Conditions: Squamous Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1021
Healthy volunteers: no

Brief summary:
This randomized, open-label study will evaluate the safety and efficacy of atezolizumab (MPDL3280A) in combination with carboplatin + paclitaxel or carboplatin + nab-paclitaxel compared with treatment with carboplatin + nab-paclitaxel in chemotherapy-naive participants with Stage IV squamous NSCLC.

Detailed description:

Arms:
arm 1: The induction phase of the study will consist of four or six cycles; atezolizumab, paclitaxel, and carboplatin will be administered on Day 1 of each 21-day cycle. The Day 1 order of drug administration is as follows: atezolizumab, then paclitaxel, then carboplatin. Participants who experience no further clinical benefit at any time during the induction phase will discontinue all study treatments. In the absence of the above criteria, after the 4- or 6-cycle induction phase, participants will begin maintenance therapy with atezolizumab. Atezolizumab will be continued as long as there is a clinical benefit to the participant. arm 2: The induction phase of the study will consist of four or six cycles; 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 drug administration is as follows: atezolizumab, then nab-paclitaxel, then carboplatin. Participants who experience no further clinical benefit at any time during the induction phase will discontinue all study treatments. In the absence of the above criteria, after the 4- or 6-cycle induction phase, participants will begin maintenance therapy with atezolizumab. Atezolizumab will be continued as long as there is a clinical benefit to the participant. arm 3: The induction phase of the study will consist of four or six cycles; 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 drug administration is as follows: nab-paclitaxel, then carboplatin. Participants who experience disease progression at any time during the induction phase will discontinue all study treatment. In the maintenance phase, participants will receive best supportive care.

Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (anti-PD-L1) antibody intervention 2: Carboplatin intervention 3: Nab-Paclitaxel intervention 4: Paclitaxel
Intervention descriptions: intervention 1: Atezolizumab 1200 milligrams (mg) intravenous infusion (IV) on day 1 of each 21-day cycle. intervention 2: Carboplatin area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles. intervention 3: Nab-paclitaxel 100 milligrams per meter squared (mg/m\^2) IV on Day 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles. intervention 4: Paclitaxel 200 mg/m\^2 IV on Day 1 of each 21-day cycle for 4 or 6 cycles. Participants of Asian race/ethnicity will be administered paclitaxel 175 mg/m\^2 IV.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTI-PD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATIN +PACLITAXEL OR 
ATEZOLIZUMAB IN COMBINATION WITH CARBOPLATIN+NAB-
PACLITAXEL VERSUS CARBOPLATIN+NAB-PACLITAXEL IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV SQUAMOUS 
NON-SMALL CELL LUNG CANCER 
NCT Number: 
NCT02367794 
Document Date: 
Protocol Version 7: 24-October-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 GO29437, Version 7
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY EVALUATING THE EFFICACY 
AND SAFETY OF ATEZOLIZUMAB (MPDL3280A, 
ANTIPD-L1 ANTIBODY) IN COMBINATION WITH
CARBOPLATIN PACLITAXEL OR ATEZOLIZUMAB IN 
COMBINATION WITH 
CARBOPLATINNAB-PACLITAXEL VERSUS 
CARBOPLATINNAB-PACLITAXEL IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV 
SQUAMOUS NONSMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29437
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003208-59
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
26 November 2014
DATES AMENDED:
Version 2:  29 March 2015
Version 3:  14 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 09:32:14
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GO29437, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol GO29437 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).

