (Section 4.1.1).

Instructions about patient withdrawal from the Roche Clinical Repository after site 
closure have been modified to indicate that the investigator must inform the Sponsor 
of patient withdrawal by emailing the study number and patient number to 
global_rcr-withdrawal@roche.com (Section 4.5.11.6).

The Medical Monitor has been changed, and the contact information has been 
revised accordingly (Section 5.4.1).

Language has been revised to account for the fact that some sites may not allow 
follow-up on partner pregnancies (Section 5.4.3.2).

Language has been updated to indicate that therapeutic or elective abortions are 
not considered adverse events unless performed because of an underlying maternal 
or embryofetal toxicity.  In such cases, the underlying toxicity should be reported as 
a serious adverse event.  Language has also been added to clarify that all abortions 
are to be reported on the paper Clinical Trial Pregnancy Reporting Form
(Section 5.4.3.3).

Language has been added for consistency with Roche's current data retention 
policy and to accommodate more stringent local requirements (if applicable)
(Section 7.6).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Protocol GO29537, Version 7
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 31
1.1
Background on Lung Cancer................................................. 31
1.1.1
First-Line Treatment for Advanced NSCLC with 
an EGFR Mutation or ALK Rearrangement ........................... 32
1.1.2
First-Line Treatment for Advanced NSCLC 
without an EGFR Mutation or ALK 
Rearrangement...................................................................... 32
1.1.3
nab-Paclitaxel Carboplatin for First-Line 
NSCLC .................................................................................. 33
1.1.4
AVASTIN and Vascular Endothelial Growth 
Factor .................................................................................... 36
1.1.4.1
Clinical Studies of Bevacizumab and 
Platinum-Based Treatment in NSCLC................................... 37
1.1.5
Targeted Therapy for NSCLC................................................ 38
1.1.6
Erlotinib or Pemetrexed Maintenance Therapy for 
NSCLC .................................................................................. 38
1.2
Background on Atezolizumab................................................ 39
1.2.1
Summary of Nonclinical Studies............................................ 40
1.3
Clinical Experience with Atezolizumab .................................. 40
1.3.1
Ongoing Clinical Studies........................................................ 40
1.3.2
Clinical Safety........................................................................ 41
1.3.2.1
Single-Agent Clinical Safety in Patients with 
NSCLC in Study PCD4989g.................................................. 41
1.3.2.2
Single-Agent Clinical Safety in Patients with 
NSCLC in Study GO28753 (POPLAR) .................................. 43
1.3.2.3
Single-Agent Clinical Safety in Patients with 
NSCLC in Study GO28915 (OAK)......................................... 44
1.3.2.4
Clinical Safety in Combination with Bevacizumab 
or Platinum-Based Doublet Chemotherapy ........................... 45
1.3.3
Clinical Activity....................................................................... 47
1.3.3.1
Single-Agent Clinical Activity in Patients with 
NSCLC in Study PCD4989g.................................................. 47


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1.3.3.2
Single-Agent Clinical Activity in Patients with 
NSCLC in Study GO28753 (POPLAR) .................................. 48
1.3.3.3
Single-Agent Clinical Activity in Patients with 
NSCLC in Study GO28915 (OAK)......................................... 50
1.3.3.4
Clinical Efficacy in Combination with Platinum-
Based Doublet Chemotherapy in Patients with 
NSCLC .................................................................................. 51
1.3.4
Clinical Pharmacokinetics and Immunogenicity..................... 51
1.3.5
Rationale for Atezolizumab Dosage ...................................... 51
1.4
Study Rationale and Benefit–Risk Assessment..................... 52
1.4.1
Rationale for Testing Atezolizumab in 
Combination with Carboplatin/nab-Paclitaxel ........................ 53
2.
OBJECTIVES.............................................................................................. 55
2.1
Efficacy Objectives ................................................................ 55
2.1.1
Co-Primary Efficacy Objectives ............................................. 55
2.1.2
Secondary Efficacy Objectives .............................................. 56
2.2
Safety Objectives................................................................... 56
2.3
Pharmacokinetic Objectives .................................................. 57
2.4
Exploratory Objectives........................................................... 57
3.
STUDY DESIGN......................................................................................... 57
3.1
Description of the Study......................................................... 57
3.1.1
Independent Data Monitoring Committee .............................. 60
3.2
End of Study.......................................................................... 61
3.3
Rationale for Study Design.................................................... 61
3.3.1
Rationale for Testing Atezolizumab in Patients 
with  PD-L1–Unselected NSCLC........................................... 61
3.3.2
Rationale for Control Arm ...................................................... 62
3.3.3
Rationale for Open-Label Study ............................................ 62
3.3.4
Rationale for Progression-Free Survival and 
Overall Survival as Co-Primary Endpoints............................. 63
3.3.5
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment until Loss of 
Clinical Benefit....................................................................... 64
3.3.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 64


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3.3.7
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens and Evaluation of PD-L1 and 
T-Effector Gene Signature..................................................... 65
3.3.8
Rationale for Blood Sampling for Biomarkers........................ 65
3.3.9
Rationale for the Collection of Mandatory Tumor 
Specimens at Radiographic Progression............................... 66
3.4
Outcome Measures ............................................................... 66
3.4.1
Efficacy Outcome Measures.................................................. 66
3.4.1.1
Co-Primary Efficacy Outcome Measures............................... 66
3.4.1.2
Secondary Efficacy Outcome Measures................................ 66
3.4.2
Safety Outcome Measures .................................................... 67
3.4.3
Pharmacokinetic Outcome Measures.................................... 67
3.4.4
Exploratory Outcome Measures ............................................ 68
4.
MATERIALS AND METHODS .................................................................... 68
4.1
Patients.................................................................................. 68
4.1.1
Inclusion Criteria.................................................................... 68
4.1.2
Exclusion Criteria................................................................... 71
4.1.2.1
Cancer-Specific Exclusions ................................................... 71
4.1.2.2
General Medical Exclusions .................................................. 72
4.1.2.3
Exclusion Criteria Related to Medications ............................. 74
4.1.2.4
Exclusions Related to Chemotherapy.................................... 75
4.2
Method of Treatment Assignment and Blinding..................... 75
4.3
Study Treatment.................................................................... 76
4.3.1
Formulation, Packaging, and Handling.................................. 76
4.3.1.1
Atezolizumab (MPDL3280A) ................................................. 76
4.3.1.2
Carboplatin and nab-Paclitaxel.............................................. 76
4.3.1.3
Erlotinib and Pemetrexed ...................................................... 76
4.3.2
Dosage, Administration, and Compliance.............................. 77
4.3.2.1
Atezolizumab......................................................................... 78
4.3.2.2
Carboplatin and nab-Paclitaxel.............................................. 80
4.3.2.3
Erlotinib and Pemetrexed ...................................................... 81
4.3.2.4
Additional Required Medication............................................. 81
4.3.3
Investigational Medicinal Product Accountability ................... 81
4.3.4
Post-Study Access to Atezolizumab ...................................... 82


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4.4
Concomitant Therapy ............................................................ 82
4.4.1
Permitted Therapy................................................................. 82
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 83
4.4.3
Prohibited Therapy ................................................................ 84
4.5
Study Assessments ............................................................... 84
4.5.1
Informed Consent Forms and Screening Log........................ 85
4.5.2
Medical History and Demographic Data ................................ 85
4.5.3
Physical Examinations........................................................... 86
4.5.4
Vital Signs.............................................................................. 86
4.5.5
Tumor and Response Evaluations......................................... 87
4.5.6
Laboratory Assessments and Biomarker 
Samples................................................................................. 89
4.5.7
Tumor Tissue Samples.......................................................... 91
4.5.7.1
Archival and Freshly Collected Tumor Tissue 
Samples for Screening .......................................................... 91
4.5.7.2
Tumor Samples at the Time of Radiographic 
Progression ........................................................................... 92
4.5.7.3
Tumor Samples at Other Timepoints..................................... 92
4.5.7.4
Use and Storage of Remaining Samples from  
Study-Related Procedures..................................................... 93
4.5.8
Anti-Therapeutic Antibody Testing......................................... 93
4.5.9
Electrocardiograms................................................................ 93
4.5.10
Patient-Reported Outcomes .................................................. 94
4.5.11
Samples for Roche Clinical Repository.................................. 96
4.5.11.1
Overview of the Roche Clinical Repository............................ 96
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 96
4.5.11.3
Sample Collection.................................................................. 96
4.5.11.4
Confidentiality........................................................................ 97
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 98
4.5.11.6
Withdrawal from the Roche Clinical Repository..................... 98
4.5.11.7
Monitoring and Oversight....................................................... 98
4.5.12
Timing of Assessments.......................................................... 99


Atezolizumab—F. Hoffmann-La Roche Ltd
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4.5.12.1
Screening and Baseline Assessments .................................. 99
4.5.12.2
Assessments during Treatment............................................. 99
4.5.12.3
Assessments for Treatment-Crossover Patients ................. 100
4.5.12.4
Assessments at Study Drug Discontinuation Visit ............... 100
4.5.12.5
Follow-Up Assessments ...................................................... 101
4.5.12.6
Assessments at Unplanned Visits ....................................... 102
4.6
Patient, Treatment, Study, and 
Site Discontinuation............................................................. 102
4.6.1
Patient Discontinuation........................................................ 102
4.6.2
Study Treatment Discontinuation......................................... 103
4.6.3
Study and Site Discontinuation............................................ 104
5.
ASSESSMENT OF SAFETY..................................................................... 105
5.1
Safety Plan .......................................................................... 105
5.1.1
Risks Associated with Atezolizumab ................................... 106
5.1.2
Risks Associated with Carboplatin....................................... 106
5.1.3
Risks Associated with nab-Paclitaxel .................................. 106
5.1.4
Risks Associated with Erlotinib............................................ 107
5.1.5
Risks Associated with Pemetrexed...................................... 107
5.1.6
General Plan to Manage Safety Concerns .......................... 107
5.1.6.1
Monitoring............................................................................ 107
5.1.7
Dose Modification................................................................ 108
5.1.7.1
General Notes Regarding Dose Modification....................... 108
5.1.7.2
Atezolizumab Dose Modification.......................................... 108
5.1.8
Management of Atezolizumab-Specific Adverse 
Events.................................................................................. 109
5.1.9
Carboplatin and nab-Paclitaxel Dose Modification 
and Management of Specific Adverse Events ..................... 110
5.1.9.1
Hematologic Toxicity ........................................................... 110
5.1.9.2
Gastrointestinal Toxicity....................................................... 111
5.1.9.3
Neurological Toxicity ........................................................... 112
5.1.9.4
Hepatic Toxicity (nab-Paclitaxel Only) ................................. 112
5.1.9.5
Pulmonary Events and Pneumonitis:  
Atezolizumab and nab-Paclitaxel, or 
nab-Paclitaxel without Atezolizumab ................................... 113


Atezolizumab—F. Hoffmann-La Roche Ltd
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5.1.9.6
Other Toxicities.................................................................... 115
5.1.10
Erlotinib and Pemetrexed Dose Modification and 
Management of Specific Adverse Events ............................ 116
5.1.11
Potential Overlapping Toxicities .......................................... 116
5.2
Safety Parameters and Definitions ...................................... 117
5.2.1
Adverse Events ................................................................... 117
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 117
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 118
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 119
5.3.1
Adverse Event Reporting Period ......................................... 119
5.3.2
Eliciting Adverse Event Information..................................... 120
5.3.3
Assessment of Severity of Adverse Events ......................... 120
5.3.4
Assessment of Causality of Adverse Events ....................... 121
5.3.5
Procedures for Recording Adverse Events.......................... 121
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 121
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................. 122
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 122
5.3.5.4
Abnormal Laboratory Values ............................................... 122
5.3.5.5
Abnormal Vital Sign Values ................................................. 123
5.3.5.6
Abnormal Liver Function Tests............................................ 124
5.3.5.7
Deaths ................................................................................. 124
5.3.5.8
Preexisting Medical Conditions............................................ 125
5.3.5.9
Worsening of NSCLC .......................................................... 125
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 125
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 126
5.3.5.12
Patient-Reported Outcome Data ......................................... 126
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 126
5.4.1
Emergency Medical Contacts.............................................. 127


Atezolizumab—F. Hoffmann-La Roche Ltd
9/Protocol GO29537, Version 7
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 127
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 127
5.4.2.2
Events That Occur after Study Drug Initiation...................... 127
5.4.3
Reporting Requirements for Pregnancies............................ 128
5.4.3.1
Pregnancies in Female Patients.......................................... 128
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 128
5.4.3.3
Abortions ............................................................................. 129
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 129
5.5
Follow-Up of Patients after Adverse Events ........................ 129
5.5.1
Investigator Follow-Up......................................................... 129
5.5.2
Sponsor Follow-Up .............................................................. 130
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 130
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees........................................................ 130
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 131
6.1
Determination of Sample Size ............................................. 131
6.2
Summaries of Conduct of Study.......................................... 133
6.3
Summaries of Treatment Group Comparability ................... 133
6.4
Efficacy Analyses ................................................................ 134
6.4.1
Co-Primary Efficacy Endpoints............................................ 134
6.4.2
Secondary Efficacy Endpoints............................................. 135
6.4.2.1
Progression-Free Survival and Overall Survival in 
Secondary Populations........................................................ 135
6.4.2.2
Objective Response Rate.................................................... 136
6.4.2.3
Duration of Response.......................................................... 136
6.4.2.4
Overall Survival Rate at Landmark Timepoints.................... 136
6.4.2.5
Patient-Reported Outcomes ................................................ 137
6.4.3
Handling of Missing Data..................................................... 137
6.5
Safety Analyses................................................................... 138
6.5.1
Treatment Phase................................................................. 138


Atezolizumab—F. Hoffmann-La Roche Ltd
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6.5.2
Crossover Phase (For Patients Who Entered  
Study GO29537 under Protocol Versions 1–4).................... 138
6.6
Pharmacokinetic Analyses................................................... 139
6.7
Exploratory Analyses........................................................... 139
6.7.1
Exploratory Analyses of Progression-Free 
Survival................................................................................ 139
6.7.1.1
Progression-Free Survival Rate at Landmark 
Timepoints........................................................................... 139
6.7.1.2
Non–Protocol-Specified Anti-Cancer Therapy..................... 139
6.7.1.3
Subgroup Analysis............................................................... 139
6.7.1.4
Sensitivity Analyses............................................................. 140
6.7.2
Exploratory Analyses of Overall Survival............................. 140
6.7.2.1
Loss to Follow-Up................................................................ 140
6.7.2.2
Subgroup Analysis............................................................... 140
6.7.2.3
Overall Survival Rate at Three-Year Landmark................... 140
6.7.2.4
Milestone Overall Survival Analysis..................................... 141
6.7.3
Exploratory Biomarker Analysis........................................... 141
6.7.4
EQ-5D-3L Health Status Data ............................................. 141
6.7.5
Patient-Reported Outcome Analyses .................................. 141
6.8
Interim Analyses .................................................................. 141
6.8.1
Planned Interim Analysis ..................................................... 141
6.8.2
Optional Interim Analysis..................................................... 142
7.
DATA COLLECTION AND MANAGEMENT ............................................. 143
7.1
Data Quality Assurance....................................................... 143
7.2
Electronic Case Report Forms............................................. 143
7.3
Electronic Patient-Reported Outcome Data......................... 143
7.4
Source Data Documentation................................................ 144
7.5
Use of Computerized Systems ............................................ 144
7.6
Retention of Records........................................................... 145
8.
ETHICAL CONSIDERATIONS.................................................................. 145
8.1
Compliance with Laws and Regulations .............................. 145
8.2
Informed Consent................................................................ 145
8.3
Institutional Review Board or Ethics Committee.................. 147


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8.4
Confidentiality...................................................................... 147
8.5
Financial Disclosure ............................................................ 147
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 148
9.1
Study Documentation .......................................................... 148
9.2
Protocol Deviations.............................................................. 148
9.3
Site Inspections ................................................................... 148
9.4
Administrative Structure....................................................... 148
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 149
9.6
Protocol Amendments ......................................................... 149
10. REFERENCES ......................................................................................... 150


Atezolizumab—F. Hoffmann-La Roche Ltd
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LIST OF TABLES
Table 1
Randomized Phase III Trials in Patients with Previously 
Untreated NSCLC....................................................................... 35
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades................................................................ 42
Table 3
Study GO28753 (POPLAR):  Adverse Events Reported in at 
Least 10% of Patients................................................................. 44
Table 4
Adverse Events in Study GO28915 (OAK) with a Between-
Arm Difference in Frequency of at Least 5 Percentage Points.... 45
Table 5
Study GP28328:  All Reported Adverse Events.......................... 46
Table 6
Patients with NSCLC in Study PCD4989g:  Investigator-
Assessed Confirmed Objective Response Rate by Tumor 
PD-L1 Expression, Duration of Response, and Six-Month 
Progression-Free Survival Rates (according to RECIST v1.1).... 48
Table 7
Efficacy Results in Study GO28753 (POPLAR):  
Intent-to-Treat Population ........................................................... 49
Table 8
Study GO28753 (POPLAR) Efficacy Results by Combination 
PD-L1 Diagnostic Subgroups with Complementary 
Comparison Subgroupings:  Intent-to-Treat Population.............. 50
Table 9
Study GO29537 Treatment Arms................................................ 58
Table 10
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 79
Table 11
Vital Sign Measurements at Cycle 1 and All 
Subsequent Cycles..................................................................... 87
Table 12
nab-Paclitaxel and Carboplatin Permanent Dose Reductions 
Based on Nadir ANC and Platelets........................................... 111
Table 13
Carboplatin and nab-Paclitaxel Dose Modification Based on 
Gastrointestinal Toxicities in the Preceding Cycle .................... 111
Table 14
nab-Paclitaxel and Carboplatin Permanent Dose Reductions
for Neurological Toxicity............................................................ 112
Table 15
Management Guidelines for Pneumonitis:  Atezolizumab and 
nab-Paclitaxel, or nab-Paclitaxel with or without 
Atezolizumab ............................................................................ 115
Table 16
nab-Paclitaxel and Carboplatin Permanent Dose Reductions 
for Non-Hematologic, Non-Gastrointestinal, Non-Neurologic, 
and Non-Hepatic Toxicity.......................................................... 116
Table 17
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 120
Table 18
Analysis Timing and Stopping Boundaries for 
Overall Survival in the ITT-WT Population ............................... 142


Atezolizumab—F. Hoffmann-La Roche Ltd
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LIST OF FIGURES
Figure 1
Study Schema............................................................................. 60
Figure 2
Conditions for Continuing Atezolizumab in Presence of 
Increased Radiographic Tumor Size (Applicable to Arm A 
and Arm B Crossover Patients Consented under Study 
GO29537 Protocol Versions 14) ............................................. 104
Figure 3
Progression-Free Survival and Overall Survival Analysis 
Hierarchy, Alpha Allocation, and Alpha Recycling .................... 132
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 158
Appendix 2
Schedule of Pharmacokinetic, Biomarker, and 
Anti-Therapeutic Antibody Assessments .................................. 164
Appendix 3
Schedule of Pharmacokinetic, Biomarker, and 
Anti-Therapeutic Antibody Assessments for Arm B Patients 
Who Cross Over to Receive Atezolizumab as Allowed under 
Protocol Versions 14............................................................... 167
Appendix 4
American Joint Committee on Cancer NonSmall Cell Lung 
Cancer Staging, 7th Edition ...................................................... 168
Appendix 5
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication ............................... 170
Appendix 6
Modified Response Evaluation Criteria in Solid Tumors ........... 182
Appendix 7
AntiPD-L1 Immunohistochemistry........................................... 189
Appendix 8
EORTC QLQ-C30..................................................................... 190
Appendix 9
EORTC QLQ-LC13................................................................... 192
Appendix 10
EQ-5D-3L.................................................................................. 193
Appendix 11
Eastern Cooperative Oncology Group Performance 
Status Scale.............................................................................. 196
Appendix 12
Anaphylaxis Precautions........................................................... 197
Appendix 13
Preexisting Autoimmune Diseases ........................................... 198
Appendix 14
Symptoms in Lung Cancer........................................................ 199
Appendix 15
Patient Global Impression of Severity....................................... 202
Appendix 16
Additional Guidance on Chemotherapy Administration............. 203


Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol GO29537, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
OPEN-LABEL STUDY EVALUATING THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
(MPDL3280A, ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH 
CARBOPLATINNAB-PACLITAXEL FOR 
CHEMOTHERAPY-NAIVE PATIENTS WITH 
STAGE IV NON-SQUAMOUS NONSMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29537
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003206-32
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPD3280A, RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy to 
the Sponsor or their designee.


Atezolizumab—F. Hoffmann-La Roche Ltd
15/Protocol GO29537, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATINNAB-PACLITAXEL FOR 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV 
NON-SQUAMOUS NONSMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29537
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003206-32
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
PHASE:
III
INDICATION:
Non-squamous nonsmall cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
The term "wild type" (WT) refers to randomized patients who do not have a sensitizing EGFR 
mutation or ALK translocation.
The term "tumor gene expression" (tGE) refers to randomized patients with a defined level of 
expression of a PD-L1 and T-effector gene signature in tumor tissue, as analyzed through use 
of a centrally performed RNA-based assay.
Some efficacy endpoints will be analyzed in a population of randomized patients with a defined 
level of PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs), as 
analyzed through use of a centrally performed immunohistochemistry (IHC) test.
Efficacy Objectives
The co-primary objectives of this study are the following:

To evaluate the efficacy of atezolizumab carboplatin nab-paclitaxel compared with 
carboplatin nab-paclitaxel as measured by investigator-assessed progression-free survival 
(PFS) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) in the tGE-WT population and the intent-to-treat wild type (ITT-WT)
population

To evaluate the efficacy of atezolizumabcarboplatinnab-paclitaxel compared with 
carboplatinnab-paclitaxel as measured by overall survival (OS) in the ITT-WT population
The secondary efficacy objectives for this study are the following:

To evaluate the efficacy of atezolizumab as measured by OS in the tGE-WT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed PFS 
according to RECIST v1.1 and OS in the TC2/3 or IC2/3 WT population and the TC1/2/3 or 
IC1/2/3 WT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed PFS 
according to RECIST v1.1 and OS in the tGE population and the ITT population 

To evaluate the efficacy of atezolizumab as measured by investigator-assessed objective 
response rate according to RECIST v1.1 for both the tGE-WT population and the ITT-WT 
population


Atezolizumab—F. Hoffmann-La Roche Ltd
16/Protocol GO29537, Version 7

To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response according to RECIST v1.1 for both the tGE-WT population and the ITT-WT 
population

To evaluate the OS rate at 1 and 2 years in each treatment arm in the tGE-WT population 
and the ITT-WT population

To determine the impact of atezolizumab as measured by time to deterioration (TTD) in 
patient-reported lung cancer symptoms of cough, dyspnea (single-item and multi-item 
subscales), chest pain, or arm/shoulder pain, using the European Organisation for the 
Research and Treatment of Cancer (EORTC) Quality-of-Life QuestionnaireCore 30 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) in the tGE-WT 
population and the ITT-WT population

To determine the impact of atezolizumab as measured by change from baseline 
(i.e., improvement or deterioration based upon presenting symptomatology) in 
patient-reported lung cancer symptom (chest pain, dyspnea, and cough) score using the 
Symptoms in Lung Cancer (SILC) scale symptom severity score in the tGE-WT population 
and the ITT-WT population
Safety Objectives
The safety objectives for this study are the following:

To evaluate the safety and tolerability of atezolizumabcarboplatinnab-paclitaxel 
compared with carboplatinnab-paclitaxel

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, safety, and efficacy
Pharmacokinetic Objectives
The pharmacokinetic (PK) objectives for this study are the following:

To characterize the pharmacokinetics of atezolizumab when given in combination with 
carboplatin and nab-paclitaxel

To characterize the pharmacokinetics of carboplatin when given in combination with 
nab-paclitaxel with and without atezolizumab

To characterize the pharmacokinetics of nab-paclitaxel when given in combination with 
carboplatin with and without atezolizumab
Exploratory Objectives
The exploratory objectives for this study are the following:

To evaluate PFS at 6 months and at 1 year in each treatment arm

To evaluate the OS rate at 3 years in each treatment arm

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease status, mechanisms 
of resistance, and/or response to study treatment

To evaluate 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 Dimensions 3-Level (EQ-5D-3L) questionnaire to generate utility scores for use in 
economic models for reimbursement

To determine the impact of atezolizumab as measured by change from baseline in 
patient-reported outcomes of health-related quality of life, lung cancerrelated symptoms, 
and functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13


Atezolizumab—F. Hoffmann-La Roche Ltd
17/Protocol GO29537, Version 7
Study Design
Description of Study
This is a randomized, Phase III, multicenter, open-label study (IMpower130) designed to 
evaluate the safety and efficacy of atezolizumab in combination with carboplatin nab-paclitaxel 
compared with treatment with carboplatin nab-paclitaxel in approximately 
715 chemotherapy-naive patients with Stage IV non-squamous nonsmall cell lung cancer
(NSCLC).
Tumor specimens will be prospectively tested for PD-L1 expression by a central laboratory. 
Eligible patients will be stratified by sex (male vs. female), presence of liver metastases at 
baseline (yes vs. no), and by PD-L1 tumor expression by IHC (TC3 and any IC vs. TC0/1/2 and 
IC2/3 vs. TC0/1/2 and IC0/1) and randomized in a 2:1 ratio to receive one of the following 
treatment regimens.
Treatment Arm A:  Atezolizumabcarboplatinnab-paclitaxel (Induction: four or six 21-day 
cycles); atezolizumab (Maintenance: 21-day cycles)
Treatment Arm B:  Carboplatinnab-paclitaxel (Induction: four or six 21-day cycles); best 
supportive care or pemetrexed (Maintenance: 21-day cycles)
The number of cycles of induction treatment (four or six) will be at the discretion of the 
investigator and will be determined and documented prior to randomization. Induction treatment 
will be administered on a 21-day cycle until the following occurs (whichever occurs first):  
1) administration of four or six cycles or 2) disease progression (Arm B) or loss of clinical benefit 
(Arm A) is documented.  
Following the induction phase, patients who are randomized to atezolizumab (Arm A) may 
continue treatment with atezolizumab beyond radiographic disease progression according to 
RECIST v1.1, provided they 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).  Patients randomized to 
carboplatinnab-paclitaxel (Arm B) will be offered best supportive care provided they have 
non-progressive disease.  Switch maintenance to pemetrexed is also permitted for patients 
randomized to Arm B.  Switch maintenance must be administered within 6 weeks of Day 1 of 
the last induction cycle.
Patients who entered Study GO29537 under Protocol Versions 14 and are randomized to 
carboplatinnab paclitaxel will be given the option to cross over to receive atezolizumab as 
monotherapy upon progressive disease per RECIST v1.1, provided they continue to meet 
eligibility criteria.  Safety data for patients who crossed over from Arm B to receive atezolizumab 
as allowed under Protocol Versions 14 will be summarized for exploratory purposes.
For Atezolizumab-Treated Patients Only
During treatment (induction or maintenance), patients receiving atezolizumab (including patients 
in Arm B who entered Study GO29537 under Protocol Versions 14 and crossed over to 
receive atezolizumab after disease progression according to RECIST v1.1) who show evidence 
of clinical benefit will be permitted to continue atezolizumab after the criteria per RECIST v1.1 
for progressive disease are met if they meet all of the following criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values, e.g., new or 
worsening hypercalcemia) indicating unequivocal progression of disease

No decline in Eastern Cooperative Oncology Group (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 atezolizumab at the time of initial progression


Atezolizumab—F. Hoffmann-La Roche Ltd
18/Protocol GO29537, Version 7
Treatment with induction chemotherapy (Arms A and B) and pemetrexed (Arm B) as switch 
maintenance must be discontinued in all patients who exhibit evidence of progressive disease
according to RECIST v1.1.
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 48 weeks 
following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, tumor assessment will be 
required every 9 weeks.  Patients will undergo tumor assessments until 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), withdrawal of consent, study termination by Sponsor, or death, 
whichever occurs first.  Patients who discontinue treatment for reasons other than radiographic 
disease progression according to RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments until 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), 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first, 
regardless of whether patients start a new anti-cancer therapy.
All primary imaging data used for tumor assessment will be collected by the Sponsor to enable 
centralized, independent review of response endpoints.  The independent reviews of the stored 
scans will be performed when requested.
Patients in all treatment arms 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.  These data will be used to explore whether radiographic 
findings are consistent with the presence of tumor.  Additionally, these data will be analyzed to 
evaluate the association between changes in tumor tissue and clinical outcome and to 
understand further the potential mechanisms of progression and resistance to atezolizumab as 
compared with such mechanisms after treatment with chemotherapy alone.  This exploratory 
biomarker evaluation will not be used for any treatment-related decisions.  Patients in Arm A 
and patients in Arm B (who entered Study GO29537 under Protocol Versions 14) who are 
unable to undergo biopsy sample collection but who otherwise meet the criteria listed above 
may continue/crossover to receive atezolizumab.
Number of Patients
Approximately 105 sites globally will participate in the study, and approximately 715 patients will 
be randomized.
Target Population
Patients may be eligible if they have chemotherapy-naive, Stage IV, non-squamous NSCLC.
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Male or female, 18 years of age or older

ECOG performance status of 0 or 1

Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 7th 
edition)
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible 
if the major histological component appears to be non-squamous.

No prior treatment for Stage IV non-squamous NSCLC
Patients with a sensitizing mutation in the EGFR gene must have experienced disease 
progression (during or after treatment) or intolerance to treatment with one or more 
EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, or another EGFR TKI 
appropriate for the treatment of EGFR-mutant NSCLC.
Patients known to have an ALK fusion oncogene must have experienced disease 
progression (during or after treatment) or intolerance to treatment with one or more ALK 


Atezolizumab—F. Hoffmann-La Roche Ltd
19/Protocol GO29537, Version 7
inhibitors (e.g., crizotinib) appropriate for the treatment of NSCLC in patients having an 
ALK fusion oncogene.  
Patients with unknown EGFR and ALK status require test results at screening.  ALK 
and/or EGFR may be assessed locally or at a central laboratory.
Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, 
or chemoradiotherapy with curative intent for non-metastatic disease must have 
experienced a treatment-free interval of at least 6 months from randomization since the 
last chemotherapy, radiotherapy, or chemoradiotherapy cycle.

Patients with a history of treated asymptomatic central nervous system (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.

Known PD-L1 tumor status 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.  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.  This specimen must be accompanied by the 
associated pathology report.
Fine-needle aspiration (defined as samples that do not preserve tissue architecture and 
yield cell suspension and/or cell smears), brushing, cell pellet specimens (e.g., from 
pleural effusion, and lavage samples) are not acceptable.  
Tumor tissue from bone metastases that is subject to decalcification is not acceptable.  
For core-needle biopsy specimens, preferably at least three cores embedded in a single 
paraffin block, should be submitted for evaluation. 

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease. 


Atezolizumab—F. Hoffmann-La Roche Ltd
20/Protocol GO29537, Version 7

Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 14 days prior to randomization:
ANC 1500 cells/L without granulocyte colony-stimulating factor support
Lymphocyte count 500/L
Platelet count 100,000/L without transfusion 
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
INR or aPTT 1.5upper limit of normal (ULN)
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
AST, ALT, and alkaline phosphatase 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase 5ULN.
Serum bilirubin 1.25ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN may be 
enrolled.
Serum creatinine 1.5ULN

For female patients of childbearing potential agreement (by patient and/or partner) to use a 
highly effective form(s) of contraception that results in a low failure rate [1% per year] 
when used consistently and correctly, and to continue its use for 5 months after the last 
dose of atezolizumab or for 30 days after the last dose of nab-paclitaxel, whichever is later.  
Women must refrain from donating eggs during this same period.  For male patients with 
female partners of childbearing potential, agreement (by patient and/or partner) to use a 
highly effective form(s) of contraception that results in a low failure rate [1% per year] 
when used consistently and correctly, and to continue its use for 6 months after the last 
dose of nab-paclitaxel and/or carboplatin, whichever is later.  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, intrauterine 
hormone-releasing system, bilateral tubal occlusion or vasectomized partner (on the 
understanding that this is the only one partner during the whole study duration), and sexual 
abstinence.  Male patients should not donate sperm during this study and for at least 
6 months after the last dose of nab-paclitaxel and/or carboplatin, whichever is later.

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 clinical study if they have a partner of childbirth 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 criteria below will be excluded from study entry:
Cancer-Specific Exclusions

Active or untreated CNS metastases as determined by computed tomography 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


Atezolizumab—F. Hoffmann-La Roche Ltd
21/Protocol GO29537, Version 7

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 locoregional therapy, if appropriate, 
prior to randomization.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or Ca 12 mg/dL 
or corrected serum calcium ULN) 
Patients who are receiving denosumab prior to randomization must be willing and 
eligible to receive a bisphosphonate instead while in the study.

Malignancies other than NSCLC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS 90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous cell skin cancer, localized prostate cancer treated surgically with 
curative intent, ductal carcinoma in situ treated surgically with curative intent)

Known tumor PD-L1 expression status as determined by an IHC assay from other clinical 
studies (e.g., patients whose PD-L1 expression status was determined during screening for 
entry into a study with antiPD-1 or antiPD-L1 antibodies but were not eligible are 
excluded)
General Medical Exclusions

Women who are pregnant, lactating, or intending to become pregnant during the study

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study.


Atezolizumab—F. Hoffmann-La Roche Ltd
22/Protocol GO29537, Version 7
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 previous 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high-potency or oral steroids)

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test for HIV
All patients will be tested for HIV prior to inclusion into the study; patients who test 
positive for HIV will be excluded from the clinical study.

Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible only if they are negative for HBV DNA.
Patients who are positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible.

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within the 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 transplant

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live, attenuated vaccine will be required during the study

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
renders the patient at high risk from treatment complications

Illness or condition that interferes with the patient’s capacity to understand, follow and/or 
comply with study procedures


Atezolizumab—F. Hoffmann-La Roche Ltd
23/Protocol GO29537, Version 7
Exclusion Criteria Related to Medications

Any approved anti-cancer therapy, including hormonal therapy within 21 days prior to 
initiation of study treatment; the following exceptions are allowed:
TKIs approved for treatment of NSCLC discontinued 7 days prior to randomization.  
The baseline scan must be obtained after discontinuation of prior TKIs.

Treatment with any other investigational agent with therapeutic intent within 28 days prior to 
randomization

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, antiPD-1, 
and antiPD-L1 therapeutic antibodies
Patients who have had prior antiCTLA-4 treatment may be enrolled, provided the 
following requirements are met:
Last dose of antiCTLA-4 at least 6 weeks prior to randomization
No history of severe immune-mediated adverse effects from antiCTLA-4 
(National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] Grades 3 and 4)

Treatment with systemic immunostimulatory agents (including but not limited to IFNs, IL-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 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 is allowed.
Exclusions Related to Chemotherapy

Known history of severe allergic reactions to platinum-containing compounds or mannitol

Known sensitivity to any component of nab-paclitaxel

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0

Known history of severe hypersensitivity reactions to products containing Cremophor® EL 
(e.g., cyclosporin for injection concentrate and teniposide for injection concentrate)
Length of Study
The final PFS analysis will be conducted when all of the following criteria have been met:  
approximately 225 PFS events have occurred in the tGE-WT population, approximately 
475 PFS events have occurred in the ITT-WT population, and the last patient has been enrolled 
in the study.  This is expected to occur approximately 32 months after the first patient is 
enrolled.  
The final OS analysis will be conducted when approximately 457 OS events have occurred in 
the ITT-WT population.  This is expected to occur approximately 42 months after the first patient 
is enrolled.
End of Study
The end of study is defined as the date of the last follow-up visit of the last patient or when all 
patients have been enrolled into an extension study.  The Sponsor may decide to terminate the 
study at any time.  If the Sponsor decides to end the study, patients who are still receiving 
study treatment or are in survival follow-up may be offered enrollment in an extension study 
or a non-interventional study.


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Outcome Measures
Efficacy Outcome Measures
The co-primary 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 according to RECIST v1.1 or death from any cause, 
whichever occurs first in the tGE-WT population and the ITT-WT population

OS, defined as the time from randomization to death from any cause, in the ITT-WT 
population
The secondary efficacy outcome measures for this study are the following:

OS in the tGE-WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the TC2/3 or 
IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the tGE 
population and the ITT population

Objective response, defined as a partial response or a complete response as determined by 
the investigator according to RECIST v1.1 for the tGE-WT population and the ITT-WT 
population

DOR, defined as the time interval from first occurrence of a documented objective response 
to the time of disease progression as determined by the investigator using RECIST v1.1 or 
death from any cause, whichever occurs first for the tGE-WT population and the ITT-WT 
population

OS rates at 1 and 2 years for the tGE-WT population and the ITT-WT population

TTD in patient-reported lung cancer symptoms, defined as time from randomization to 
deterioration (10-point change) on each of the EORTC QLQ-C30 and EORTC QLQ-LC13 
symptom subscales (cough, dyspnea [single item], dyspnea [multi-item subscale], chest 
pain, and arm/shoulder pain) in the tGE-WT population and the ITT-WT population

Change from baseline in patient-reported lung cancer symptoms (chest pain, dyspnea, and 
cough) on the symptom severity score of the SILC scale in the tGE-WT population and the 
ITT-WT population
Safety Outcome Measures
The safety outcome measures for this study are the following:

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 the following:

For patients randomized to atezolizumabcarboplatinnab-paclitaxel:
Maximum observed serum atezolizumab concentration (Cmax) after infusion on Cycle 1, 
Day 1
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at 
selected cycles, at treatment discontinuation, and at 120 days (30 days) after the last 
dose of atezolizumab
Plasma concentrations for carboplatin (Arms A and B)
Plasma concentrations for nab-paclitaxel reported as total paclitaxel (Arms A and B)


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
For patients randomized to carboplatin nab-paclitaxel who crossed over to receive open-
label atezolizumab as monotherapy (allowed under Study GO29537 Protocol 
Versions 14):
Cmax of serum atezolizumab after infusion on Day 1 of the first cycle following crossover 
to atezolizumab as monotherapy
Cmin of serum atezolizumab prior to infusion on Day 1 at selected cycles following 
crossover to atezolizumab as monotherapy, 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 the following:

PFS at 6 months and at 1 year

OS rate at 3 years

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 in combination with chemotherapy

Status of ICs and other exploratory biomarkers in mandatory biopsy specimens and blood 
collected at progression

Utility scores of the EQ-5D-3L 

Change from baseline in patient-reported outcomes of HRQoL, lung cancer-related 
symptoms, and functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13 
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal products (IMPs) for this study are atezolizumab and erlotinib.
Atezolizumab (1200 mg IV) will be administered on Day 1 of each 21–day cycle.  Atezolizumab 
will be administered to patients who are randomized to Arm A and to patients in Arm B who 
cross over at progression.
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients who had 
already started switch maintenance treatment with erlotinib under Protocol Versions 14 may be 
allowed to continue treatment with erlotinib upon discussion of the risks, potential benefits and 
alternative treatment options with the investigator.  For those patients who receive switch 
maintenance, institutions should follow the dosage and administration instructions in the 
prescribing information.  
Comparator
Nab-paclitaxel (100 mg/m2 IV) will be administered on Days 1, 8, and 15 of each 21-day cycle 
for four or six cycles during the induction phase.  Nab-paclitaxel will be considered an IMP for 
study purposes in countries where nab-paclitaxel is considered an IMP by local regulations.
Non-Investigational Medicinal Products
Comparator 
Carboplatin will be administered by IV infusion to achieve an initial target area under the 
concentrationtime curve of 6 mg/mL/min on Day 1 of each 21-day cycle for four or six cycles 
during the induction phase.
Carboplatin and nab-paclitaxel will be administered to patients in all treatment arms.
Statistical Methods
Primary Analysis
The co-primary efficacy endpoints are PFS as assessed by the investigator using RECIST v1.1 
and OS.  PFS will be analyzed in the tGE-WT population and the ITT-WT population.  OS will 
be analyzed in the ITT-WT population.  The timing of the final PFS and OS analyses is 


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described below (see "Determination of Sample Size").  At least one interim OS analysis will be 
performed.
PFS is defined as the time between the date of randomization and the date of first documented 
disease progression or death, whichever occurs first.  Patients who have not experienced 
disease progression or death at the time of analysis will be censored at the time of the last 
tumor assessment.  Patients with no post-baseline tumor assessment will be censored at the 
date of randomization plus 1 day.  
OS is defined as the time between the date of randomization and death from any cause.  Data 
for patients who are not reported as having died at the time of analysis will be censored at the 
date when they were last known to be alive.  Data for patients who do not have post-baseline 
information will be censored at the date of randomization plus 1 day.
The following analyses will be performed for both PFS and OS.  PFS and OS will be compared 
between treatment arms with the use of the stratified log-rank test.  The HR for PFS and OS for 
treatment comparisons will be estimated using a stratified Cox regression model, respectively.  
The 95% CI for the HR will be provided.
The stratification factors will be those used during randomization, (i.e., sex [male vs. female], 
presence of liver metastases at baseline [yes vs. no], and PD-L1 tumor expression by IHC [TC3 
and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1]), as recorded in an interactive voice or 
Web-based response system.  
Results from an unstratified analysis will also be presented.  Kaplan-Meier methodology will be 
used to estimate the median PFS and the median OS for each treatment arm, and a 
Kaplan-Meier curve will be constructed to provide a visual description of the difference between 
treatment arms.  The Brookmeyer-Crowley methodology will be used to construct the 95% CI 
for the median PFS and the median OS for each treatment arm.
Analyses will be conducted according to an analysis hierarchy and an -spending algorithm to 
control for the type I error rate and to account for an interim analysis.
To control the overall type I error rate for the one-sided test at 0.025, a one-sided type I error 
() of 0.003 and 0.022 (ratio of 3:22) will be allocated to PFS and OS, respectively.
The hypothesis testing will be performed in the order described below:
1.
PFS in the tGE-WT population will be tested at 0.003 (one sided).  If the estimate of the 
HR is 1 and the one-sided p-value corresponding to the stratified log-rank test is 0.003, 
the null hypothesis will be rejected and it will be concluded that 
atezolizumabcarboplatinnab-paclitaxel prolongs the duration of PFS relative to control 
treatment in the tGE-WT population.
2.
If the null hypothesis is rejected in the tGE-WT population (Step 1), PFS in the ITT-WT 
population will be tested at 0.003 (one sided).
3.
recycling from PFS to OS will be conducted as follows: 
a.
If the null hypothesis is not rejected for the PFS analysis in the ITT-WT population 
(Step 2), OS in the ITT-WT population will be tested at 0.022 (one sided). 
b.
If the null hypothesis is rejected for the PFS analysis in the ITT-WT population (Step 2), 
OS in the ITT-WT population will be tested at 0.025 (one sided).
Determination of Sample Size
This study will randomize approximately 715 patients.  The ITT-WT population will include 
approximately 650 patients, assuming a prevalence of approximately 10% for sensitizing EGFR 
mutations or ALK translocations.  The tGE-WT population will include approximately 
325 patients, assuming a 50% prevalence with the chosen tGE cutoff.
The sample size of this study is based on the number of events required to demonstrate 
efficacy with regard to both PFS and OS (co-primary endpoints).


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The estimate of the number of events required to demonstrate efficacy with regard to PFS in the 
comparison of Arm A versus Arm B is based on the following assumptions:

93% power to detect an HR of 0.55, corresponding to an improvement in median PFS from 
6 months to 10.9 months in the tGE-WT population with a one-sided of 0.003

95% power to detect an HR of 0.65, corresponding to an improvement in median PFS from 
6 months to 9.2 months in the ITT-WT population with a one-sided of 0.003

No interim analyses for PFS

Dropout rate of 5% per 12 months
The estimate of the number of events required to demonstrate efficacy with regard to OS in the 
comparison of Arm A versus Arm B is based on the following assumptions:

80% power to detect an HR of 0.75, corresponding to an improvement in median OS from 
12 months to 16 months in the ITT-WT population with a one-sided of 0.022

One interim OS analysis performed at the time of the final PFS analysis, at which time 
approximately 77% of the total number of OS events required for the final analysis are 
expected to have occurred as determined through use of the Lan-DeMets approximation to 
the O'Brien-Fleming boundary

Dropout rate of 5% per 24 months
With these assumptions, approximately 715 patients in total will be enrolled in this study, with 
approximately 650 patients in the ITT-WT population.  The final PFS analysis will be conducted 
when all of the following criteria have been met:  approximately 225 PFS events have occurred 
in the tGE-WT population, approximately 475 PFS events have occurred in the ITT-WT 
population, and the last patient has been enrolled in the study.  The final PFS analysis is 
expected to occur approximately 32 months after the first patient is enrolled.  These numbers of 
events would allow for a minimum detectable difference corresponding to an HR of 0.68 in the 
tGE-WT population and 0.76 in the ITT-WT population, respectively.
With a sample size of 650 patients, approximately 457 OS events are expected to occur in the 
ITT-WT population.  The final OS analysis is expected to occur approximately 42 months after 
the first patient is enrolled.  This number of events would allow for a minimum detectable 
difference corresponding to an HR of 0.81 in the ITT-WT population.
Interim Analyses
There are no interim analyses planned for PFS in this study.  An external independent Data 
Monitoring Committee (iDMC) will be set up to evaluate safety data on an ongoing basis.  All 
summaries/analyses by treatment arm for the iDMC’s review will be prepared by an 
independent Data Coordinating Center.  Members of the iDMC will be external to the Sponsor 
and will follow a charter that outlines their roles and responsibilities.  Any outcomes of these 
safety reviews that affect study conduct will be communicated in a timely manner to the 
investigators for notification of the Institutional Review Boards and Ethics Committees.  A 
detailed plan will be included in the iDMC Charter.
If approximately 352 OS events have occurred in the ITT-WT population at the time of the PFS 
final analysis, an interim OS analysis will be conducted in the ITT-WT population.  If there are 
significantly fewer than the expected 352 OS events at the final PFS analysis, a nominal of 
0.01% (negligible impact on overall type I error rate) will be spent on the OS analysis at the time 
of the PFS final analysis and a second interim OS analysis will then be conducted after 
approximately 352 OS events have occurred.
The final OS analysis will be conducted when approximately 457 OS events have occurred in 
the ITT-WT population.  This is expected to occur approximately 42 months after the first patient 
is enrolled.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ALK
anaplastic lymphoma kinase
anti-HBc
antibody to hepatitis B core antigen
ATA
anti-therapeutic antibody
AUC
area under the concentrationtime curve
BSC
best supportive care
CL
clearance
Cmax
maximum observed serum concentration
Cmin
minimum observed serum concentration
CR
complete response
CRC
colorectal cancer
CRCL
creatinine clearance
CRF
Case Report Form
ctDNA
circulating-tumor DNA
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 Dimensions 3-Level Version
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FOLFOX
oxaliplatin, leucovorin, and 5-fluorouracil
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
Ig
immunoglobulin
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
IRB
Institutional Review Board
IRF
Independent Review Facility
ITT
intent to treat
IV
intravenous
IxRS
interactive voice or Web-based response system
LFT
liver function test
MTD
maximum tolerated dose
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
PET
positron emission tomography
PFS
progression-free survival
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
PVC
polyvinylchloride
Q3W
every 3 weeks
QLQ-C30
Quality-of-Life Questionnaire Core 30
QLQ-LC13
Quality-of-Life Questionnaire Lung Cancer Module
qRT-PCR
quantitative reverse transcriptasepolymerase chain reaction
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RRR
response rate ratio
SAP
Statistical Analysis Plan


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Abbreviation
Definition
SILC
Symptoms in Lung Cancer
TC
tumor cell
TE
thromboembolic events
tGE
tumor gene expression
TIR
time in response
TKI
tyrosine kinase inhibitor
TNF
tumor necrosis factor
TSH
thyroid-stimulating hormone
TTD
time to deterioration
UBC
urothelial bladder cancer
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
Vss
volume of distribution at steady state
WT
wild type


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1.
BACKGROUND
1.1
BACKGROUND ON LUNG CANCER
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most 
common cancer in both men and women and accounted for approximately 13% of all 
new cancers in 2008 (Jemal et al. 2011).  In 2012, it was estimated that there would be 
226,160 new cases of lung cancer and 160,340 lung cancer deaths in the United States 
alone (Siegel et al. 2012).  Similar data from Europe estimate that there were 
288,000 new cases of lung cancer and 253,000 deaths in 2008 (GLOBOCAN 2008). 
Nonsmall cell lung cancer (NSCLC) is the predominant subtype of lung cancer, 
accounting for approximately 85% of all cases (Molina et al. 2008; Howlader et al. 2011). 
NSCLC can be divided into two major histologic types:  adenocarcinoma and squamous 
cell carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for more than 
half of all NSCLC, while squamous cell histology accounts for approximately 25% 
(Langer et al. 2010).  The remaining cases of NSCLC are represented by large cell 
carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated 
histology.
The overall 5-year survival rate for advanced disease is 2%4%, depending on 
geographic location (Cetin et al. 2011).  Poor prognostic factors for survival in patients 
with NSCLC include advanced stage of disease at the time of initial diagnosis, poor 
performance status, and a history of unintentional weight loss.  More than half of the 
patients with NSCLC are diagnosed with distant disease, which directly contributes to 
poor survival prospects.
There are recognized differences in disease characteristics between adenocarcinoma and 
squamous NSCLC.  First, squamous tumors commonly present in the central airways and 
typically remain localized in the bronchial epithelium (Hirsch et al. 2008), whereas 
non-squamous tumors are more commonly located in the lung parenchyma distal to the 
central airways. Evaluation of NSCLC tumor tissue will reveal cytological differences 
between the squamous cell type (keratinization, intracellular bridges, and central necrosis) 
and adenocarcinoma (glandular architecture).  In cases where the tumor sample is poorly 
differentiated or there is limited tissue available, immunohistochemical markers may 
support the histologic diagnosis.  Thyroid transcription factor1 is infrequently expressed 
in squamous cells and strongly expressed in adenocarcinoma.  In contrast, p63, CK5/6, 
and 34E12 are strongly expressed in squamous cell carcinoma and less frequently in 
adenocarcinoma (Travis et al. 2011).
Genetic changes that have prognostic and/or predictive significance in NSCLC include 
mutations in the EGFR, the rearrangement in the ALK genes, 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 
10%40% of patients with adenocarcinoma NSCLC but are infrequently observed in 


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squamous NSCLC (Herbst et al. 2008).  Similarly, the ALK fusion oncogene, recognized 
as a driver of lung tumorigenesis, is observed in approximately 7% of patients with 
adenocarcinoma but is very rare in the squamous histology (Herbst et al. 2008; 
Langer et al. 2010).  In addition, KRAS mutations are very rare in squamous NSCLC, 
while they can be observed in up to 30% of cases of adenocarcinoma NSCLC 
(Travis et al. 2011). 
1.1.1
First-Line Treatment for Advanced NSCLC with an EGFR
Mutation or ALK Rearrangement
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC characterized by alterations of 
driver oncogenes, including sensitizing EGFR mutations and ALK rearrangements.  
However, these mutations are more prevalent in adenocarcinoma NSCLC and are very 
rare in squamous NSCLC.  Randomized Phase III studies of gefitinib (IPASS), erlotinib 
(EURTAC), and afatinib (LUX-Lung 3) showed significant improvement of progression-
free survival (PFS) and objective response rate (ORR) compared with platinum doublet 
chemotherapy (Fukuoka et al. 2011; Rosell et al. 2012; Sequist et al. 2013; 
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; 
XALKORI® U.S. Package Insert).  Both EGFR tyrosine kinase inhibitors (TKIs) and 
crizotinib have been shown to be generally well tolerated.  
1.1.2
First-Line Treatment for Advanced NSCLC without an EGFR
Mutation or ALK Rearrangement
Patients with previously untreated advanced NSCLC that does not harbor a driver 
mutation that confers sensitivity to a targeted agent are typically treated with 
chemotherapy.  The first evidence that chemotherapy produced a significant survival 
benefit in patients with advanced NSCLC came in 1995; a meta-analysis showed that 
platinum-based doublet chemotherapy conferred a 2-month improvement in median 
survival over best supportive care (BSC) (NSCLC Collaborative Group 1995).  More 
recently, the European Big Lung Trial demonstrated the potential benefits of 
chemotherapy.  In this study, 725 patients with advanced NSCLC were randomly 
assigned to BSC plus cisplatin-based chemotherapy or BSC alone (Spiro et al. 2004).  
Patients allocated to chemotherapy had a significantly longer median survival than did 
those managed with BSC (8 vs. 5.7 months; hazard ratio [HR]0.77, 95% CI: 0.66, 0.89).
The globally recognized standard of care for patients with inoperable Stage IIIB and 
Stage IV NSCLC is platinum-based chemotherapy for four to six cycles followed by 
maintenance treatment until progression.  This standard of care applies to both 
non-squamous and squamous NSCLC (Pfister et al. 2004; D’Addario et al. 2010; 
De Marinis et al. 2011; National Comprehensive Cancer Network [NCCN] 2014).  
Agents that have been partnered with either cisplatin or carboplatin include the 


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taxanes (paclitaxel, docetaxel), vinorelbine, gemcitabine, and pemetrexed.  
Combinations of these drugs with platinum analogs are superior to single-agent 
therapy and have been shown to prolong survival (Azzoli et al. 2009).  
The Eastern Cooperative Oncology Group (ECOG) conducted a Phase III study 
(Study E1594) to compare four commonly used platinum-based doublets in patients with 
Stage IIIB/IV NSCLC who had not previously received chemotherapy 
(Schiller et al. 2002).  Gemcitabine cisplatin, docetaxelcisplatin, 
and paclitaxelcarboplatin were compared with paclitaxelcisplatin.  No significant 
clinical advantage of any one of the chemotherapy regimens over the others was 
observed; the median survival rates of the four treatment arms were approximately the 
same:  approximately 8 months.  The regimen of paclitaxelcarboplatin was chosen as 
the reference regimen for ECOG’s future studies because of its more favorable toxicity 
profile.
Recently, immune checkpoint inhibitors, including PD-L1 and 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 (TCs).  Patients with sensitizing mutation of the EGFR gene or 
translocation of the ALK gene were excluded from this study.  In this study, median PFS 
was 10.3 months in the pembrolizumab group versus 6.0 months in the chemotherapy 
group (HR 0.50; 95% CI: 0.37, 0.68; p<0.001).  The estimated rate of overall survival 
(OS) at 6 months was 80.2% (95% CI: 72.9%, 85.7%) in the pembrolizumab group 
versus 72.4% (95% CI: 64.5%, 78.9%) in the chemotherapy group; median OS was not 
reached in either group.  OS was significantly longer in the pembrolizumab group than in 
the chemotherapy group (HR 0.60; 95% CI: 0.41, 0.89; p 0.005) (Reck et al. 2016).  
On the basis of this study, pembrolizumab was approved for the first-line treatment of 
metastatic NSCLC in patients whose tumors have high PD-L1 expression (tumor 
proportion score 50%) with no EGFR or ALK gene aberrations.
1.1.3
nab-PaclitaxelCarboplatin for First-Line NSCLC
Socinski et al. (2012) conducted a Phase III randomized study evaluating the efficacy 
and safety of albumin-bound paclitaxel (nab-paclitaxel; ABRAXANE)carboplatin 
compared with solvent-based paclitaxelcarboplatin in 1052 previously untreated 
patients with NSCLC.  The primary efficacy endpoint of this study was ORR with 
secondary endpoints of PFS and OS.  Patients treated with nab-paclitaxelcarboplatin 
demonstrated a significantly improved ORR compared with patients treated with 
paclitaxelcarboplatin (33% vs. 25%; response rate ratio [RRR]1.31; p0.005), with 
patients with squamous histology experiencing the greatest improvement (41% vs. 
24%; RRR1.68; p0.001).  In patients with non-squamous histology, nab-
paclitaxelcarboplatin achieved a similar ORR as paclitaxelcarboplatin (26% vs. 


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25%, respectively).  There was a comparable improvement in PFS (6.3 months vs. 
5.8 months; HR0.902; 95% CI: 0.767, 1.060) and OS (12.1 months vs. 11.2 months; 
HR0.922; 95% CI: 0.797, 1.066) in patients treated with nab-paclitaxelcarboplatin 
compared with paclitaxelcarboplatin in the intent-to-treat (ITT) population, 
respectively.  No clinically meaningful differences were seen with respect to PFS 
(6.9 months [nab-paclitaxelcarboplatin] vs. 6.5 months [paclitaxelcarboplatin]; 
HR0.933) or OS (13.1 months [nab-paclitaxelcarboplatin] vs. 13.0 months 
[paclitaxelcarboplatin]; HR0.950) in the non-squamous subgroups.  A statistically 
non-significant improvement in OS was seen in patients with squamous histology 
(10.7 months [nab-paclitaxelcarboplatin] vs. 9.5 months [paclitaxelcarboplatin]; 
HR0.890; 95% CI: 0.719, 1.101), with no difference in PFS observed in this 
subgroup.  On the basis of these comparable clinical results, the regimen of 
nab-paclitaxelcarboplatin was approved for the treatment of NSCLC in the first-line 
setting in all histologies. 
Despite modest gains, the benefit conferred by platinum-based chemotherapy 
regimens appears to have reached a plateau in the objective response rate 
(approximately 15%25%) and median survival (711 months).  Pemetrexed 
(ALIMTA®) has recently demonstrated activity in the first-line setting where patients 
with non-squamous carcinoma had improved survival when treated with cisplatin and 
pemetrexed compared with those treated with cisplatin and gemcitabine (11.8 vs. 
10.4 months; p0.005) (Scagliotti et al. 2008).  In addition, cisplatin and pemetrexed 
was associated with better tolerability and safety and necessitated less supportive 
care.  More recently, the addition of bevacizumab to carboplatin and paclitaxel in 
patients with non-squamous NSCLC resulted in an increase in response rate from 
15% to 35% and an increase in median OS from 10 to 12 months (see Table 1). 


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Table 1
Randomized Phase III Trials in Patients with Previously Untreated 
NSCLC
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


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Table 1
Randomized Phase III Studies in Patients with Previously 
Untreated NSCLC (cont.)
Treatment Group
ORR
(%)
Median 
PFS
(Months)
Median 
OS
(Months)
OS HR
(95% CI)
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
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)
45
10.3
Not 
reached
0.60
0.410.89
Platinum-based chemotherapies, PD-L1 
positive (50%) (n151)
28
6.0
Not 
reached
HRhazard ratio; NRnot reported; NSCLCnonsmall cell lung cancer; 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.
1.1.4
AVASTIN® and Vascular Endothelial Growth Factor
AVASTIN® (bevacizumab) is a recombinant humanized monoclonal antibody to vascular 
endothelial growth factor (VEGF) that recognizes all isoforms of VEGF.  It may exert a direct 
anti-angiogenic effect by binding to and clearing VEGF from the tumor environment.  
Additional anti-tumor activity may be on tumor vasculature, interstitial pressure, and blood 
vessel permeability, providing for enhanced chemotherapy delivery to TCs (Jain 2001).


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1.1.4.1
Clinical Studies of Bevacizumab and 
Platinum-Based Treatment in NSCLC 
Two Phase III studies have demonstrated the benefit of bevacizumab in combination 
with platinum-based chemotherapy as first-line treatment of patients with unresectable, 
advanced, metastatic or recurrent non-squamous NSCLC. 
The first study, conducted by the ECOG (Study E4599) was an open-label, randomized, 
Phase III study comparing the regimen of 15 mg/kg bevacizumab every 3 weeks (Q3W) 
in combination with carboplatin and paclitaxel versus carboplatin and paclitaxel alone as 
first-line treatment of patients with advanced non-squamous NSCLC.  The Phase III 
study was based on a randomized Phase II study in patients with recurrent or advanced 
NSCLC that evaluated carboplatin and paclitaxel (up to six cycles) with or without 
bevacizumab (7.5 or 15 mg/kg) and found that the combination of bevacizumab 
15 mg/kg with carboplatin and paclitaxel for up to six cycles followed by maintenance 
bevacizumab until disease progression resulted in increased response rates (31.5% vs. 
18.8%) and prolonged time to progression (7.4 vs. 4.2 months; p0.023) compared with 
chemotherapy alone (Johnson et al. 2004).  There was also a non-significant 
improvement in OS (17.7 vs. 14.9 months) (Johnson et al. 2004).  A higher incidence of 
bleeding was noted in the bevacizumab-treated patients.  Severe pulmonary 
hemorrhage, which was observed in 6 patients (9.1%) and led to 4 fatalities, was more 
common in patients with squamous cell histology, tumor necrosis, and cavitation, and 
central tumors (Johnson et al. 2004).  On the basis of the results of this Phase II study, 
patients with squamous cell histology were excluded from this and other studies utilizing 
bevacizumab in NSCLC.  In Study E4599, patients who received six cycles of 
bevacizumab plus chemotherapy without disease progression continued on single-agent 
bevacizumab until progression.  A total of 878 patients were enrolled.  Median OS was 
12.3 months versus 10.3 months (HR0.79; p0.003); PFS was 6.2 months versus 
4.5 months (HR0.66; p0.001), and the response rate was 35% (133 of 381 patients) 
versus 15% (59 of 392 patients) (p0.001) for patients treated with bevacizumab versus 
chemotherapy alone (Sandler et al. 2006). 
The second study (Study BO17704 or AVAiL) was a randomized, double-blind, 
multicenter, two-stage, Phase III study of bevacizumab in combination with cisplatin and 
gemcitabine versus placebo, cisplatin, and gemcitabine as first-line treatment in patients 
with advanced or recurrent non-squamous NSCLC.  A total of 1043 patients were 
randomized.  Bevacizumab-based therapy until disease progression reduced the risk of 
disease progression.  Bevacizumab at a dose level of 7.5 mg/kg resulted in an HR for 
PFS of 0.75 (median PFS, 6.7 vs. 6.1 months; p0.003), and bevacizumab at a dose 
level of 15 mg/kg resulted in an HR of 0.82 (median, 6.5 months vs. 6.1 months, 
p0.03).  These results were maintained with a longer follow-up.  OS was a secondary 
endpoint, and the PFS benefit did not translate into a significant OS benefit.  
Nevertheless, median OS in all treatment arms of the study exceeded 13 months 
(Reck et al. 2009; Reck et al. 2010). 


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In summary, 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, the current standard of care is a platinum 
doublet with either cisplatin or carboplatin and a taxane or pemetrexed, with or without 
bevacizumab.  However, these regimens are associated with substantial toxicities (such 
as febrile neutropenia, myelosuppression, nausea, alopecia, nephropathy, and 
neuropathy) and are generally poorly tolerated by elderly and poor performance status 
patients.  Therefore, novel therapies that deliver an improved therapeutic index are 
urgently needed for non-squamous NSCLC.
1.1.5
Targeted Therapy for NSCLC
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC (mainly non-squamous histology) 
characterized by alterations of driver oncogenes, including sensitizing EGFR mutations 
and ALK rearrangement.  Randomized Phase III studies of gefitinib (IPASS), erlotinib 
(EURTAC), and afatinib (LUX-Lung 3) showed significant improvement of PFS and ORR 
compared with platinum doublet chemotherapy (Fukuoka et al. 2011, Rosell et al. 2012, , 
and Sequist et al. 2013, respectively).  Similarly, the ALK inhibitors crizotinib and 
ceritinib have demonstrated efficacy in patients with NSCLC positive for ALK
rearrangement as defined by fluorescence in situ hybridization (Crino et al. 2011; 
Camidge et al. 2012; Shaw et al. 2012; Shaw and Engleman 2014; XALKORI® USPI;
ZykadiaUSPI).
Despite progress with new targeted treatments and new chemotherapy combinations, 
survival rates for advanced disease remain low and acquired resistance to targeted 
agents is a major clinical problem.  Therefore, alternative treatment options that yield 
durable responses and enhance OS remain an important focus of research.  Against this 
background, immunotherapeutic agents, such as cancer vaccines and antibodies that 
modulate immune cell activity, offer an alternative treatment approach that could 
potentially improve the prognosis of patients with this disease.
1.1.6
Erlotinib or Pemetrexed Maintenance Therapy for NSCLC
NCCN guidelines (2014) on chemotherapy for Stage IV NSCLC recommend that 
cytotoxic regimens consisting of two drugs should be given for no more than six cycles.  
The guidelines also recommend stopping first-line cytotoxic chemotherapy at disease 
progression.  At study initiation, switch maintenance treatment with erlotinib in 
unselected patients or pemetrexed in those with non-squamous histology could be 
considered for patients with stable disease or continued response to therapy after four to 
six cycles of chemotherapy (NCCN 2014).  This recommendation was based on two 
randomized Phase III studies, which had shown a PFS and OS benefit after the initiation 
of pemetrexed or erlotinib after induction treatment in patients with non-progressive 
disease.  In the sequential Tarceva unresectable NSCLC study (SATURN), the median 


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PFS in patients receiving maintenance therapy with erlotinib was significantly longer 
than in patients receiving placebo (12.3 vs. 11.1 weeks; HR0.71; 95% CI: 0.62, 0.81; 
p0.0001).  Maintenance treatment with erlotinib also yielded a statistically significant 
yet clinically modest improvement in OS (12.0 vs. 11.0 months; HR0.81; 95% CI: 0.70, 
0.95; p0.0088).  A statistically significant improvement in PFS and OS was seen in 
patients with EGFR wild-type and EGFR mutationpositive tumors 
(Cappuzzo et al. 2010).  In the JMEN 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).  These Phase III studies resulted in regulatory approval 
(U.S. Food and Drug Administration [FDA] and European Medicines Agency) for erlotinib 
and pemetrexed, respectively, 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.  However, recent data from Study BO25460, a 
Phase III, randomized, double-blind, placebo-controlled study, have demonstrated that 
patients with advanced or recurrent (Stage IIIB) or metastatic (Stage IV) NSCLC whose 
tumor did not harbor an EGFR-activating mutation did not achieve benefit from first-line 
maintenance therapy with erlotinib compared with placebo.  OS was not superior in 
patients who were randomized to receive maintenance erlotinib followed by 
chemotherapy or best supportive care upon disease progression compared with patients 
who were randomized to receive maintenance placebo followed by erlotinib upon 
disease progression (HR1.02; 95% CI: 0.85, 1.22; p0.82).  In the maintenance 
phase, patients who received erlotinib also did not have superior PFS compared with 
patients who received placebo (HR0.94; 95% CI: 0.80, 1.11; p0.48).  This change in 
the benefitrisk assessment of erlotinib as switch maintenance therapy in patients 
whose tumors do not harbor an activating EGFR mutation has led to the removal of this 
treatment option from this protocol.
1.2
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody consisting of 
two heavy chains (448 amino acids) and two light chains (214 amino acids) and is 
produced in Chinese hamster ovary cells.  Atezolizumab was engineered to eliminate 
Fc-effector function via a single amino acid substitution at position 298 on the 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.


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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 carcinoma after prior 
chemotherapy.
1.2.1
Summary of Nonclinical Studies
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab.
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid 
in projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical studies in patients.
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.3
CLINICAL EXPERIENCE WITH ATEZOLIZUMAB
1.3.1
Ongoing Clinical Studies
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  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 Q3W
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 GP28328:  A Phase Ib study assessing the safety and pharmacology of 
atezolizumab in combination with bevacizumab and/or chemotherapy in patients 
with advanced solid tumors
1.3.2
Clinical Safety
1.3.2.1
Single-Agent Clinical Safety in Patients with NSCLC in 
Study PCD4989g
Study PCD4989g, in which atezolizumab is being used as a single agent in patients with 
locally advanced or metastatic solid tumors or hematologic malignancies, provides the 
majority of data (with 558 safety-evaluable patients as of the data extraction date of 
11 May 2015) for the safety profile of atezolizumab as monotherapy.
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined.
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications.  The most common cancer types for these patients include NSCLC, 
urothelial bladder cancer (UBC), melanoma, and renal cell carcinoma (RCC).  Safety 
data for NSCLC are also derived from Studies GO28625 (FIR), GO28915 (OAK), and 
Study GO28753 (POPLAR).
Adverse Events
Of the 558 patients, 520 patients (93.2%) experienced at least one adverse event, 
including 376 patients (67.4%) who experienced one treatment-related adverse event.  
Commonly reported events (reported in10% of all patients) included fatigue, decreased 
appetite, nausea, pyrexia, constipation, and cough (see Table 2).  


Atezolizumab—F. Hoffmann-La Roche Ltd
42/Protocol GO29537, Version 7
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades
Adverse Event
All Grades
n (%)
All Grades 
Related
n (%)
Grades 34
n (%)
Grades 34 
Related
n (%)
Any adverse event
520 (93.2)
376 (67.4)
239 (42.8)
66 (11.8)
Fatigue
192 (34.4)
115 (20.6)
13 (2.3)
6 (1.1)
Decreased appetite
142 (25.4)
62 (11.1)
4 (0.7)
0 (0.0)
Nausea
136 (24.4)
65 (11.6)
5 (0.9)
2 (0.4)
Pyrexia
117 (21.0)
63 (11.3)
2 (0.4)
0 (0.0)
Constipation
116 (20.8)
8 (1.4)
2 (0.4)
0 (0.0)
Cough
113 (20.3)
11 (2.0)
1 (0.2)
1 (0.2)
Dyspnea
112 (20.1)
18 (3.2)
18 (3.2)
4 (0.7)
Diarrhea
110 (19.7)
53 (9.5)
2 (0.4)
1 (0.2)
Anemia
104 (18.6)
26 (4.7)
23 (4.1)
5 (0.9)
Vomiting
96 (17.2)
28 (5.0)
3 (0.5)
2 (0.4)
Asthenia
88 (15.8)
53 (9.5)
8 (1.4)
4 (0.7)
Back pain
85 (15.2)
9 (1.6)
8 (1.4)
1 (0.2)
Headache
83 (14.9)
32 (5.7)
2 (0.4)
1 (0.2)
Arthralgia
79 (14.2)
35 (6.3)
2 (0.4)
0 (0.0)
Pruritus
75 (13.4)
55 (9.9)
0 (0.0)
0 (0.0)
Rash
73 (13.1)
53 (9.5)
0 (0.0)
0 (0.0)
Abdominal pain
63 (11.3)
12 (2.2)
8 (1.4)
0 (0.0)
Insomnia
62 (11.1)
7 (1.3)
1 (0.2)
0 (0.0)
Peripheral edema
59 (10.6)
7 (1.3)


Chills
57 (10.2)
31 (5.6)
0 (0.0)
0 (0.0)
Note:  "" refers to missing Common Terminology Criteria grade.
Grade 3 or 4 adverse events (on the basis of National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4 [NCI CTCAE v4.0]) were reported in 
239 patients (42.8%), of which 66 patients (11.8%) were considered related.  Grade 3 or
4 adverse events considered related by the investigator included dyspnea, pneumonitis, 
increased ALT, increased AST, increased gamma-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 adverse events 
observed in patients treated with atezolizumab.


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Immune-Mediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
atezolizumab clinical program.  These include potential dermatologic, hepatic, 
endocrine, gastrointestinal, and respiratory events.  
Refer to the Atezolizumab Investigator’s Brochure for details on immune-mediated 
adverse events that were observed in patients treated with atezolizumab.  Guidelines for 
the management of immune-mediated adverse events are described in Section 5.1.8.
1.3.2.2
Single-Agent Clinical Safety in Patients with NSCLC 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 the POPLAR study who reported any 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
Study GO28753 (POPLAR):  Adverse Events Reported in at 
Least 10% of Patients
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.
1.3.2.3
Single-Agent Clinical Safety in Patients with NSCLC in Study 
GO28915 (OAK)
As of the 7 July 2016 data cutoff date for the primary analysis, the 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 


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(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
3.9%
11.2%
Stomatitis
3.1%
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.
1.3.2.4
Clinical Safety in Combination with Bevacizumab or 
Platinum-Based Doublet Chemotherapy
Study GP28328 is a Phase Ib study of atezolizumab in combination with bevacizumab or 
cytotoxic chemotherapy in patients with multiple tumor types including NSCLC, triple 
negative breast cancer, and colorectal cancer.  As of 10 February 2015, 144 patients 
had been enrolled in this study:  39 patients in Arm A (atezolizumabbevacizumab), 
36 patients in Arm B (atezolizumabbevacizumab and FOLFOX), 14 patients in Arm C 
(atezolizumabcarboplatin and paclitaxel), 24 patients in Arm D 
(atezolizumabcarboplatin and pemetrexed), 20 patients in Arm E 
(atezolizumabcarboplatin and nab-paclitaxel), and 11 patients in Arm F 
(atezolizumabnab-paclitaxel).  The treatment combinations have been generally well 
tolerated.  No DLTs have been reported during the dose-escalation stage in any study 
arm.  Patients are being enrolled in safety and biopsy expansion cohorts in Arms A 
and B as well as in additional arms testing atezolizumab in combination with commonly 
used NSCLC chemotherapy doublets.  


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A total of 141 of 144 patients (97.9%) reported at least one adverse event while 
receiving study drug.  The majority of these events were Grade 2 or 3 in severity.  The 
five most commonly reported adverse events across the study arms (10% of patients) 
included fatigue, nausea, diarrhea, decreased appetite, and pyrexia.  The adverse 
events were consistent with the known safety profile of each agent (atezolizumab 
monotherapy and chemotherapy).  No additive effects were observed when 
atezolizumab was administered with chemotherapy.
Table 5
Study GP28328:  All Reported Adverse Events
Parameter
Arm A
(n 39)
No. (%)
Arm B
(n 36)
No. (%)
Arm C
(n 14)
No. (%)
Arm D
(n 24)
No. (%)
Arm E
(n 20)
No. (%)
Arm F
(n 12)
No. (%)
All 
Patients
(n 145)
No. (%)
Any AEs
39 (100)
36 (100)
14 (100)
24 (100)
19 (95.0)
10 (83.3)
142 (97.9)
Related AEs
29 (74.4)
28 (77.8)
12 (85.7)
19 (79.2)
19 (95.0)
6 (50.0)
113 (77.9)
Grade 35 AEs
20 (51.3)
29 (80.6)
12 (85.7)
17 (70.8)
18 (90.0)
6 (50.0)
102 (70.3)
Related Grade 35 
AEs
1 (2.6)
7 (19.4)
4 (28.6)
4 (16.7)
11 (55.0)
4 (33.3)
31 (21.4)
Serious AEs
14 (35.9)
15 (41.7)
5 (35.7)
10 (41.7)
8 (40.0)
3 (25.0)
55 (37.9)
Related serious AEs
0 (0)
1 (2.8)
1 (7.1)
2 (8.3)
2 (10.0)
2 (16.7)
8 (5.5)
AEs leading to 
discontinuation
1 (2.6)
4 (11.1)
0 (0)
1 (4.2)
1 (5.0)
0 (0)
8 (5.6)
AEs leading to 
death (Grade 5)
0 (0)
2 (2.8)
1 (7.1)
2 (8.3)
2 (10.0)
1 (8.3)
7 (4.8)
Related AEs leading to 
death (Grade 5)
0 (0)
0 (0)
0 (0)
1 (4.2)
0 (0)
0 (0)
1 (0.7)
Immune-mediated AEs
12 (30.8)
28 (77.8)
8 (57.1)
11 (45.8)
11 (55.0)
2 (16.7)
72 (49.7)
AEadverse event.
All 39 patients who were enrolled in Arm A reported 1 or more adverse events.  The 
5 most frequently reported events were consistent with the overall population and 
included fatigue, nausea, diarrhea, decreased appetite, and pyrexia.  There were 
36 patients enrolled in Arm B, and 97% of patients reported at least 1 adverse event.  
The most frequently reported adverse events (20% of patients) included fatigue, 
pyrexia, peripheral neuropathy, neutropenia, anemia, diarrhea, decreased appetite, 
temperature intolerance, constipation, vomiting, and nausea.  
All patients who were enrolled in Arms C and D experienced an adverse event; 95% of 
patients who were enrolled in Arm E experienced an adverse event, and 83.3% of 
patients enrolled in Arm F experienced an adverse event.  The adverse events 
commonly reported in 2 or more patients in Arms C, D, and E included anemia, 
decreased appetite, hypomagnesemia, nausea, neutropenia, constipation, vomiting, 


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fatigue, rash, cough, and diarrhea.  Adverse events commonly reported in 2 or more 
patients in Arm F included dermatitis, upper respiratory infection, alopecia, peripheral 
sensory neuropathy, fever, constipation, neutrophil count decreased, anemia, diarrhea, 
headache, nausea, and fatigue.
1.3.3
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)based responses (i.e., RECIST v1.1 responses), has been observed in 
patients with different tumor types treated with atezolizumab monotherapy in 
Study PCD4989g. 
Refer to the Atezolizumab Investigator’s Brochure for updated details on clinical activity 
in all patients treated to date, regardless of tumor type.
1.3.3.1
Single-Agent Clinical Activity in Patients with NSCLC in 
Study PCD4989g
As of the clinical data cutoff of 2 December 2014, the efficacy evaluable population 
included 88 patients with locally advanced or metastatic NSCLC.  The median age was 
60.5 years (range: 2484 years) and represented a heavily pre-treated patient 
population:  97% of the patients had received 2 prior systemic therapies, and 77.3% 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 squamous and non-squamous NSCLC (4 in 
21 patients and 16 in 67 patients, respectively).  A total of 8 of the 20 responding 
patients have continued to respond at the time of the clinical data cutoff.  
Table 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-infiltrating immune cells (ICs) 
and TCs 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 in 
patients with NSCLC treated to date.


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Table 6
Patients with NSCLC in Study PCD4989g:  Investigator-Assessed 
Confirmed Objective Response Rate by Tumor PD-L1 
Expression, Duration of Response, and Six-Month 
Progression-Free Survival Rates (according to 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 v1.1Response Evaluation 
Criteria in Solid Tumors, Version 1.1; TCtumor cell.
Notes: This table is based on a data cutoff of 02 Dec 2014 of NSCLC patients. ORR includes 
confirmed responses. “” denotes a censored value.
1.3.3.2
Single-Agent Clinical Activity in Patients with NSCLC in 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: 


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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%
Duration of response
Median (months)
95% CI
14.3 
11.6, NE
7.2
5.6, 12.5
NEnot estimable.
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).


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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 NSCLC.
1.3.3.3
Single-Agent Clinical Activity in Patients with NSCLC 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 
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 according to 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).


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1.3.3.4
Clinical Efficacy in Combination with Platinum-Based Doublet 
Chemotherapy in Patients with NSCLC
As of the 10 February 2015 data cutoff, 58 patients with NSCLC were enrolled in
Arms C, D, or E of the Phase Ib study GP28328.  Patients who had received their first 
dose of atezolizumab by 10 November 2014 were evaluable for efficacy (n41). 
Patients who were enrolled in Arms C, D, and E received 15 mg/kg atezolizumab 
administered Q3W in combination with carboplatinpaclitaxel, carboplatinpemetrexed, 
and carboplatinnab-paclitaxel, respectively.  All patients had histologically or 
cytologically documented Stage IIIB, Stage IV, or recurrent NSCLC and had not received 
prior chemotherapy for advanced disease.  The median age was 65 years, and 79% of 
patients had non-squamous histology.  The overall confirmed ORR according to
RECIST v1.1 in all three arms combined was 63% (26 of 41 patients). The ORR was 
50% (95% CI: 16%, 84%) in Arm C (4 partial responses [PRs] among 8 patients), 77% 
(95% CI: 50%, 93%) in Arm D (13 PRs among 17 patients), and 56% (95% CI: 30%, 
80%) in Arm E (5 PRs and 4 complete responses [CRs] among 16 patients). Patients 
with high levels of PD-L1 expression appeared to have higher response rates, but 
responses were also seen in patients with lower PD-L1 expression levels 
(Liu et al. 2015).
1.3.4
Clinical Pharmacokinetics and Immunogenicity
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab appeared
to show linear pharmacokinetics at doses 1 mg/kg.  For the 1-mg/kg and 20-mg/kg 
dose groups, the mean apparent clearance (CL) and the mean volume of distribution at 
steady state (Vss) had a range of 3.11 to 4.14 mL/kg and 48.1 to 67.0 mL/kg, 
respectively, which is consistent with the expected profile of an IgG1 antibody in 
humans.
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses from 10 to 20 mg/kg.  
Patients who were 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 between the detection of ATAs and adverse events or infusion reactions has 
been observed.
1.3.5
Rationale for Atezolizumab Dosage
The fixed dose of 1200 mg (equivalent to an average body weightbased dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below.
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 


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target trough concentration (Ctrough) was projected to be 6 g/mL on the basis of several 
assumptions, including the following:  1) 95% tumor-receptor saturation is needed for 
efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue 
distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, 
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 Q3W regimen (or 
fixed-dose equivalent) for Phase II and Phase III studies would be sufficient to both 
maintain Ctrough 6 g/mL and further safeguard against both interpatient variability and 
the potential effect of ATAs that could lead to subtherapeutic levels of atezolizumab 
relative to the 10-mg/kg atezolizumab Q3W regimen (or fixed-dose equivalent).  From 
inspection of available observed Ctrough data, moving further to the 20-mg/kg 
atezolizumab Q3W regimen does not appear to be warranted to maintain targeted Ctrough 
relative to the proposed 15-mg/kg atezolizumab Q3W level. 
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose or a dose adjusted for weight.  Therefore, a fixed dose 
of 1200 mg has been selected (equivalent to an average body weightbased dose of 
15 mg/kg).  Selection of an every-21-day dosing interval is supported by this preliminary 
pharmacokinetics evaluation.
Refer to the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
1.4
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012).
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1. PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is sustained in 
states of chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008). Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of 
T cells.  B7.1 is a molecule expressed on antigen-presenting cells and activated T cells.  
PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate 
downregulation of immune responses, including inhibition of T-cell activation and 
cytokine production (Butte et al. 2007; Yang et al. 2011).