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
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 32
1.1
Background on Lung Cancer................................................. 32
1.1.1
First-Line Treatment for Advanced NonSmall 
Cell Lung Cancer with an EGFR Mutation or ALK 
Rearrangement...................................................................... 33
1.1.2
First-Line Treatment for NSCLC without an 
EGFR Mutation or ALK Rearrangement ................................ 33
1.1.3
Platinum-Based Regimens for First-Line NSCLC.................. 34
1.1.4
nab-Paclitaxel Carboplatin for First-Line 
NSCLC .................................................................................. 37
1.1.5
Erlotinib Maintenance Therapy for Squamous 
NSCLC .................................................................................. 38
1.2
Background on Atezolizumab (MPDL3280A) ........................ 39
1.2.1
Summary of Nonclinical Studies............................................ 39
1.3
Clinical Experience with Atezolizumab .................................. 40
1.3.1
Ongoing Clinical Studies........................................................ 40
1.3.2
Clinical Safety........................................................................ 40
1.3.2.1
Single-Agent Clinical Safety in Patients with 
NSCLC in Study PCD4989g.................................................. 40
1.3.2.2
Single-Agent Clinical Safety in Patients with 
NSCLC in Study GO28753 (POPLAR) .................................. 42
1.3.2.3
Single-Agent Clinical Safety in Patients with 
NSCLC in the Study GO28915 (OAK)................................... 43
1.3.2.4
Clinical Safety in Combination with Bevacizumab 
or Platinum-Based Doublet Chemotherapy ........................... 44
1.3.3
Clinical Activity....................................................................... 46
1.3.3.1
Single-Agent Clinical Activity in Patients with 
NSCLC in Study PCD4989g.................................................. 46
1.3.3.2
Single-Agent Clinical Activity in Patients with 
NSCLC in Study GO28753 (POPLAR) .................................. 47
1.3.3.3
Single-Agent Clinical Activity in Patients with 
NSCLC in Study GO28915 (OAK)......................................... 49


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1.3.3.4
Clinical Efficacy in Combination with 
Platinum-Based Doublet Chemotherapy in 
Patients with NSCLC ............................................................. 50
1.3.4
Clinical Pharmacokinetics and Immunogenicity..................... 50
1.3.5
Rationale for Atezolizumab Dosage ...................................... 50
1.4
Study Rationale and Benefit-Risk Assessment...................... 51
1.4.1
Rationale for Testing Atezolizumab in 
Combination with Carboplatin/Paclitaxel or 
Carboplatin/nab-Paclitaxel..................................................... 52
2.
OBJECTIVES.............................................................................................. 54
2.1
Efficacy Objectives ................................................................ 54
2.1.1
Co-Primary Efficacy Objectives ............................................. 54
2.1.2
Secondary Efficacy Objectives .............................................. 54
2.2
Safety Objectives................................................................... 55
2.3
Pharmacokinetic Objectives .................................................. 55
2.4
Exploratory Objectives........................................................... 56
3.
STUDY DESIGN......................................................................................... 56
3.1
Description of the Study......................................................... 56
3.1.1
Independent Data Monitoring Committee .............................. 59
3.2
End of Study.......................................................................... 60
3.3
Rationale for Study Design.................................................... 60
3.3.1
Rationale for Testing Atezolizumab in Patients 
with PD-L1Unselected NSCLC............................................ 60
3.3.2
Rationale for Control Arm ...................................................... 61
3.3.3
Rationale for Open-Label Study ............................................ 62
3.3.4
Rationale for Progression-Free Survival and 
Overall Survival as Co-Primary Endpoints............................. 62
3.3.5
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment until Loss of 
Clinical Benefit....................................................................... 63
3.3.6
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 63
3.3.7
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens and Evaluation of PD-L1 and 
T-Effector Gene Signature..................................................... 64
3.3.8
Rationale for Blood Sampling for Biomarkers........................ 65


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3.3.9
Rationale for the Collection of Mandatory Tumor 
Specimens at Radiographic Progression............................... 65
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 .................................................... 66
3.4.3
Pharmacokinetic Outcome Measures.................................... 67
3.4.4
Exploratory Outcome Measures ............................................ 67
4.
MATERIALS AND METHODS .................................................................... 67
4.1
Patients.................................................................................. 67
4.1.1
Inclusion Criteria.................................................................... 67
4.1.2
Exclusion Criteria................................................................... 70
4.1.2.1
Cancer-Specific Exclusions ................................................... 70
4.1.2.2
General Medical Exclusions .................................................. 71
4.1.2.3
Exclusion Criteria Related to Medications ............................. 73
4.1.2.4
Exclusions Related to Chemotherapy.................................... 73
4.2
Method of Treatment Assignment and Blinding..................... 74
4.3
Study Treatment.................................................................... 74
4.3.1
Formulation, Packaging, and Handling.................................. 74
4.3.1.1
Atezolizumab (MPDL3280A) ................................................. 74
4.3.1.2
Carboplatin, Paclitaxel, and nab-Paclitaxel............................ 74
4.3.1.3
Erlotinib.................................................................................. 75
4.3.2
Dosage, Administration, and Compliance.............................. 75
4.3.2.1
Atezolizumab......................................................................... 77
4.3.2.2
Paclitaxel, nab-Paclitaxel, and Carboplatin............................ 79
4.3.2.3
Erlotinib.................................................................................. 81
4.3.3
Additional Required Medication............................................. 81
4.3.3.1
Prophylactic Measures for Carboplatin.................................. 81
4.3.3.2
Premedication for Paclitaxel .................................................. 81
4.3.4
Investigational Medicinal Product Accountability ................... 81
4.3.5
Post-Study Access to Atezolizumab ...................................... 82
4.4
Concomitant Therapy ............................................................ 82