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Overexpression of PD-L1 on TCs has been reported to impede anti-tumor immunity, 
resulting in immune evasion (Blank and Mackensen 2007).  Therefore, interruption of the 
PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific 
T-cell immunity.
PD-L1 expression is prevalent in many human tumors, and elevated PD-L1 expression 
is associated with a poor prognosis in patients with NSCLC (Mu et al. 2011).
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies and who have failed standard of care therapies.  At the time 
of Study GO29537 initiation, Study PCD4989g, a Phase Ia dose-escalation and 
expansion study of patients treated with atezolizumab as a single agent had the 
following clinical activity:  345 evaluable patients were dosed by 21 October 2013 (data 
cutoff date as of 21 April 2014) with a minimum of 6 months of follow-up; 62 patients 
experienced objective responses according to RECIST v1.1 with an ORR of 18.0% 
(95% CI: 14.1%, 22.3%).  Objective responses were observed across a broad range of 
malignancies, including NSCLC, RCC, melanoma, and UBC.  In Studies GO28753 
(POPLAR) and GO28915 (OAK), there was significant improvement in OS with 
atezolizumab compared with docetaxel in patients with previously treated advanced 
NSCLC.
1.4.1
Rationale for Testing Atezolizumab in Combination with 
Carboplatin/nab-Paclitaxel
Platinum-based regimens remain the standard first-line option for patients with locally 
advanced or metastatic NSCLC not harboring EGFR mutations or ALK gene 
rearrangements.  However, the survival benefit conferred by cytotoxic chemotherapy has 
reached a plateau, with overall response rates of approximately 20% and 1-year survival 
ranging from 31%36% (Schiller et al. 2002), leaving considerable room for 
improvement in outcomes.  TC killing by cytotoxic chemotherapy can reasonably be 
expected to expose the immune system to high levels of tumor antigens, and 
invigorating tumor-specific T-cell immunity in this setting by inhibiting PD-L1/PD-1 
signaling may result in deeper and more durable responses compared with standard 
chemotherapy alone (Merritt et al. 2003; Apetoh et al. 2007).  Evaluating the safety and 
efficacy of these treatment combinations in patients with NSCLC will enable future tests 
of this hypothesis.
Nivolumab, a fully human IgG4 PD-1 antibody, was evaluated in combination with 
platinum-based doublet therapy in PD-1unselected, chemotherapy-naive patients with 
NSCLC, and interim results were presented at the American Society of Clinical Oncology 
2014 meeting (Antonia et al. 2014).  The ORR for patients treated with 
gemcitabinecisplatin, pemetrexedcisplatin, and paclitaxelcarboplatin, in addition to 
10 mg nivolumab, was 33% (n12), 47% (n15), and 47% (n15), respectively.  The 
median DOR ranged from 24 weeks with nivolumab in combination with 
paclitaxelcarboplatin to 45 weeks with nivolumab in combination with 


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gemcitabinecisplatin.  The 1-year OS for patients treated with gemcitabinecisplatin, 
pemetrexedcisplatin, and paclitaxelcarboplatin in addition to 10 mg nivolumab was 
50%, 87%, and 60%, respectively.  Grade 3/4 treatment-related adverse events were 
reported in 45% of patients across all treatment arms with the most common 
treatment-related Grade 3/4 adverse events being pneumonitis (7%), fatigue (5%), and 
acute renal failure (5%) (Antonia et al. 2014).
Although the patient numbers are limited, these data, along with the preliminary efficacy 
and safety results from Study GP28328, offer evidence of an acceptable safety profile 
when combining a PD-L1/PD-1 inhibitor with platinum-based doublet chemotherapy in a 
nonPD-L1selected population.  
Carboplatinnab-paclitaxel was approved for the first-line treatment of patients with 
NSCLC on the basis of results from the randomized Phase III study comparing 
nab-paclitaxelcarboplatin with solvent-based paclitaxelcarboplatin.  In nonclinical 
models, the combination with of nab-paclitaxelatezolizumab demonstrated significantly 
greater anti-tumor activity than either agent alone.
In light of these observations, Study GO29537 is designed to evaluate whether the 
anti-tumor effect seen in atezolizumab-treated patients would translate into a statistically 
significant and clinically relevant improvement in prolonged PFS when used in 
combination with carboplatinnab-paclitaxel compared with carboplatinnab-paclitaxel 
in patients with non-squamous NSCLC.  This study will allow for the evaluation of the 
efficacy of atezolizumab in both the ITT population, as well as in patients with 
PD-L1selected tumors (defined by expression of PD-L1 in TCs and/or ICs).  A PD-L1 
immunohistochemistry (IHC) assay will be used to identify patients by their tumor PD-L1 
expression (see Appendix 7).  
Study GO29537 will enroll patients with Stage IV non-squamous NSCLC who are naive 
to chemotherapy treatment and for whom the experimental arm can represent a valuable 
treatment option and a reasonable benefitrisk balance.  Patients whose tumors are 
known to harbor sensitizing EGFR mutations or ALK rearrangements must have 
experienced disease progression during or have proven intolerance during or after 
treatment with an EGFR tyrosine kinase or at least one ALK inhibitor, respectively (see 
specific inclusion criteria in Section 4.1.1), before they can enroll in the study. 
In order to account for the possibility of pseudoprogression/tumor-immune infiltration 
(i.e., radiographic increase in tumor volume due to the influx of immune cells) 
(Hales et al. 2010) and the potential for delayed anti-tumor activity, this study will allow 
patients treated with atezolizumab to receive treatment beyond the initial apparent 
radiographic progression (see Section 3.3.5 and Section 4.6) and will use modified 
RECIST (in addition to RECIST v1.1) to evaluate clinical benefit.  Because it is not yet 
possible to reliably differentiate pseudoprogression/tumor-immune infiltration from true 
tumor progression, the risk exists that some patients who are not responding to 


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treatment but yet continuing to receive atezolizumab may experience further progression 
of NSCLC and delay treatment with subsequent therapies for which they are eligible.  
Investigators should make every effort to fully inform patients of this risk.
Atezolizumab has been generally well tolerated (see Section 1.3.2); adverse events with 
potentially immune-mediated causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis, 
have been observed in Study PCD4989g.  To date, these events have been 
manageable with treatment.
In summary, treatment with atezolizumab offers the potential for clinical benefit in 
patients with NSCLC, in addition to carboplatinnab-paclitaxel.  Patients will be fully 
informed of the risk of continuing study treatment in spite of apparent radiographic 
progression and investigators should make a careful assessment of the potential benefit 
of doing so, considering radiographic data, biopsy results, and the clinical status of 
the patient.
2.
OBJECTIVES
The following objectives will be assessed in chemotherapy-naive patients with Stage IV 
non-squamous NSCLC.  
2.1
EFFICACY OBJECTIVES
The term "wild type" (WT) refers to randomized patients who do not have a sensitizing 
EGFR mutation or ALK translocation.
The term "tumor gene expression" (tGE) refers to randomized patients with a defined 
level of expression of a PD-L1 and T-effector gene signature in tumor tissue, as
analyzed through use of a centrally performed RNA-based assay.
Some efficacy endpoints will be analyzed in a population of randomized patients with a 
defined level of PD-L1 expression on TCs and ICs, as analyzed through use of a 
centrally performed IHC test.
2.1.1
Co-Primary Efficacy Objectives
The co-primary objectives of this study are the following:

To evaluate the efficacy of atezolizumabcarboplatinnab-paclitaxel compared 
with carboplatinnab-paclitaxel as measured by investigator-assessed PFS 
according to RECIST v1.1 in the tGE-WT population and the ITT-WT population

To evaluate the efficacy of atezolizumabcarboplatin nab-paclitaxel compared 
with carboplatin nab-paclitaxel as measured by OS in the ITT-WT population


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2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are the following:

To evaluate the efficacy of atezolizumab as measured by OS in the tGE-WT
population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
PFS according to RECIST v1.1 and OS in the TC2/3 or IC2/3 WT population and
the TC1/2/3 or IC1/2/3 WT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
PFS according to RECIST v1.1 and OS in the tGE population and the ITT 
population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
ORR according to RECIST v1.1 for the tGE-WT population and the ITT-WT 
population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
DOR according to RECIST v1.1 for the tGE-WT population and the ITT-WT 
population

To evaluate the OS rate at 1 and 2 years in each treatment arm in the tGE-WT 
population and the ITT-WT population

To determine the impact of atezolizumab as measured by time to deterioration 
(TTD) in patient-reported lung cancer symptoms of cough, dyspnea (single-item and 
multi-item subscales), chest pain, or arm/shoulder pain, using the European 
Organisation for the Research and Treatment of Cancer (EORTC) Quality-of-Life 
QuestionnaireCore 30 (QLQ-C30) and the supplemental lung cancer module 
(QLQ-LC13) in the tGE-WT population and the ITT-WT population

To determine the impact of atezolizumab as measured by change from baseline 
(i.e., improvement or deterioration based upon presenting symptomatology) in 
patient-reported lung cancer symptom (chest pain, dyspnea, and cough) score using 
the Symptoms in Lung Cancer (SILC) scale symptom severity score in the tGE-WT 
population and the ITT-WT population
2.2
SAFETY OBJECTIVES
The safety objectives for this study are the following:

To evaluate the safety and tolerability of atezolizumabcarboplatinnab-paclitaxel 
compared with carboplatinnab-paclitaxel

To evaluate the incidence and titers of ATAs against atezolizumab and to explore 
the potential relationship of the immunogenicity response with pharmacokinetics, 
safety, and efficacy


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2.3
PHARMACOKINETIC OBJECTIVES
The PK objectives for this study are the following:

To characterize the pharmacokinetics of atezolizumab when given in combination 
with carboplatin and nab-paclitaxel

To characterize the pharmacokinetics of carboplatin when given in combination with 
nab-paclitaxel with and without atezolizumab

To characterize the pharmacokinetics of nab-paclitaxel when given in combination 
with carboplatin with and without atezolizumab
2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are the following:

To evaluate PFS at 6 months and at 1 year in each treatment arm

To evaluate the OS rate at 3 years in each treatment arm

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in 
archival and/or fresh tumor tissue and blood and their association with disease 
status, mechanisms of resistance, and/or response to study treatment

To evaluate 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 Dimensions 3-Level (EQ-5D-3L) questionnaire to generate utility scores for use in 
economic models for reimbursement

To determine the impact of atezolizumab as measured by change from baseline in 
patient-reported outcomes 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 THE STUDY
This is a randomized, Phase III, multicenter, open-label study (IMpower130) designed to 
evaluate the safety and efficacy of atezolizumab in combination with 
carboplatinnab-paclitaxel compared with treatment with carboplatinnab-paclitaxel in 
approximately 715 chemotherapy-naive patients with Stage IV non-squamous NSCLC.  
Figure 1 illustrates the study design.  The schedules of assessments are provided in 
Appendix 1 through Appendix 3.
Tumor specimens will be prospectively tested for PD-L1 expression by a central 
laboratory. Eligible patients will be stratified by sex (male vs. female), presence of liver 
metastases at baseline (yes vs. no), and by PD-L1 tumor expression by IHC (TC3 and 
any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1). Patients will be randomized in a 
2:1 ratio to receive one of the following treatment regimens detailed in Table 9.


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Table 9
Study GO29537 Treatment Arms
Treatment 
Arm
Induction 
(Four or Six 21-Day Cycles)
Maintenance 
(21-Day Cycles)
A
Atezolizumabcarboplatinnab-paclitaxel
Atezolizumab
B
Carboplatinnab-paclitaxel
Best supportive care 
or pemetrexed
The number of cycles of induction treatment (four or six) will be at the discretion of the 
investigator and will be determined and documented prior to randomization. Induction 
treatment will be administered on a 21-day cycle until one of the following occurs
(whichever occurs first):  1) administration of four or six cycles or 2) disease progression 
(Arm B) or loss of clinical benefit (Arm A) is documented.  
Following the induction phase, patients who are randomized to atezolizumab (Arm A) 
may continue treatment with atezolizumab beyond radiographic disease progression 
according to RECIST v1.1, provided they 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).  Patients randomized to carboplatinnab-paclitaxel (Arm B) will be offered best 
supportive care provided they have non-progressive disease.  Switch maintenance to 
pemetrexed is also permitted for patients randomized to Arm B.  Switch maintenance 
must be administered within 6 weeks of Day 1 of the last induction cycle.
Patients who entered Study GO29537 under Protocol Versions 14 and are randomized 
to carboplatin nab-paclitaxel will be given the option to cross over to receive 
atezolizumab as monotherapy upon progressive disease according to RECIST v1.1, 
provided they continue to meet eligibility criteria (see Section 4.1.1).  Safety data for 
patients who crossed over from Arm B to receive atezolizumab as allowed under 
Protocol Versions 14 will be summarized for exploratory purposes.
For Atezolizumab-Treated Patients Only
During treatment (induction or maintenance), patients receiving atezolizumab (including 
patients in Arm B who entered Study GO29537 under Protocol Versions 14 and
crossed over to receive atezolizumab after disease progression according to
RECIST v1.1) who show evidence of clinical benefit will be permitted to continue 
atezolizumab after the criteria according to RECIST v1.1 for progressive disease are met 
if they meet all of the following criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values, 
e.g., new or worsening hypercalcemia) indicating unequivocal progression of 
disease


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
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 atezolizumab at the time of initial progression
Treatment with induction chemotherapy (Arms A and B) and pemetrexed (Arm B) as 
switch maintenance must be discontinued in all patients who exhibit evidence of 
progressive disease according to RECIST v1.1.
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 
48 weeks following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, tumor 
assessment will be required every 9 weeks.  Patients will undergo tumor assessments 
until 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), withdrawal of 
consent, study termination by Sponsor, or death, whichever occurs first.  Patients who 
discontinue treatment for reasons other than radiographic disease progression according 
to RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor 
assessments until 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), 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first, 
regardless of whether patients start a new anti-cancer therapy.
All primary imaging data used for tumor assessment will be collected by the Sponsor to 
enable centralized, independent review of response endpoints.  The independent 
reviews of the stored scans will be performed when requested.
Patients in all treatment arms 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.  These data will be used to explore 
whether radiographic findings are consistent with the presence of tumor.  Additionally, 
these data will be analyzed to evaluate the association between changes in tumor tissue 
and clinical outcome and to understand further the potential mechanisms of progression 
and resistance to atezolizumab as compared with such mechanisms after treatment with 
chemotherapy alone.  This exploratory biomarker evaluation will not be used for any 
treatment-related decisions.  Patients in Arm A and patients in Arm B (who entered 
Study GO29537 under Protocol Versions 14) who are unable to undergo biopsy sample 
collection but who otherwise meet the criteria listed above may continue/crossover to 
receive atezolizumab.


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Figure 1
Study Schema
Chemotherapy-Naive Patients with Stage IV Non-Squamous NSCLC
(n=approximately 715)
Arm A:
Atezolizumab (1200 mg IV)
+Carboplatin (AUC=6 IV)
+nab-Paclitaxel (100 mg/m2 IV)
Treat with  Atezolizumab until 
Loss of Clinical Benefit
Treat until 
Disease Progression per RECIST v1.1
Survival Follow-Up
2:1 Randomization
Stratification Factors:
•
Sex
•
Liver metastases
•
PD-L1 expression (by central 
testing for PD-L1 status)
Induction Treatment:  Four or Six, 21-Day Cycles
Arm A:
Atezolizumab
(1200 mg IV)
Arm B:
Best Supportive Care
(switch maintenance to 
pemetrexed may be considered) 
No Crossover Permitted
Arm B:
Carboplatin (AUC=6 IV)
+nab-Paclitaxel 
(100 mg/m2 IV)
Maintenance Treatment:  Every 21 Days
AUCarea under the concentrationtime curve; IVintravenous; NSCLCnonsmall cell lung 
cancer; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
3.1.1
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will be used to evaluate safety 
during the study.  Unblinded safety data will be reviewed by the iDMC on a periodic 
basis, approximately every 6 months from the point of first patient in (FPI).  The safety 
data will include demographic data, adverse events, serious adverse events, and 
relevant laboratory data.
The Sponsor will remain blinded to the efficacy results until the final analysis of PFS.  All 
summaries and analyses by treatment arm for the iDMC review will be prepared by an 
external independent Data Coordinating Center (iDCC).  Following the data review, the 
iDMC will provide a recommendation as to whether the study may continue, whether 
amendment(s) to the protocol should be implemented, or whether the study should be 
stopped.  The final decision will rest with the Sponsor.
Members of the iDMC will be external to the Sponsor and will follow a separate iDMC 
Charter that outlines their roles and responsibilities, as well as a detailed monitoring 
plan. 


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Any outcomes of these safety or efficacy reviews that affect study conduct will be
communicated in a timely manner to the investigators for notification of the Institutional 
Review Boards/Ethics Committees (IRBs/ECs). 
3.2
END OF STUDY
The end of study is defined as the date of the last follow-up visit of the last patient or 
when all patients have been enrolled into an extension study.  The Sponsor may decide 
to terminate the study at any time.  If the Sponsor decides to end the study, patients 
who are still receiving study treatment or are in survival follow-up may be offered 
enrollment in an extension study or a non-interventional study. 
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Testing Atezolizumab in Patients with 
PD-L1–Unselected NSCLC
Despite recent improvements in treatment, the prognosis for patients with advanced 
NSCLC remains dismal, with a median OS of approximately 12.3 months 
(Sandler et al. 2006).  Patients who receive second-line treatment for their disease have 
an even more limited prognosis, with 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.
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).
Atezolizumab monotherapy has demonstrated clinical efficacy and is generally 
well-tolerated in patients with squamous or non-squamous NSCLC (Besse et al. 2015; 
Horn et al. 2015; Spigel et al. 2015; Fehrenbacher et al. 2016).  In the second- and 
third-line setting, the POPLAR study, the first randomized Phase II study of atezolizumab 
in advanced NSCLC, showed significant improvement in OS with atezolizumab (12.6 vs. 
9.7 months; HR0.73; 95% CI: 0.53, 0.99; p0.04) versus docetaxel (Fehrenbacher et 
al. 2016). In the Phase III study GO28915 (OAK), which investigated the efficacy and 
safety of atezolizumab compared with docetaxel in patients with previously treated 
locally advanced or metastatic NSCLC, OS was significantly prolonged with 
atezolizumab (median OS 13.8 months vs 9.6 months, HR0.73; 95% CI: 0.62, 0.87;
p0.0003).  In patients with squamous and non-squamous disease, OS was 8.9 versus 
7.7 months (HR 0.73; 95% CI: 0.54, 0.98), and 15.6 versus 11.2 months (HR 0.73;
95% CI: 0.60, 0.89), respectively, in the atezolizumab arm compared with the docetaxel 
arm (Rittmeyer et al. 2017).


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On the basis of promising efficacy of atezolizumab as a single agent (Study GO28753
[POPLAR], Study PCD4989g) and in combination with platinum-doublet therapy
(Study GP28328) and the safety findings from Study GP28328 indicating no additive 
toxicity of atezolizumab in combination with platinum-based chemotherapy, this study 
will evaluate atezolizumab in combination with platinum-based chemotherapy.  TC killing 
by cytotoxic chemotherapy may expose the immune system to high levels of tumor 
antigens, and invigorating tumor-specific T-cell immunity in this setting by inhibiting 
PD-L1/PD-1 signaling may result in deeper and more durable responses compared with 
standard chemotherapy alone (Merritt et al. 2003; Apetoh et al. 2007), and this may 
reasonably occur in tumors regardless of PD-L1 expression.
3.3.2
Rationale for Control Arm
In this study, the control group will receive the platinum doublet of 
carboplatin nab-paclitaxel, an approved regimen in the first-line treatment of advanced 
stage non-squamous NSCLC.  Patients enrolled into the experimental arm will receive 
this standard chemotherapy regimen in addition to atezolizumab.  The emerging safety 
profile of atezolizumab suggests that there is minimal risk of significant additive toxicity 
when it is administered with chemotherapy and that patients will be able to receive 
standard treatment for their disease in the setting of this clinical study.  In addition, 
treatment with this chemotherapy regimen does not require premedication with steroids, 
which may attenuate potential beneficial immunologic effects of treatment with 
atezolizumab.  This control group will be instrumental in assessing the relative benefit 
and safety of atezolizumab in combination with carboplatin nab-paclitaxel compared 
with chemotherapy alone in the front-line treatment setting.
Based on the results from a randomized Phase III study that has shown a PFS and OS 
benefit after the initiation of pemetrexed after induction treatment in patients with 
non-progressive disease, pemetrexed is approved as maintenance treatment for patients 
with NSCLC in the first-line setting.  Therefore, in accordance with the NCCN guidelines, 
switch maintenance therapy with pemetrexed may be considered for patients who are 
randomized to the control arm.
3.3.3
Rationale for Open-Label Study
An open-label study design was chosen for this study for the following reasons.  A 
blinded study would require prolonged administration of placebo during the maintenance 
phase for patients who are randomized to Arm B, which could pose a significant burden 
to patients. Furthermore, because of the potential for pseudoprogression in patients 
randomized to atezolizumab-containing arms, a blinded study would require the option 
that all patients continue treatment until loss of clinical benefit regardless of whether they 
were receiving atezolizumab.  In the absence of pseudoprogression, this could then 
delay subsequent treatment with approved therapies for NSCLC in patients assigned to 
any treatment arm, as well as increase the complexity of treatment decisions.


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Adequate steps have been taken to ensure the validity of data in an open-label study 
design. This includes performing a sensitivity analysis to demonstrate the robustness of 
the primary endpoint, defining progression using established response evaluation criteria 
(RECIST v1.1), performing tumor assessments at the same frequency in all arms, 
adhering to protocol-defined schedules, and determining the strategy for the final 
analysis of the primary endpoint prior to database lock for the primary efficacy analyses, 
including predefined methods for handling missing data and censoring rules. Efficacy 
analyses will be performed only at the prespecified analysis timepoints in the protocol.
3.3.4
Rationale for Progression-Free Survival and Overall Survival 
as Co-Primary Endpoints
Investigator-assessed PFS and OS are the co-primary endpoints for this study.
The co-primary endpoint of OS has been added to the PFS primary endpoint because 
recent data suggest that OS may be a more sensitive endpoint for cancer 
immunotherapy than PFS.  For example, in the randomized Phase II Study GO28753 
(POPLAR) in patients with advanced NSCLC, an OS benefit in the atezolizumab arm 
compared with the docetaxel arm was observed in the ITT population (HR0.73; 95% 
CI: 0.53, 0.99).  PFS in the ITT population was similar between both treatment arms 
(HR0.94; 95% CI: 0.72, 1.23) (Fehrenbacher et al. 2016).  In addition, OS is the most 
objective and best measure of clinical benefit for patients with advanced, unresectable, 
or metastatic lung cancer.
However, given that the majority of patients in this study will likely receive subsequent 
anti-cancer therapies and/or palliative care (Temel et al. 2010) post-disease progression, 
the OS analysis may be confounded (Miller et al. 2012).  Therefore, PFS is being 
retained as a co-primary endpoint and crossover from the control arm to the 
experimental arm after the disease progression will not be permitted, with the aim of 
preserving the study’s ability to potentially demonstrate treatment benefit of 
atezolizumab on OS.
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit.  Whether an improvement in PFS represents a direct 
clinical benefit or a surrogate for clinical benefit depends on the magnitude of the effect 
and the benefitrisk profile of the new treatment compared with available therapies 
(Guidance for Industry 2007; European Medicines Agency 2012).  To ensure the validity 
of investigator-assessed PFS as a co-primary endpoint, a number of measures have 
been implemented:  a substantial target magnitude of benefit (target HR0.55 in the 
tGE-WT population and HR  0.65 in the ITT-WT population), and study assessments 
that will allow a robust evaluation of risk-benefit (standard RECIST to define progression 
with fixed assessment intervals that are identical in all treatment arms and a robust 
definition of PFS and prospectively defined methods to assess, quantify, and analyze 
PFS, including sensitivity analyses).


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New treatment modalities, such as targeted therapies and immunotherapy, are emerging 
as highly effective regimens that are providing improvements in patient outcomes far 
beyond what was achieved before (Ellis et al. 2014).  In particular, immunotherapy has 
been correlated/associated with durable responses, significant prolongation of PFS, and 
improvement of quality of life.  In addition, meta-analyses have indicated that PFS can 
be considered a good measure of clinical benefit for patients with locally 
advanced/metastatic NSCLC (Laporte et al. 2013). 
3.3.5
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment until Loss of Clinical Benefit 
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure.  Because of the potential for 
pseudoprogression/tumor-immune infiltration, this study will allow patients randomized to 
the atezolizumab treatment arm and those patients who crossed over (patients who 
entered Study GO29537 under Protocol Versions 14) to remain on atezolizumab after 
apparent radiographic progression, provided the benefitrisk ratio is judged to be 
favorable.  Patients should be discontinued for unacceptable toxicity or symptomatic 
deterioration attributed to disease progression as determined by the investigator after an 
integrated assessment of radiographic data and clinical status (see Section 3.1).
3.3.6
Rationale for Patient-Reported Outcome Assessments
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on health-related quality 
of life (HRQoL) (Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).  
This is especially true for studies that use PFS as a primary endpoint, where it is 
important to better understand in what regard the delay in disease progression is 
meaningful to patients.
Chest pain, dyspnea, and cough have been regarded as the most frequent and clinically 
relevant disease-related symptoms experienced by patients with NSCLC.  The BR.21 
study (erlotinib vs. best supportive care in second- or third-line NSCLC) demonstrated 
that longer TTD in the pain, dyspnea, and cough scales of the EORTC QLQ-C30 and 
EORTC QLQ-LC13 was consistent with superior PFS, OS, and quality-of-life benefits in 
the erlotinib arm compared with the placebo arm (Aaronson et al. 1993; 
Bergman et al. 1994; Bezjak et al. 2006).  Patients in the afatinib LUX-Lung 3 first-line 
study also reported significant delay of TTD in lung cancer symptoms (chest pain, 
dyspnea, and cough) as measured by the EORTC QLQ-C30 and EORTC QLQ-LC13. 
(Yang et al. 2013).  In this study, the validated EORTC QLQ-C30 and EORTC 
QLQ-LC13 will be used to assess HRQoL and symptom severity. 
In addition, the SILC scale will be used to assess the effect/impact of atezolizumab on 
TTD of specific lung cancer symptoms (chest pain, dyspnea, and cough) in patients with 
Stage IV, non-squamous NSCLC in the first-line setting.


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The single-item Patient Global Impressions of Severity (PGIS) and the EQ-5D-3L 
instrument are included in the study to generate HRQoL and utility scores to confirm 
construct validity of the SILC scale and for use in economic models for reimbursement, 
respectively.  Results from the PGIS and EQ-5D-3L are not planned to be used for 
market authorization.
3.3.7
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens and Evaluation of PD-L1 and T-Effector
Gene Signature
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),
GO28625 (FIR) (Spigel et al. 2015), GO28754 (BIRCH) (Besse et al. 2015), GO28753 
(POPLAR) (Fehrenbacher et al. 2016), and GO28915 (OAK) (Rittmeyer et al. 2017).  In 
addition, POPLAR data suggest higher expression of genes related to PD-L1 and T-
effector biology in tumor tissue is associated with improved efficacy of atezolizumab 
compared with docetaxel (Fehrenbacher et al. 2016). Similar observations have been 
reported for other PD-L1 or PD-1 inhibitors (Higgs et al. 2015; Muro et al. 2015; Seiwert 
et al. 2015). Furthermore, expression of PD-L1 on ICs was reported to be associated 
with expression of T-effector gene signature, therefore representing a preexisting 
immunity (Fehrenbacher et al. 2016).
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 screening period.  
Patients will be stratified by PD-L1 expression.  The primary analysis of this study will
evaluate the efficacy of atezolizumab in the ITT population, as well as in patients with a 
defined level of expression of a PD-L1 and T-effector gene signature (tGE population). 
Both populations will exclude patients with a sensitizing EGFR mutation or ALK 
translocation.  On the basis of an analysis of independent cohorts of patients with 
NSCLC, it is estimated that the primary tGE cutoff for this study will identify a population 
corresponding to approximately 50% of the first-line NSCLC patient population.
In addition to the assessment of PD-L1 status and T-effector gene signature status, 
other exploratory markers, such as potential predictive and prognostic markers related to 
the clinical benefit of atezolizumab, tumor immunobiology, mechanisms of resistance, or 
tumor type, may also be analyzed. DNA and/or RNA extraction and analysis may be 
performed to enable identification of somatic mutations by use of next-generation 
sequencing (NGS) and to evaluate expression of genes (including but not limited to 
PD-L1, PD-1, T-effector and others) to assess their association with efficacy and to 
increase understanding of disease pathobiology.
3.3.8
Rationale for Blood Sampling for Biomarkers
An exploratory objective of this study is to evaluate surrogate biomarkers (that may 
include circulating-tumor DNA [ctDNA], gene expression, tumor burden biomarkers, and 


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others) in blood samples.  Evaluation of blood biomarkers may provide evidence for 
biologic activity of atezolizumab in patients with NSCLC and may allow for the 
development of blood-based biomarkers to help predict which patients may benefit from 
atezolizumab. 
In addition, potential correlations of these biomarkers with the safety and activity of 
atezolizumab will be explored.  
3.3.9
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 
radiological 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).  
If clinically feasible, collection of a mandatory tumor biopsy at the time of radiographic 
progression is required in order to evaluate the utility of the biopsy in distinguishing 
pseudoprogression/tumor-immune infiltration from true progression.  Additionally, 
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 identification of somatic mutations, by use 
of NGS, 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
Co-Primary Efficacy Outcome Measures
The co-primary 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 according to RECIST v1.1 or death 
from any cause, whichever occurs first in the tGE-WT population and the ITT-WT 
population

OS, defined as the time from randomization to death from any cause, in the ITT-WT 
population
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are the following:

OS in the tGE-WT population


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
PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
TC2/3 or IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
tGE population and the ITT population 

Objective response, defined as PR or CR as determined by the investigator 
according to RECIST v1.1 for the tGE-WT population and the ITT-WT population

DOR, defined as the time interval from first occurrence of a documented objective 
response to the time of disease progression as determined by the investigator using 
RECIST v1.1 or death from any cause, whichever occurs first for the tGE-WT 
population and the ITT-WT population

OS rates at 1 and 2 years for the tGE-WT population and the ITT-WT population

TTD in patient-reported lung cancer symptoms, defined as time from randomization 
to deterioration (10-point change) on each of the EORTC QLQ-C30 and EORTC 
QLQ-LC13 symptom subscales (cough, dyspnea [single item], dyspnea [multi-item 
subscale], chest pain, and arm/shoulder pain) in the tGE-WT population and the 
ITT-WT population

Change from baseline in patient-reported lung cancer symptoms (chest pain, 
dyspnea, and cough) on the symptom severity score of the SILC scale in the 
tGE-WT population and the ITT-WT population
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are the following:

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
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are the following:

For patients randomized to atezolizumabcarboplatinnab-paclitaxel:
Maximum observed serum atezolizumab concentration (Cmax) after infusion on 
Cycle 1, Day 1
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at 
selected cycles, at treatment discontinuation, and at 120 days (30 days) after 
the last dose of atezolizumab

Plasma concentrations for carboplatin (Arms A and B)

Plasma concentrations for nab-paclitaxel reported as total paclitaxel (Arms A and B)


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
For patients randomized to carboplatinnab-paclitaxel who crossed over to receive 
open-label atezolizumab as monotherapy (allowed under Study GO29537 Protocol 
Versions 14):
Cmax of serum atezolizumab after infusion on Day 1 of the first cycle following 
crossover to atezolizumab as monotherapy
Cmin of serum atezolizumab prior to infusion on Day 1 at selected cycles 
following crossover to atezolizumab as monotherapy, 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 the following:

PFS at 6 months and at 1 year

OS rate at 3 years

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 in combination with 
chemotherapy

Status of ICs and other exploratory biomarkers in mandatory biopsy specimens and 
blood collected at progression

Utility scores of the EQ-5D-3L 

Change from baseline in patient-reported outcomes of HRQoL, lung cancer-related 
symptoms, and functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients may be eligible if they have chemotherapy-naive, Stage IV, non-squamous 
NSCLC.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Male or female, 18 years of age or older

ECOG performance status of 0 or 1 (see Appendix 11)

Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the 
Union Internationale contre le Cancer/American Joint Committee on Cancer staging 
system, 7th edition; Detterbeck et al. 2009; see Appendix 4).
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are 
eligible if the major histological component appears to be non-squamous.

No prior treatment for Stage IV non-squamous NSCLC


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Patients with a sensitizing mutation in the EGFR gene must have experienced 
disease progression (during or after treatment) or intolerance to treatment with 
one or more EGFR TKIs, such as erlotinib, gefitinib, or another EGFR TKI 
appropriate for the treatment of EGFR-mutant NSCLC.
Patients known to have an ALK fusion oncogene must have experienced 
disease progression (during or after treatment) or intolerance to treatment with 
one or more ALK inhibitors (e.g., crizotinib) appropriate for the treatment of 
NSCLC in patients having an ALK fusion oncogene.
Patients with unknown EGFR and ALK status require test results at screening.  
ALK and/or EGFR may be assessed locally or at a central laboratory.
Patients who have received prior neo-adjuvant, adjuvant chemotherapy, 
radiotherapy, or chemoradiotherapy with curative intent for non-metastatic 
disease must have experienced a treatment-free interval of at least 6 months 
from randomization since the last 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 
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.


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
Known PD-L1 tumor status 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.  
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.  This 
specimen must be accompanied by the associated pathology report.
Fine-needle aspiration (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or cell smears), brushing, cell pellet 
specimens (e.g., from pleural effusion, and lavage samples) are not acceptable.  
Tumor tissue from bone metastases that is subject to decalcification is not 
acceptable.  
For core-needle biopsy specimens, preferably at least three cores embedded in 
a single paraffin block, should be submitted for evaluation. 

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can only be considered as measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of disease. 

Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to randomization:
ANC 1500 cells/L without granulocyte colony-stimulating factor support
Lymphocyte count 500/L
Platelet count 100,000/L without transfusion 
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
INR or aPTT 1.5upper limit of normal (ULN)
This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation should be on a 
stable dose.
AST, ALT, and alkaline phosphatase 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase 
5ULN.
Serum bilirubin 1.25ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN 
may be enrolled.
Serum creatinine 1.5ULN


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
For female patients of childbearing potential agreement (by patient and/or partner) 
to use a highly effective form(s) of contraception that results in a low failure rate 
(1% per year) when used consistently and correctly, and to continue its use for 
5 months after the last dose of atezolizumab or for 30 days after the last dose of 
nab-paclitaxel, whichever is later.  Women must refrain from donating eggs during 
this same period.  For male patients with female partners of childbearing potential, 
agreement (by patient and/or partner) to use a highly effective form(s) of 
contraception that results in a low failure rate (1% per year) when used 
consistently and correctly, and to continue its use for 6 months after the last dose of 
nab-paclitaxel and/or carboplatin, whichever is later.  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 whole study duration), and sexual abstinence.  Male patients 
should not donate sperm during this study and for at least 6 months after the last 
dose of nab-paclitaxel and/or carboplatin, whichever is later.

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 clinical 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 below will be excluded from study entry.
4.1.2.1
Cancer-Specific Exclusions

Active or untreated CNS metastases as determined by CT or 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


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
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 locoregional therapy, if appropriate, prior to randomization.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX®) are allowed.

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or Ca 
12 mg/dL or corrected serum calcium ULN) 
Patients who are receiving denosumab prior to randomization must be willing 
and eligible to receive a bisphosphonate instead while in the study.

Malignancies other than NSCLC within 5 years prior to randomization, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 
5-year OS 90%) treated with expected curative outcome (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized 
prostate cancer treated surgically with curative intent, ductal carcinoma in situ 
treated surgically with curative intent)

Known tumor PD-L1 expression status as determined by an IHC assay from other 
clinical studies (e.g., patients whose PD-L1 expression status was determined 
during screening for entry into a study with antiPD-1 or antiPD-L1 antibodies but 
were not eligible are excluded)
4.1.2.2
General Medical Exclusions

Women who are pregnant, lactating, or intending to become pregnant during 
the study

History of severe allergic, anaphylactic, or other hypersensitivity reactions 
to chimeric or humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary cells or any component of the atezolizumab formulation

History of autoimmune disease, including, but not limited to, myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 13 for 
a more comprehensive list of autoimmune diseases)


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Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid replacement hormone are eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable dose of 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 previous 
12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, 
high-potency or oral steroids).

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test for HIV
All patients will be tested for HIV prior to inclusion into the study; patients who 
test positive for HIV will be excluded from the clinical study.

Patients with active hepatitis B (chronic or acute; defined as having a positive 
hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of 
HBsAg) are eligible only if they are negative for HBV DNA.
Patients who are positive for hepatitis C virus (HCV) antibody are eligible only if 
PCR is negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible.


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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 transplant

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or renders the patient at high risk from treatment 
complications

Illness or condition that interferes with the patient’s capacity to understand, follow,
and/or comply with study procedures
4.1.2.3
Exclusion Criteria Related to Medications

Any approved anti-cancer therapy, including hormonal therapy within 21 days prior 
to initiation of study treatment; the following exceptions are allowed:
TKIs approved for treatment of NSCLC discontinued 7 days prior to 
randomization; the baseline scan must be obtained after discontinuation of prior 
TKIs.

Treatment with any other investigational agent with therapeutic intent within 28 days 
prior to randomization

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
antiPD-1, and antiPD-L1 therapeutic antibodies
Patients who have had prior antiCTLA-4 treatment may be enrolled, provided 
the following requirements are met:
Last dose of antiCTLA-4 at least 6 weeks prior to randomization
No history of severe immune-mediated adverse effects from antiCTLA-4 
(NCI CTCAE Grades 3 and 4)

Treatment with systemic immunostimulatory agents (including, but not limited to, 
IFNs, IL-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to 
randomization
Prior treatment with cancer vaccines is allowed.


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
Treatment with systemic immunosuppressive medications (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization
Patients who have received acute, low-dose (10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in the 
study.
The use of corticosteroids (10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension, and low-dose supplemental 
corticosteroids for adrenocortical insufficiency is allowed.
4.1.2.4
Exclusions Related to Chemotherapy

Known history of severe allergic reactions to platinum-containing compounds 
or mannitol

Known sensitivity to any component of nab-paclitaxel

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 

Known history of severe hypersensitivity reactions to products containing 
Cremophor® EL (e.g., cyclosporin for injection concentrate and teniposide for 
injection concentrate)
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label study.
After written informed consent has been obtained and eligibility has been established, 
the study site will enter demographic and baseline characteristics in the interactive voice
or Web-based response system (IxRS).  For those patients who are eligible for 
enrollment, the study site will obtain the patient’s randomization number and treatment 
assignment from the IxRS.  The number of cycles of induction treatment (four or six) will 
be determined by the investigator and documented prior to randomization.
Randomization to one of the two treatment arms will occur in a 2:1 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)

Presence of liver metastases at baseline (yes vs. no)

PD-L1 expression by IHC (TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and 
IC0/1) (see Section 6.4.1)
Patients should receive their first dose of study drug on the day of randomization if 
possible.  If this is not possible, the first dose should occur within 5 days after 
randomization.


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Following disease progression, patients consented under Protocol GO29537, 
Versions 14, and randomized to Arm B will be given the option to receive atezolizumab 
monotherapy provided they continue to meet crossover eligibility criteria (except for no 
prior treatment for Stage IV non-squamous NSCLC and no prior treatment with immune 
checkpoint blockade therapy).
4.3
STUDY TREATMENT 
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab (MPDL3280A)
The atezolizumab (MPDL3280A) drug product is provided 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
Carboplatin and nab-Paclitaxel
Carboplatin will be obtained in commercially available formulations.  nab-Paclitaxel will 
be supplied to the sites by the Sponsor.  For countries in which the Sponsor is required 
to provide all study drugs, including standard-of-care drugs, carboplatin will be provided 
by Roche or its designee. 
For information on the formulation, packaging, and handling of carboplatin and 
nab-paclitaxel, see the prescribing information for each drug.
4.3.1.3
Erlotinib and Pemetrexed
Switch maintenance to pemetrexed is permitted for patients randomized to Arm B.  
Switch maintenance to erlotinib is no longer permitted.  However, patients randomized to 
Arm B who had already started switch maintenance treatment with erlotinib under 
Protocol Versions 14 may be allowed to continue treatment with erlotinib upon 
discussion of the risks, potential benefits, and alternative treatment options with the 
investigator.  Because erlotinib is considered an investigational medicinal product (IMP), 
erlotinib will be provided by the Sponsor if required by local health authority regulations.  
Pemetrexed will be obtained from commercial sources at each participating site.  For 
information on the formulation, packaging, and handling of pemetrexed, see the 
prescribing information.


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4.3.2
Dosage, Administration, and Compliance
Study treatment will be assigned by the IxRS. The induction phase of the study will 
consist of four or six cycles of chemotherapy.  Atezolizumab and carboplatin will be 
administered on Day 1 of each 21-day cycle.  nab-Paclitaxel will be administered on 
Days 1, 8, and 15 of each 21-day cycle.  The Day 1 order of administration is as follows:
Arm A:  Atezolizumab nab-paclitaxel carboplatin
Arm B:  nab-Paclitaxel carboplatin
During the induction phase, a chemotherapy cycle counts toward the prespecified 
number of induction chemotherapy cycles (four or six) as long as at least one 
chemotherapy component has been administered at least once during a 21-day cycle.  
Cycles in which no chemotherapy component is given do not count toward the total 
number of induction chemotherapy cycles.  Additional guidance is provided in 
Appendix 16.
Patients who experience no further clinical benefit (for patients enrolled in Arm A, see 
Section 3.1 for definition) or disease progression (for patients enrolled in Arm B) at any 
time during the induction phase will discontinue all study treatment.  In the absence of 
the above criteria, after the 4- or 6-cycle induction phase, patients randomized to Arm A 
will begin maintenance therapy with atezolizumab.  Patients randomized to Arm B will 
receive best supportive care until disease progression.  Switch maintenance to 
pemetrexed is also permitted for patients who are randomized to Arm B.  Switch 
maintenance must be administered within 6 weeks of Day 1 of the last induction cycle.
During treatment (induction or maintenance), patients randomized to Arm A who show 
evidence of clinical benefit will be permitted to continue atezolizumab after RECIST v1.1 
for progressive disease are met if they meet all criteria listed in Section 3.1.  Treatment 
with chemotherapy must be discontinued.  
Patients should receive anti-emetics and IV hydration for platinum-based treatments 
according to the local standard of care and manufacturer’s instruction.  On days of 
scheduled infusions of atezolizumab (Arm A), carboplatin and nab-paclitaxel (i.e., Day 1 
of every cycle) chemotherapy should be administered in the following manner:
1.
Arm A only:  Atezolizumab administered over 60 (15) minutes (for the first infusion, 
shortening to 30 [10] minutes for subsequent infusions; see Table 10) followed by
2.
nab-Paclitaxel (100 mg/m2) IV administered over 30 minutes followed immediately 
by
3.
Carboplatin IV administered over 1530 minutes to achieve an initial target area 
under the concentrationtime curve (AUC) of 6 mg/mL/min (Calvert formula dosing)
On Days 8 and 15, nab-paclitaxel (100 mg/m2) IV will be administered over 30 minutes.


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Chemotherapy infusion times may be adapted in accordance with local standard of care 
in lieu of the suggested infusion times. Chemotherapy dose modifications are allowed 
only to address toxicities (see Section 5.1.7.1 and Section 5.1.9 for guidelines).  The 
investigator may use discretion in modifying or accelerating the chemotherapy dose 
modification, 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.
Guidelines for dose modification and treatment interruption or discontinuation for 
carboplatin and nab-paclitaxel are provided in Section 5.1.7 and Section 5.1.9. 
4.3.2.1
Atezolizumab 
Patients randomized to atezolizumab will receive 1200 mg of atezolizumab administered 
by IV infusion every 21 days in a monitored setting where there is immediate access to 
trained personnel and adequate equipment/medicine to manage potentially serious 
reactions.
Atezolizumab infusions will be administered per the instructions outlined in Table 10.


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Table 10 Administration of First and Subsequent Infusions 
of Atezolizumab
First Infusion
Subsequent Infusions
No premedication administered for 
atezolizumab specifically is permitted 
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 60 min before starting 
infusion.
Infuse atezolizumab (1200 mg in a 250 mL 
0.9% NaCl IV infusion bag) over 60 (15) 
min.
If clinically indicated:  record patient’s vital 
signs (pulse rate, respiratory rate, blood 
pressure, and temperature) during the 
infusion at 15 min, 30 min, 45 min, and 
60 min (5-min windows are allowed for all 
timepoints).
If clinically indicated:  record patient’s vital 
signs (pulse rate, respiratory rate, blood 
pressure, and temperature) at 30 min 
(10 min) after the infusion.
Patients will be informed about the possibility 
of delayed post-infusion symptoms and 
instructed to contact their study physician if 
they develop such symptoms.
If patient experienced infusion-related 
reaction during any previous infusion, 
premedication with antihistamines may be 
administered for Cycles 2 at the 
discretion of the treating physician.
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 60 min 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) min. 
If no reaction occurs, subsequent 
infusions may be delivered over 30 (10) 
minutes.
Continue to record vital signs within 
60 minutes before starting infusion.  
Record vital signs during and after the 
infusion if clinically indicated.
If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be delivered 
over 60 (15) min.
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion if 
clinically indicated or patient experienced 
symptoms during the previous infusion. 
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) 30 min (10 min) after the 
infusion if clinically indicated or patient 
experienced symptoms during previous 
infusion.
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are
provided in Sections 5.1.7, 5.1.7.2, and 5.1.8.
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, 
and administration.


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4.3.2.2
Carboplatin and nab-Paclitaxel
nab-Paclitaxel
nab-Paclitaxel injection must be diluted prior to infusion.  nab-Paclitaxel should be 
diluted in 0.9% sodium chloride injection to a final concentration of 5 mg/mL.  Sites 
should follow their institutional standard of care for determining nab-paclitaxel dose 
adjustments in the event of patient weight changes.  The infusion site should be closely 
monitored for possible infiltration during drug administration.  Limiting the infusion of 
nab-paclitaxel to 30 minutes, as directed, reduces the likelihood of infusion-related 
reactions.  Following administration, the IV line should be flushed with sodium chloride 
9 mg/mL (0.9%) solution for injection to ensure administration of the complete dose, 
according to local practice.
See the nab-paclitaxel prescribing information for more information.
Carboplatin
Carboplatin should be administered by IV infusion, immediately after the completion of 
nab-paclitaxel administration, over 1530 minutes to achieve an initial target AUC of 
6 mg/mL/min (Calvert formula dosing) and with standard anti-emetics per local practice 
guidelines.  
The carboplatin dose of AUC 6 will be calculated using the Calvert formula 
(Calvert et al. 1989):
Calvert Formula
Total dose (mg)(target AUC)(glomerular filtration rate [GFR]25)
NOTE:  The GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min. 
For the purposes of this protocol, the GFR is considered to be equivalent to the 
creatinine clearance (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.


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If a patient’s GFR is estimated based on serum creatinine measurements by the isotope 
dilution mass spectroscopy method, the FDA recommends that physicians consider 
capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity 
due to overdosing. Based on the Calvert formula described in the carboplatin label, the 
maximum doses can be calculated as follows:
Maximum carboplatin dose (mg)target AUC (mg min/mL)(GFR25 mL/min)
The maximum dose is based on a GFR estimate that is capped at 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.
Refer to the FDA’s communication regarding carboplatin dosing using the following URL 
for more details:  
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm
228974.htm. 
4.3.2.3
Erlotinib and Pemetrexed
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients 
who had already started switch maintenance treatment with erlotinib under Study 
GO29537 Protocol Versions 14 may be allowed to continue treatment with erlotinib 
upon discussion of the risks, potential benefits, and alternative treatment options with the 
investigator.  For those patients who receive switch maintenance, institutions should 
follow the dosage and administration instructions in the prescribing information.  
For those patients receiving switch maintenance treatment with erlotinib see the 
prescribing information for erlotinib for more information on erlotinib dosing.
For those patients receiving switch maintenance treatment with pemetrexed, see the 
prescribing information for pemetrexed for more information on pemetrexed dosing.
4.3.2.4
Additional Required Medication
Prophylactic Measures for Carboplatin
Carboplatin is considered moderately to highly emetogenic.  Therefore, appropriate 
anti-emetic medication should be given prior to initiation of chemotherapy according to 
the local practice and standard of care. 
4.3.3
Investigational Medicinal Product Accountability
The IMPs for this study are atezolizumab and erlotinib.  Depending on local 
classification, in this study, nab-paclitaxel may either be considered a non-investigational 
medicinal product (NIMP) or an IMP.  IMPs required for completion of this study will be 
provided by the Sponsor if required by local health authority regulations.  The Sponsor or 


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appointed designee will supply other medicinal products in accordance with local 
regulations.  
The study site will acknowledge receipt of the IMPs using IxRS to confirm shipment 
condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Atezolizumab
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 from 
7 days prior to screening until the treatment discontinuation visit.  All such medications 
should be reported to the investigator. 
4.4.1
Permitted Therapy
Premedication with antihistamines may be administered for any atezolizumab infusions 
after Cycle 1.
The following therapies should continue while patients are in the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level)


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
Palliative radiotherapy (e.g., treatment of known bony metastases) provided it does 
not interfere with the assessment of tumor target lesions (e.g., the lesion being 
irradiated is not the only site of disease as that would render the patient not 
evaluable for response by tumor assessments according to RECIST v1.1)
It is not a requirement to withhold atezolizumab during palliative radiotherapy.

Inactive influenza vaccinations 

Megastrol 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
Switch maintenance therapy with pemetrexed is permitted and can be considered for 
patients randomized to Arm B only.  Switch maintenance therapy with erlotinib is no 
longer permitted.  However, patients who had already started treatment with erlotinib 
under Study GO29537 Protocol Versions 14 may be allowed to continue treatment with 
erlotinib upon discussion of the risks, potential benefits, and alternative treatment 
options with the investigator.  
Switch maintenance must be administered within 6 weeks of Day 1 of the last induction 
cycle.  Investigators should follow the NCCN guidelines and dosage and administration 
instructions in the prescribing information for pemetrexed.  
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2-receptor antagonist 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).  Erlotinib and pemetrexed use will be 
recorded on separate erlotinib and pemetrexed administration eCRFs.
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 


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physician.  If the alternatives are not feasible, systemic corticosteroids and TNF-
inhibitors may be administered at the discretion of the treating physician except in the 
case of patients for whom CT scans with contrast are contraindicated (i.e., patients with 
contrast allergy or impaired renal clearance) (see also Section 4.4.3). 
Systemic corticosteroids are recommended, with caution at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with 
atezolizumab therapy.  Guidelines for the management of immune-mediated adverse 
events are described in Section 5.1.8.
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 while in the study, unless otherwise noted:

Denosumab; patients who are receiving denosumab prior to enrollment must be 
willing and eligible to receive a bisphosphonate instead while in the study. 

Any live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to randomization, 
during treatment, or within 5 months after 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 as 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 that are intended for the treatment of cancer are prohibited.
4.5
STUDY ASSESSMENTS
Flowcharts of scheduled study assessments are provided in Appendix 1, Appendix 2, 
and Appendix 3.
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient.


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Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Patients who are treated with atezolizumab and who show apparent radiographic 
progression according to 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 
have a biopsy of the progressing lesion (if clinically feasible) and to acknowledge 
deferring other treatment options available to them in favor of continuing treatment with
atezolizumab.
Patients who entered Study GO29537 under Protocol Versions 14, who were assigned 
to the control arm, and who show disease progression by RECIST v1.1 must sign a 
consent to cross over to atezolizumab treatment at the time of progression to 
acknowledge deferring other treatment options.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to the screening visit. 
NSCLC cancer history will include prior cancer therapies, procedures, and an 
assessment of tumor mutational status (e.g., sensitizing EGFR mutation, ALK fusion 
status).  For patients not previously tested for tumor mutational status, testing will be 
required at screening.  For patients not previously tested for tumor mutational status or 
who have not been previously treated with an EGFR TKI or ALK inhibitor, testing can 
either be performed locally or submitted for central evaluation during the screening 
period.  If EGFR mutations or ALK status testing is not performed locally, additional 
tumor sections may be required for central evaluation of the mutational status of these 
genes.  The tissue requirements for central evaluation may be reviewed 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 should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of temperature, pulse rate, respiratory rate, and 
systolic and diastolic blood pressures while the patient is in a seated position.
Vital signs will be measured and recorded as described in Table 11.


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Table 11 Vital Sign Measurements at Cycle 1 and All Subsequent Cycles
Cycle 1
Treatment Arm
Timepoints
Arm A 
Within 60 minutes prior to atezolizumab infusion
During the infusion at 15 min, 30 min, 45 min, and 60 min
(5-min window) and within 30 (10) minutes after atezolizumab
infusion if clinically indicated
Within 30 (10) minutes after carboplatin infusion
Arm B
Within 60 minutes prior to nab-paclitaxel infusion
Within 30 (10) minutes after carboplatin infusion
Subsequent Cycles
Treatment Arm
Timepoints
Arm A 
Within 60 minutes prior to atezolizumab infusion
During (every 15 [5] minutes) and within 30 (10) minutes after
atezolizumab infusion if clinically indicated or symptoms occurred
during prior infusion
Arm B
Within 60 minutes prior to nab-paclitaxel infusion
During infusion if clinically indicated or if symptoms occurred
during the prior infusions
Within 30 (10) minutes after carboplatin infusion if clinically
indicated or if symptoms occurred during the prior infusion
For patients in the atezolizumab arm, also refer to Table 10.
4.5.5
Tumor and Response Evaluations
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRIs of the chest and abdomen.  A CT or MRI scan of the pelvis is 
required at screening and as clinically indicated or as per local standard of care at 
subsequent response evaluations.  A spiral CT scan of the chest may be obtained but is 
not a requirement.
A CT (with contrast if not contraindicated) or MRI scan of the head must be done at 
screening to exclude CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.  
Patients with active or untreated CNS metastases are not eligible for the study 
(see Section 4.1.2.1).


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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 
according to 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 using 
RECIST v1.1 and modified RECIST.  Tumor assessments will be performed according to 
RECIST v1.1 and modified RECIST for patients in the atezolizumab-containing 
treatment arm (Arm A) and only according to RECIST v1.1 for patients in the 
carboplatin nab-paclitaxel treatment arm (Arm B).
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits.  Results must be reviewed by the investigator before dosing at 
the next cycle. 
Tumor assessments should occur every 6 weeks (7 days) for 48 weeks following 
Cycle 1, Day 1, and then every 9 weeks (7 days) after completion of the 
Week 48 tumor assessment, regardless of treatment delays until radiographic disease 
progression according to RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who had continued treatment with atezolizumab beyond 
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 according to RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments until 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), 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 according to RECIST v1.1 will continue scheduled tumor assessments until 


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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 treated with atezolizumab continuing to experience clinical benefit, despite 
evidence of radiographic progression, will continue tumor assessments as per the 
schedule listed above.  
Scans will be submitted to an IRF.
4.5.6
Laboratory Assessments and Biomarker Samples
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin)

Coagulation (aPTT or INR)

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed on Day 1 of each 
cycle during treatment prior to administration of study treatment.  If a urine
pregnancy test is positive, it must be confirmed by a serum pregnancy test.
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being 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 to be tested only at sites where free T3 testing is not performed.

HBV serology:  hepatitis B surface antigen (HBsAg), antibodies against HBsAg, and 
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.  HBV DNA test 
must be negative.

HCV serology:  hepatitis C virus antibody (anti-HCV)
HCV RNA test must be performed prior to randomization if the patient tests 
positive for anti-HCV.

HIV testing  
All patients will be tested for HIV prior to inclusion into the study, and 
HIV-positive patients 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 by the Sponsor.  Instruction manuals 
and supply kits will be provided for all central laboratory assessments.  Samples for the 
following laboratory tests will be sent to one or several central laboratories or to the 
Sponsor for analysis:  

ATA assays (all atezolizumab-treated patients)
Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of validated immunoassays.  Accompanying PK samples will be collected 
at the same timepoints.

PK assays 
Blood samples for PK assessments will be obtained according to the schedule 
in Appendix 2 and Appendix 3.  
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.
At selected sites, a subset of 20 patients in each arm will undergo the additional 
PK assessments for carboplatin and nab-paclitaxel. 
Plasma carboplatin and nab-paclitaxel concentrations (reported as total 
paclitaxel) will be assayed using validated methods.

Biomarker assays in blood samples
Blood samples will be obtained for biomarker evaluation (including but not 
limited to biomarkers that are related to NSCLC or tumor immune biology)
from all eligible patients according to the schedule in Appendix 2 and 
Appendix 3.  Samples will be processed to obtain plasma and serum for the 
determination of changes in blood-based biomarkers (e.g., ctDNA, cytokines).  
Whole blood samples may be processed to obtain their derivatives (e.g., RNA 
and DNA) and evaluated for immune-related, tumor typerelated, and other 
exploratory biomarkers (e.g., alterations in gene expression or 
single nucleotide polymorphisms).

For patients who consent to the optional collection of samples for the Roche Clinical 
Repository (RCR), any leftover material from the above sample collection will be 
stored and used for exploratory analyses as indicated in Section 4.5.11.  For 
patients who consent to RCR optional future research on their whole blood samples 
collected at screening but are determined to be ineligible for study participation, 
these samples and their derivatives (e.g., DNA, RNA, protein) may be used for 
future development of biomarker and/or diagnostic tests as indicated in
Section 4.5.11.


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4.5.7
Tumor Tissue Samples
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 at screening for determination of PD-L1 status prior to study 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 
and T-effector gene signature will be evaluated. Exploratory biomarkers (including, but 
not limited to, markers related to immune or NSCLC biology, such as T-cell markers or 
non-inherited biomarkers identified through NGS on extracted DNA and/or RNA) may
also be evaluated.  The biomarkers will be identified by IHC, quantitative reverse 
transcriptase-polymerase chain reaction (qRT-PCR), NGS, and/or other methods.
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 TCs that preserve cellular context and 
tissue architecture regardless of needle gauge or retrieval method:

Core-needle biopsies for deep tumor tissue:  at least three cores, embedded into a 
single paraffin block, should be submitted for evaluation.

Excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous or 
mucosal lesions 

Tumor tissue resections
Fine-needle aspiration (defined as a samples that do not preserve tissue architecture 
and yield cell suspension and/or cell smears), brushing, cell pellets (e.g., from pleural 
effusion), and lavage samples are not acceptable.
Tumor tissue from bone metastases that is subject to decalcification 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.
ALK and/or EGFR status may be assessed locally or at a central laboratory if unknown.


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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 the following:

Core-needle biopsies for deep tumor tissue; at least three cores, embedded into a 
single paraffin block, should be submitted for evaluation.

Excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions

Tumor tissue resection
The status of immune-related and tumor typerelated and other exploratory biomarkers 
(including but not limited to T-cell markers and non-inherited biomarkers identified
through NGS on extracted DNA and/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 U.S. 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 Roche Clinical Repository (RCR) optional consent will be 
requested (but not required) to also submit these optional fresh 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 for 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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4.5.7.4
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 4.5.11), 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.
4.5.8
Anti-Therapeutic Antibody Testing
Treatment with atezolizumab may elicit an immune response. Patients with signs of any 
potential immune response to atezolizumab will be closely monitored.  Validated 
screening and confirmatory assays will be employed to detect ATAs at multiple 
timepoints before, during, and after treatment with atezolizumab (see Appendix 1, 
Appendix 2, and Appendix 3 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.
4.5.9
Electrocardiograms
A 12-lead ECG is required at screening and thereafter as clinically indicated.  ECGs 
should be obtained on the same machine whenever possible.  Lead placement should
be as consistent as possible.  ECG recordings should be performed after the patient has 
been resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.


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4.5.10
Patient-Reported Outcomes
PRO data will be collected via the EORTC QLQ-C30, the EORTC QLQ-LC13, SILC, 
PGIS, and EQ-5D-3L to more fully characterize the clinical profile of atezolizumab.  
The questionnaires will be translated as required in the local language.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires scheduled for administration during a clinic visit will be completed in their 
entirety by the patient prior to the performance of non-PRO assessments and the 
administration of study treatment. 
Patients will use an electronic PRO (ePRO) device to capture PRO data.  The ePRO 
device and/or instructions for completing the PRO questionnaires electronically will be 
provided by the investigator staff.  The data will be transmitted via a prespecified 
transmission method (e.g., Web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the Internet.  
The EORTC QLQ-C30 (see Appendix 8) 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 15 minutes to complete.  This questionnaire will 
be completed on the ePRO tablet at each scheduled cycle visit during the treatment 
induction phase and then according to the tumor assessment schedule during the 
treatment maintenance phase.  During survival follow-up, the questionnaire will be 
completed at 3 months and 6 months following disease progression (or loss of clinical 
benefit for atezolizumab-treated patients who had continued treatment after radiographic 
disease progression according to RECIST v1.1).  
The EORTC QLQ-LC13 (see Appendix 9) module incorporates one multiple-item scale 
to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, 
dysphagia, peripheral neuropathy, alopecia, and hemoptysis.  The EORTC QLQ-LC13 
module takes approximately 15 minutes to complete.  This questionnaire will be 
completed on the ePRO tablet at each scheduled cycle visit during the treatment 
induction phase and then according to the tumor assessment schedule during the 
treatment maintenance phase.  During survival follow-up, the questionnaire will be 
completed at 3 months and 6 months following disease progression (or loss of clinical 
benefit for atezolizumab-treated patients who had continued treatment after radiographic 
disease progression according to RECIST v1.1).  
The SILC scale will be used to assess patient-reported severity of lung cancer 
symptoms (chest pain, dyspnea, and cough). The SILC scale is a 9-item content valid 


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self-report measure of lung cancer symptoms. It measures severity of cough, dyspnea, 
and chest pain with a symptom severity score. This questionnaire will be completed 
using an ePRO device at the patient’s home on a weekly basis, then during survival 
follow-up every month for 6 months following disease progression (or loss of clinical 
benefit for atezolizumab-treated patients who had continued treatment after radiographic 
disease progression according to RECIST v1.1).
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 each scheduled cycle visit during the treatment 
induction phase and then according to the tumor assessment schedule during the 
treatment maintenance phase.  During survival follow-up, the questionnaire will be 
completed at 3 months and 6 months following disease progression (or loss of clinical 
benefit for atezolizumab-treated patients who had continued treatment after disease 
progression according to RECIST v1.1).  
The PGIS consists of a single question used to assess patient global impression of 
disease severity.  This question will be completed on the ePRO tablet at each scheduled
cycle visit during the treatment induction phase and then according to the tumor 
assessment schedule during the treatment maintenance phase. The PGIS is not 
required during survival follow-up.
Patients who discontinue study treatment for any reason other than progressive 
disease or loss of clinical benefit will complete the EORTC QLQ-C30, EORTC 
QLQ-LC13, PGIS, and EQ-5D-3L at each tumor assessment visit and will complete the 
SILC at home on a weekly basis, until 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) as 
determined by the investigator (unless the patient withdraws consent or the Sponsor 
terminates the study).
The Sponsor will not derive adverse events reports from PRO data.  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.
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 exempt from completing all ePRO assessments.


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4.5.11
Samples for Roche Clinical Repository
4.5.11.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the 
future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or 
disease progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RCR sampling, this section of the protocol 
(Section 4.5.11) will not be applicable at that site.
4.5.11.3
Sample Collection
The following samples may be collected for patients who have signed the RCR optional 
consent:

Optional fresh biopsy samples

Leftover tumor tissue samples

Remaining fluids (serum, plasma, blood cell derivatives) after study-related tests 
have been performed 

Remaining FFPE tissue (with the exception of archival FFPE blocks, which will be 
returned to sites) after study-related tests have been performed

Whole blood samples collected at screening (for screen-fail patients only)
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)


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


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4.5.11.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research.
4.5.11.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the study is ongoing, must enter the date of withdrawal on the RCR 
Research Sample Withdrawal of Informed Consent eCRF. A patient's withdrawal from 
Study GO29537 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 GO29537.
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
4.5.11.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality, as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RCR for the purposes of verifying 
the data provided to Roche.  The site will permit monitoring, audits, IRB/EC review, and 
health authority inspections by providing direct access to source data and documents 
related to the RCR samples.


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4.5.12
Timing of Assessments
4.5.12.1
Screening and Baseline Assessments
Screening tests and evaluations will be performed within 28 days prior to Cycle 1, Day 1.  
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 28 days prior to Cycle 1, Day 1 may be used; such tests do not need 
to be repeated for screening. 
See Appendix 1 for the schedule of screening assessments and Appendix 2 and 
Appendix 3 for the schedule of PK, ATA, and biomarker sampling.
4.5.12.2
Assessments during Treatment
All visits must occur 3 days from the scheduled date unless otherwise noted 
(see Appendix 1). All assessments will be performed on the day of the specified visit 
unless a time window is specified.  Assessments scheduled on the day of study 
treatment administration (Day 1) of each cycle should be performed prior to study 
treatment infusion unless otherwise noted. 
Patients who are randomized to Arm B who had started erlotinib (allowed under Study 
GO29537 Protocol Versions 14) or pemetrexed switch maintenance after the induction 
phase will continue with cycle visits as outlined in Appendix 1 for the maintenance phase
until erlotinib or pemetrexed treatment termination, disease progression, withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first.
Patients who are randomized to Arm B who receive BSC after the induction phase are 
not required to continue with cycle visits.  Their treatment discontinuation visit will take 
place when patients discontinue BSC. 
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing continuing on a 21-day schedule.  If treatment was postponed 
for fewer than 3 days, the patient can resume the original schedule.
After completion of the induction phase one of three cycles may be delayed by 1 week 
(28 days instead of 21 days for one cycle) to allow for vacations/holidays.  Following the 
delay, the next cycle must be delivered 21 days from the previous dose administration: 
two consecutive 28 cycles are not permitted.  If a dose modification is required due to 
toxicity, refer to Section 5.1.
Tumor assessments should occur every 6 weeks (7 days) for 48 weeks following 
Cycle 1, Day 1, and every 9 weeks (7 days) after the completion of the Week 48 tumor 
assessment, regardless of treatment delays, until radiographic disease progression 
according to RECIST v1.1 (or loss of clinical benefit for patients who had continue 
treatment with atezolizumab after disease progression according to RECIST v1.1), 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs 


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first. Patients who discontinue treatment for reasons other than radiographic disease 
progression according to RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments until 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), withdrawal of consent, study termination by Sponsor, or 
death, whichever occurs first.
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 on Day 1, Cycle 1.
Local hematology tests must also be performed prior to nab-paclitaxel infusions on 
Day 8 and Day 15.
See Appendix 1 for the schedule of assessments performed during the treatment period 
and Appendix 2 and Appendix 3 for the schedule of PK, pharmacodynamic, ATA, 
and biomarker sampling. 
4.5.12.3
Assessments for Treatment-Crossover Patients
The same treatment-phase schedule of assessments and procedures will apply to 
patients in Arm B who crossed over to Arm A (allowed under Study GO29537 Protocol 
Versions 14). That is, patients will begin on Cycle 1 (now to be called Cycle 1A) and 
will follow the same assessments and procedures as outlined in this protocol for this 
cycle (with the exception of an alternate schedule for PK and pharmacodynamic 
assessments [see Appendix 3] and a biopsy upon progression will not be requested for 
these patients), as well as for all subsequent cycles (i.e., Cycle 2, which will now be 
called Cycle 2A, etc.).
In addition, patients who crossed over from Arm B to Arm A following disease 
progression (allowed under Study GO29537 Protocol Versions 14) will not follow the 
treatment-phase schedule for PRO assessments during crossover. These patients will 
complete PRO assessments according to the post-progression schedule (i.e., SILC 
monthly for the first 6 months only and EORTC QLQ-C30, QLQ-LC13, and EQ-5D 3L at 
3 and 6 months only).  
4.5.12.4
Assessments at Study Drug Discontinuation Visit
When a patient discontinues all study treatment (including pemetrexed and erlotinib
[allowed under Study GO29537 Protocol Versions 14] switch maintenance, and BSC),
regardless of the reason for discontinuation, the patient will be asked to return to the 
clinic within 30 days after the treatment for the study drug discontinuation visit.  The visit 


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at which the decision is made to discontinue treatment (e.g., loss of clinical benefit is 
confirmed) may be used as the study drug discontinuation visit.
Arm B Crossover Patients Allowed under Study GO29537, Protocol 
Versions 1–4
For patients who entered Study GO29537 under Protocol Versions 14, who were 
assigned to the control arm, and who are allowed to cross over to receive atezolizumab, 
the study drug discontinuation visit must be repeated when they discontinue receiving 
atezolizumab.  The same study drug discontinuation visit procedures as listed below and 
in Appendix 1 must be performed for both study drug discontinuation visits.
See Appendix 1, Appendix 2, and Appendix 3 for the schedule of follow-up 
assessments.
4.5.12.5
Follow-Up Assessments
After the study drug discontinuation visit, adverse events should be followed as outlined 
in Section 5.3.1.
For patients who discontinue study treatment (including chemotherapy induction, switch 
maintenance of erlotinib [allowed under Study GO29537 Protocol Versions 14] or 
pemetrexed switch maintenance for patients randomized to Arm B) for any reason other 
than radiographic progressive disease according to RECIST v1.1, tumor assessments 
should continue at the same frequency as would have been followed if the patient had 
remained on study treatment until radiographic disease progression (or loss of clinical 
benefit for patients treated with atezolizumab [Arm A patients and Arm B patients who 
cross over] who had continued treatment with atezolizumab after disease progression 
according to RECIST v1.1), withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.  
Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression according to RECIST v1.1 should continue tumor assessments according to 
the protocol schedule of response assessments until radiographic disease progression 
according to RECIST v1.1, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first.
Follow-up data collection will also include ePROs (the SILC will be completed monthly 
only for the first 6 months after disease progression [or loss of clinical benefit for 
atezolizumab-treated patients who had continued treatment with atezolizumab after 
radiographic disease progression according to RECIST v1.1] using an ePRO device at 
the patient’s home and EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L will be 
completed 3 and 6 months after disease progression [or loss of clinical benefit for 
atezolizumab-treated patients] at the site using the ePRO tablet), study 
treatmentrelated adverse events (including serious adverse events), subsequent 
anti-cancer therapies, and date and cause of death.  Patients who discontinue study 


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treatment for any reason other than progressive disease or loss of clinical benefit will 
complete the EORTC QLQ-C30, EORTC QLQ-LC13, PGIS, and EQ-5D-3L at each 
tumor assessment visit and will complete the SILC at home on a weekly basis, until 
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) 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 every 3 months or more frequently until death, loss to follow-
up, or study termination by the Sponsor, whichever occurs first.  All patients will be 
periodically contacted for survival and new anti-cancer therapy information unless the 
patient requests to be withdrawn from the study (this request must be documented in the 
source documents and signed by the investigator).  If the patient withdraws from study, 
the study staff may use a public information source (e.g., county records), when 
permissible, to obtain information about survival status only.
See Appendix 1, Appendix 2, and Appendix 3 for the schedule of follow-up 
assessments.
4.5.12.6
Assessments at Unplanned Visits
Assessments for unscheduled visits related to a patient’s underlying NSCLC, study drug, 
or adverse event should be performed as clinically indicated and entered on the 
Unscheduled Visit eCRFs.  
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance
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.


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4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status.

Intolerable toxicity related to atezolizumab, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Intolerable toxicity related to other components of the study treatment 

If one component of study treatment is discontinued permanently due to tolerability 
concerns, the patient may continue with other components of study treatment until 
disease progression or loss of clinical benefit (for atezolizumab-treated patients who 
continue treatment after disease progression according to RECIST v1.1) if agreed 
upon by the investigator and patient

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another nonprotocol-specified anti-cancer therapy (see Section 4.4.3)

Pregnancy

Radiographic disease progression according to RECIST v1.1 

Exception for atezolizumab treatment:  patients randomized to atezolizumab 
treatment will be permitted to continue atezolizumab after RECIST v1.1 for 
progressive disease are met if they meet all of the following criteria (see Figure 2 for 
the schematic representation):
Evidence of clinical benefit as assessed by the investigator
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease
No decline in ECOG performance status 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be readily managed and stabilized by protocol-allowed 
medical interventions prior to repeat dosing
Patients must provide written consent to acknowledge deferring any standard 
treatment options that may exist in favor of continuing atezolizumab treatment 
at the time of initial progression
A mandatory biopsy sample collection, unless not clinically feasible as 
assessed by the investigators, at the site of local or metastatic progression
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 


Study and Site Discontinuation
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Figure 2
Conditions for Continuing Atezolizumab in Presence of Increased 
Radiographic Tumor Size (Applicable to Arm A and Arm B 
Crossover Patients Consented under Study GO29537 Protocol 
Versions 14)
ECOG PSEastern Cooperative Oncology Group performance status; ICF Informed Consent 
Form; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
4.6.3
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.


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
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 and 
published data on similar molecules.
5.1
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (see Sections 4.1.1
and 4.1.2) and close monitoring (as indicated below and in Section 4.5).  
See Section 5.3 (Methods and Timing for Capturing and Assessing Safety Parameters) 
for complete details regarding safety reporting for this study.
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
All serious adverse events and adverse events of special interest will be recorded during 
the study and for up to 90 days after the last dose of study treatment (inclusive of 
erlotinib or pemetrexed switch maintenance for patients randomized to Arm B who 
receive erlotinib [allowed under Study GO29537 Protocol Versions 14] or pemetrexed 
switch maintenance) or until 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 
(inclusive of erlotinib or pemetrexed switch maintenance for patients randomized to Arm 
B who receive erlotinib [allowed under previous versions of this protocol] or pemetrexed 
switch maintenance) or until initiation of new systemic anti-cancer therapy after the last 
dose of study treatment, whichever occurs first.  
After the adverse event reporting period, all deaths should continue to be reported. In 
addition, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event or adverse event of special interest that is believed to be related to prior 


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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
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy 
may increase the risk of immune-mediated adverse events, specifically the induction or 
enhancement of autoimmune conditions.  Adverse events with potentially 
immune-mediated causes, including rash, hypothyroidism, hepatitis/transaminitis, colitis, 
pneumonitis, myositis, and myasthenia gravis, have been observed in the Phase Ia 
Study PCD4989g.  For further details regarding clinical safety, including a detailed 
description of the anticipated safety risks for atezolizumab, see the Atezolizumab 
Investigator’s Brochure.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications (Di Giacomo et al. 2010).  
Suggested workup procedures for suspected immune-mediated adverse events are 
provided in Section 6 (Guidance for the Investigator) of the Atezolizumab Investigator’s 
Brochure.
5.1.2
Risks Associated with Carboplatin 
Carboplatin is known to cause bone marrow suppression including myelosuppression, 
anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is considered to be 
moderately emetogenic.  Patients will be monitored for carboplatin-related adverse 
events.
For more details regarding the safety profile of carboplatin, refer to the prescribing 
information for carboplatin.
5.1.3
Risks Associated with nab-Paclitaxel 
In clinical studies, nab-paclitaxel has been associated with alopecia, myelosuppression 
(neutropenia, anemia, thrombocytopenia), peripheral neuropathy, cranial nerve palsies, 
hypersensitivity reactions, pneumonitis, gastrointestinal events (i.e., nausea, vomiting, 
diarrhea), myalgia, anthralgia, cardiotoxicity (myocardial disorders, cardiac failure, 
angina, tachycardia, ventricular arrhythmia), cystoid macular edema, Stevens-Johnson 
syndrome/toxic epidermal necrolysis, sepsis, drug-induced lupus erythematous, infusion 
site reactions/extravasation, hepatic toxicity (drug-induced liver injury), acute renal 
failure, and hemolytic-uremic syndrome.
Patients will be monitored for nab-paclitaxelrelated adverse events, including 
hematologic, gastrointestinal and hepatic toxicities, and peripheral neuropathy.


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For more details regarding the safety profile of nab-paclitaxel, refer to the nab-paclitaxel 
prescribing information.
5.1.4
Risks Associated with Erlotinib
This section applies to patients already receiving erlotinib switch maintenance therapy 
under Study GO29537 Protocol Versions 14.  The most commonly reported adverse 
drug reactions with erlotinib were rash and diarrhea.  Most were Grade 1 or 2 in severity 
and were manageable without intervention.  In general, rash manifests as a mild or 
moderate erythematous and papulopustular rash and may occur or worsen in sun-
exposed areas.  For patients who are exposed to the sun, protective clothing and/or the 
use of sunscreen (e.g., mineral-containing) may be advisable.
For more details regarding the safety profile of erlotinib, refer to the prescribing 
information for erlotinib.
5.1.5
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.
5.1.6
General Plan to Manage Safety Concerns
5.1.6.1
Monitoring
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events defined and graded according to NCI CTCAE v4.0.  Patients 
will be assessed for safety (including laboratory values) according to the schedule in 
Appendix 1.  Laboratory values must be reviewed prior to each infusion.
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts 
(see Appendix 1 for the list and timing of study assessments).
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.
All serious adverse events and protocol-defined events of special interest will be 
reported in an expedited fashion (see Sections 5.2.2 and 5.2.3).  In addition, the iDMC 
and Medical Monitor will review and evaluate observed adverse events on a regular 
basis.


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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 Section 5.3.1, 5.3.5.7, 5.5, and 5.6.
5.1.7
Dose Modification
5.1.7.1
General Notes Regarding Dose Modification
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v4.0 grading 
system.

For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator 
feels it is appropriate.  For example, if a patient has Grade 1 asthenia at baseline 
that increases to Grade 2 during treatment, this will be considered a shift of one 
grade and treated as Grade 1 toxicity for dose-modification purposes.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.

If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
component of the study treatment (i.e., atezolizumab, carboplatin, or nab-paclitaxel) 
and the dose of that component is delayed or modified in accordance with the 
guidelines below, other components may be administered if there is no 
contraindication.

When treatment is temporarily interrupted because of toxicity caused by, 
atezolizumab, carboplatin and/or nab-paclitaxel, the treatment cycles will be 
restarted such that the atezolizumab infusions remain synchronized and aligned 
with the chemotherapy schedule.

If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one chemotherapy drug, the dose of the other chemotherapy drug does not 
require modification.  (Exception for nab-paclitaxel and carboplatin:  In the case of 
peripheral neuropathy, hematologic, and gastrointestinal toxicities, nab-paclitaxel 
and carboplatin require modification.  See Section 5.1.9)
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.
5.1.7.2
Atezolizumab Dose Modification
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 more than 105 days beyond the last dose, then 
the patient will be discontinued from atezolizumab treatment and will be followed for 


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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 beyond 105 days from the last dose until steroids are 
discontinued or reduced to prednisone dose (or dose equivalent) 10 mg/day.  The 
acceptable length of interruption will depend on agreement between the investigator and 
the Medical Monitor.
5.1.8
Management of Atezolizumab-Specific Adverse Events
Management of systemic immune activation is presented below.  Refer to the 
Atezolizumab Investigator’s Brochure for details on management of atezolizumab-
specific adverse events.
Refer to Appendix 12 for precautions for anaphylaxis.
Refer to Section 5.1.9.5 and Table 15 for management of pulmonary events and 
pneumonitis when atezolizumab and nab-paclitaxel are administered together, or when 
nab-paclitaxel is administered without atezolizumab.
Systemic Immune Activation
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternate etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the 
following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations.