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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........................................................... 85
4.5.4
Vital Signs.............................................................................. 86
4.5.5
Tumor and Response Evaluations......................................... 86
4.5.6
Laboratory Assessments and Biomarker 
Samples................................................................................. 88
4.5.7
Tumor Tissue Samples.......................................................... 90
4.5.7.1
Archival and Freshly Collected Tumor Tissue 
Samples for Screening .......................................................... 90
4.5.7.2
Tumor Samples at the Time of Radiographic 
Progression ........................................................................... 91
4.5.7.3
Tumor Samples at Other Timepoints..................................... 91
4.5.7.4
Use and Storage of Remaining Samples from 
Study-Related Procedures..................................................... 92
4.5.8
Anti-Therapeutic Antibody Testing......................................... 92
4.5.9
Electrocardiograms................................................................ 92
4.5.10
Patient-Reported Outcomes .................................................. 92
4.5.11
Samples for Roche Clinical Repository.................................. 94
4.5.11.1
Overview of the Roche Clinical Repository............................ 94
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 95
4.5.11.3
Sample Collection.................................................................. 95
4.5.11.4
Confidentiality........................................................................ 96
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 96
4.5.11.6
Withdrawal from the Roche Clinical Repository..................... 97
4.5.11.7
Monitoring and Oversight....................................................... 97
4.5.12
Timing of Assessments.......................................................... 97
4.5.12.1
Screening and Baseline Assessments .................................. 97


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4.5.12.2
Assessments during Treatment............................................. 98
4.5.12.3
Assessments at Study Drug Discontinuation Visit ................. 99
4.5.12.4
Follow-Up Assessments ........................................................ 99
4.5.12.5
Assessments at Unplanned Visits ....................................... 100
4.6
Patient, Treatment, Study, and 
Site Discontinuation............................................................. 101
4.6.1
Patient Discontinuation........................................................ 101
4.6.2
Study Treatment Discontinuation......................................... 101
4.6.3
Study and Site Discontinuation............................................ 103
5.
ASSESSMENT OF SAFETY..................................................................... 104
5.1
Safety Plan .......................................................................... 104
5.1.1
Risks Associated with Atezolizumab ................................... 105
5.1.2
Risks Associated with Carboplatin....................................... 105
5.1.3
Risks Associated with Paclitaxel.......................................... 105
5.1.4
Risks Associated with nab-Paclitaxel .................................. 105
5.1.5
Risks Associated with Erlotinib............................................ 106
5.1.6
General Plan to Manage Safety Concerns .......................... 106
5.1.6.1
Monitoring............................................................................ 106
5.1.7
Dose Modification................................................................ 107
5.1.7.1
General Notes Regarding Dose Modification....................... 107
5.1.7.2
Atezolizumab Dose Modification.......................................... 107
5.1.8
Management of Atezolizumab-Specific Adverse 
Events.................................................................................. 108
5.1.9
Carboplatin and Paclitaxel Dose Modification and 
Management of Specific Adverse Events ............................ 109
5.1.9.1
Hematologic Toxicity ........................................................... 109
5.1.9.2
Gastrointestinal Toxicity....................................................... 111
5.1.9.3
Hepatic Toxicity (Paclitaxel Only) ........................................ 111
5.1.9.4
Cardiovascular Toxicity (Paclitaxel Only)............................. 112
5.1.9.5
Neurologic Toxicity (Paclitaxel Only) ................................... 113
5.1.9.6
Allergic Reaction/Hypersensitivity (Paclitaxel 
Only).................................................................................... 113
5.1.9.7
Other Toxicities.................................................................... 113