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5.1.9
Carboplatin and nab-Paclitaxel Dose Modification and 
Management of Specific Adverse Events
Dose reductions, holds, and discontinuations for each study drug may be made as 
outlined below.  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.
When a treatment cycle is delayed or interrupted because of toxicity resulting from either 
component of the regimen, all study treatment should generally be withheld and 
resumed together to remain synchronized.  However, if it is anticipated that 
chemotherapy will be delayed by 2 weeks, then atezolizumab should be given without 
the chemotherapy if there is no contraindication; this should be discussed with the 
Medical Monitor prior to re-initiating therapy.
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.
Dose modifications of carboplatin and nab-paclitaxel are allowed as described in the 
following sections.
5.1.9.1
Hematologic Toxicity
In general, ANC must be 1500 cells/L and platelet count must be 100,000/L on 
Day 1 of each cycle. When nab-paclitaxel is administered on Day 1, it should not be 
administered on Days 8 or 15 of the cycle unless ANC 500 cells/L and platelets 
50,000 cells/L.  In certain situations, a cycle may begin with the administration of 
atezolizumab alone (without nab-paclitaxel on Day 1).  If Day 1 of a cycle begins with 
only atezolizumab but without the administration of nab-paclitaxel due to low platelet or 
ANC levels, nab-paclitaxel should not be administered subsequently within that cycle 
until ANC 1500 cells/L and platelet count ≥100,000/L. If the delay in re-starting nab-
paclitaxel is 7 days (i.e., counts do not recover until Day 15), dosing should be 
resumed with applicable reductions.  If the start of a cycle is delayed (i.e., both 
atezolizumab and nab-paclitaxel are withheld) for low counts, postpone Day 1 and 
resume dosing when counts recover.  If nab-paclitaxel cannot be administered on 
Day 15 of the cycle, the next dose of nab-paclitaxel should be administered with 
carboplatin on Day 1 of the following cycle when ANC and platelets counts have 
recovered to permissible levels.  When dosing resumes, the carboplatin and 
nab-paclitaxel doses should be permanently reduced as outlined in Table 12.


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Table 12 nab-Paclitaxel and Carboplatin Permanent Dose Reductions 
Based on Nadir ANC and Platelets
Hematologic Toxicity
Occurrence
Weekly 
nab-Paclitaxel 
Dose (mg/m2)
Every-3-Week 
Carboplatin Dose 
(AUC mgmin/mL)
Neutropenic fever (ANC 500 cells/L
with fever 38°C)
OR
Delay of next scheduled dose by
7 days for 
ANC 1500 cells/L
OR
ANC500 cells/L for 7 days
First
75
4.5
Second
50
3
Third
Discontinue treatment
Platelet count 50,000 cells/L
First
75
4.5
Second
Discontinue treatment
AUCarea under the concentrationtime curve.
5.1.9.2
Gastrointestinal Toxicity
For Grade 3 or 4 gastrointestinal toxicities, treatment should be delayed until resolution 
to less than or equal to the patient’s baseline value.  Dose reductions at the start of the 
subsequent cycle will be based on gastrointestinal toxicities from the dose administered 
in the preceding cycle.  Table 12 provides the relevant dose adjustments for 
gastrointestinal toxicities.
Table 13 Carboplatin and nab-Paclitaxel Dose Modification Based on 
Gastrointestinal Toxicities in the Preceding Cycle
Toxicity
Occurrence
Adjusted 
Carboplatin
Dose as % of 
Previous Dose a
Adjusted 
nab-Paclitaxel
Dose as % of 
Previous Dose
Grade 3 diarrhea
OR
Grade 3 
mucositis/stomatitis
OR
Grade 3 or 4 
nausea/vomiting
First
75%
75%
Second
50%
50%
Third
Discontinue treatment
Grade 4 oral 
mucositis/stomatitis
NA
Discontinue treatment
Grade 4 diarrhea
NA
Discontinue treatment
AUCarea under the concentrationtime curve.
a If deemed appropriate by the treating physician, adjust carboplatin dose 
to the specified percentage of the previous AUC.


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Nausea and/or vomiting should be controlled with adequate anti-emetics.  If Grade 3 or 4 
nausea/vomiting occurs despite administration of anti-emetics, the dose should be 
reduced by 25% for the next and subsequent courses.
If, on Day 1 of any treatment cycle, the patient has oral mucositis/stomatitis, the 
treatment should be withheld until the oral mucositis/stomatitis is cleared.  If the oral 
mucositis/stomatitis has not cleared in 3 weeks, the patient’s chemotherapy will be 
discontinued.  See Table 13 for additional details on dose reductions.  Dose reductions 
listed are permanent.
5.1.9.3
Neurological Toxicity 
nab-Paclitaxel and carboplatin should be withheld for Grade 34 peripheral neuropathy.  
nab-Paclitaxel and carboplatin may be resumed at reduced doses (see Table 14) when 
peripheral neuropathy recovers to Grade 1 or completely resolves.
Table 14 nab-Paclitaxel and Carboplatin Permanent Dose Reductions for 
Neurological Toxicity 
Adverse Reaction
Occurrence
Weekly nab-Paclitaxel 
Dose (mg/m2)
Every-3-Week 
Carboplatin Dose 
(AUC mgmin/mL)
Grade 3 or 4 sensory 
neuropathy
First
75
4.5
Second
50
3
Third
Discontinue treatment
AUCarea under the concentrationtime curve.
5.1.9.4
Hepatic Toxicity (nab-Paclitaxel Only)
For patients with no hepatic metastases at baseline who develop severe enzyme 
elevations during study treatment (ALT and/or AST 5ULN or total bilirubin3ULN), 
study treatment should be interrupted, hepatic toxicity must resolve to baseline levels
prior to dosing.  If nab-paclitaxel is withheld because of hepatic toxicity, carboplatin 
should also be withheld and administered when the nab-paclitaxel is resumed.  If 
nab-paclitaxel is withheld, hepatic values must recover to baseline levels within 3 weeks 
or the patient’s nab-paclitaxel treatment will be discontinued.  No dose reductions for 
carboplatin will be made for hepatic toxicity.
For patients with mild hepatic impairment (total bilirubin 1 to 1.5ULN and ALT/AST 
5ULN), no dose adjustments are required.  Treat with the same doses as patients 
with normal hepatic function.
If moderate to severe hepatic elevations (total bilirubin1.55.0ULN or ALT and/or 
AST 510ULN) occur at any time, the nab-paclitaxel dose should be permanently 
reduced to 80% of the starting dose (i.e., to 80 mg/m2).  nab-Paclitaxel will be 
discontinued for patients with total bilirubin5ULN or AST10ULN. 


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The investigator should make all efforts to exclude malignant disease progression as a 
cause of liver enzyme derangement.  All study treatment must be discontinued if the 
disease under investigation has progressed.
5.1.9.5
Pulmonary Events and Pneumonitis:  Atezolizumab and 
nab-Paclitaxel, or nab-Paclitaxel without Atezolizumab
Note:  When atezolizumab is administered without nab-paclitaxel, refer to the 
Atezolizumab Investigator’s Brochure for management of pulmonary events, including 
pneumonitis. 
Atezolizumab

Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab and have primarily been 
observed in patients with underlying NSCLC.
Mild to moderate events of pneumonitis have been reported with atezolizumab.  All 
pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension:

Measurement of oxygen saturation (i.e., arterial blood gas)

High-resolution CT scan of the chest

Bronchoscopy with bronchoalveolar lavage and biopsy

Pulmonary function tests (diffusion capacity of the lung for carbon monoxide 
[DLCO])

Pulmonary function testing with a pulmonary embolism protocol
Patients will be assessed for pulmonary signs and symptoms throughout the study, and 
will also have CT scans of the chest at every tumor assessment.  See Table 15 for 
management guidelines for pulmonary events and pneumonitis.
nab-Paclitaxel 

Interstitial pneumonitis has been observed in 1% of patients with nab-paclitaxel 
monotherapy and 4% with the use of nab-paclitaxel in combination with 
gemcitabine.  Patients should be monitored closely for signs and symptoms of 
pneumonitis. 
nab-Paclitaxel should be permanently discontinued upon ruling out infectious etiology 
and making a diagnosis of pneumonitis. Promptly initiate appropriate treatment and 
supportive measures.
Infections should be ruled out with routine microbiological and/or immunologic methods.


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After ruling out an infectious etiology, high-dose IV corticosteroid therapy should be 
instituted without delay, with appropriate premedication and secondary pathogen 
coverage.  Patients with an added immunological component may also require immune 
modulation with azathioprine or cyclophosphamide.
Table 15 details the management of pulmonary events/pneumonitis when atezolizumab 
and nab-paclitaxel are administered together, or when nab-paclitaxel is administered 
alone.
Note:  When atezolizumab is administered alone, refer to the Atezolizumab 
Investigator’s Brochure for management of pulmonary events, including pneumonitis.


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Table 15 Management Guidelines for Pneumonitis:  Atezolizumab and 
nab-Paclitaxel, or nab-Paclitaxel with or without Atezolizumab
Severity
Atezolizumab
(in Combination with nab-Paclitaxel)
nab-Paclitaxel
(with or without Atezolizumab)
Grade 1
Withhold atezolizumab with close 
monitoring.
Resume when event improves to Grade 0.
Re-evaluate on serial imaging.
Consider pulmonary consultation.
Permanently discontinue 
nab-paclitaxel.
After ruling out infection, 
start high-dose IV 
corticosteroids with 
appropriate premedication 
and secondary pathogen 
coverage.
Grade 2
Withhold atezolizumab.
Pulmonary and infectious disease 
consultation with consideration for 
bronchoscopy/BAL.
Start 60 mg prednisone or equivalent per 
day.
When improves to Grade 0 or Grade 1, then 
taper steroids over 1 month.
Atezolizumab may be resumed if the event 
improves to Grade 0 or Grade 1 within 
12 weeks, and corticosteroids have been 
reduced to the equivalent of oral prednisone 
10 mg daily or less.
Treat as Grade 34 if recurrent episode of 
pneumonitis.
Permanently discontinue 
nab-paclitaxel.
After ruling out infection, 
start high-dose IV 
corticosteroids with 
appropriate premedication 
and secondary pathogen 
coverage.
Grade 
3or4
Permanently discontinue atezolizumab and 
contact the Medical Monitor.
Bronchoscopy/BAL is recommended.
Start 60 mg prednisone or equivalent per 
day.
Taper steroids over 1 month after 
symptoms improve to Grade 0 or Grade 1.
If not improving after 48 hours or worsening, 
add additional immunosuppression (e.g., 
infliximab, cyclophosphamide, IV Ig, or 
mycophenolate mofetil).
Permanently discontinue 
nab-paclitaxel.
After ruling out infection, 
start high-dose IV
corticosteroids with 
appropriate premedication 
and secondary pathogen 
coverage.
BALbroncho-alveolar lavage; Igimmunoglobulin; IV intravenous.
5.1.9.6
Other Toxicities
For any Grade 3 or 4 toxicity not mentioned above, carboplatin or nab-paclitaxel should 
be withheld until the patient recovers completely or to Grade 1 toxicity.  nab-Paclitaxel 
and carboplatin may be resumed at reduced doses (see Table 16) when toxicity 
recovers to Grade 1 or completely resolves.  If recovery to Grade 1 toxicity does not 
occur within 3 weeks, the patient’s chemotherapy will be discontinued.  For Grade 1 and 
2 toxicities, no dose reduction should be made.


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Table 16 nab-Paclitaxel and Carboplatin Permanent Dose Reductions for 
Non-Hematologic, Non-Gastrointestinal, Non-Neurologic, and 
Non-Hepatic Toxicity
Adverse Reaction
Occurrence
Weekly nab-Paclitaxel 
Dose (mg/m2)
Every 3-Week 
Carboplatin Dose 
(AUC mg min/mL)
Grade 3 or 4 
non-hematologic, 
non-GI, 
non-neurologic, 
non-hepatic toxicity 
First
75
4.5
Second
50
3
Third
Discontinue treatment
AUCarea under the concentrationtime curve; GIgastrointestinal.
For guidelines on the dosing of other study drugs when carboplatin or nab-paclitaxel are 
withheld, see Section 5.1.7.
5.1.10
Erlotinib and Pemetrexed Dose Modification and Management 
of Specific Adverse Events
For patients who had started switch maintenance therapy with erlotinib (allowed under
Study GO29537 Protocol Versions 14) and for patients who receive pemetrexed, refer 
to the prescribing information for erlotinib and pemetrexed for dose modifications for 
adverse event management.
5.1.11
Potential Overlapping Toxicities 
To date, on the basis of safety data from Study GP28328, the risk of overlapping 
toxicities between atezolizumab, carboplatin, and nab-paclitaxel is thought to be 
minimal.  Nevertheless, the attribution and management of certain adverse events that 
have been associated with each agent separately (e.g., hepatotoxicity, skin, and 
gastrointestinal toxicity) may not be unambiguous when the agents are administered 
together.  It is theoretically possible that allergic or inflammatory adverse events 
associated with these chemotherapeutic agents (e.g., hepatotoxicity) could be 
exacerbated by the immunostimulatory activity of atezolizumab. 
Toxicities should initially be managed according to the recommendations in 
Sections 5.1.7 and 5.1.8, with dose holds and modifications (if applicable) applied to the 
component of the study drug judged to be the primary cause.  For severe (Grade 3) or 
persistent Grade 1 or 2 diarrhea, an endoscopic evaluation should be considered.  
Additional tests, such as autoimmune serology or biopsies, may be used to determine a 
possible immunogenic etiology for adverse events listed above.  If, in the opinion of the 
investigator, atezolizumab is a potential inciting factor, the dose of atezolizumab may be 
withheld for a maximum of 105 days beyond the last dose (see Section 5.1.7.2).  
Exceptions require Medial Monitor approval.  Prompt symptomatic management is 
appropriate for mild immune-mediated adverse events.  In severe cases, 


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immune-mediated toxicities may be acutely managed with topical corticosteroids, 
systemic corticosteroids, or TNF-inhibitors.  These cases should be discussed with the 
Medical Monitor. 
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest; measurement of 
protocol-specified safety laboratory assessments; measurement of protocol-specified 
vital signs; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (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.


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
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Confirmed treatment-emergent autoimmune conditions:
Pneumonitis
Grade 3 hypoxia or dyspnea 
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


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
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 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein-transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient who was exposed to a medicinal product.  This term 
applies only when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
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 treatment, all serious adverse events and adverse events of 
special interest, regardless of relationship to study treatment, will be reported until 
90 days after the last dose of study treatment (inclusive of switch maintenance with 
pemetrexed or erlotinib [for patients who received switch maintenance with erlotinib 
under Study GO29537 Protocol Versions 14]) or until initiation of new systemic anti-
cancer therapy after the last dose of study treatment, whichever occurs first.  All other 
adverse events, regardless of relationship to study treatment, will be reported until 
30 days after the last dose of study treatment (inclusive of switch maintenance with 
pemetrexed or erlotinib [for patients who received switch maintenance with erlotinib 
under Study GO29537 Protocol Versions 14]) or until initiation of new systemic 
anti-cancer therapy after the last dose of study treatment, whichever occurs first.  


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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 17 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 17 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.


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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
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
For all adverse events, a diagnosis (if known) 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.


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5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity) of the event will be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, the 
most extreme intensity should also be recorded on the Adverse Event eCRF.  If the 
event becomes serious, it should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning that the event became serious; see Section 5.4.2 for 
reporting instructions).  The Adverse Event eCRF should be updated by changing the 
event from “non-serious” to “serious,” providing the date that the event became serious, 
and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it is a change from baseline and meets any of 
the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with 
clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of NSCLC should be recorded only on the 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).  An 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. 


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5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
5.3.5.9
Worsening of NSCLC
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration or 
to perform an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Adverse Events Associated with an Overdose or Error in 
Drug Administration
Study overdose is the accidental or intentional use of a drug in an amount higher than 
the dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Study Drug Administration eCRF.
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2).
5.3.5.12
Patient-Reported Outcome Data
Adverse 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 study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Adverse events of special interest

Pregnancies
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results


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
Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor:
, M.D. (Primary)
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D., Ph.D. (Secondary)
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events that are caused by a protocol-mandated intervention should be 
reported.  The Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
provided to investigators should be completed and submitted to Roche or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment (inclusive of 
switch maintenance with pemetrexed or erlotinib [for patients who received switch 
maintenance with erlotinib under Study GO29537 Protocol Versions 14]) or until 
initiation of new systemic anti-cancer therapy after the last dose of study treatment, 
whichever occurs first.  All other adverse events, regardless of relationship to study 
treatment, will be reported until 30 days after the last dose of study treatment (inclusive 


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of switch maintenance with pemetrexed or erlotinib [for patients who received switch 
maintenance with erlotinib under Study GO29537 Protocol Versions 14) or until 
initiation of new systemic anti-cancer therapy after the last dose of study treatment, 
whichever occurs first.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting 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 30 days after the last dose of nab-paclitaxel.  A Clinical 
Trial Pregnancy Reporting Form should be completed and submitted to the Sponsor or 
its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form with use of the fax number or 
email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
6 months after the last dose of nab-paclitaxel and/or carboplatin.  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), 


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either by faxing or by scanning and emailing the form with use of the fax number or 
email address provided to investigators. Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient 
exposed to study drug.  When permitted by the site, the pregnant partner would need to 
sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow 
for follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician.
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 to be related to study drug or study-related procedures 
until a final outcome can be reported.


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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.
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 as reference:

Atezolizumab Investigator’s Brochure

Tarceva® (erlotinib) Summary of Product Characteristics (SmPC)/Local Label

Abraxane® (nab-paclitaxel) Summary of Product Characteristics (SmPC)/Local 
Label


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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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a Phase III, randomized, multicenter, open-label study designed to evaluate the 
safety and efficacy of atezolizumab in combination with carboplatinnab-paclitaxel 
compared with treatment with carboplatinnab-paclitaxel alone in approximately 
715 patients with Stage IV, non-squamous NSCLC in the first-line setting.  
Efficacy analyses will be performed in one or more populations (tGE-WT, ITT-WT, tGE, 
ITT, TC2/3 or IC2/3 WT, or TC1/2/3 or IC1/2/3 WT), with patients grouped according to 
the treatment assigned at randomization, regardless of whether they received any 
assigned study treatment.
Safety analyses for the primary treatment phase will be performed on all randomized 
patients who received any amount of any component of protocol treatment, with patients 
grouped according to whether any full or partial dose of atezolizumab was received.  
Safety analyses for the crossover phase (for patients who entered Study GO29537
under Protocol Versions 14) will be performed on patients assigned to the control arm 
who received any amount of atezolizumab as subsequent treatment.  
6.1
DETERMINATION OF SAMPLE SIZE
The primary endpoint of PFS will be analyzed in the tGE-WT population and in the ITT-
WT population, and the primary endpoint of OS will be analyzed in the ITT-WT 
population.  Analyses of PFS and OS will be conducted according to an analysis 
hierarchy and an -spending algorithm to control for the type I error rate (see Figure 3) 
and to account for an interim OS analysis (see Section 6.8.1).  The PFS and OS 
analysis hierarchy and allocation, including possible recycling, are shown in 
Figure 3.  A detailed description of the hypothesis testing is provided in Section 6.4.1.


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Figure 3
Progression-Free Survival and Overall Survival Analysis 
Hierarchy, Alpha Allocation, and Alpha Recycling
0.022
0.003
PFS
OS
1. PFS in tGE-WT
α=0.003
3. OS in ITT-WT
If Step 1 or Step 2 is not statistically significant, α=0.022
If Step 2 is statistically significant, α=0.025
Arm A vs. Arm B
1-sided α=0.025 a
2. PFS in ITT-WT
If Step 1 is statistically significant, α=0.003
ITT intent to treat; OS overall survival; PFS progression-free survival; tGE tumor gene 
expression; WT wild type
a To control the overall type I error rate for the one-sided test at 0.025, a one-sided type I error 
() of 0.003 and 0.022 (ratio of 3:22) will be allocated to PFS and OS, respectively, for 
comparison of Arm A versus Arm B.
This study will randomize approximately 715 patients.  The ITT-WT population will 
include approximately 650 patients, assuming a prevalence of approximately 10% for 
sensitizing EGFR mutations or ALK translocations.  The tGE-WT population will include
approximately 325 patients, assuming a 50% prevalence with the chosen tGE cutoff.
The sample size of this study is based on the number of events required to demonstrate 
efficacy with regard to both PFS and OS (co-primary endpoints).
The estimate of the number of events required to demonstrate efficacy with regard to 
PFS in the comparison of Arm A versus Arm B is based on the following assumptions:

93% power to detect an HR of 0.55, corresponding to an improvement in median 
PFS from 6 months to 10.9 months in the tGE-WT population with a one-sided of 
0.003

95% power to detect an HR of 0.65, corresponding to an improvement in median 
PFS from 6 months to 9.2 months in the ITT-WT population with a one-sided of 
0.003

No interim analyses for PFS

Dropout rate of 5% per 12 months


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The estimate of the number of events required to demonstrate efficacy with regard to OS 
in the comparison of Arm A versus Arm B is based on the following assumptions:

80% power to detect an HR of 0.75, corresponding to an improvement in median 
OS from 12 months to 16 months in the ITT-WT population with a one-sided of 
0.022

One interim OS analysis performed at the time of the final PFS analysis, at which 
time approximately 77% of the total number of OS events required for the final 
analysis are expected to have occurred, as determined through use of the 
Lan-DeMets approximation to the O'Brien-Fleming boundary

Dropout rate of 5% per 24 months
With these assumptions, approximately 715 patients in total will be enrolled in this study, 
with approximately 650 patients in the ITT-WT population. The final PFS analysis will be 
conducted when all of the following criteria have been met:  approximately 225 PFS 
events have occurred in the tGE-WT population, approximately 475 PFS events have 
occurred in the ITT-WT population, and the last patient has been enrolled in the study.  
The final PFS analysis is expected to occur approximately 32 months after the first 
patient is enrolled.  These numbers of events would allow for a minimum detectable 
difference corresponding to an HR of 0.68 in the tGE-WT population and 0.76 in the 
ITT-WT population, respectively.
With a sample size of 650 patients, approximately 457 OS events are expected to occur 
in the ITT-WT population.  The final OS analysis is expected to occur approximately 
42 months after the first patient is enrolled. This number of events would allow for a 
minimum detectable difference corresponding to an HR of 0.81 in the ITT-WT 
population.
6.2
SUMMARIES OF CONDUCT OF STUDY
Study enrollment, study drug administration, reasons for discontinuation from the study 
drug, and reasons for study termination will be summarized by treatment arm for the tGE
population, the tGE-WT population, the ITT population, and the ITT-WT population.  
Major protocol deviations, including major deviations with regard to inclusion/exclusion 
criteria, will be reported and summarized by treatment arm for the ITT-WT population.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic characteristics such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG performance status), will be summarized by treatment arms 
for the tGE-WT population and the ITT-WT population.  Descriptive statistics (mean, 
median, standard deviation, and range) will be presented for continuous data, and 
frequencies and percentages will be presented for categorical data.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of protocol treatment.


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6.4
EFFICACY ANALYSES
6.4.1
Co-Primary Efficacy Endpoints
The co-primary efficacy endpoints are PFS as assessed by the investigator using 
RECIST v1.1 and OS.  PFS will be analyzed in the tGE-WT population and the ITT-WT 
population.  OS will be analyzed in the ITT-WT population.  The timing of the final PFS 
and OS analyses is described in Section 6.1.  At least one interim OS analysis will be 
performed (see Section 6.8.1).
PFS is defined as the time between the date of randomization and the date of first 
documented disease progression or death, whichever occurs first.  Patients who have 
not experienced disease progression or death at the time of analysis will be censored 
at the time of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored at the date of randomization plus 1 day.  
OS is defined as the time between the date of randomization and death from any cause.  
Data for patients who are not reported as having died at the time of analysis will be 
censored at the date when they were last known to be alive.  Data for patients who do 
not have post-baseline information will be censored at the date of randomization plus 
1 day.
The following analyses will be performed for both PFS and OS.  PFS and OS will be 
compared between treatment arms with the use of the stratified log-rank test.  The HR
for PFS and OS for treatment comparisons will be estimated using a stratified Cox 
regression model, respectively.  The 95% CI for the HR will be provided.
The stratification factors will be those used during randomization (i.e., sex [male vs. 
female], presence of liver metastases at baseline [yes vs. no], and PD-L1 tumor 
expression by IHC [TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1]), as 
recorded in the IxRS.
Results from an unstratified analysis will also be presented.  Kaplan-Meier methodology 
will be used to estimate the median PFS and the median OS for each treatment arm, 
and a Kaplan-Meier curve will be constructed to provide a visual description of the 
difference between treatment arms.  The Brookmeyer-Crowley methodology will be used 
to construct the 95% CI for the median PFS and the median OS for each treatment arm 
(Brookmeyer and Crowley 1982).
Analyses will be conducted according to an analysis hierarchy and an -spending 
algorithm to control for the type I error rate (see Figure 3 in Section 6.1) and to account 
for an interim analysis (see Section 6.8.1).  
To control the overall type I error rate for the one-sided test at 0.025, a one-sided type I 
error () of 0.003 and 0.022 (ratio of 3:22) will be allocated to PFS and OS, respectively. 


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The hypothesis testing will be performed in the order described below:
1.
PFS in the tGE-WT population will be tested at 0.003 (one sided).  If the estimate 
of the HR is 1 and the one-sided p-value corresponding to the stratified log-rank 
test is 0.003, the null hypothesis will be rejected and it will be concluded that 
atezolizumabcarboplatinnab-paclitaxel prolongs the duration of PFS relative to 
control treatment in the tGE-WT population. 
2.
If the null hypothesis is rejected in the tGE-WT population (Step 1), PFS in the 
ITT-WT population will be tested at 0.003 (one sided). 
3.
recycling from PFS to OS will be conducted as follows: 
a.
If the null hypothesis is not rejected for the PFS analysis in the ITT-WT
population (Step 2), OS in the ITT-WT population will be tested at 0.022 (one 
sided). 
b.
If the null hypothesis is rejected for the PFS analysis in the ITT-WT population 
(Step 2), OS in the ITT-WT population will be tested at 0.025 (one sided).
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
6.4.2.1
Progression-Free Survival and Overall Survival in Secondary 
Populations
PFS will be analyzed in the TC2/3 or IC2/3 WT population, the TC1/2/3 or IC1/2/3 WT 
population, the tGE population, and the ITT population, through use of the same 
methods described for the primary PFS analysis (see Section 6.4.1).
OS will be analyzed in the tGE-WT population, the TC2/3 or IC2/3 WT population, the 
TC1/2/3 or IC1/2/3 WT population, the tGE population, and the ITT population, through 
use of the same methods described for the primary OS analysis (see Section 6.4.1). 
If the difference in OS between Arm A and Arm B in the ITT-WT population is statistically 
significant, a comparison of Arm A versus Arm B will be conducted in the tGE population 
and ITT population.  The allocation will follow the same -spending algorithm and 
allocation ratio described for analysis of the co-primary efficacy endpoints (see 
Section 6.4.1).


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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 using RECIST v1.1.  Patients not meeting these criteria, including 
patients without any post-baseline tumor assessment, will be considered 
non-responders.  
ORR is defined as the proportion of patients who had an objective response.  ORR will 
be analyzed in the tGE-WT population and the ITT-WT population.  Patients must have 
measurable disease at baseline to be included in the analysis.  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 Mantel-Haenszel test.  The stratification factors of this 
analysis will be the same as those described in Section 6.4.1.  
6.4.2.3
Duration of Response
DOR will be analyzed in the tGE-WT population and the ITT-WT population.  DOR will 
be assessed in patients who had an objective response as determined by the 
investigator using RECIST v1.1.  DOR is defined as the time interval from the date of the 
first occurrence of a complete or partial response (whichever status is recorded first) 
until the first date that progressive disease or death is documented, whichever occurs 
first.  Patients who have not progressed and who have not died at the time of analysis 
will be censored at the time of last tumor assessment date.  If no tumor assessments 
were performed after date of the first occurrence of a complete or partial response, DOR 
will be censored at the date of the first occurrence of a complete or partial response plus 
1 day.  
DOR is based on a non-randomized subset of patients (specifically, patients who 
achieve an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between treatment arms will be made for 
descriptive purposes.  The methodology detailed for the PFS analysis will be used for 
the analysis of DOR. 
6.4.2.4
Overall Survival Rate at Landmark Timepoints
OS rate at 1 and 2 years will be analyzed in the tGE-WT population and the ITT-WT 
population.  The OS rates at 1 and 2 years will be estimated using Kaplan-Meier 
methodology for each treatment arm, along with 95% CIs calculated using the standard 
error derived from the Greenwood formula.  The 95% CI for the difference in OS rates 
between the two treatment arms will be estimated using the normal approximation 
method.


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6.4.2.5
Patient-Reported Outcomes
TTD in lung cancer symptoms as determined by EORTC and change from baseline in 
lung cancer symptoms as determined by SILC will be analyzed in the tGE-WT 
population and the ITT-WT population.
TTD using EORTC is defined as the time from baseline to the first time the patient’s 
score shows a 10-point increase above baseline in any of the following 
EORTC-transformed symptom subscale scores (whichever comes first):  cough, 
dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain.  
A10-point change in the symptoms subscale score is perceived by patients as clinically 
significant (Osoba et al. 1998). 
Change from baseline per SILC scale will be analyzed in patients with a baseline and a 
post-baseline PRO assessment.
Further details regarding all PRO analyses will be described in the Statistical Analysis 
Plan (SAP).
6.4.3
Handling of Missing Data 
For PFS, patients without a date of disease progression will be analyzed as censored 
observations on the date of the last tumor assessment.  If no post-baseline tumor 
assessment is available, PFS will be censored at the date of randomization plus 1 day.  
Data for patients with a PFS event who missed two or more scheduled assessments 
immediately prior to the PFS event will be handled as described in the sensitivity 
analysis in Section 6.7.1.4. 
For objective response, patients without any post-baseline assessment will be 
considered non-responders.
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 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 using EORTC, data for patients who have not deteriorated at the time of 
analysis will be censored at the last time they completed an assessment.  If no 
post-baseline assessment is performed, data for patients will be censored at the 
randomization date plus 1 day.


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6.5
SAFETY ANALYSES
For the primary treatment phase, safety analyses will include all treated patients, defined 
as randomized patients who received any amount of any component of study treatment.  
Safety data will be summarized by treatment arm for treated patients in a primary safety-
evaluable population consisting of patients in the tGE-WT population and/or the ITT-WT 
population (depending on the results of the primary endpoint analyses).  Safety data will 
also be summarized by treatment arm for treated patients not included in the primary 
safety-evaluable population.
Safety analyses for patients who entered Study GO29537 under Protocol Versions 14
in the crossover phase will be performed on the patients assigned to the control arm who 
received any amount of atezolizumab as subsequent treatment.
6.5.1
Treatment Phase
Drug exposure will be summarized to include treatment duration, number of doses, and 
dose intensity. 
Verbatim description of adverse events will be mapped to MedDRA thesaurus terms and 
graded according to NCI CTCAE v4.0.  All adverse events occurring during or after the 
first study drug dose will be summarized by treatment arm and NCI CTCAE grade.  In 
addition, serious adverse events, severe adverse events (Grade 3), adverse events of 
special interest, and adverse events leading to study drug discontinuation or interruption 
will be summarized accordingly.  Multiple occurrences of the same event will be counted 
once at the maximum severity.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized by treatment arm and grade.
Changes in vital signs will be summarized by treatment arm.
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion/discontinuation will be summarized by 
treatment arm.
6.5.2
Crossover Phase (For Patients Who Entered Study GO29537
under Protocol Versions 1–4)
Crossover is no longer permitted; however, patients who were randomized to the control 
arm and who entered Study GO29537 under Protocol Versions 14 have the option for 
crossover to atezolizumab following disease progression according to RECIST v1.1.  
Drug exposure and safety data after receiving atezolizumab as subsequent treatment for 
the patients in the control arm will be summarized separately from the safety analyses.  
The analyses for drug exposure and adverse events described for that phase will be 
conducted.


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6.6
PHARMACOKINETIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 2 and Appendix 3.  
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, and standard 
deviations, as appropriate.
Plasma concentrations of carboplatin and nab-paclitaxel (reported as total paclitaxel) will 
be collected in this study as outlined in Appendix 2.  The concentrations of carboplatin 
and paclitaxel will be summarized using descriptive statistics as described above.
Additional PK analyses will be conducted, as appropriate, based on the availability 
of data.
6.7
EXPLORATORY ANALYSES
6.7.1
Exploratory Analyses of Progression-Free Survival
6.7.1.1
Progression-Free Survival Rate at Landmark Timepoints
The PFS rates at various timepoints (e.g., at 6 months and at 1 year after randomization) 
will be estimated using Kaplan-Meier methodology for each treatment arm, along with 
95% CIs calculated using Greenwood’s formula.  The 95% CI for the difference in PFS 
rates between the two arms will be estimated using the normal approximation method.
6.7.1.2
Non–Protocol-Specified Anti-Cancer Therapy
The impact of nonprotocol-specified anti-cancer therapy on PFS will be assessed 
depending on the number of patients who receive nonprotocol-specified anti-cancer 
therapy before a PFS event.  If 5% of patients received nonprotocol-specified 
anti-cancer therapy before a PFS event in any treatment arm, a sensitivity analysis will 
be performed in which data for patients who receive nonprotocol-specified anti-cancer 
therapy before a PFS event will be censored at the last tumor assessment date before 
receiving nonprotocol-specified anti-cancer therapy.
6.7.1.3
Subgroup Analysis
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG 
performance status, presence of liver metastases at baseline), and PD-L1 tumor 
expression status, the duration of PFS in these subgroups will be examined.  Summaries 
of PFS, including unstratified HRs estimated from Cox proportional hazards models and 
Kaplan-Meier estimates of median PFS, will be produced separately for each level of the 
categorical variables.


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6.7.1.4
Sensitivity Analyses 
Sensitivity analyses will be performed to evaluate the potential impact of missing 
scheduled tumor assessments on the primary analysis of PFS, as determined by the 
investigator using a PFS event imputation rule.  The following two imputation rules will 
be considered:

If a patient missed two or more scheduled tumor assessments immediately prior to 
the date of the PFS event according to RECIST v1.1, the patient will be censored at 
the last tumor assessment prior to the first of these missed visits.

If a patient missed two or more scheduled tumor assessments immediately prior to 
the date of the PFS event according to RECIST v1.1, the patient will be counted as 
having progressed on the date of the first of these missing assessments.
The imputation rule will be applied to patients in both treatment arms.  Statistical 
methodologies analogous to those used in the primary analysis of PFS as specified in 
Section 6.4.1 will be used for this sensitivity analysis.
6.7.2
Exploratory Analyses of Overall Survival
6.7.2.1
Loss to Follow-Up
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  If 5% of patients are lost to follow-up for OS in either 
treatment arm, a sensitivity analysis will be performed in which patients who are lost to 
follow-up will be considered as having died at the last date they were known to be alive.
6.7.2.2
Subgroup Analysis
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG 
performance status, presence of liver metastases at baseline), and PD-L1 tumor 
expression status, the duration of OS in these subgroups will be examined.  Summaries 
of survival, including unstratified HRs estimated from Cox proportional hazards models 
and Kaplan-Meier estimates of median survival time, will be produced separately for 
each level of the categorical variables for the comparisons.
6.7.2.3
Overall Survival Rate at Three-Year Landmark
The methodologies for landmark OS analysis that are outlined in Section 6.4.2.4 will 
be used.


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6.7.2.4
Milestone Overall Survival Analysis
To assess the effect of long-term survival and delayed clinical effects, a milestone OS 
analysis will be conducted (Chen 2015).  The milestone OS is an OS endpoint with 
cross-sectional assessment at a pre-specified timepoint.  The milestone OS analysis will 
be performed using the same methods as those specified for the primary OS analysis, 
and the specific definition of milestone will be documented in the SAP.
6.7.3
Exploratory Biomarker Analysis
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with study drug response, including efficacy and/or adverse 
events.  The tumor biomarkers include, but are not limited to, PD-L1 and CD8, as 
defined by IHC, qRT-PCR, or other methods.  Additional pharmacodynamic analyses will 
be conducted as appropriate.
6.7.4
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.
6.7.5
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
INTERIM ANALYSES
6.8.1
Planned Interim Analysis
There are no interim analyses planned for PFS in this study.  An external iDMC will be 
set up to evaluate safety data on an ongoing basis.  All summaries/analyses by 
treatment arm for the iDMC’s review will be prepared by an iDCC.  Members of the 
iDMC will be external to the Sponsor and will follow a charter that outlines their roles and 
responsibilities.  Any outcomes of these safety reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the IRBs/ECs.  
A detailed plan will be included in the iDMC Charter. 
If approximately 352 OS events have occurred in the ITT-WT population at the time of 
the PFS final analysis (see criteria for final PFS analysis in Section 6.1), an interim OS 
analysis will be conducted in the ITT-WT population.  If there are significantly fewer than 
the expected 352 OS events at the final PFS analysis, a nominal of 0.01% (negligible 
impact on overall type I error rate) will be spent on the OS analysis at the time of the 


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PFS final analysis and a second interim OS analysis will then be conducted after 
approximately 352 OS events have occurred. 
The final OS analysis will be conducted when approximately 457 OS events have 
occurred in the ITT-WT population.  This is expected to occur approximately 42 months 
after the first patient is enrolled.
Stopping boundaries for the interim and final OS analyses will be computed through use 
of the Lan-DeMets approximation to the O'Brien-Fleming boundary.  The stopping 
boundaries are provided in Table 18.
Table 18 Analysis Timing and Stopping Boundaries for Overall Survival 
in the ITT-WT Population
Analysis Timing
Stopping Boundary:  HR (p-value)
If 0.022
If 0.025
Interim OS analysis
HR0.766
(p0.0091)
HR0.771
(p0.0107)
Final OS analysis
HR0.814
(p0.0193)
HR0.819
(p0.0218)
HRhazard ratio; ITTintent to treat; OSoverall survival. 
Note:  values and p-values are one-sided.  The p-value will be used to claim crossing of a 
boundary.
6.8.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis for the co-primary endpoints of PFS 
and OS beyond what is specified in Section 6.8.1.  Below are the specifications in place 
to ensure that the study continues to meet the highest standards of integrity when an 
optional interim analysis is executed.
The interim analysis will be conducted by an external statistical group and reviewed by 
the iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified 
in the iDMC Charter. 
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the Statistical Analysis Plan 
(SAP), and the SAP will be submitted to relevant health authorities at least 2 months 
prior to the conduct of the interim analysis.  The iDMC Charter will document potential 
recommendations the iDMC can make to the Sponsor as a result of the analysis 
(e.g., stop the study for positive efficacy, stop the study for futility), and the iDMC Charter 
will also be made available to relevant health authorities.


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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 through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected electronically through use of electronic devices 
provided by an ePRO vendor.  The electronic device is designed for entry of data in a 
way that is attributable, secure, and accurate, in compliance with U.S. 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 study and system 
documentation will be archived.  The Sponsor will receive all data entered by patients on 
the e-diary and tablet device and all study documentation.
Details regarding patient reported data and the electronic device are 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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 


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that shows the original data, as well as the reason for the change, the name of the 
person making the change, and the date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final 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 laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining samples for optional exploratory research.  The investigator or authorized 
designee will explain to each patient the objectives of the exploratory research.  Patients 


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will be told that they are free to refuse to participate and may withdraw their specimens 
at any time and for any reason during the storage period.  A separate, specific signature 
will be required to document a patient's agreement to allow any remaining specimens to 
be used for exploratory research.  Patients who decline to participate will not provide a 
separate signature.
The Informed Consent Form will also contain the following additional signature pages:

A signature page for patients receiving atezolizumab who wish, if approved by the 
treating physician, to continue treatment beyond initial radiographic disease 
progression according to RECIST v1.1 and meet criteria specified in Section 4.6.  
This separate consent is to be signed after initial radiographic disease progression 
according to 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 (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.


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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 U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.


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9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor or designee 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 105 sites globally will participate in the study, and approximately 
715 patients will be randomized.
Randomization will occur through an IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests, and PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.


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9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical studies in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical study results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical studies in 
patients involving an IMP for which a marketing authorization application has been filed 
or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and 
statistically sound.
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors’ authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol GO29537, Version 7
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Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol GO29537, Version 7
Appendix 1
Schedule of Assessments
Procedure
Screening
Induction Phase
Cycles 1 to 4 or 6
(21-Day Cycle) a
Maintenance Phase
(21-Day Cycle) a
Treatment 
Discontinuation
Visit
Survival Follow-Up 
Days –28
to –1
Day 1
(3 Days) b
Day 1
(3 Days) b
30 Days after 
Last Dose of Study 
Treatment
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Informed consent 
x
Tumor tissue specimen for PD-L1 testing (15 FFPE 
slides required; blocks preferred) c
Fresh or archival tissue can be used
x
ALK and/or EGFR assessment if status is unknown 
(may be done locally or centrally)
x
Demographic data
x
Medical history and baseline conditions
x
NSCLC cancer history
x
Vital signs d
x
x d
x d
x
Weight
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examination e
x
x
x
ECOG performance status
x
x
x
x
12-Lead ECG
x
x f
x f
x f
Hematology g
x
x
x
x
Serum chemistry h
x
x
x
x
Coagulation test (aPTT or INR)
x
x


Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol GO29537, Version 7
Appendix 1
Schedule of Assessments (cont.)
Procedure
Screening
Induction Phase
Cycles 1 to 4 or 6 
(21-Day Cycle) a
Maintenance Phase
(21-Day Cycle) a
Treatment 
Discontinuation 
Visit
Survival Follow-Up
Days –28
to –1
Day 1
(3 Days) b
Day 1
(3 Days) b
30 Days after 
Last Dose of Study 
Treatment
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Pregnancy test (women of childbearing-potential 
ONLY)
x i
x j
x j
x j
TSH, free T3, free T4 k
x
x k
x k
x
HIV, HBV, HCV serology l
x
Urinalysis m
x
x
x
x
Determination of duration of induction treatment
x
Induction treatment administration:
Arm A: atezolizumab carboplatinnab-paclitaxel
Arm B: carboplatin nab-paclitaxel
x n
Maintenance treatment administration:
Arm A: atezolizumab
Arm B: Best supportive care (switch maintenance
to pemetrexed permitted)
x n
Tumor response assessment
x o
x p
x p
x q
Serum sample for atezolizumab ATA assessment 
(atezolizumab-treated patients only) r
x
x
x
120 (30) days after last 
dose of atezolizumab
Serum sample for PK sampling (atezolizumab-
treated patients only) r
x
x
x
120 (30) days after last 
dose of atezolizumab
Carboplatin and nab-paclitaxel PK sampling 
(20 patients per arm) r
x


Atezolizumab—F. Hoffmann-La Roche Ltd
160/Protocol GO29537, Version 7
Appendix 1
Schedule of Assessments (cont.)
Procedure
Screening
Induction Phase
Cycles 1 to 4 or 6 
(21-Day Cycle) a
Maintenance Phase
(21-Day Cycle) a
Treatment 
Discontinuation 
Visit
Survival Follow-Up
Days –28
to –1
Day 1
(3 Days) b
Day 1
(3 Days) b
30 Days after 
Last Dose of Study 
Treatment
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit
Blood samples for PD biomarkers r
x
x
x
x
120 (30) days after last 
dose of atezolizumab
Optional blood for DNA extraction 
(RCR only) r, s
x
Informed consent to continue treatment beyond 
radiographic progression (Arm A 
atezolizumab-treated patients)
At time of radiographic progression
Tumor biopsy
At time of radiographic progression t
Optional tumor biopsy at other timepoints 
(RCR only)
Any time during study treatment or during survival follow-up
Adverse events u
x
x
x
x
x
Concomitant medications
From 
7 days 
before 
screening
x
x
x
Patient-reported outcomes v
x v
x v
x v
Survival and anti-cancer therapy follow-up w
x


Atezolizumab—F. Hoffmann-La Roche Ltd
161/Protocol GO29537, Version 7
Appendix 1
Schedule of Assessments (cont.)
ATAanti-therapeutic antibody; ECOGEastern Cooperative Oncology Group; EORTCEuropean Organization for Research and Treatment of Cancer; 
ePROelectronic Patient-Reported Outcome; EQ-5D-3LEuro QoL5 Dimensions 3-Level Version; FFPEformalin-fixed, paraffin-embedded; HBcAbhepatitis 
B core antibody; HBVhepatitis B virus; HCVhepatitis C virus; IVintravenous; LC13Lung Cancer module; NSCLCnonsmall cell lung cancer; 
PDpharmacodynamic; PGISPatient Global Impression of Severity; PKpharmacokinetic; QLQ-C30Quality-of-Life Questionnaire Core 30; RCRRoche 
Clinical Repository; SILCSymptoms in Lung Cancer; TSHthyroid-stimulating hormone.
Notes:  Patients who are randomized to Arm B who received erlotinib switch maintenance allowed under Study GO29537 Protocol Versions 14,or who receive 
pemetrexed switch maintenance, will continue with cycle visits at the same frequency as those patients randomized to Arm A until disease progression, 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.
The same treatment-phase schedule of assessments and procedures will apply to the crossover patients, i.e., patients will begin on Cycle 1 (now called Cycle 1A) 
and will follow the same assessments and procedures as outlined in this protocol for this cycle (with the exception of an alternate schedule for PK and 
pharmacodynamic assessments (see Appendix 3) and a biopsy upon progression will not be requested for these patients), as well as for all subsequent cycles 
(i.e., Cycle 2, which will now be called Cycle 2A, etc.).  In addition, patients who entered Study GO29537 under Protocol Versions 14 and who cross over to 
atezolizumab following disease progression will not follow the treatment-phase schedule for ePRO assessments during crossover.   These patients will complete 
ePRO assessments according to the post progression schedule (i.e., SILC monthly for the first 6 months only and EORTC QLQ-C30, QLQ, LC13 and EQ-5D-3L 
at 3 and 6 months only).
a
Assessments should be performed before study drug infusion unless otherwise noted. 
b
Cycle 1, Day 1, must be performed within 5 days after the patient is randomized.  Screening assessments performed 96 hours before Cycle 1, Day 1 are not 
required to be repeated for Cycle 1, Day 1.  In addition, ECOG performance status, limited physical examination, and local laboratory tests may be performed 
96 hours before Day 1 of each cycle as specified in Section 4.5.12.2.
c
If a representative FFPE tumor specimen in paraffin block (preferred) or 15 (or more) freshly cut, unstained 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 a 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 may occur outside the 28-day screening period prior to enrollment.  See Section 4.1.1, Inclusion Criteria, and Section 4.5.7.1. 
d
Vital signs include pulse rate, respiratory rate, blood pressures, and temperature.  Vital signs should be recorded as described in Section 4.5.4.
e
Symptom-directed physical examinations; see Section 4.5.3 for details. 
f
ECG recordings will be obtained when clinically indicated.
g
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, 
basophils, and other cells), and platelet count.  Hematology tests must be performed prior to Day 1 infusions and for nab-paclitaxel administration, also prior to 
Day 8 and Day 15 infusions. See Section 5.1.9.1 (Table 11) for dose modifications due to hematologic toxicities.


Atezolizumab—F. Hoffmann-La Roche Ltd
162/Protocol GO29537, Version 7
Appendix 1
Schedule of Assessments (cont.)
h
Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. See Section 5.1.9.1 (Table 15) for carboplatin and nab-paclitaxel dose 
modification management due to serum chemistry toxicities.
i
Serum pregnancy test within 14 days before Cycle 1, Day 1.
j
Urine pregnancy tests; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
k
Thyroid-function testing (thyroid-stimulating hormone [TSH], free T3, free T4) collected at Cycle 1, Day 1, and every fourth cycle thereafter.  Total T3 will be 
tested only at sites at sites where free T3 testing is not tested.
l
All patients will be tested for HIV prior to the inclusion into the study, and HIV-positive patients will be excluded from the clinical study. 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 only if their HBV DNA test is negative.  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.
m Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood).
n
For atezolizumab, the initial dose will be delivered over 60 (15) minutes.  If the first infusion is well tolerated, all subsequent infusions may be delivered over 
30 (10) minutes.  For carboplatin nab-paclitaxel, administer nab-paclitaxel over 30 minutes followed immediately by carboplatin administered over 1530
minutes.  Administer nab-paclitaxel alone on Days 8 and 15.  See Section 4.3.2.2 for details. Atezolizumab will be delivered as monotherapy during the 
maintenance phase (Arm A only) and for patients who cross over from Arm B (allowed under Study GO29537 Protocol Versions 14). See Section 4.3.2.2 for 
details.
o
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.
p
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) after the 
completion of the Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression (loss of clinical benefit for patients 
assigned to atezolizumab who continue treatment after disease progression according to RECIST v1.1), withdrawal of consent, death, or study termination by 
the Sponsor, whichever occurs first.  See Section 4.5.5 for details.
q
If a patient discontinues study treatment for any reason other than radiographic disease progression according to RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration, tumor assessments will continue at the same frequency as would have been followed if the patient had remained on study treatment until 
radiographic disease progression (loss of clinical benefit for patients treated with atezolizumab who continue treatment after disease progression according to 
RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if the patient starts another anti-cancer therapy 
after study treatment discontinuation.
r
See Appendix 2 for detailed schedule.
s
The optional RCR whole blood sample requires an additional informed consent and may be collected at any time during the course of the study.


Atezolizumab—F. Hoffmann-La Roche Ltd
163/Protocol GO29537, Version 7
Appendix 1
Schedule of Assessments (cont.)
t
A mandatory biopsy is required, 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).
u
All serious adverse events and adverse events of special interest, regardless of relationship to study treatment, will be reported until 90 days after the last dose 
of study treatment (inclusive of erlotinib [allowed under Study GO29537 Protocol Versions 14] or pemetrexed switch maintenance for patients randomized to 
Arm B who receive switch maintenance) or initiation of new systemic anti-cancer therapy.  All other adverse events, regardless of relationship to study 
treatment, will be reported until 30 days after the last dose of study treatment (inclusive of erlotinib [allowed under Study GO29537 Protocol Versions 14] or 
pemetrexed switch maintenance for patients randomized to Arm B who receive switch maintenance) or initiation of new non-protocol systemic anti-cancer 
therapy after last dose of study treatment.  After this period, all deaths will be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event or adverse event of special interest that is believed to be related to prior exposure to study treatment (see Section 5.6).
v
EORTC QLQ-C30, EORTC QLQ-LC13, PGIS, and EQ-5D-3L questionnaires will be completed by the patients on the ePRO tablet at each scheduled cycle
visit during the induction period and then according to the tumor assessment schedule during the treatment maintenance phase prior to administration of study 
drug and prior to any other study assessment(s).  SILC will be completed on an ePRO device at the patient’s home on a weekly basis.  During survival follow-
up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L will be completed at 3 and 6 months following disease progression or loss of clinical benefit (for 
atezolizumab-treated patients).  The SILC will be completed monthly during survival follow-up for 6 months following disease progression or following loss of 
clinical benefit for patients treated with atezolizumab who continue after disease progression according to RECIST v1.1.  The PGIS is not required during 
survival follow-up.  Patients who discontinue study treatment for any reason other than progressive disease or loss of clinical benefit will complete the EORTC 
QLQ-C30, EORTC QLQ-LC13, PGIS, and EQ-5D-3L at each tumor assessment visit and will complete the SILC at home on a weekly basis, until 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) as determined by the investigator (unless the patient withdraws consent or the Sponsor terminates the study).  Study 
personnel should review all questionnaires for completeness before the patient leaves the investigational site.  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.
w Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits every 3 months or more frequently 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.


Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol GO29537, Version 7
Appendix 2
Schedule of Pharmacokinetic, Biomarker,
and Anti-Therapeutic Antibody Assessments
Study Visit
Time
Arm A
Arm B
Screening
N/A
Biomarkers b
Biomarkers b
Cycle 1, 
Day 1 e
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Carboplatin pharmacokinetics a
nab-Paclitaxel pharmacokinetics a
Biomarkers d
Carboplatin 
pharmacokinetics a
nab-Paclitaxel 
pharmacokinetics a
Biomarkers d
30 min (10 min) 
after end of 
atezolizumab
infusion
Atezolizumab pharmacokinetics
510 min before the 
end of nab-paclitaxel 
infusion a
nab-Paclitaxel pharmacokinetics a
nab-Paclitaxel 
pharmacokinetics a
1 hr after end of nab-
paclitaxel infusion a
nab-Paclitaxel pharmacokinetics a
nab-Paclitaxel 
pharmacokinetics a
510 min before the 
end of carboplatin 
infusion a
Carboplatin pharmacokinetics a
Carboplatin 
pharmacokinetics a
1 hr after end of 
carboplatin infusion a
Carboplatin pharmacokinetics a
Carboplatin 
pharmacokinetics a
Cycle 2, 
Day 1 
(3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers d 
Biomarkers d


Appendix 2
Schedule of Pharmacokinetic, Biomarker, 
and Anti-Therapeutic Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol GO29537, Version 7
Study Visit
Time
Arm A
Arm B
Cycle 3, 
Day 1 
(3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Carboplatin pharmacokinetics a
nab-Paclitaxel pharmacokinetics a
Biomarkers d 
Carboplatin 
pharmacokinetics a
nab-Paclitaxel 
pharmacokinetics a
Biomarkers d
30 min (10 min) 
after end of 
atezolizumab
infusion
Atezolizumab pharmacokinetics
510 min before the 
end of nab-paclitaxel 
infusion a
nab-Paclitaxel pharmacokinetics a
nab-Paclitaxel 
pharmacokinetics a
1 hr after end of nab-
paclitaxel infusion a
nab-Paclitaxel pharmacokinetics a
nab-Paclitaxel 
pharmacokinetics a
510 min before the 
end of carboplatin 
infusion a
Carboplatin pharmacokinetics a
Carboplatin 
pharmacokinetics a
1 hr after end of 
carboplatin infusion a
Carboplatin pharmacokinetics a
Carboplatin 
pharmacokinetics a
Cycles 4, 8, 
and 16,
Day 1 
(3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers d 
Biomarkers d
After 
Cycle 16 and 
every eighth 
cycle, Day 1 
(3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers d
Biomarkers d
At time of 
fresh biopsy 
(on-treatment 
or at 
progression, 
including 
during 
follow-up)
At visit
Biomarkers d
Biomarkers d


Appendix 2
Schedule of Pharmacokinetic, Biomarker, 
and Anti-Therapeutic Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol GO29537, Version 7
Study Visit
Time
Arm A
Arm B
Treatment 
discontinuation 
visit
At visit
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers d
Biomarkers d
12030 days 
after last dose 
of 
atezolizumab
At visit
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers d
At any 
timepoint 
during study 
(RCR consent 
required)
Optional RCR blood (DNA 
extraction) c
Optional RCR blood 
(DNA extraction) c
ATAanti-therapeutic antibody; RCRRoche Clinical Repository.
Note:  Serum pharmacokinetic samples for atezolizumab; plasma pharmacokinetic samples for 
carboplatin, and nab-paclitaxel.
a At selected centers, 20 patients in each treatment arm will undergo the additional PK 
assessments for carboplatin and nab-paclitaxel.
b Whole blood for biomarkers.
c The optional RCR blood sample (for DNA extraction) requires an additional informed consent 
and can be collected at any time during the course of the study.
d Plasma and serum for biomarkers.
e
Biomarker sampling before Cycle 1, Day 1 should be performed before patients are treated with the first 
dose of steroids.


Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol GO29537, Version 7
Appendix 3
Schedule of Pharmacokinetic, Biomarker, and Anti-Therapeutic
Antibody Assessments for Arm B Patients Who Cross Over to 
Receive Atezolizumab as Allowed under Protocol Versions 14
Study Visit
Time
Arm B Crossover Patients
Cycle 1A, 
Day 1
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers a
30 min (10 min) after 
end of atezolizumab
infusion
Atezolizumab pharmacokinetics
Cycle 2A, 
Day 1 (3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers b 
Cycle 3A, 
Day 1 (3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers b 
30 min (10 min) after 
end of atezolizumab
infusion
Atezolizumab pharmacokinetics
Cycles 4A, 8A, 
and 16A, Day 1 
(3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers b 
After Cycle 16A, 
every eighth 
cycle, Day 1 
(3 days)
Pre-dose (same day 
as treatment 
administration)
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers b
Treatment 
discontinuation 
visit
At visit
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers b
12030 days 
after last dose of 
atezolizumab
At visit
Atezolizumab ATA
Atezolizumab pharmacokinetics
Biomarkers b
ATAanti-therapeutic antibody.
Notes:  Serum pharmacokinetic samples for atezolizumab.
a Plasma, serum, and whole blood for biomarkers.
b Plasma and serum for biomarkers.


Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol GO29537, Version 7
Appendix 4
American Joint Committee on Cancer
NonSmall Cell Lung Cancer Staging, 7th Edition


Appendix 4
American Joint Committee on Cancer 
NonSmall Cell Lung Cancer Staging, 7th Edition (cont.)
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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 5
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 CT or MRI scan (CT/MRI scan slice thickness/interval no greater 
than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

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 
                                           
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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Modified Excerpt from Original Publication (cont.)
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masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
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.


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Modified Excerpt from Original Publication (cont.)
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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.
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).
Chest X-Ray.  Chest CT 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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Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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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Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study


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


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


Appendix 5
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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to apply to non-measurable disease, the very nature of that disease makes it impossible 
to do so; therefore, the increase must be substantial.
e.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


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Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Table 1  Timepoint Response:  Patients with Target Lesions (with 
or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not 
all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2  Timepoint Response:  Patients with Non-Target 
Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
b.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
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 


Appendix 5
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and, during the study, only two lesions were assessed, but 
those gave a sum of 80 mm; the patient will have achieved PD status, regardless of the 
contribution of the missing lesion.
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.


Appendix 5
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Table 3  Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD 
was met; otherwise, PD
CR
PD
SD, provided minimum duration for SD 
was met; otherwise, PD
CR
NE
SD, provided minimum duration for SD 
was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD 
was met; otherwise, PD
PR
NE
SD, provided minimum duration for SD 
was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
c.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 


Appendix 5
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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 6
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.


Appendix 6
Modified Response Evaluation Criteria in Solid Tumors (cont.)
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A.1
MEASURABLE LESIONS
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.
A.2
NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
A.3
SPECIAL CONSIDERATIONS REGARDING LESION 
MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions.
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
Blastic bone lesions are non-measurable.


Appendix 6
Modified Response Evaluation Criteria in Solid Tumors (cont.)
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Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.
B.
TUMOR RESPONSE EVALUATION
B.1
DEFINITIONS OF TARGET/NON-TARGET LESIONS
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one 
or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-target lesions (even if the size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance, the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  


Appendix 6
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol GO29537, Version 7
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm but 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of 10 mm are considered non-pathological and should not be 
recorded or followed.
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions.
Non-Target Lesions
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required.
It is possible to record multiple non-target lesions involving the same organ as a single 
item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).
After baseline, changes in non-target lesions will contribute only in the assessment 
of 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 according to 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 according to 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 


Appendix 6
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol GO29537, Version 7
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.


Appendix 6
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol GO29537, Version 7
B.3
RESPONSE CRITERIA
Timepoint Response
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
Complete Response (CR):  Disappearance of all target and non-target lesions.  Lymph 
nodes that shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
Note: the appearance of new measurable lesions is factored into the overall tumor 
burden, but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and selected new measurable lesions, taking as reference the smallest sum on 
study (nadir SLD; this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution to 
total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response.
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is 
considered not evaluable (NE) at that timepoint.  If only a subset of lesion 
measurements are made at an assessment, usually the case is also considered NE at 
that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This 
would only happen in the case of PD.  For example, if a patient had a baseline sum of 
50 mm with three measured lesions and at follow-up only two lesions were assessed but 


Appendix 6
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol GO29537, Version 7
those gave a sum of 80 mm, the patient will be assigned PD status, regardless of the 
contribution of the missing lesion.
Table 1  Modified RECIST Timepoint Response Definitions
% Change in Sum of the Diameters a
Non-Target Lesion 
Response 
Assessment
Overall Modified RECIST 
Timepoint Response
100% from baseline b
CR
CR
100% from baseline b
Non-CR or not all 
evaluated
PR
30% from baseline
Any
PR
30% to 20%
Any
SD
Not all evaluated
Any
NE
20%from nadir SLD
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
RECIST Response Evaluation Criteria in Solid Tumors; SD stable disease; SLDsum of the 
longest diameter.
a Percent change in sum of the diameters (including measurable new lesions when present).
b When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met, because 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 7
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 GO29537, the antiPD-L1 (SP142) IHC assay will be used for investigational 
purposes only.
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody is intended for 
laboratory use in the semi-quantitative immunohistochemical assessment of the PD-L1 
protein in formalin-fixed, paraffin-embedded nonsmall cell lung carcinoma (NSCLC) 
tissue stained on a Ventana BenchMark ULTRA automated slide stainer.  It is indicated 
as an aid in the selection of patients with NSCLC with locally advanced or metastatic 
disease who might benefit from treatment with atezolizumab.
This assay is for investigational use only.  The performance characteristics of this 
product have not been established.
DEVICE DESCRIPTION
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody is a pre-dilute, 
ready-to-use antibody product optimized for use with the Ventana Medical Systems 
OptiView DAB IHC Detection Kit and the OptiView Amplification Kit on Ventana Medical 
Systems automated BenchMark ULTRA platforms.  One 5-mL dispenser of antiPD-L1 
(SP142) rabbit monoclonal primary antibody contains approximately 36 g of rabbit
monoclonal antibody directed against the PD-L1 protein and contains sufficient reagent 
for 50 tests.  The reagents and the IHC procedure are optimized for use on the 
BenchMark ULTRA automated slide stainer, utilizing Ventana system software (VSS). 
SCORING SYSTEM
PD-L1 staining with antiPD-L1 (SP142) rabbit monoclonal primary antibody in NSCLC 
can be observed in both tumor cells and tumor-infiltrating immune cells.
Details of the criteria for PD-L1 diagnostic assessment are described in the IDI 
document.


Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol GO29537, Version 7
Appendix 8
EORTC QLQ-C30


Atezolizumab—F. Hoffmann-La Roche Ltd
191/Protocol GO29537, Version 7
Appendix 8
EORTC QLQ-C30 (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol GO29537, Version 7
Appendix 9
EORTC QLQ-LC13


Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol GO29537, Version 7
Appendix 10
EQ-5D-3L


Atezolizumab—F. Hoffmann-La Roche Ltd
194/Protocol GO29537, Version 7
Appendix 10
EQ-5D-3L (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
195/Protocol GO29537, Version 7
Appendix 10
EQ-5D-3L (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
196/Protocol GO29537, Version 7
Appendix 11
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead


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197/Protocol GO29537, Version 7
Appendix 12
Anaphylaxis Precautions
EQUIPMENT NEEDED

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, 
the following procedures should be performed:

Stop the study drug infusion.

Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug.  Do not obstruct arterial flow in the limb.

Maintain an adequate airway.

Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.

Continue to observe the patient and document observations


Atezolizumab—F. Hoffmann-La Roche Ltd
198/Protocol GO29537, Version 7
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 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty about autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune thrombocytopenic 
purpura
Behcet’s disease
Bullous pemphigold
Chronic fatigue syndrome
Chronic inflammatory demyelinating 
polyneuropathy
Chung-Strauss syndrome
Crohn’s disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular autoimmune 
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada 
disease
Wegener’s granulomatosis


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 14
Symptoms in Lung Cancer


Atezolizumab—F. Hoffmann-La Roche Ltd
200/Protocol GO29537, Version 7
Appendix 14
Symptoms in Lung Cancer (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
201/Protocol GO29537, Version 7
Appendix 14
Symptoms in Lung Cancer (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
202/Protocol GO29537, Version 7
Appendix 15
Patient Global Impression of Severity


Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol GO29537, Version 7
Appendix 16
Additional Guidance on Chemotherapy Administration
For the purposes of this protocol, the Sponsor defines a chemotherapy cycle during the 
induction phase as the administration of at least one chemotherapy component at least 
once during a 21-day cycle.  Cycles in which no chemotherapy component is given do 
not count toward the total number of induction chemotherapy cycles.
In the event that chemotherapy cannot be given, owing to toxicity, atezolizumab should 
be given without chemotherapy if there is no contraindication.  
If only atezolizumab but no chemotherapeutic partner has been administered during a 
cycle in the induction phase, the cycle does not count toward the total number of 
induction chemotherapy cycles.  For example, if four cycles of induction chemotherapy 
were planned, but no component of chemotherapy could be administered during 
Cycle 4, Cycle 5 counts as the fourth cycle of induction chemotherapy (as shown below). 
All chemotherapy components may be withheld for up to a maximum of 2 cycles.  If an 
interruption of all chemotherapy is indicated for a third cycle, all chemotherapy should be 
permanently discontinued.
Within a 4-cycle induction regimen, chemotherapy may be paused for a total of two 
consecutive or non-consecutive cycles before chemotherapy should be permanently 
discontinued.  Within a 6-cycle induction regimen, chemotherapy may be paused for a
Administration of at 
least 1 chemotherapy  
component for at least 
one time during the 
cycle
Cycle 1
Cycle 4
Cycle 3
Cycle 2
1 Cycle
All chemotherapy 
components skipped 
by 1 cycle
3 Cycles
2 Cycles 
2 Cycles
Induction Phase
Example: 4 Cycles
2 Cycles 
4 Cycles
3 Cycles
1 Cycle
Cycle 5
All chemotherapy 
components skipped 
by 2 cycles
2 Cycles
3 Cycles
2 Cycles
3 Cycles
1 Cycle
4 Cycles
Cycle 6
4 Cycles


Appendix 16
Additional Guidance on Chemotherapy Administration (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
204/Protocol GO29537, Version 7
total of two consecutive or a total of three non-consecutive cycles before chemotherapy 
should be permanently discontinued.
The recommended time window for administration of all study treatment components 
within a cycle is 3 days.  If atezolizumab was given but chemotherapy could not be 
administered on the same day, and the delay between the first and last component of 
study treatment would be more than 3 days, carboplatin should be delayed until Day 1 of 
the next cycle and nab-paclitaxel administered on Day 8 and/or Day 15 of the current 
cycle if there is no contraindication.
If it is anticipated that a component of study treatment cannot be administered, it is 
recommended to delay all study treatment for up to 2 weeks.  However, if it is anticipated 
that chemotherapy will be delayed by more than 2 weeks, then atezolizumab should be 
given without chemotherapy, which will be delayed until the next cycle, provided there is 
no contraindication.
eCRF Data Entry for Recording Interruption and Re-Introduction of 
Chemotherapy
Because of the complex nature and possible permutations of such dosage interruptions 
and reintroductions, site personnel should contact the Monitor, and the Monitor will 
instruct the site on how to open the appropriate visits and electronic Case Report Form 
(eCRF) so that the site can then record the interruption and reintroduction accordingly on 
the eCRF.


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 GO29537 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATIN  NAB-PACLITAXEL 
FOR CHEMOTHERAPYNAIVE PATIENTS WITH STAGE IV 
NON-SQUAMOUS NONSMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
GO29537 
STUDY DRUG: 
Atezolizumab (RO5541267) 
VERSION NUMBER: 
4 
IND NUMBER: 
117296 
EUDRACT NUMBER: 
2014-003206-32 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Ph.D. 
DATE FINAL: 
19 May 2017 
DATE AMENDED 
Version 2:  17 October 2017 
Version 3:  13 March 2018 
Version 4:  See electronic date stamp below 
Name                                                             Reason for Signing                              Date and Time
(UTC)
04-May-2018 17:22:12
Company Signatory




Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan GO29537 
 
TABLE OF CONTENTS 
 
1. 
BACKGROUND ............................................................................................ 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 8 
2.2 
Outcome Measures ................................................................. 8 
2.2.1 
Primary Efficacy Measures ...................................................... 8 
2.2.2 
Secondary Efficacy Measures ................................................. 8 
2.2.3 
Exploratory Efficacy Measures ................................................ 9 
2.2.4 
Pharmacokinetic Outcome Measures .................................... 10 
2.2.5 
Safety Outcome Measures .................................................... 10 
2.3 
Determination of Sample Size ............................................... 10 
2.4 
Analysis Timing ..................................................................... 12 
2.4.1 
Primary Analysis Timing for PFS ........................................... 12 
2.4.2 
Interim and Final Analysis Timing for OS ............................... 12 
3. 
STUDY CONDUCT ..................................................................................... 13 
3.1 
Randomization Issues ........................................................... 13 
3.2 
Independent Review Facility .................................................. 14 
3.3 
Data Monitoring ..................................................................... 14 
4. 
STATISTICAL METHODS .......................................................................... 14 
4.1 
Analysis Populations ............................................................. 14 
4.1.1 
Efficacy Analysis Populations ................................................ 14 
4.1.2 
Pharmacokinetic-Evaluable Population ................................. 15 
4.1.3 
Safety Population .................................................................. 15 
4.2 
Analysis of Study Conduct ..................................................... 15 
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 PFS and OS in the ITT Population ....................................... 18 


Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan GO29537 
 
4.4.2.2 PFS and OS in PD-L1 Expression and PD-L1 
Expression WT Populations ............................................................... 18 
4.4.2.3 Objective Response Rate ..................................................... 18 
4.4.2.4 Duration of Response ........................................................... 18 
4.4.2.5 OS Rate at the 1- and 2-Year Landmark 
Timepoints .......................................................................................... 19 
4.4.2.6 Patient-Reported Outcomes ................................................. 19 
4.4.3 
Exploratory Efficacy Endpoints .............................................. 21 
4.4.3.1 PFS, OS, ORR, and DOR in Teff-High and Teff-
High WT Populations .......................................................................... 21 
4.4.3.2 Progression-Free Survival Rates at 6 Months 
and 1 Year .......................................................................................... 21 
4.4.3.3 Overall Survival Rate at 3 Years .......................................... 21 
4.4.3.4 EQ-5D-3L Health Status Data .............................................. 21 
4.4.3.5 Additional Patient-Reported Outcome Analyses .................. 21 
4.4.4 
Sensitivity Analyses ............................................................... 22 
4.4.4.1 Missing Tumor Assessment ................................................. 22 
4.4.4.2 Non-Proportional Hazard ...................................................... 22 
4.4.4.3 Loss to Follow-up ................................................................. 23 
4.4.4.4 Progression-Free Survival by Independent 
Review Facility ................................................................................... 24 
4.4.5 
Subgroup Analyses ............................................................... 24 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 24 
4.6 
EXPLORATORY BIOMARKER ANALYSES ......................... 25 
4.7 
Safety Analyses ..................................................................... 25 
4.7.1 
Exposure of Study Medication ............................................... 25 
4.7.2 
Adverse Events ..................................................................... 25 
4.7.3 
Laboratory Data ..................................................................... 26 
4.7.4 
Vital Signs .............................................................................. 26 
4.7.5 
Anti-Drug Antibody ................................................................ 26 
4.8 
Missing Data .......................................................................... 26 
5. 
REFERENCES ........................................................................................... 27 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan GO29537 
 
 
LIST OF TABLES 
Table 1 
Primary Analysis for Progression-Free Survival .......................... 12 
Table 2 
Analysis for Overall Survival ....................................................... 13 
Table 3 
Analysis Timing and Stopping Boundary for Overall Survival 
in the Intent-to-Treat Wild-Type Population ................................ 13 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................... 7 
Figure 2 
Progression-Free Survival and Overall Survival Analysis 
Hierarchy, α Allocation, and α Recycling .................................... 11 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 28 
Appendix 2 
Schedule of Assessments ........................................................... 41 
Appendix 3 
Schedule of Pharmacokinetic, Biomarker, and Anti-Drug 
Antibody Assessments ................................................................ 47 


Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan GO29537 
 
1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study GO29537 (IMpower130), “A Phase III, Multicenter, 
Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab 
(MPDL3280A, Anti−PD-L1 Antibody) in Combination with Carboplatin + Nab-Paclitaxel 
for Chemotherapy−Naïve Patients with Stage IV Non-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, multicenter, open-label study designed to evaluate the 
efficacy and safety of atezolizumab in combination with carboplatin + nab-paclitaxel as 
compared with treatment with carboplatin + nab-paclitaxel in approximately 
715 chemotherapy−naïve patients with Stage IV non-squamous non−small cell lung 
cancer (NSCLC). 
Eligible patients were stratified by sex (male vs. female), presence of liver metastases at 
baseline (yes vs. no), and programmed death−ligand 1 (PD-L1) tumor expression by 
immunohistochemistry (IHC) (tumor cell [TC] 3 and any tumor-infiltrating immune cell [IC] 
vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1) tested by a central laboratory.  TC0, TC1, 
TC2, and TC3 are defined as PD-L1 staining in < 1%, ≥ 1% to < 5%, ≥ 5% to < 50%, 
and ≥ 50% of the TCs, respectively.  IC0, IC1, IC2, and IC3 are defined as 
PD-L1−stained ICs covering < 1%, ≥ 1% to < 5%, ≥ 5% to < 10%, and ≥ 10% of the tumor 
area, respectively. 
Eligible patients were randomized in a 2:1 ratio to one of the following treatment 
regimens: 
• 
Treatment Arm A:  Atezolizumab + carboplatin + nab-paclitaxel (induction: four or six 
21-day cycles); atezolizumab (maintenance: 21-day cycles) 
• 
Treatment Arm B:  Carboplatin + nab-paclitaxel (induction: four or six 21-day cycles); 
best supportive care, erlotinib (only for patients who started switch maintenance 
treatment under Versions 1−4 of the protocol) or pemetrexed 
 
Patients who were randomized to Arm A may continue treatment with atezolizumab 
beyond radiographic progression by Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1), provided they 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). 
In Protocol GO29537, Versions 1−4, patients who are randomized to Arm B following 
disease progression will be given the option to receive atezolizumab monotherapy 
provided they continue to meet crossover eligibility criteria.  In Protocol GO29537, 


Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Statistical Analysis Plan GO29537 
 
Version 5 and thereafter, crossover from the control arm to the experimental arm after 
the disease progression will not be permitted, with the aim to preserve the study’s ability 
to potentially demonstrate treatment benefit of atezolizumab on overall survival (OS). 
Figure 1 illustrates the study design of which details can be found in the study protocol. 
Figure 1 Study Schema 
 
AUC  area under the concentrationtime curve; IV  intravenously; NSCLC  nonsmall cell lung 
cancer; PD-L1  programmed deathligand 1; RECIST v.1.1  Response Evaluation Criteria in 
Solid Tumors, Version 1.1 
  
Patients undergo tumor assessments at baseline and every 6 weeks (  7 days) for the 
first 48 weeks following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, 
tumor assessment is required every 9 weeks (  7 days).  Patients undergo tumor 
assessments until radiographic disease progression per RECIST v1.1 or loss of clinical 
benefit (for atezolizumab-treated patients who continue treatment after radiographic 
disease progression according to RECIST v1.1), withdrawal of consent, study 
termination by Sponsor, or death, whichever occurs first.  Patients who discontinue 
treatment for reasons other than radiographic disease progression per RECIST v1.1 
(e.g., toxicity) will continue scheduled tumor assessments until radiographic disease 
progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab-treated patients 
Chemotherapy-Naive Patients with Stage IV Non-Squamous NSCLC
(n=approximately 715)
Arm A:
Atezolizumab (1200 mg IV)
+Carboplatin (AUC=6 IV)
+nab-Paclitaxel (100 mg/m2 IV)
Treat with  Atezolizumab until 
Loss of Clinical Benefit
Treat until 
Disease Progression per RECIST v1.1
Survival Follow-Up
2:1 Randomization
Stratification Factors:
•
Sex
•
Liver metastases
•
PD-L1 expression (by central 
testing for PD-L1 status)
Induction Treatment:  Four or Six, 21-Day Cycles
Arm A:
Atezolizumab
(1200 mg IV)
Arm B:
Best Supportive Care
(switch maintenance to 
pemetrexed may be considered) 
No Crossover Permitted
Arm B:
Carboplatin (AUC=6 IV)
+nab-Paclitaxel 
(100 mg/m2 IV)
Maintenance Treatment:  Every 21 Days


Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Statistical Analysis Plan GO29537 
 
who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever 
occurs first, regardless of whether patients start a new anti-cancer therapy. 
The co-primary efficacy endpoints are progression-free survival (PFS) as assessed by 
the investigator using RECIST v1.1 and OS.  See Section 2.2 for details on co-primary 
efficacy endpoints, secondary endpoints, and other endpoints such as safety, 
pharmacokinetic (PK), and exploratory outcome measures. 
The primary analyses of PFS and all OS analyses will be performed on all randomized 
patients excluding patients with an activating EGFR mutation or ALK translocation 
ITT−WT.  EGFR mutations include all EGFR-activating mutations in exons 18 through 21.  
See Section 4.1 for details on analysis populations. 
There are no interim analyses planned for PFS and one interim analysis planned for OS 
in this study.  See Section 2.4 for detailed analysis timing. 
An external independent Data Monitoring Committee (iDMC) will be set up to evaluate 
safety data on an ongoing basis. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedules of 
Assessments in Appendix 2 and Appendix 3. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Measures 
The co-primary efficacy outcome measures for this study are the following: 
• 
PFS, defined as the time between the date of randomization and the date of first 
documented disease progression as determined by the investigator according to 
RECIST v1.1 or death from any cause, whichever occurs first, in the ITT−WT 
population 
• 
OS, defined as the time between the date of randomization and date of death from 
any cause in the ITT−WT population 
 
2.2.2 
Secondary Efficacy Measures 
The secondary efficacy outcome measures for this study are the following: 
• 
PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
ITT population 
• 
PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
PD-L1 expression population (as described in Section 4.1.1), and the 
aforementioned population excluding patients with an activating EGFR mutation or 
ALK translocation, namely, the PD-L1 expression WT population 


Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Statistical Analysis Plan GO29537 
 
• 
Objective response, defined as either complete response (CR) or partial response 
(PR), as determined by the investigator according to RECIST v1.1 in the same 
populations as defined in the PFS measure: ITT−WT, ITT, PD-L1 expression, PD-L1 
expression WT; confirmation of objective response is not required 
• 
Duration of response (DOR), 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 according to RECIST v1.1 or death 
from any cause, whichever occurs first, in the same populations as defined in the 
objective response measure: ITT−WT, ITT, PD-L1 expression, PD-L1 expression 
WT  
• 
OS rates at 1 and 2 years, defined as the proportion of patients alive at 1 and 
2 years after randomization estimated using Kaplan-Meier (KM) methodology in the 
same populations as defined in the OS measure:  ITT−WT, ITT, PD-L1 expression, 
PD-L1 expression WT  
• 
Time to deterioration (TTD) in patient-reported lung cancer symptoms, defined as 
time from randomization to confirmed deterioration (10-point change) on the 
combined European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire−Core (EORTC QLQ-C30) and supplemental lung 
cancer module (EORTC QLQ-LC13) symptom subscales in the ITT−WT population 
• 
Change from baseline in patient-reported lung cancer symptoms (cough, dyspnea, 
and chest pain) on the symptom severity score of the Symptoms in Lung Cancer 
(SILC) scale for the ITT−WT population 
 
2.2.3 
Exploratory Efficacy Measures 
The exploratory efficacy measures for this study are the following: 
• 
PFS, ORR, and DOR, as determined by the investigator according to RECIST v1.1, 
and OS in the T-effector high (Teff-high) population (with Teff gene signature 
expression in tumor tissue as described in Section 4.4.3.1, previously referred to as 
tGE) and the aforementioned population excluding patients with an activating EGFR 
mutation or ALK translocation, namely, the Teff-high WT 
• 
PFS rates at 6 months and 1 year, defined as the proportion of patients alive and 
without progression as assessed by the investigator according to RECIST v1.1 at 
6 months and 1 year after randomization estimated using KM methodology 
• 
OS rate at 3 years, defined as the proportion of patients alive at 3 years after 
randomization estimated using KM methodology 
• 
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 in combination with 
chemotherapy 
• 
Status of ICs and other exploratory biomarkers in mandatory biopsy specimens and 
blood collected at progression 


Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Statistical Analysis Plan GO29537 
 
• 
Utility scores of the Euro QoL5 Dimensions 3−Level Version (EQ-5D-3L) 
• 
Change from baseline and the number and proportion of patients with a clinically 
meaningful change in patient-reported outcomes (PROs) of health-related quality of 
life (HRQoL), lung cancer−related symptoms, and health status as assessed by the 
EORTC QLQ-C30 and EORTC QLQ-LC13, as described in Section 4.4.2.6 
 
2.2.4 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are: 
• 
For patients randomized to atezolizumab + carboplatin + nab-paclitaxel: 
Maximum observed serum atezolizumab concentration (Cmax) after infusion on 
Cycle 1, Day 1 
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at 
selected cycles, at treatment discontinuation, and at 120 days ( ± 30 days) after 
the last dose of atezolizumab 
• 
Plasma concentrations for carboplatin (Arms A and B) 
• 
Plasma concentrations for nab-paclitaxel reported as total paclitaxel (Arms A and B) 
• 
For patients randomized to carboplatin + nab-paclitaxel who crossed over to receive 
open-label atezolizumab as monotherapy (allowed under Protocol GO29537, 
Versions 1−4): 
Cmax of serum atezolizumab after infusion on Day 1 of the first cycle following 
crossover to atezolizumab as monotherapy 
Cmin of serum atezolizumab prior to infusion on Day 1 at selected cycles 
following crossover to atezolizumab as monotherapy, 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 in Adverse Events, Version 4.0 
(NCI CTCAE v4.0) 
• 
Changes in vital signs and clinical laboratory results during and following 
atezolizumab administration 
• 
Incidence of anti-drug antibody (ADA), also known as anti-therapeutic antibody 
(ATA), response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
This study randomized approximately 715 patients.  Patients with an activating 
EGFR mutation or ALK translocations will be excluded from the primary analysis 
populations.  There are expected to be approximately 650 patients in the ITT−WT 
population given the approximately 10% prevalence of these genetic variations. 