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5.1.10
Carboplatin and nab-Paclitaxel Dose Modification 
and Management of Specific Adverse Events ..................... 114
5.1.10.1
Hematologic Toxicity ........................................................... 114
5.1.10.2
Gastrointestinal Toxicity....................................................... 115
5.1.10.3
Neurological Toxicity ........................................................... 116
5.1.10.4
Hepatic Toxicity (nab-Paclitaxel Only) ................................. 117
5.1.10.5
Pulmonary Events and Pneumonitis:  
Atezolizumab with nab-Paclitaxel, or 
nab-Paclitaxel with or without Atezolizumab........................ 117
5.1.10.6
Other Toxicities.................................................................... 119
5.1.11
Erlotinib Dose Modification and Management of 
Specific Adverse Events...................................................... 120
5.1.12
Potential Overlapping Toxicities .......................................... 120
5.2
Safety Parameters and Definitions ...................................... 121
5.2.1
Adverse Events ................................................................... 121
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 121
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 122
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 123
5.3.1
Adverse Event Reporting Period ......................................... 123
5.3.2
Eliciting Adverse Event Information..................................... 124
5.3.3
Assessment of Severity of Adverse Events ......................... 124
5.3.4
Assessment of Causality of Adverse Events ....................... 125
5.3.5
Procedures for Recording Adverse Events.......................... 125
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 125
5.3.5.2
Adverse Events That are Secondary to Other 
Events.................................................................................. 126
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 126
5.3.5.4
Abnormal Laboratory Values ............................................... 126
5.3.5.5
Abnormal Vital Sign Values ................................................. 127
5.3.5.6
Abnormal Liver Function Tests............................................ 128
5.3.5.7
Deaths ................................................................................. 128
5.3.5.8
Preexisting Medical Conditions............................................ 129


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5.3.5.9
Worsening of NSCLC .......................................................... 129
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 129
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 130
5.3.5.12
Patient-Reported Outcome Data ......................................... 130
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 130
5.4.1
Emergency Medical Contacts.............................................. 131
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 131
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 131
5.4.2.2
Events That Occur after Study Drug Initiation...................... 131
5.4.3
Reporting Requirements for Pregnancies............................ 132
5.4.3.1
Pregnancies in Female Patients.......................................... 132
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 132
5.4.3.3
Abortions ............................................................................. 133
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 133
5.5
Follow-Up of Patients after Adverse Events ........................ 133
5.5.1
Investigator Follow-Up......................................................... 133
5.5.2
Sponsor Follow-Up .............................................................. 134
5.6
Adverse Events That Occur After The Adverse 
Event Reporting Period........................................................ 134
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 134
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 135
6.1
Determination of Sample Size ............................................. 135
6.2
Summaries of Conduct of Study.......................................... 138
6.3
Summaries of Treatment Group Comparability ................... 138
6.4
Efficacy Analyses ................................................................ 138
6.4.1
Co-Primary Efficacy Endpoints............................................ 138
6.4.2
Secondary Efficacy Endpoints............................................. 141
6.4.2.1
Progression-Free Survival and Overall Survival in 
Secondary Populations........................................................ 141
6.4.2.2
Objective Response Rate.................................................... 141


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6.4.2.3
Duration of Response.......................................................... 141
6.4.2.4
Overall Survival Rate at Landmark Timepoints.................... 142
6.4.2.5
Patient-Reported Outcomes ................................................ 142
6.4.3
Handling of Missing Data..................................................... 142
6.5
Safety Analyses................................................................... 143
6.6
Pharmacokinetic Analyses................................................... 144
6.7
Exploratory Analyses........................................................... 144
6.7.1
Exploratory Analyses of Progression-Free 
Survival................................................................................ 144
6.7.1.1
Progression-Free Survival Rate at Landmark 
Timepoints........................................................................... 144
6.7.1.2
NonProtocol-Specified Anti-Cancer Therapy..................... 144
6.7.1.3
Subgroup Analysis............................................................... 144
6.7.1.4
Sensitivity Analyses............................................................. 145
6.7.2
Exploratory Analyses of Overall Survival............................. 145
6.7.2.1
Loss to Follow-Up................................................................ 145
6.7.2.2
Subgroup Analysis............................................................... 145
6.7.2.3
Overall Survival Rate at Three-Year Landmark................... 145
6.7.2.4
Milestone Overall Survival Analysis..................................... 145
6.7.3
Exploratory Biomarker Analysis........................................... 146
6.7.4
EQ-5D-3L Health Status Data ............................................. 146
6.7.5
Patient-Reported Outcome Analyses .................................. 146
6.8
Interim Analyses .................................................................. 146
6.8.1
Planned Interim Analysis ..................................................... 146
6.8.2
Optional Interim Analysis..................................................... 148
7.
DATA COLLECTION AND MANAGEMENT ............................................. 149
7.1
Data Quality Assurance....................................................... 149
7.2
Electronic Case Report Forms............................................. 149
7.3
Electronic Patient-Reported Outcome Data......................... 149
7.4
Source Data Documentation................................................ 150
7.5
Use of Computerized Systems ............................................ 150
7.6
Retention of Records........................................................... 151
8.
ETHICAL CONSIDERATIONS.................................................................. 151