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Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Statistical Analysis Plan GO29537 
 
The estimates of the number of events required with regard to OS in the primary 
comparisons are based on the following assumptions: 
• 
One-sided significance level of 0.022 in the ITT−WT population 
• 
80% power to detect an HR of 0.75, corresponding to an improvement in 
median OS from 12 months to 16 months in the ITT−WT population 
• 
One OS interim analyses performed when approximately 77% of the total OS events 
required for the final analysis have occurred using the Lan-DeMets approximation to 
the O’Brien-Fleming boundary 
• 
Dropout rate of 5% per 24 months 
 
With these assumptions, approximately 715 patients in total were planned to be 
randomized into this study, in order to have approximately 650 patients in the ITT−WT 
population.  Note that the OS boundaries have been updated to use the Lan-DeMets 
approximation to the Pocock boundaries (described in Section 2.4.2); therefore the 
overall power for the OS in the ITT-WT population is reduced from 80% to 77% (Table 2). 
2.4 
ANALYSIS TIMING 
2.4.1 
Primary Analysis Timing for PFS 
No interim analyses are planned for the co-primary endpoint of PFS in this study.  
The PFS primary analysis will be conducted at the time of the OS interim analysis 
(see Section 2.4.2).  At this timepoint, it is expected that approximately 475 PFS events 
will have occurred in the ITT−WT population based on the assumptions specified in 
Section 2.3.  These numbers of events correspond to a minimum detectable difference 
(MDD) in HR of approximately 0.76 in the ITT−WT population. 
Table 1 
Primary Analysis for Progression-Free Survival 
Population 
Analysis Timing 
(Months from FPI) 
No. of Events 
(Event Ratio, %) 
MDD in Hazard Ratio 
Power, % 
ITT-WT 
32 
475 (73) 
0.76 
95 
FPI = first patient in; ITT = intent-to-treat; MDD = minimum detectable difference; WT = wild 
type. 
 
2.4.2 
Interim and Final Analysis Timing for OS 
There is one interim analysis planned for the co-primary endpoint of OS. 
The timing of the primary efficacy analysis will be driven by the number of events 
required for the OS interim analysis, which will be conducted by the Sponsor when 
approximately 352 OS events have occurred in the ITT−WT population.  Based on the 
assumptions in Section 2.3, the OS interim analysis is expected to occur approximately 
32 months after the first patient is randomized. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Statistical Analysis Plan GO29537 
 
The final OS analysis will be conducted when there are approximately 457 OS events in 
the ITT−WT population.  The OS final analysis is expected to occur approximately 
42 months after the first patient is randomized. 
The expected analysis timing for the OS interim and final analyses is shown in Table 2. 
Table 2 
Analysis for Overall Survival 
Type of Analysis 
Analysis Timing 
ITT-WT Population 
Months from 
FPI 
Percentage 
Information, % 
No. of Events 
(Event Ratio, %) 
Power, % a 
OS interim analysis 
32 
77 
352 (54) 
68  
OS final analysis 
42 
100 
457 (70) 
77 
FPI = first patient in; ITT = intent-to-treat; OS = overall survival; WT = wild type. 
a Power is calculated using one-sided α of 0.022. 
 
The stopping boundaries for the interim and final OS analyses considering different 
scenarios with α recycling are calculated using the Lan-DeMets approximation to the 
Pocock boundary, assuming the specified observed number of events (352 and 457, 
respectively), and are shown in Table 3.  The p-value will be used to claim crossing of 
the boundaries.  For example, if approximately 352 events have occurred in the ITT−WT 
population at the time of the OS interim analysis, statistical significance of the OS 
endpoint in ITT−WT population will be declared if p ≤ 0.0211 when PFS has claimed 
significance in the ITT−WT population. 
Table 3 
Analysis Timing and Stopping Boundary for Overall Survival 
in the Intent-to-Treat Wild-Type Population 
Analysis 
Stopping Boundary in HR (p-value) 
If α = 0.022 
If α = 0.025 
OS interim analysis 
HR ≤ 0.790   
(p-value ≤ 0.0185) 
HR ≤ 0.795   
(p-value ≤ 0.0211) 
OS final analysis 
HR ≤ 0.795   
(p-value ≤ 0.0103) 
HR ≤ 0.799   
(p-value ≤ 0.0119) 
HR = hazard ratio; OS = overall survival. 
Note:  α and p-value are one-sided. 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Randomization to the treatment and control arms will occur in a 2:1 ratio using a 
permuted-block randomization method.  Randomization will be stratified by the following 
factors: 
• 
Sex (male vs. female) 
• 
Presence of liver metastases at baseline (yes vs. no) 


Atezolizumab—F. Hoffmann-La Roche Ltd 
14/Statistical Analysis Plan GO29537 
 
• 
PD-L1 expression by IHC (TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC 0/1/2 and 
IC0/1) 
 
3.2 
INDEPENDENT REVIEW FACILITY 
An Independent Review Facility (IRF) will be used to conduct a blinded radiology review 
of the imaging data and will provide an independent assessment of tumor response and 
progression for all patients according to a separate IRF Charter.  IRF-assessed 
endpoints may be used for sensitivity analyses (see Section 4.4.4). 
3.3 
DATA MONITORING 
An external iDMC will be used to evaluate safety during the study on a periodic basis, 
approximately every 6 months from the point of first patient in until the time the database 
is locked and the study is unblinded for the primary PFS analysis and interim 
OS analysis.  All summaries and analyses by treatment arm for the iDMC review will be 
prepared by an independent data coordinating center.  Following the data review, the 
iDMC will provide a recommendation as to whether the study may continue, whether 
amendment(s) to the protocol should be implemented, or whether the study should be 
stopped.  The final decision will rest with the Sponsor. 
Members of the iDMC will be external to the Sponsor and will follow a separate 
iDMC Charter that outlines their roles and responsibilities, as well as a detailed 
monitoring plan. 
4. 
STATISTICAL METHODS 
The analyses described in this SAP will supersede those specified in Protocol GO29537 
for the purposes of a regulatory filing. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Efficacy Analysis Populations 
The randomized population or ITT population is defined as all randomized patients, 
whether or not the patient received the assigned treatment. 
The ITT−WT population is defined as the ITT population excluding patients with an 
activating EGFR mutation or ALK translocation. 
The PD-L1 expression population is defined as one of the following: PD-L1 IHC TC1/2/3 
or IC1/2/3 population, defined as ITT patients with PD-L1 IHC TC1/2/3 or 
IC1/2/3 expression in baseline tumor tissue; PD-L1 IHC TC2/3 or IC2/3 population, 
defined as ITT patients with PD-L1 IHC TC2/3 or IC2/3 expression in baseline tumor 
tissue; PD-L1 IHC TC3 or IC3 population, defined as ITT patients with PD-L1 IHC TC3 
or IC3 expression in baseline tumor tissue.  The PD-L1 expression WT population is 
defined as the PD-L1 expression population excluding patients with an activating EGFR 
mutation or ALK translocation.  


Atezolizumab—F. Hoffmann-La Roche Ltd 
15/Statistical Analysis Plan GO29537 
 
Analyses of primary and select secondary efficacy endpoints will be performed in the 
PD-L1 IHC TC1/2/3 or IC1/2/3 population and the PD-L1 IHC TC1/2/3 or IC1/2/3-WT 
population.  Analyses of primary and select secondary efficacy endpoints may be 
conducted in other PD-L1 expression populations and PD-L1 expression WT populations 
(e.g., TC2/3 or TC2/3-WT, TC3 or IC3-WT, TC2/3 or IC2/3, TC3 or IC3, and the 
corresponding complementary groups, as well as TC0 and IC0-WT, TC0 and IC0). 
The primary analyses of PFS and all OS analyses will be performed on the ITT−WT 
population.  Patients are grouped according to the treatment assigned at randomization, 
regardless of whether they received any assigned study drug. 
Objective response rate (ORR; confirmation not required) will be analyzed for patients in 
the aforementioned populations who have measurable disease as assessed by 
investigator at baseline. 
DOR will be assessed in patients in the aforementioned populations who have an 
objective response and measurable disease as assessed by investigator at baseline. 
OS rate at the 1- and 2-year landmark timepoints will be analyzed in the same 
populations as defined for the OS analyses. 
TTD analyses will be conducted on the ITT−WT population.  Change from baseline 
analysis in PROs will be performed for patients in the ITT−WT population who have both 
a non-missing baseline assessment and at least one non-missing post-baseline 
assessment. 
4.1.2 
Pharmacokinetic-Evaluable Population 
The pharmacokinetic-evaluable population is defined as all patients who received any 
dose of atezolizumab, carboplatin, or nab-paclitaxel and who have evaluable 
PK samples. 
4.1.3 
Safety Population 
The safety population includes treated patients, defined as randomized patients who 
received any protocol treatment.  For the safety analyses, patients will be grouped 
according to whether any full or partial dose of atezolizumab was received, including 
when atezolizumab was received in error.  Specifically, for patients randomized to Arm B, 
if atezolizumab was received in error, the patients will be grouped to Arm A for the safety 
analyses. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Study enrollment, major protocol deviations, including major deviations from 
inclusion/exclusion criteria, and reasons for study termination will be summarized overall 
and by treatment arm for the ITT population.  Analysis of study conduct may also be 
summarized for the ITT−WT if needed.  Study treatment administration and reasons for 
discontinuation from study treatment will be summarized for the safety population. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
16/Statistical Analysis Plan GO29537 
 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics, such as age, race/ethnicity, baseline disease 
characteristics (e.g., Eastern Cooperative Oncology Group [ECOG] performance status), 
and stratification factors (sex, presence of liver metastasis at baseline, PD-L1 tumor 
expression by IHC) will be summarized by treatment arms for the ITT−WT population.  
Other populations may also be summarized as deemed needed.  Descriptive statistics 
(mean, median, standard deviation, and range) will be presented for continuous data, 
and frequencies and percentages will be presented for categorical data. 
Unless otherwise stated, baseline values are the last available data obtained prior to the 
patient receiving the first dose of any component of study treatment on Cycle 1, Day 1. 
4.4 
EFFICACY ANALYSIS 
Patients will be grouped for efficacy analyses according to the treatment assigned at 
randomization, whether or not the assigned treatment was received. 
4.4.1 
Primary Efficacy Endpoint 
The co-primary efficacy endpoints are PFS and OS. 
PFS is defined as the time from randomization to the first documented disease 
progression as determined by the investigator with the 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 analysis will be censored at the date of 
the last tumor assessment.  Data for patients with no post-baseline tumor assessment 
will be censored at the date of randomization plus 1 day.  
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 analysis will be censored at the date 
last known to be alive.  Data for patients who do not have post-baseline information will 
be censored at the date of randomization plus 1 day. 
The null and alternative hypotheses regarding PFS and OS in a population can be 
phrased in terms of the survival functions SA(t) for the atezolizumab arm (Arm A) and 
SB(t) for the control arm (Arm B): 
H0:  SA(t) = SB(t) versus H1:  SA(t) > SB(t) 
 
The HRs, λA/λB where λA, and λB represent the hazard of having a PFS event in Arm A 
and Arm B, respectively, comparing the treatment effect between the two treatment arms 
will be estimated using a stratified Cox regression model with the same stratification 
variables used for the stratified log-rank test, and the 95% CI will be provided. 
For PFS and OS analyses in the ITT−WT population, the stratification factors will be sex 
(male vs. female), presence of liver metastases at baseline (yes vs. no), and PD-L1 
tumor expression by IHC ([TC3 and any IC, TC0/1/2 and IC2/3 combined] vs. TC0/1/2 


Atezolizumab—F. Hoffmann-La Roche Ltd 
17/Statistical Analysis Plan GO29537 
 
and IC0/1).  The stratification factors will be those used during randomization as 
recorded in the interactive voice/web response system.  Due to the potential risk of over-
stratification (Akazawa et al. 1997), if at least one stratum (i.e., a combination of 
stratification factor levels across sex, presence of liver metastasis at baseline, and 
PD-L1 tumor expression by IHC per IxRS) has less than 15 events (PFS or OS events), 
the stratification factor (one of three stratification factors: sex, presence of liver 
metastasis at baseline, and PD-L1 tumor expression by IHC 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 15 events (PFS or OS events).  The final set of stratification factors used 
in stratified analyses will be applied to all endpoints where stratified analyses are 
planned.  The analyses 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. 
Treatment comparisons will be conducted by comparing Arm A versus Arm B based on 
stratified log-rank tests in the ITT−WT population for the PFS and the OS endpoints.  For 
each comparison, analyses will be conducted according to an analysis hierarchy and an 
α−spending algorithm to control for the type I error rate (see Figure 2 in Section 2.3) and 
to account for an interim analysis (see Section 2.4.2). 
To control the overall type I error rate for the one-sided test at 0.025, the hypothesis 
testing will be done at the specified significance levels in the order described below: 
1. PFS in the ITT−WT population will be tested at α = 0.003 (one-sided).  If the 
estimate of the HR is < 1 and the one-sided p-value corresponding to the 
stratified log-rank test is ≤  0.003, the null hypothesis will be rejected, and it will 
be concluded that atezolizumab + carboplatin + nab-paclitaxel prolongs the 
duration of PFS relative to the control arm in the ITT−WT population. 
2. α recycling from PFS to OS will be conducted as follows: 
a) If PFS result is not statistically significant in the ITT−WT population, then OS 
in the ITT−WT population will be tested at α = 0.022 (one-sided). 
b) If PFS result is statistically significant in the ITT−WT population, then OS in 
the ITT−WT population will be tested at α = 0.025 (one-sided). 
 
KM methodology will be used to estimate median PFS and OS and to construct survival 
curves for each treatment arm for a visual description of the difference among arms.  
The Brookmeyer-Crowley methodology will be used to construct the 95% CI for the 
median PFS and OS (Brookmeyer and Crowley 1982). 
Follow-up for OS, defined as the time from randomization to death or last known date 
alive, will be summarized for all patients included in the analysis (whether patient is alive 
or has died).  Follow-up will be summarized using the KM method with data for patients 
who died censored at the date of death. 


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4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
PFS and OS in the ITT Population 
PFS and OS in the ITT populations will be analyzed using the same methods as 
described in Section 4.4.1.  PFS and OS in patients with an activating EGFR mutation or 
ALK translocation may be analyzed using the same methods to provide the evaluation of 
the population complementary to the ITT-WT population.  
If the difference in OS between Arm A and Arm B in the ITT−WT population is 
statistically significant, a comparison of Arm A versus Arm B will be conducted in the 
ITT population, similarly as shown in Figure 2.  The α allocation will follow the same 
α-spending algorithm and allocation ratio (3:22) described for analysis of the co-primary 
efficacy endpoints as described in Section 2.3.  
4.4.2.2 
PFS and OS in PD-L1 Expression and PD-L1 Expression WT 
Populations 
PFS and OS in the TC1/2/3 or IC1/2/3−WT, and the TC1/2/3 or IC1/2/3 populations will 
be analyzed using similar methods as described in Section 4.4.1.  Analyses of PFS and 
OS may be conducted in other PD-L1 expression populations and PD-L1 expression WT 
populations (e.g., TC2/3 or TC2/3-WT, TC3 or IC3-WT, TC2/3 or IC2/3, TC3 or IC3, and 
the corresponding complementary groups, as well as TC0 and IC0-WT, TC0 and IC0). 
4.4.2.3 
Objective Response Rate 
ORR (confirmation not required) is defined as the proportion of patients with an objective 
response, either CR or PR, with the use of RECIST v1.1, as determined by the 
investigator.  Patients not meeting these criteria, including those without any 
post-baseline assessment, will be considered non-responders.  Confirmation of 
response according to RECIST v1.1 is not required, but for exploratory purposes, ORR 
with confirmation may be reported.  ORR will be compared between treatment arms 
using the stratified Cochran-Mantel-Haenszel test.  The 95% CI for the difference in 
ORRs between the two treatment arms will be computed using the normal approximation 
to the binomial distribution.  An estimate of ORR and its 95% CI will be calculated for 
each treatment arm using the Clopper-Pearson 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 using RECIST v1.1, or death from any cause, whichever occurs first.  
Data for patients who are alive and who have not experienced disease progression at 
the time of analysis will be censored at the date of the last tumor assessment.  If no 
tumor assessments were performed after the date of the first occurrence of the objective 
response (CR or PR), DOR will be censored at the date of the first occurrence of the 
objective response.  Because the determination of DOR is based on a non-randomized 
subset of patients, formal hypothesis testing will not be performed.  DOR will be 


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estimated using KM methodology.  Comparisons between treatment arms will be made 
using the stratified and unstratified log-rank test for descriptive purposes only. 
Confirmation of response according to RECIST v1.1 will not be required, but for 
exploratory purposes, DOR for patients with confirmed response may be reported. 
4.4.2.5 
OS Rate at the 1- and 2-Year Landmark Timepoints 
The OS rate at the 1- and 2-year landmark time points after randomization will be 
estimated for each treatment arm using KM methodology, along with 95% CI calculated 
with the standard error derived from the Greenwood formula.  The 95% CI for the 
difference in OS rates between the two treatment arms will be estimated using the 
normal approximation method, with standard errors computed using the Greenwood 
method. 
4.4.2.6 
Patient-Reported Outcomes 
Through the use of the SILC scale, the EORTC QLQ-C30, and EORTC QLQ-LC13, lung 
cancer symptom data will be collected about symptoms commonly associated with 
cancer treatments, and disease and treatment impact on patients’ functioning. 
The EORTC QLQ-C30 and EORTC QLQ-LC13 will be scored according to the 
EORTC scoring manual (Fayers et al. 2001).  The QLQ-C30 and QLQ-LC13 consist of 
both multi-item scales and single-item measures such as functional scales, symptom 
scales, and a global health status/quality-of-life scale. 
For multi-item subscales, if ≤ 50% of items within the multi-item subscale are missing at a 
given timepoint, the multi-item score will be calculated on the basis of the non-missing 
items.  If > 50% of items are missing or if a single-item measure is missing, the subscale 
is missing. 
All EORTC scales and single-item measures will be linearly transformed so that each 
score has a range of 0 − 100.  A high score for a functional scale represents a high or 
healthy level of functioning, and a high score for the global health status and HRQoL 
represents a high HRQoL; however, a high score for a symptom scale or item represents 
a high level of symptomatology or problems. 
The SILC questionnaire comprises three individual symptoms (dyspnea, cough, chest 
pain) and will be scored at the individual symptom level, thus will have a dyspnea score, 
chest pain score, and cough score.  Each individual symptom score will be calculated as 
the average of responses for the symptom items (e.g., Chest Pain Score = mean [item 1; 
item 2]).  An increase in score is suggestive of a worsening in symptomology (i.e., 
frequency or severity).  A score change of ≥ 0.3 points for the dyspnea and cough 
symptom scores is considered to be clinically significant; whereas a score change of 
≥ 0.5 points for the chest pain score is considered to be clinically significant. 


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Time to Deterioration in Patient-Reported Outcomes 
TTD with use of the EORTC is defined as the time from baseline to the first confirmed 
clinically meaningful deterioration in the EORTC symptom score. 
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.  
In this instance, symptom deterioration will be determined as confirmed clinically 
meaningful deterioration in any of the listed symptom scores, whichever occurs first 
(cough, chest pain, and dyspnea multi-item scale).  Confirmed clinically meaningful 
deterioration in lung cancer symptoms is defined as a ≥ 10-point increase above baseline 
in a symptom score that must be held for at least two consecutive assessments or an 
initial ≥ 10-point increase above baseline followed by death within 3 weeks from the last 
assessment.  A ≥ 10-point change in the EORTC scale score is perceived by patients as 
clinically significant (Osoba et al. 1998). 
TTD analyses will be performed for the ITT−WT population and will include all data 
collected through disease progression and survival follow up.  TTD analyses may be 
performed for the ITT population when a PFS or an OS benefit has been demonstrated 
for the ITT population.  The methodologies that are outlined for the analysis of OS will be 
used for the analyses of TTD for prespecified symptoms of the EORTC QLQ-C30 and 
EORTC QLQ-LC13 measures.  TTD of prespecified symptoms will be summarized using 
the KM method.  Comparison of TTD using the EORTC QLQ-C30 and 
EORTC QLQ-LC13 measures between treatment arms will be performed using the 
stratified log-rank test; the stratified HRs and 95% CIs will also be reported.  If no 
baseline or post-baseline assessment is performed, patients will be censored at the 
randomization date plus 1 day.  Patients without deterioration at the time of analysis will 
be censored at the last time they were known to have not deteriorated.  There will be no 
imputation for missing baseline or post-baseline data for the TTD analysis. 
Change from Baseline per SILC Scale 
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) of the 
change from baseline per SILC scale may be provided.  The analysis may be performed 
for patients in the ITT−WT population with a non-missing baseline and a non-missing 
post-baseline PRO assessment.  Graphs of the mean changes and standard errors over 
time from the baseline assessment for the total score and subscales may be provided for 
each treatment arm. 
The analysis of SILC change from baseline may be performed at all on-treatment 
timepoints, as well as at the time of disease progression per RECIST v1.1 
(PRO assessment completed within ± 7 days of date of radiographic disease 
progression), at the last dose of treatment received before treatment discontinuation for 
any cause, and at the survival follow-up visits through 6 months. 


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4.4.3 
Exploratory Efficacy Endpoints 
4.4.3.1 
PFS, OS, ORR, and DOR in Teff-High and Teff-High WT 
Populations 
The Teff-high (−1.91) population is defined as the ITT patients with a Teff signature 
score ≥ −1.91 in baseline tumor tissues.  The Teff-high (−0.91) population is defined as 
ITT patients with a Teff signature score ≥−0.91 in baseline tumor tissues.  The Teff-high 
(−2.38) population is defined as ITT patients with a Teff signature score ≥−2.38 in 
baseline tumor tissues.  The Teff-high (−2.93) population is defined as ITT patients with 
a Teff signature score ≥−2.93 in baseline tumor tissues.  The Teff signature score is 
derived from the average expression of PD-L1 (CD274), CXCL9, and interferon-gamma 
(IFN-γ) genes relative to a reference gene using RNA isolated from the patient’s 
formalin−fixed paraffin-embedded tumor tissue, as measured using a quantitative real-
time polymerase chain reaction on a Roche Molecular System Cobas 4800 platform.  
The Teff-high WT population is defined as either of the above-described Teff populations 
excluding patients with an activating EGFR mutation or ALK translocation. 
Analyses of PFS, ORR, and DOR, as assessed by investigator using RECIST v1.1, and 
OS in the Teff-high and Teff-high WT populations may not be included in the Clinical 
Study Report (CSR) for this study. 
4.4.3.2 
Progression-Free Survival Rates at 6 Months and 1 Year 
PFS rates at 6 months and 1 year will be estimated and analyzed using the same 
method as described in Section 4.4.2.5. 
4.4.3.3 
Overall Survival Rate at 3 Years 
OS rate at 3 years will be estimated and analyzed using the same method as described 
in Section 4.4.2.5. 
4.4.3.4 
EQ-5D-3L Health Status Data 
The EQ-5D-3L questionnaire will also be collected to generate HRQoL and utility scores 
for use in economic models for reimbursement. 
Health status is assessed by the EQ-5D-3L.  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 used in this study for economic modeling.  This 
analysis will not be included in the CSR for this study. 
4.4.3.5 
Additional Patient-Reported Outcome Analyses 
EORTC score changes from baseline will be descriptively analyzed using means, SDs, 
medians, and range by treatment arm for patients with a baseline assessment and at 


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least one post-baseline assessment.  The analyses will be performed at timepoints 
similar to those used for the analyses of change from baseline per SILC scale. 
TTD may also be documented for each of the following individual lung cancer symptoms 
(i.e., cough, dyspnea, chest pain) with use of the EORTC. 
To help interpret the results from the change from baseline analyses, the number and 
proportion of patients with a clinically meaningful change may be summarized by 
treatment arm, for the EORTC QLQ-C30 global health status and physical function scale 
scores and for the SILC cough, chest pain, and dyspnea scale scores at each cycle 
post-baseline. 
Compliance rates will be summarized by listing the number and proportion of patients in 
the PRO-evaluable subset who completed the PRO assessments at each timepoint by 
treatment arm.  Reasons for non-completion will be summarized if available in the CRF. 
These additional PRO analyses may not be included in the CSR for this study. 
4.4.4 
Sensitivity Analyses 
4.4.4.1 
Missing Tumor Assessment 
The impact of missing scheduled tumor assessments on PFS will be assessed 
depending on the number of patients who missed assessments scheduled immediately 
prior to the date of disease progression per RECIST v1.1 or the data cutoff.  If > 5% of 
patients missed two or more assessments scheduled immediately prior to the date of 
disease progression per RECIST v1.1 or death in any treatment arm, the following two 
sensitivity analyses will be performed: 
• 
Patients who missed two or more scheduled assessments immediately prior to the 
date of disease progression per RECIST v1.1 or death will be censored at the last 
tumor assessment prior to the missed visits. 
• 
Patients who missed two or more scheduled assessments immediately prior to the 
date of disease progression per RECIST v1.1 or death will be counted as having 
progressed on the date of the first of these missing assessments. 
 
Statistical methodologies analogous to those used in the primary analysis of PFS as 
specified in Section 4.4.4.1 will be used for this sensitivity analysis. 
4.4.4.2 
Non-Proportional Hazard 
Non−Protocol-Specified Anti-Cancer Therapy 
The impact of non−protocol-specified anti-cancer therapy (NPT) on PFS as determined 
by the investigator will be assessed, depending on the number of patients who received 
NPT before a PFS event.  If > 5% of patients received NPT before a PFS event in the 
control arm, a sensitivity analysis may be performed for the comparisons between two 
treatment arms in which data from patients who receive NPT before a PFS event will be 
censored at the last tumor assessment date before receipt of NPT. 


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The impact of subsequent NPT on OS will be assessed depending on the number of 
patients who received NPT.  If > 10% of patients received a NPT in the control arm, the 
following analyses may be performed to compare treatment arms: 
• 
The discount method uses a ‘discounted’ survival time after switching for patients 
who switch treatments based on a user-specified assumption for the effect on OS.  
OS may be discounted according to a range of possible effects on OS of the 
subsequent NPT after treatment switching occurred (e.g., 10%, 20%, 30%, etc.). 
• 
Rank preserving structural failure time provides an estimate of the OS time for the 
control group had NPT not occurred (Robins and Tsiatis 1991).  It estimates OS 
measured from the time of NPT by applying an estimate of the benefit of the NPT.  
The total OS time (sum of time to NPT and the estimated survival time after NPT 
started) may then be analyzed using the same methodology as for the primary 
analysis of OS. 
• 
The inverse probability of censoring weighting method censors patients at start of 
NPT and uses the control arm patients to create weights that represent how NPT 
treated patient is like a non−NPT-treated patient (Robins and Finkelstein 2000).  
These time-varying weights are included into the OS analysis to correct the effect of 
NPT by giving increased weight to non-censored patients with similar characteristics 
to censored patients. 
 
Delayed Clinical Effect 
If a delayed separation of the KM curves is observed at the beginning of the curves and 
the delay is ≥ 3 months, the following analyses may be conducted to assess a potential 
delayed clinical effect for the treatment group. 
• 
Weighted Log-Rank Analysis 
Where the delayed clinical effect is > 10% of the median survival time of the control 
group, an analysis of OS may be performed using the weighted log-rank test based 
on the Rho-Gamma weight function family (Fleming and Harrington 1991) or piece-
wise linear weight functions (Lin and Leon 2017) that weight more on late events to 
account for the delayed clinical effect (Fine et al. 2007).  In addition, in order to 
enhance clinical interpretation of the treatment effect that varies over time, hazard 
ratio estimates may also be provided based on the corresponding Cox models (Lin 
and Leon 2017), for example, the models that assume a minimal treatment effect 
during the first few months (e.g., 3 months, 6 months) then a full treatment effect 
afterwards. 
4.4.4.3 
Loss to Follow-up 
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  If > 5% of patients are lost to follow-up for OS in either 
treatment arm, a sensitivity analysis may be performed for the comparisons between two 
treatment arms in which patients who are lost to follow-up will be considered as having 
died at the last date they were known to be alive. 


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4.4.4.4 
Progression-Free Survival by Independent Review Facility 
PFS as assessed by the IRF is defined as the time from randomization to the first 
documented disease progression as determined by the IRF using RECIST v1.1 or death 
from any cause, whichever occurs first. 
PFS as assessed by the IRF may be examined as a sensitivity analysis using the same 
methods that will be used for PFS as assessed by the investigator. 
4.4.5 
Subgroup Analyses 
The consistency of PFS and OS results in subgroups will be examined in the populations 
where PFS and/or OS benefit has been demonstrated.  The subgroups are defined by 
the following: 
• 
Demographics (age, sex, race/ethnicity) 
• 
Baseline disease characteristics (e.g., ECOG performance status; presence of liver 
metastases at baseline; smoking status; metastatic sites such as brain, bone, etc.; 
EGFR mutation status; KRAS mutation status) 
• 
PD-L1 IHC status (e.g., TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3, and their 
corresponding complementary groups as determined by the SP142 assay; 
subgroups with PD-L1 expression on at least 1%, 25%, or 50% of TC [and their 
corresponding complementary subgroups] as determined by the SP263 assay may 
also be performed pending data availability) 
• 
Intended cycles during induction phase (4 cycles vs. 6 cycles) 
 
Summaries of PFS and OS, including the unstratified HR estimated from a 
Cox proportional hazards model and KM estimates of median PFS and OS, will be 
produced separately for each level of the subgroup for the comparisons between 
treatment arms and displayed in a forest plot (Lewis and Clarke 2001).  KM plots of PFS 
and/or OS will also be produced for selected subgroups. 
Summaries of ORR by subgroup will also be provided. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Atezolizumab PK samples will be collected in this study as outlined in Appendix 3.  
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, and standard 
deviations, as appropriate. 
Plasma concentrations of carboplatin and nab-paclitaxel will be collected in this study as 
outlined in Appendix 3.  The concentrations of carboplatin and nab-paclitaxel will be 
summarized using descriptive statistics as described above. 
Additional PK analyses will be conducted, as appropriate, based on the availability of 
data.  These additional analyses may not be included in the CSR for this study. 


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4.6 
EXPLORATORY BIOMARKER ANALYSES 
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with response to study drug, including efficacy (PFS, OS, 
and/or ORR).  The biomarkers include but are not limited to tumor mutational burden (in 
blood and/or tumor tissue).  Additional predictive, prognostic, and pharmacodynamic 
exploratory biomarkers in archival and/or fresh tumor tissue and/or blood may be 
examined for their association with disease status and/or clinical outcomes.  These 
exploratory analyses will not be included in the CSR for this study. 
4.7 
SAFETY ANALYSES 
The safety population includes treated patients, defined as randomized patients who 
received any protocol treatment.  For the safety analyses, patients will be grouped 
according to whether any full or partial dose of atezolizumab was received, including 
when atezolizumab was received in error.  Specifically, for patients randomized to Arm B, 
if atezolizumab was received in error, the patients will be grouped to Arm A for the safety 
analyses. 
Patients who were consented prior to approval of Protocol GO29537, Version 5 and are 
randomized to carboplatin + nab-paclitaxel will be given the option to cross over to 
receive atezolizumab as monotherapy upon progressive disease per RECIST v1.1, 
provided they continue to meet eligibility criteria.  Safety data observed after those 
patients who crossed over from Arm B to receive atezolizumab (as allowed under 
previous protocol versions) may be summarized separately. 
4.7.1 
Exposure of Study Medication 
Study drug exposure, including treatment duration, number of cycles, and dose intensity, 
will be summarized for each treatment arm with descriptive statistics. 
4.7.2 
Adverse Events 
Verbatim description of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities 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, serious adverse events, treatment-related serious 
adverse events, severe adverse events (Grade ≥ 3), adverse events of special interest, 
immune-mediated adverse events, and adverse events that lead to study drug 
discontinuation or interruption will be summarized. 
“Treatment emergent” is defined for all events with onset on or after the first study drug 
treatment up to the data cutoff date. 


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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. 
4.7.3 
Laboratory Data 
Change from baseline and values outside the normal ranges may also be summarized.  
Additionally, selected laboratory data will be classified according to NCI CTCAE and will 
be summarized by grade.  Shift tables from baseline to the highest NCI CTCAE grade 
during the study post-baseline will be presented. 
4.7.4 
Vital Signs 
Changes in selected vital signs will be summarized by treatment arm. 
4.7.5 
Anti-Drug Antibody  
Incidence of ADAs against atezolizumab will be summarized.  The analyses of PK, key 
efficacy, and safety by ADA status will be conducted to explore the potential impact of 
immunogenicity as appropriate. 
4.8 
MISSING DATA 
Please refer to Sections 4.4.1 and 4.4.2 for methods of handling missing data for the 
primary and secondary efficacy endpoints. 


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5. 
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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. 
Burman CF, Sonesson C, Guilbaud O, et al. A recycling framework for the construction 
of Bonferroni-based multiple tests. Stat Med 2009;28:739−61. 
Chen TT. Milestone survival: a potential intermediate endpoint for immune checkpoint 
inhibitors. J Natl Cancer Inst 2015;107(9). 
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual. 3rd 
ed. Brussels: European Organisation for Research and Treatment of Cancer, 2001. 
Fine GD. Consequences of delayed treatment effects on analysis of time-to-event 
endpoints. Ther Innov Regul Sci 2007;41:535−9. 
Fleming TR, Harrington DP. Counting processes and survival analysis. New York: John 
Wiley & Sons, 1991. 
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479−80. 
Lin RS, Leon LF. Estimation of treatment effects in weighted log-rank tests. Contemp 
Clin Trials Commun. 2017;8:147-55. 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality-of-life scores. J clin oncol. 1998;16:139-44. 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Commun Stat Theory Methods 
1991;20:2609−31. 
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in 
an AIDS clinical trial with inverse probability of censoring weighted (IPCW) 
log-rank tests. Biometrics 2000;56:779−88. 