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8.1
Compliance with Laws and Regulations .............................. 151
8.2
Informed Consent................................................................ 151
8.3
Institutional Review Board or Ethics Committee.................. 153
8.4
Confidentiality...................................................................... 153
8.5
Financial Disclosure ............................................................ 153
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 154
9.1
Study Documentation .......................................................... 154
9.2
Protocol Deviations.............................................................. 154
9.3
Site Inspections ................................................................... 154
9.4
Administrative Structure....................................................... 154
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 154
9.6
Protocol Amendments ......................................................... 155
10. REFERENCES ......................................................................................... 156


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LIST OF TABLES
Table 1
Randomized Phase III Studies in Patients with Previously 
Untreated NSCLC....................................................................... 35
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades................................................................ 41
Table 3
Study GO28753 (POPLAR):  Adverse Events Reported in at 
Least 10% of Patients................................................................. 43
Table 4
Adverse Events in Study GO28915 (OAK) with a Between-
Arm Difference in Frequency of at Least 5 Percentage Points.... 44
Table 5
Study GP28328:  All Reported Adverse Events.......................... 45
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 (per RECIST, 
Version 1.1)................................................................................. 47
Table 7
Efficacy Results in Study GO28753 (POPLAR):  
Intent-to-Treat Population ........................................................... 48
Table 8
Study GO28753 (POPLAR) Efficacy Results by Combination 
PD-L1 Diagnostic Subgroup with Complementary 
Comparison Subgroupings:  Intent-to-Treat Population.............. 49
Table 9
Treatment Arms in Study GO29437............................................ 57
Table 10
Suggested Premedication for Induction Treatment for Arm A..... 76
Table 11
Treatment Regimen and Order of Administration for 
All Treatment Arms ..................................................................... 77
Table 12
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 78
Table 13
Vital Sign Measurements at Cycle 1 and All Subsequent 
Cycles ......................................................................................... 86
Table 14
Dosing Based on ANC and Febrile Neutropenia—Paclitaxel 
and Carboplatin......................................................................... 109
Table 15
Dosing Based on Nadir Platelet Count—Paclitaxel and 
Carboplatin................................................................................ 110
Table 16
Carboplatin and Paclitaxel Dose Modification Based on 
Gastrointestinal Toxicities in the Preceding Cycle .................... 111
Table 17
Dose Modifications for Paclitaxel for Hepatic Toxicity............... 112
Table 18
Paclitaxel Dose Modification for Neurologic Toxicity................. 113
Table 19
nab-Paclitaxel and Carboplatin Permanent Dose Reductions 
Based on Nadir Absolute Neutrophil Count and Platelets......... 115
Table 20
Carboplatin and nab-Paclitaxel Dose Modification Based on 
Gastrointestinal Toxicities in the Preceding Cycle .................... 116
Table 21
nab-Paclitaxel and Carboplatin Permanent Dose Reductions 
for Neurological Toxicity............................................................ 117
Table 22
Management Guidelines for Pneumonitis:  Atezolizumab with 
nab-Paclitaxel, or nab-Paclitaxel with or without 
Atezolizumab ............................................................................ 119