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Appendix 1 Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTI−PD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATIN + NAB-PACLITAXEL FOR 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV 
NON-SQUAMOUS NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
GO29537 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2014-003206-32 
IND NUMBER: 
117296 
TEST PRODUCT: 
Atezolizumab (MPDL3280A, RO5541267) 
PHASE: 
III 
INDICATION: 
Non-squamous non−small cell lung cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
The term "wild-type" (WT) refers to randomized patients who do not have a sensitizing 
EGFR mutation or ALK translocation. 
The term "tumor gene expression" (tGE) refers to randomized patients with a defined level of 
expression of a programmed death−ligand 1 (PD-L1) and T-effector gene signature in tumor 
tissue, as analyzed through use of a centrally performed RNA-based assay. 
Some efficacy endpoints will be analyzed in a population of randomized patients with a 
defined level of PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells 
(ICs), as analyzed through use of a centrally performed immunohistochemistry (IHC) test. 
Efficacy Objectives 
The co-primary objectives of this study are the following: 
• 
To evaluate the efficacy of atezolizumab + carboplatin + nab-paclitaxel compared with 
carboplatin + nab-paclitaxel as measured by investigator-assessed progression-free survival 
(PFS) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) in the tGE-WT population and the intent-to-treat wild-type (ITT-WT) 
population 
• 
To evaluate the efficacy of atezolizumab + carboplatin + nab-paclitaxel compared with 
carboplatin + nab-paclitaxel as measured by overall survival (OS) in the ITT-WT population 
 
The secondary efficacy objectives for this study are the following: 
• 
To evaluate the efficacy of atezolizumab as measured by OS in the tGE-WT population 
• 
To evaluate the efficacy of atezolizumab as measured by investigator-assessed PFS 
according to RECIST v1.1 and OS in the TC2/3 or IC2/3 WT population and the TC1/2/3 
or IC1/2/3 WT population 


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• 
To evaluate the efficacy of atezolizumab as measured by investigator-assessed PFS 
according to RECIST v1.1 and OS in the tGE population and the ITT population  
• 
To evaluate the efficacy of atezolizumab as measured by investigator-assessed objective 
response rate according to RECIST v1.1 for both the tGE-WT population and the ITT-WT 
population 
• 
To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response according to RECIST v1.1 for both the tGE-WT population and the ITT-WT 
population 
• 
To evaluate the OS rate at 1 and 2 years in each treatment arm in the tGE-WT population 
and the ITT-WT population 
• 
To determine the impact of atezolizumab as measured by time to deterioration (TTD) in 
patient-reported lung cancer symptoms of cough, dyspnea (single-item and multi-item 
subscales), chest pain, or arm/shoulder pain, using the European Organisation for the 
Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire−Core 30 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) in the tGE-WT 
population and the ITT-WT population 
• 
To determine the impact of atezolizumab as measured by change from baseline 
(i.e., improvement or deterioration based upon presenting symptomatology) in 
patient-reported lung cancer symptom (chest pain, dyspnea, and cough) score using the 
Symptoms in Lung Cancer (SILC) scale symptom severity score in the tGE-WT population 
and the ITT-WT population 
 
Safety Objectives 
The safety objectives for this study are the following: 
• 
To evaluate the safety and tolerability of atezolizumab + carboplatin + nab-paclitaxel 
compared with carboplatin + nab-paclitaxel 
• 
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, safety, and efficacy 
 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for this study are the following: 
• 
To characterize the pharmacokinetics of atezolizumab when given in combination with 
carboplatin and nab-paclitaxel 
• 
To characterize the pharmacokinetics of carboplatin when given in combination with 
nab-paclitaxel with and without atezolizumab 
• 
To characterize the pharmacokinetics of nab-paclitaxel when given in combination with 
carboplatin with and without atezolizumab 
 
Exploratory Objectives 
The exploratory objectives for this study are the following: 
• 
To evaluate PFS at 6 months and at 1 year in each treatment arm 
• 
To evaluate the OS rate at 3 years in each treatment arm 
• 
To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease status, mechanisms 
of resistance, and/or response to study treatment 
• 
To evaluate 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 Dimensions 3-Level (EQ-5D-3L) questionnaire to generate utility scores for use 
in economic models for reimbursement 


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• 
To determine the impact of atezolizumab as measured by change from baseline in 
patient-reported outcomes of health-related quality of life, lung cancer-related symptoms, 
and functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13 
 
Study Design 
Description of Study 
This is a randomized, Phase III, multicenter, open-label study (IMpower130) designed to 
evaluate the safety and efficacy of atezolizumab in combination with carboplatin + nab-paclitaxel 
compared with treatment with carboplatin + nab-paclitaxel in approximately 
715 chemotherapy−naive patients with Stage IV non-squamous non−small cell lung cancer 
(NSCLC). 
Tumor specimens will be prospectively tested for PD-L1 expression by a central laboratory.  
Eligible patients will be stratified by sex (male vs. female), presence of liver metastases at 
baseline (yes vs. no), and by PD-L1 tumor expression by IHC (TC3 and any IC vs. TC0/1/2 and 
IC2/3 vs. TC0/1/2 and IC0/1) and randomized in a 2:1 ratio to receive one of the following 
treatment regimens. 
Treatment Arm A:  Atezolizumab + carboplatin + nab-paclitaxel (Induction: four or six 21-day 
cycles); atezolizumab (Maintenance: 21-day cycles) 
Treatment Arm B:  Carboplatin + nab-paclitaxel (Induction: four or six 21-day cycles); best 
supportive care or pemetrexed (Maintenance: 21-day cycles) 
 
The number of cycles of induction treatment (four or six) will be at the discretion of the 
investigator and will be determined and documented prior to randomization.  Induction treatment 
will be administered on a 21-day cycle until the following occurs (whichever occurs first):  
1) administration of four or six cycles or 2) disease progression (Arm B) or loss of clinical benefit 
(Arm A) is documented. 
Following the induction phase, patients who are randomized to atezolizumab (Arm A) may 
continue treatment with atezolizumab beyond radiographic disease progression according to 
RECIST v1.1, provided they 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).  Patients randomized to 
carboplatin + nab-paclitaxel (Arm B) will be offered best supportive care provided they have 
non-progressive disease.  Switch maintenance to pemetrexed is also permitted for patients 
randomized to Arm B.  Switch maintenance must be administered within 6 weeks of Day 1 of 
the last induction cycle. 
Patients who entered Study GO29537 under Protocol Versions 1 − 4 and are randomized to 
carboplatin + nab paclitaxel will be given the option to cross over to receive atezolizumab as 
monotherapy upon progressive disease per RECIST v1.1, provided they continue to meet 
eligibility criteria.  Safety data for patients who crossed over from Arm B to receive atezolizumab 
as allowed under Protocol Versions 1 − 4 will be summarized for exploratory purposes. 
For Atezolizumab-Treated Patients Only 
During treatment (induction or maintenance), patients receiving atezolizumab (including patients 
in Arm B who entered Study GO29537 under Protocol Versions 1 − 4 and crossed over to 
receive atezolizumab after disease progression according to RECIST v1.1) who show evidence 
of clinical benefit will be permitted to continue atezolizumab after the criteria per RECIST v1.1 
for progressive disease are met if they meet all of the following criteria: 
• 
Evidence of clinical benefit as assessed by the investigator 
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g., new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
• 
No decline in Eastern Cooperative Oncology Group (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 


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• 
Patients must provide written consent to acknowledge deferring other treatment options in 
favor of continuing atezolizumab at the time of initial progression 
 
Treatment with induction chemotherapy (Arms A and B) and pemetrexed (Arm B) as switch 
maintenance must be discontinued in all patients who exhibit evidence of progressive disease 
according to RECIST v1.1. 
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 48 weeks 
following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, tumor assessment will be 
required every 9 weeks.  Patients will undergo tumor assessments until 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), withdrawal of consent, study termination by Sponsor, 
or death, whichever occurs first.  Patients who discontinue treatment for reasons other than 
radiographic disease progression according to RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration) will continue scheduled tumor assessments until 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), withdrawal of consent, study termination by Sponsor, 
or death, whichever occurs first, regardless of whether patients start a new anti-cancer therapy. 
All primary imaging data used for tumor assessment will be collected by the Sponsor to enable 
centralized, independent review of response endpoints.  The independent reviews of the stored 
scans will be performed when requested. 
Patients in all treatment arms 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.  These data will be used to explore whether radiographic 
findings are consistent with the presence of tumor.  Additionally, these data will be analyzed to 
evaluate the association between changes in tumor tissue and clinical outcome and to 
understand further the potential mechanisms of progression and resistance to atezolizumab as 
compared with such mechanisms after treatment with chemotherapy alone.  This exploratory 
biomarker evaluation will not be used for any treatment-related decisions.  Patients in Arm A 
and patients in Arm B (who entered Study GO29537 under Protocol Versions 1 − 4) who are 
unable to undergo biopsy sample collection but who otherwise meet the criteria listed above 
may continue/crossover to receive atezolizumab. 
Number of Patients 
Approximately 105 sites globally will participate in the study, and approximately 715 patients will 
be randomized. 
Target Population 
Patients may be eligible if they have chemotherapy-naive, Stage IV, non-squamous NSCLC. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry: 
• 
Signed Informed Consent Form 
• 
Male or female, 18 years of age or older 
• 
ECOG performance status of 0 or 1 
• 
Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 
7th edition) 
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible 
if the major histological component appears to be non-squamous. 


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• 
No prior treatment for Stage IV non-squamous NSCLC 
Patients with a sensitizing mutation in the EGFR gene must have experienced disease 
progression (during or after treatment) or intolerance to treatment with one or more 
EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, or another EGFR TKI 
appropriate for the treatment of EGFR-mutant NSCLC. 
Patients known to have an ALK fusion oncogene must have experienced disease 
progression (during or after treatment) or intolerance to treatment with one or more 
ALK inhibitors (e.g., crizotinib) appropriate for the treatment of NSCLC in patients 
having an ALK fusion oncogene.   
Patients with unknown EGFR and ALK status require test results at screening.  
ALK and/or EGFR may be assessed locally or at a central laboratory. 
Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, 
or chemoradiotherapy with curative intent for non-metastatic disease must have 
experienced a treatment-free interval of at least 6 months from randomization since the 
last chemotherapy, radiotherapy, or chemoradiotherapy cycle. 
• 
Patients with a history of treated asymptomatic central nervous system (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. 
• 
Known PD-L1 tumor status 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.  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.  This specimen must be accompanied by the 
associated pathology report. 
Fine-needle aspiration (defined as samples that do not preserve tissue architecture and 
yield cell suspension and/or cell smears), brushing, cell pellet specimens (e.g., from 
pleural effusion, and lavage samples) are not acceptable. 
Tumor tissue from bone metastases that is subject to decalcification is not acceptable. 
For core-needle biopsy specimens, preferably at least three cores embedded in a single 
paraffin block, should be submitted for evaluation.  
• 
Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease. 


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• 
Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 14 days prior to randomization: 
ANC ≥ 1500 cells/µL without granulocyte colony-stimulating factor support 
Lymphocyte count ≥ 500/µL 
Platelet count ≥ 100,000/µL without transfusion  
Hemoglobin ≥ 9.0 g/dL 
Patients may be transfused to meet this criterion. 
INR or aPTT ≤ 1.5 × upper limit of normal (ULN) 
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose. 
AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions: 
Patients with documented liver metastases:  AST and/or ALT ≤ 5 × ULN 
Patients with documented liver or bone metastases:  alkaline phosphatase ≤ 5 × ULN. 
Serum bilirubin ≤ 1.25 × ULN 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be 
enrolled. 
Serum creatinine ≤ 1.5 × ULN  
• 
For female patients of childbearing potential agreement (by patient and/or partner) to use a 
highly effective form(s) of contraception that results in a low failure rate [< 1% per year] 
when used consistently and correctly, and to continue its use for 5 months after the last 
dose of atezolizumab or for 30 days after the last dose of nab-paclitaxel, whichever is later.  
For male patients with female partners of childbearing potential, agreement (by patient 
and/or partner) to use a highly effective form(s) of contraception that results in a low failure 
rate [< 1% per year] when used consistently and correctly, and to continue its use for 
6 months after the last dose of nab-paclitaxel and/or carboplatin, whichever is later.  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, 
intrauterine hormone-releasing system, bilateral tubal occlusion or vasectomized partner 
(on the understanding that this is the only one partner during the whole study duration), and 
sexual abstinence.  Male patients should not donate sperm during this study and for at least 
6 months after the last dose of nab-paclitaxel and/or carboplatin, whichever is later. 
• 
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 clinical study if they have a partner of childbirth 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 criteria below will be excluded from study entry: 
Cancer-Specific Exclusions 
• 
Active or untreated CNS metastases as determined by computed tomography 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 


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• 
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 locoregional therapy, if appropriate, 
prior to randomization. 
• 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
• 
Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL 
or corrected serum calcium > ULN)  
Patients who are receiving denosumab prior to randomization must be willing and 
eligible to receive a bisphosphonate instead while in the study. 
• 
Malignancies other than NSCLC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous cell skin cancer, localized prostate cancer treated surgically with 
curative intent, ductal carcinoma in situ treated surgically with curative intent) 
• 
Known tumor PD-L1 expression status as determined by an IHC assay from other clinical 
studies (e.g., patients whose PD-L1 expression status was determined during screening for 
entry into a study with anti−PD-1 or anti−PD-L1 antibodies but were not eligible are 
excluded) 
 
General Medical Exclusions 
• 
Women who are pregnant, lactating, or intending to become pregnant during the study 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
• 
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
• 
History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis  
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study. 
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study 


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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 previous 12 months (not 
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high-potency or oral steroids) 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Positive test for HIV 
All patients will be tested for HIV prior to inclusion into the study; patients who test 
positive for HIV will be excluded from the clinical study. 
• 
Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible only if they are negative for HBV DNA. 
Patients who are positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA. 
• 
Active tuberculosis 
• 
Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
• 
Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to 
randomization 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible. 
• 
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within the 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 transplant 
• 
Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live, attenuated vaccine will be required during the study 
• 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
renders the patient at high risk from treatment complications 
• 
Illness or condition that interferes with the patient’s capacity to understand, follow and/or 
comply with study procedures 
 
Exclusion Criteria Related to Medications 


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• 
Any approved anti-cancer therapy, including hormonal therapy within 21 days prior to 
initiation of study treatment; the following exceptions are allowed: 
TKIs approved for treatment of NSCLC discontinued > 7 days prior to randomization.  
The baseline scan must be obtained after discontinuation of prior TKIs. 
• 
Treatment with any other investigational agent with therapeutic intent within 28 days prior to 
randomization 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, 
and anti−PD-L1 therapeutic antibodies 
Patients who have had prior anti−cytotoxic T-lymphocyte-associated protein 4 (anti−CTLA-4) 
treatment may be enrolled, provided the following requirements are met: 
Last dose of anti−CTLA-4 at least 6 weeks prior to randomization 
No history of severe immune-mediated adverse effects from anti−CTLA-4 (National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Grades 3 and 4) 
• 
Treatment with systemic immunostimulatory agents (including but not limited to interferons 
and 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 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 is allowed. 
 
Exclusions Related to Chemotherapy 
• 
Known history of severe allergic reactions to platinum-containing compounds or mannitol 
• 
Known sensitivity to any component of nab-paclitaxel 
• 
Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v4.0 
• 
Known history of severe hypersensitivity reactions to products containing Cremophor EL 
(e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) 
 
Length of Study 
The final PFS analysis will be conducted when all of the following criteria have been met:  
approximately 225 PFS events have occurred in the tGE-WT population, approximately 
475 PFS events have occurred in the ITT-WT population, and the last patient has been 
enrolled in the study.  This is expected to occur approximately 32 months after the first patient 
is enrolled. 
The final OS analysis will be conducted when approximately 457 OS events have occurred in 
the ITT-WT population.  This is expected to occur approximately 42 months after the first 
patient is enrolled. 
End of Study 
The end of study is defined as when the required number of deaths for the final analysis of OS 
has been observed.  Additionally, 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 into an extension study or a non-
interventional study. 


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Outcome Measures 
Efficacy Outcome Measures 
The co-primary 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 according to RECIST v1.1 or death from any cause, 
whichever occurs first in the tGE-WT population and the ITT-WT population 
• 
OS, defined as the time from randomization to death from any cause, in the ITT-WT 
population 
The secondary efficacy outcome measures for this study are the following: 
• 
OS in the tGE-WT population 
• 
PFS, as determined by the investigator according to RECIST v1.1, and OS in the TC2/3 
or IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population 
• 
PFS, as determined by the investigator according to RECIST v1.1, and OS in the tGE 
population and the ITT population 
• 
Objective response, defined as a partial response or a complete response as determined by 
the investigator according to RECIST v1.1 for the tGE-WT population and the ITT-WT 
population 
• 
DOR, defined as the time interval from first occurrence of a documented objective response 
to the time of disease progression as determined by the investigator using RECIST v1.1 or 
death from any cause, whichever occurs first  for the tGE-WT population and the ITT-WT 
population 
• 
OS rates at 1 and 2 years for the tGE-WT population and the ITT-WT population 
• 
TTD in patient-reported lung cancer symptoms, defined as time from randomization to 
deterioration (10-point change) on each of the EORTC QLQ-C30 and EORTC QLQ-LC13 
symptom subscales (cough, dyspnea [single item], dyspnea [multi-item subscale], chest 
pain, and arm/shoulder pain) in the tGE-WT population and the ITT-WT population 
• 
Change from baseline in patient-reported lung cancer symptoms (chest pain, dyspnea, and 
cough) on the symptom severity score of the SILC scale in the tGE-WT population and the 
ITT-WT population 
 
Safety Outcome Measures 
The safety outcome measures for this study are the following: 
• 
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 the following: 
• 
For patients randomized to atezolizumab + carboplatin + nab-paclitaxel: 
Maximum observed serum atezolizumab concentration (Cmax) after infusion on Cycle 1, 
Day 1 
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at 
selected cycles, at treatment discontinuation, and at 120 days (± 30 days) after the last 
dose of atezolizumab 
Plasma concentrations for carboplatin (Arms A and B) 
Plasma concentrations for nab-paclitaxel reported as total paclitaxel (Arms A and B) 


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• 
For patients randomized to carboplatin + nab-paclitaxel who crossed over to receive open-
label atezolizumab as monotherapy (allowed under Study GO29537 Protocol, 
Versions 1 − 4): 
Cmax of serum atezolizumab after infusion on Day 1 of the first cycle following crossover 
to atezolizumab as monotherapy 
Cmin of serum atezolizumab prior to infusion on Day 1 at selected cycles following 
crossover to atezolizumab as monotherapy, 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 the following: 
• 
PFS at 6 months and at 1 year 
• 
OS rate at 3 years 
• 
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 in combination with chemotherapy 
• 
Status of ICs and other exploratory biomarkers in mandatory biopsy specimens and blood 
collected at progression 
• 
Utility scores of the EQ-5D-3L  
• 
Change from baseline in patient-reported outcomes 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) 
The investigational medicinal products (IMPs) for this study are atezolizumab and erlotinib. 
Atezolizumab (1200 mg IV) will be administered on Day 1 of each 21–day cycle.  Atezolizumab 
will be administered to patients who are randomized to Arm A and to patients in Arm B who 
cross over at progression. 
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients who had 
already started switch maintenance treatment with erlotinib under Protocol Versions 1−4 may 
be allowed to continue treatment with erlotinib upon discussion of the risks, potential benefits 
and alternative treatment options with the investigator.  For those patients who receive switch 
maintenance, institutions should follow the dosage and administration instructions in the 
prescribing information. 
Comparator 
Nab-paclitaxel (100 mg/m2 IV) will be administered on Days 1, 8, and 15 of each 21-day cycle 
for four or six cycles during the induction phase.  Nab-paclitaxel will be considered an IMP for 
study purposes in countries where nab-paclitaxel is considered an IMP by local regulations. 
Non-Investigational Medicinal Products 
Comparator  
Carboplatin will be administered by IV infusion to achieve an initial target area under the 
concentration−time curve of 6 mg/mL/min on Day 1 of each 21-day cycle for four or six cycles 
during the induction phase. 
Carboplatin and nab-paclitaxel will be administered to patients in all treatment arms. 
Statistical Methods 
Primary Analysis 
The co-primary efficacy endpoints are PFS as assessed by the investigator using RECIST v1.1 
and OS.  PFS will be analyzed in the tGE-WT population and the ITT-WT population.  
OS will be analyzed in the ITT-WT population.  The timing of the final PFS and OS analyses 


Atezolizumab—F. Hoffmann-La Roche Ltd 
39/Statistical Analysis Plan GO29537 
 
is described below (see "Determination of Sample Size").  At least one interim OS analysis 
will be performed. 
PFS is defined as the time between the date of randomization and the date of first documented 
disease progression or death, whichever occurs first.  Patients who have not experienced 
disease progression or death at the time of analysis will be censored at the time of the last 
tumor assessment.  Patients with no post-baseline tumor assessment will be censored at the 
date of randomization plus 1 day. 
OS is defined as the time between the date of randomization and death from any cause.  Data 
for patients who are not reported as having died at the time of analysis will be censored at the 
date when they were last known to be alive.  Data for patients who do not have post-baseline 
information will be censored at the date of randomization plus 1 day. 
The following analyses will be performed for both PFS and OS.  PFS and OS will be compared 
between treatment arms with the use of the stratified log-rank test.  The hazard ratio (HR) for 
PFS and OS for treatment comparisons will be estimated using a stratified Cox regression 
model, respectively.  The 95% CI for the HR will be provided. 
The stratification factors will be those used during randomization, (i.e., sex [male vs. female], 
presence of liver metastases at baseline [yes vs. no], and PD-L1 tumor expression by IHC [TC3 
and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1]), as recorded in an interactive voice or 
Web-based response system.   
Results from an unstratified analysis will also be presented.  Kaplan-Meier methodology will be 
used to estimate the median PFS and the median OS for each treatment arm, and a 
Kaplan-Meier curve will be constructed to provide a visual description of the difference between 
treatment arms.  The Brookmeyer-Crowley methodology will be used to construct the 95% CI 
for the median PFS and the median OS for each treatment arm. 
Analyses will be conducted according to an analysis hierarchy and an α-spending algorithm 
to control for the type I error rate and to account for an interim analysis. 
To control the overall type I error rate for the one-sided test at 0.025, a one-sided type I error 
(α) of 0.003 and 0.022 (ratio of 3:22) will be allocated to PFS and OS, respectively. 
The hypothesis testing will be performed in the order described below: 
1. PFS in the tGE-WT population will be tested at α = 0.003 (one-sided).  If the estimate of 
the HR is < 1 and the one-sided p-value corresponding to the stratified log-rank test 
is < 0.003, the null hypothesis will be rejected and it will be concluded that 
atezolizumab + carboplatin + nab-paclitaxel prolongs the duration of PFS relative to 
control treatment in the tGE-WT population. 
2. If the null hypothesis is rejected in the tGE-WT population (Step 1), PFS in the ITT-WT 
population will be tested at α= 0.003 (one-sided). 
3. α recycling from PFS to OS will be conducted as follows:  
a. 
If the null hypothesis is not rejected for the PFS analysis in the ITT-WT population 
(Step 2), OS in the ITT-WT population will be tested at α = 0.022 (one-sided).  
b. 
If the null hypothesis is rejected for the PFS analysis in the ITT-WT population 
(Step 2), OS in the ITT-WT population will be tested at α = 0.025 (one-sided). 
 
Determination of Sample Size 
This study will randomize approximately 715 patients.  The ITT-WT population will include 
approximately 650 patients, assuming a prevalence of approximately 10% for sensitizing 
EGFR mutations or ALK translocations.  The tGE-WT population will include approximately 
325 patients, assuming a 50% prevalence with the chosen tGE cutoff. 
The sample size of this study is based on the number of events required to demonstrate 
efficacy with regard to both PFS and OS (co-primary endpoints). 


Atezolizumab—F. Hoffmann-La Roche Ltd 
40/Statistical Analysis Plan GO29537 
 
The estimate of the number of events required to demonstrate efficacy with regard to PFS in the 
comparison of Arm A versus Arm B is based on the following assumptions: 
• 
93% power to detect an HR of 0.55, corresponding to an improvement in median PFS from 
6 months to 10.9 months in the tGE-WT population with a one-sided α of 0.003 
• 
95% power to detect an HR of 0.65, corresponding to an improvement in median PFS from 
6 months to 9.2 months in the ITT-WT population with a one-sided α of 0.003 
• 
No interim analyses for PFS 
• 
Dropout rate of 5% per 12 months 
 
The estimate of the number of events required to demonstrate efficacy with regard to OS in the 
comparison of Arm A versus Arm B is based on the following assumptions: 
• 
80% power to detect an HR of 0.75, corresponding to an improvement in median OS from 
12 months to 16 months in the ITT-WT population with a one-sided α of 0.022 
• 
One interim OS analysis performed at the time of the final PFS analysis, at which time 
approximately 77% of the total number of OS events required for the final analysis are 
expected to have occurred as determined through use of the Lan-DeMets approximation to 
the O'Brien-Fleming boundary 
• 
Dropout rate of 5% per 24 months 
 
With these assumptions, approximately 715 patients in total will be enrolled in this study, 
with approximately 650 patients in the ITT-WT population.  The final PFS analysis will be 
conducted when all of the following criteria have been met:  approximately 225 PFS events 
have occurred in the tGE-WT population, approximately 475 PFS events have occurred in the 
ITT-WT population, and the last patient has been enrolled in the study.  The final PFS 
analysis is expected to occur approximately 32 months after the first patient is enrolled.  
These numbers of events would allow for a minimum detectable difference corresponding to an 
HR of 0.68 in the tGE-WT population and 0.76 in the ITT-WT population, respectively. 
With a sample size of 650 patients, approximately 457 OS events are expected to occur in the 
ITT-WT population.  The final OS analysis is expected to occur approximately 42 months 
after the first patient is enrolled.  This number of events would allow for a minimum 
detectable difference corresponding to an HR of 0.81 in the ITT-WT population. 
Interim Analyses 
There are no interim analyses planned for PFS in this study.  An external independent Data 
Monitoring Committee (iDMC) will be set up to evaluate safety data on an ongoing basis.  All 
summaries/analyses by treatment arm for the iDMC’s review will be prepared by an 
independent Data Coordinating Center.  Members of the iDMC will be external to the Sponsor 
and will follow a charter that outlines their roles and responsibilities.  Any outcomes of these 
safety reviews that affect study conduct will be communicated in a timely manner to the 
investigators for notification of the Institutional Review Boards and Ethics Committees.  
A detailed plan will be included in the iDMC Charter. 
If approximately 352 OS events have occurred in the ITT-WT population at the time of the 
PFS final analysis, an interim OS analysis will be conducted in the ITT-WT population.  If 
there are significantly fewer than the expected 352 OS events at the final PFS analysis, a 
nominal α of 0.01% (negligible impact on overall type I error rate) will be spent on the OS 
analysis at the time of the PFS final analysis and a second interim OS analysis will then be 
conducted after approximately 352 OS events have occurred. 
The final OS analysis will be conducted when approximately 457 OS events have occurred in 
the ITT-WT population.  This is expected to occur approximately 42 months after the first 
patient is enrolled. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
41/Statistical Analysis Plan GO29537 
Appendix 2 Schedule of Assessments 
 
Procedure 
Screening 
Induction Phase 
Cycles 1 to 4 or 6  
(21-Day Cycle) a 
Maintenance Phase 
(21-Day Cycle) a 
Treatment 
Discontinuation 
Visit 
Survival Follow-Up  
Days –28 
to –1 
Day 1 
(± 3 Days) b 
Day 1 
(± 3 Days) b 
 ≤ 30 Days after 
Last Dose of Study 
Treatment 
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit 
Informed consent  
x 
 
 
 
 
Tumor tissue specimen for PD-L1 testing (15 FFPE 
slides required; blocks preferred) c 
Fresh or archival tissue can be used 
x 
 
 
 
 
ALK and/or EGFR assessment if status is unknown 
(may be done locally or centrally) 
x 
 
 
 
 
Demographic data 
x 
 
 
 
 
Medical history and baseline conditions 
x 
 
 
 
 
NSCLC cancer history 
x 
 
 
 
 
Vital signs d 
x 
x d 
x d 
x 
 
Weight 
x 
x 
x 
x 
 
Height 
x 
 
 
 
 
Complete physical examination 
x 
 
 
 
 
Limited physical examination e 
 
x 
x 
x 
 
ECOG performance status 
x 
x 
x 
x 
 
12-Lead ECG 
x 
x f 
x f 
x f 
 
Hematology g 
x 
x 
x 
x 
 
Serum chemistry h 
x 
x  
x  
x 
 
Coagulation test (aPTT or INR) 
x 
 
 
x 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
42/Statistical Analysis Plan GO29537 
Appendix 2 Schedule of Assessments (cont.) 
 
Procedure 
Screening 
Induction Phase 
Cycles 1 to 4 or 6  
(21-Day Cycle) a 
Maintenance Phase 
(21-Day Cycle) a 
Treatment 
Discontinuation 
Visit 
Survival Follow-Up 
Days –28 
to –1 
Day 1 
(± 3 Days) b 
Day 1 
(± 3 Days) b 
 ≤ 30 Days after 
Last Dose of Study 
Treatment 
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit 
Pregnancy test  (women of childbearing-potential 
ONLY) 
x i 
x j 
x j 
x j 
 
TSH, free T3, free T4 k 
x 
x k 
x k 
x 
 
HIV, HBV, HCV serology l 
x 
 
 
 
 
Urinalysis m 
x 
x 
x 
x 
 
Determination of duration of induction treatment 
x 
 
 
 
 
Induction treatment administration: 
Arm A: atezolizumab + carboplatin + nab-paclitaxel 
Arm B: carboplatin + nab-paclitaxel  
 
x n 
 
 
 
Maintenance treatment administration: 
Arm A: atezolizumab 
Arm B: Best supportive care (switch maintenance 
to pemetrexed permitted) 
 
 
x n 
 
 
Tumor response assessment  
x o 
x p 
x p 
 
x q 
Serum sample for atezolizumab ATA assessment 
(atezolizumab-treated patients only) r 
 
x 
x 
x 
120 (± 30) days after last 
dose of atezolizumab 
Serum sample for PK sampling (atezolizumab-
treated patients only) r 
 
x 
x 
x 
120 (± 30) days after last 
dose of atezolizumab 
Carboplatin and nab-paclitaxel PK sampling 
(20 patients per arm) r 
 
x 
 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
43/Statistical Analysis Plan GO29537 
Appendix 2 Schedule of Assessments (cont.) 
 
Procedure 
Screening 
Induction Phase 
Cycles 1 to 4 or 6  
(21-Day Cycle) a 
Maintenance Phase 
(21-Day Cycle) a 
Treatment 
Discontinuation 
Visit 
Survival Follow-Up 
Days –28 
to –1 
Day 1 
(± 3 Days) b 
Day 1 
(± 3 Days) b 
 ≤ 30 Days after 
Last Dose of Study 
Treatment 
Every 3 Months after 
Disease Progression or 
Loss of Clinical Benefit 
Blood samples for PD biomarkers r 
x 
x 
x 
x 
120 (± 30) days after last 
dose of atezolizumab 
Optional blood for DNA extraction  
(RCR only) r, s 
 
x 
Informed consent to continue treatment beyond 
radiographic progression (Arm A 
atezolizumab-treated patients) 
 
At time of radiographic progression 
 
 
Tumor biopsy 
 
At time of radiographic progression t 
 
 
Optional tumor biopsy at other timepoints 
(RCR only) 
 
Any time during study treatment or during survival follow-up 
Adverse events u 
x 
x 
x 
x 
x 
Concomitant medications 
From 
7 days 
before 
screening 
x 
x 
x 
 
Patient-reported outcomes v 
 
x v 
x v 
 
x v 
Survival and anti−cancer therapy follow-up w 
 
 
 
 
x 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
44/Statistical Analysis Plan GO29537 
Appendix 2 Schedule of Assessments (cont.) 
 
ATA = anti-therapeutic antibody; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organization for Research and Treatment of Cancer; 
ePRO = electronic Patient-Reported Outcome; EQ-5D-3L = Euro QoL5 Dimensions 3-Level Version; FFPE = formalin-fixed, paraffin-embedded; HBcAb = hepatitis 
B core antibody; HBV = hepatitis B virus; HCV = hepatitis C virus; IV = intravenous; LC13 = Lung Cancer module; NSCLC = non−small cell lung cancer; 
PD = pharmacodynamic; PGIS = Patient Global Impression of Severity; PK = pharmacokinetic; QLQ-C30 = Quality-of-Life Questionnaire Core 30; RCR = Roche 
Clinical Repository; SILC = Symptoms in Lung Cancer; TSH = thyroid-stimulating hormone. 
Notes:  Patients who are randomized to Arm B who received erlotinib switch maintenance allowed under Study GO29537 Protocol Versions 1 − 4,or who receive 
pemetrexed switch maintenance, will continue with cycle visits at the same frequency as those patients randomized to Arm A until disease progression, 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first. 
The same treatment-phase schedule of assessments and procedures will apply to the crossover patients, i.e., patients will begin on Cycle 1 (now called Cycle 1A) 
and will follow the same assessments and procedures as outlined in this protocol for this cycle (with the exception of an alternate schedule for PK and 
pharmacodynamic assessments (see Appendix 3 of Protocol GO29537) and a biopsy upon progression will not be requested for these patients), as well as for all 
subsequent cycles (i.e., Cycle 2, which will now be called Cycle 2A, etc.).  In addition, patients who entered Study GO29537 under Protocol Versions 1 − 4 and 
who cross over to atezolizumab following disease progression will not follow the treatment-phase schedule for ePRO assessments during crossover.   These 
patients will complete ePRO assessments according to the post progression schedule (i.e., SILC monthly for the first 6 months only and EORTC QLQ-C30, QLQ, 
LC13 and EQ-5D-3L at 3 and 6 months only). 
a Assessments should be performed before study drug infusion unless otherwise noted.  
b Cycle 1, Day 1, must be performed within 5 days after the patient is randomized.  Screening assessments performed ≤ 96 hours before Cycle 1, Day 1 are not 
required to be repeated for Cycle 1, Day 1.  In addition, ECOG performance status, limited physical examination, and local laboratory tests may be performed 
≤ 96 hours before Day 1 of each cycle as specified in Section 4.5.12.2 of Protocol GO29537. 
c If a representative FFPE tumor specimen in paraffin block (preferred) or 15 (or more) freshly cut, unstained 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 a 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 may occur outside the 28-day screening period prior to enrollment.  See Section 4.1.1 of Protocol GO29537, Inclusion Criteria, and Section 4.5.7.1 of 
Protocol GO29537. 
d Vital signs include pulse rate, respiratory rate, blood pressures, and temperature.  Vital signs should be recorded as described in Section 4.5.4 of 
Protocol GO29537. 
e Symptom-directed physical examinations; see Section 4.5.3 of Protocol GO29537 for details.  
f ECG recordings will be obtained when clinically indicated. 
g Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, monocytes, 
basophils, and other cells), and platelet count.  Hematology tests must be performed prior to Day 1 infusions and for nab-paclitaxel administration, also prior to 
Day 8 and Day 15 infusions. See Section 5.1.9.1 (Table 11) of Protocol GO29537 for dose modifications due to hematologic toxicities. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
45/Statistical Analysis Plan GO29537 
Appendix 2 Schedule of Assessments (cont.) 
 
h Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  See Section 5.1.9.1 of Protocol GO29537 for carboplatin and nab-paclitaxel 
dose modification management due to serum chemistry toxicities. 
 i Serum pregnancy test within 14 days before Cycle 1, Day 1. 
j 
Urine pregnancy tests; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
k Thyroid-function testing (thyroid-stimulating hormone [TSH], free T3, free T4) collected at Cycle 1, Day 1, and every fourth cycle thereafter.  Total T3 will be 
tested only at sites at sites where free T3 testing is not tested. 
l 
All patients will be tested for HIV prior to the inclusion into the study, and HIV-positive patients will be excluded from the clinical study.  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 only if their HBV DNA test is negative.  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. 
m Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood). 
n For atezolizumab, the initial dose will be delivered over 60 (± 15) minutes.  If the first infusion is well tolerated, all subsequent infusions may be delivered over 
30 (± 10) minutes.  For carboplatin + nab-paclitaxel, administer nab-paclitaxel over 30 minutes followed immediately by carboplatin administered over 15 − 30 
minutes.  Administer nab-paclitaxel alone on Days 8 and 15.  See Section 4.3.2.2 of Protocol GO29537 for details.  Atezolizumab will be delivered as 
monotherapy during the maintenance phase (Arm A only) and for patients who cross over from Arm B (allowed under Study GO29537 Protocol, 
Versions 1 − 4).  See Section 4.3.2.2 of Protocol GO29537 for details 
o 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 of Protocol GO29537 for details. 
p 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) after the 
completion of the Week 48 tumor assessment, regardless of treatment delays, until radiographic disease progression (loss of clinical benefit for patients 
assigned to atezolizumab who continue treatment after disease progression according to RECIST v1.1), withdrawal of consent, death, or study termination by 
the Sponsor, whichever occurs first.  See Section 4.5.5 of Protocol GO29537 for details. 
q If a patient discontinues study treatment for any reason other than radiographic disease progression according to RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration, tumor assessments will continue at the same frequency as would have been followed if the patient had remained on study treatment until 
radiographic disease progression (loss of clinical benefit for patients treated with atezolizumab who continue treatment after disease progression according to 
RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if the patient starts another anti-cancer therapy 
after study treatment discontinuation. 
r See Appendix 2 of Protocol GO29537 for detailed schedule. 
s The optional RCR whole blood sample requires an additional informed consent and may be collected at any time during the course of the study 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
46/Statistical Analysis Plan GO29537 
Appendix 2 Schedule of Assessments (cont.) 
 
t A mandatory biopsy is required, 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 of Protocol GO29537). 
u All serious adverse events and adverse events of special interest, regardless of relationship to study treatment, will be reported until 90 days after the last dose 
of study treatment (inclusive of erlotinib [allowed under Study GO29537 Protocol Versions 1−4] or pemetrexed switch maintenance for patients randomized to 
Arm B who receive switch maintenance) or initiation of new systemic anti-cancer therapy.  All other adverse events, regardless of relationship to study 
treatment, will be reported until 30 days after the last dose of study treatment (inclusive of erlotinib [allowed under Study GO29537 Protocol Versions 1 − 4] or 
pemetrexed switch maintenance for patients randomized to Arm B who receive switch maintenance) or initiation of new non-protocol systemic anti-cancer 
therapy after last dose of study treatment.  After this period, all deaths will 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 of Protocol GO29537). 
v EORTC QLQ-C30, EORTC QLQ-LC13, PGIS, and EQ-5D-3L questionnaires will be completed by the patients on the ePRO tablet at each scheduled -cycle 
visit during the induction period and then according to the tumor assessment schedule during the treatment maintenance phase prior to administration of study 
drug and prior to any other study assessment(s).  SILC will be completed on an ePRO device at the patient’s home on a weekly basis.  During survival 
follow-up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L will be completed at 3 and 6 months following disease progression or loss of clinical 
benefit (for atezolizumab-treated patients).  The SILC will be completed monthly during survival follow-up for 6 months following disease progression or 
following loss of clinical benefit for patients treated with atezolizumab who continue after disease progression according to RECIST v1.1.  The PGIS is not 
required during survival follow-up.  Patients who discontinue study treatment for any reason other than progressive disease or loss of clinical benefit will 
complete the EORTC QLQ-C30, EORTC QLQ-LC13, PGIS, and EQ-5D-3L at each tumor assessment visit and will complete the SILC at home on a weekly 
basis, until 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) as determined by the investigator (unless the patient withdraws consent or the Sponsor 
terminates the study).  Study personnel should review all questionnaires for completeness before the patient leaves the investigational site.  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. 
w Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits every 3 months or more frequently 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. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
47/Statistical Analysis Plan GO29537 
Appendix 3 Schedule of Pharmacokinetic, Biomarker, 
and Anti-Drug Antibody Assessments 
Study Visit 
Time 
Arm A 
Arm B 
Screening 
N/A 
Biomarkers b 
Biomarkers b 
Cycle 1,  
Day 1 e 
Pre-dose (same day 
as treatment 
administration) 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Carboplatin pharmacokinetics a 
Nab-Paclitaxel pharmacokinetics a 
Biomarkers d 
Carboplatin 
pharmacokinetics a 
Nab-Paclitaxel 
pharmacokinetics a 
Biomarkers d 
30 min (± 10 min) 
after end of 
atezolizumab 
infusion 
Atezolizumab pharmacokinetics 
 
5 − 10 min before the 
end of nab-paclitaxel 
infusion a 
Nab-Paclitaxel pharmacokinetics a 
Nab-Paclitaxel 
pharmacokinetics a 
1 hr after end of nab-
paclitaxel infusion a 
Nab-Paclitaxel pharmacokinetics a 
Nab-Paclitaxel 
pharmacokinetics a 
5 − 10 min before the 
end of carboplatin 
infusion a 
Carboplatin pharmacokinetics a 
Carboplatin 
pharmacokinetics a 
1 hr after end of 
carboplatin infusion a 
Carboplatin pharmacokinetics a 
Carboplatin 
pharmacokinetics a 
Cycle 2,  
Day 1 
(± 3 days)  
Pre-dose (same day 
as treatment 
administration) 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Biomarkers d  
Biomarkers d 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
48/Statistical Analysis Plan GO29537 
Appendix 3 Schedule of Pharmacokinetic, Biomarker, 
and Anti-Drug Antibody Assessments (cont.)  
Study Visit 
Time 
Arm A 
Arm B 
Cycle 3,  
Day 1 
(± 3 days)  
Pre-dose (same day 
as treatment 
administration) 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Carboplatin pharmacokinetics a 
Nab-Paclitaxel pharmacokinetics a 
Biomarkers d  
Carboplatin 
pharmacokinetics a 
Nab-Paclitaxel 
pharmacokinetics a 
Biomarkers d 
30 min (± 10 min) 
after end of 
atezolizumab 
infusion 
Atezolizumab pharmacokinetics 
 
5 − 10 min before the 
end of nab-paclitaxel 
infusion a 
Nab-Paclitaxel pharmacokinetics a 
Nab-Paclitaxel 
pharmacokinetics a 
1 hr after end of nab-
paclitaxel infusion a 
Nab-Paclitaxel pharmacokinetics a 
Nab-Paclitaxel 
pharmacokinetics a 
5 − 10 min before the 
end of carboplatin 
infusion a 
Carboplatin pharmacokinetics a 
Carboplatin 
pharmacokinetics a 
1 hr after end of 
carboplatin infusion a 
Carboplatin pharmacokinetics a 
Carboplatin 
pharmacokinetics a 
Cycles 4, 8, 
and 16,  
Day 1 
(± 3 days)  
Pre-dose (same day 
as treatment 
administration) 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Biomarkers d  
Biomarkers d 
After 
Cycle 16 and 
every eighth 
cycle, Day 1 
(± 3 days) 
Pre-dose (same day 
as treatment 
administration) 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Biomarkers d 
Biomarkers d 
At time of 
fresh biopsy 
(on-treatment 
or at 
progression, 
including 
during 
follow-up) 
At visit 
Biomarkers d 
Biomarkers d 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
49/Statistical Analysis Plan GO29537 
Appendix 3 Schedule of Pharmacokinetic, Biomarker, 
and Anti-Drug Antibody Assessments (cont.)  
Study Visit 
Time 
Arm A 
Arm B 
Treatment 
discontinuation 
visit 
At visit 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Biomarkers d 
Biomarkers d 
120 ± 30 days 
after last dose 
of 
atezolizumab 
At visit 
Atezolizumab ATA 
Atezolizumab pharmacokinetics 
Biomarkers d 
 
At any 
timepoint 
during study 
(RCR consent 
required) 
 
Optional RCR blood (DNA 
extraction) c 
Optional RCR blood 
(DNA extraction) c 
ATA = anti-therapeutic antibody; RCR = Roche Clinical Repository. 
Note:  Serum pharmacokinetic samples for atezolizumab; plasma pharmacokinetic samples for 
carboplatin, and nab-paclitaxel. 
a At selected centers, 20 patients in each treatment arm will undergo the additional PK 
assessments for carboplatin and nab-paclitaxel. 
b Whole blood for biomarkers. 
c The optional RCR blood sample (for DNA extraction) requires an additional informed consent 
and can be collected at any time during the course of the study. 
d Plasma and serum for biomarkers. 
e Biomarker sampling before Cycle 1, Day 1 should be performed before patients are treated 
with the first dose of steroids.