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Table 23
nab-Paclitaxel and Carboplatin Permanent Dose Reductions 
for Non-Hematologic, Non-Gastrointestinal, Non-Neurologic, 
and Non-Hepatic Toxicity.......................................................... 120
Table 24
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 124
Table 25
Analysis Timing and Stopping Boundaries for Overall 
Survival in the ITT Population for Arm B vs Arm C 
Comparison............................................................................... 147
Table 26
Analysis Timing and Stopping Boundaries for Overall 
Survival in the ITT Population:  Arm A vs. Arm C...................... 148
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 59
Figure 2
Criteria for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size (Atezolizumab Arms)....... 103
Figure 3
Progression-Free Survival and Overall Survival Analysis 
Hierarchy, Allocation, and Recycling .................................. 136
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 164
Appendix 2
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Therapeutic Antibody Assessments............................ 171
Appendix 3
American Joint Committee on Cancer  NonSmall Cell Lung 
Cancer Staging, 7th Edition ...................................................... 174
Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication ............................... 176
Appendix 5
Modified Response Evaluation Criteria in Solid Tumors ........... 187
Appendix 6
AntiPD-L1 Immunohistochemistry........................................... 194
Appendix 7
EORTC QLQ-C30..................................................................... 195
Appendix 8
EORTC QLQ-LC13................................................................... 197
Appendix 9
EQ-5D-3L.................................................................................. 198
Appendix 10
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 201
Appendix 11
Anaphylaxis Precautions........................................................... 202
Appendix 12
Preexisting Autoimmune Diseases ........................................... 203
Appendix 13
Symptoms in Lung Cancer........................................................ 204
Appendix 14
Patient Global Impression of Severity....................................... 207
Appendix 15
Additional Guidance on Chemotherapy Administration............. 208


Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol GO29437, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY EVALUATING THE EFFICACY
AND SAFETY OF ATEZOLIZUMAB (MPDL3280A, 
ANTIPD-L1 ANTIBODY) IN COMBINATION WITH
CARBOPLATIN PACLITAXEL OR ATEZOLIZUMAB IN 
COMBINATION WITH 
CARBOPLATIN NAB-PACLITAXEL VERSUS 
CARBOPLATIN NAB-PACLITAXEL IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV 
SQUAMOUS NONSMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29437
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003208-59
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, 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 its designee.


Atezolizumab—F. Hoffmann-La Roche Ltd
15/Protocol GO29437, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATIN PACLITAXEL OR 
ATEZOLIZUMAB IN COMBINATION WITH 
CARBOPLATIN NAB-PACLITAXEL VERSUS 
CARBOPLATIN NAB-PACLITAXEL IN CHEMOTHERAPY-NAIVE 
PATIENTS WITH STAGE IV SQUAMOUS NONSMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29437
VERSION NUMBER:
7
EUDRACT NUMBER:
2014-003208-59
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
PHASE:
III
INDICATION:
Squamous nonsmall cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Unless otherwise specified, efficacy objectives will be analyzed for the following two treatment 
comparisons:

Atezolizumabcarboplatinnab-paclitaxel (Arm B) versus
carboplatinnabpaclitaxel (Arm C)

Atezolizumabcarboplatinpaclitaxel (Arm A) versus
carboplatinnabpaclitaxel (Arm C)
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 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 population and the intent-to-treat (ITT) population

To evaluate the efficacy of atezolizumab as measured by overall survival (OS) in the ITT 
population


Atezolizumab—F. Hoffmann-La Roche Ltd
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The secondary efficacy objectives for this study are the following:

To evaluate the efficacy of atezolizumab as measured by OS in the tGE 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 population and the TC1/2/3 or 
IC1/2/3 population 

To evaluate the efficacy of atezolizumab as measured by investigator-assessed objective 
response rate (ORR) according to RECIST v1.1 in the tGE population and the ITT
population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response (DOR) according to RECIST v1.1 in the tGE population and the ITT population

To evaluate the OS rate at 1 and 2 years in each treatment arm for the tGE population and 
the ITT population n

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 population 
and the ITT 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 population and the ITT population

To evaluate the efficacy of the treatment regimen of atezolizumabcarboplatinpaclitaxel 
versus atezolizumabcarboplatinnab-paclitaxel as measured by investigator-assessed 
PFS according to RECIST v1.1 and OS in the tGE population and the ITT population
Safety Objectives
The safety objectives for this study are the following:

To evaluate the safety and tolerability of atezolizumab in each of the two treatment 
comparisons

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 paclitaxel (Arm A) or with carboplatin nab-paclitaxel (Arm B)

To characterize the pharmacokinetics of carboplatin when given in combination with 
paclitaxel and atezolizumab (Arm A) or with nab-paclitaxel with and without atezolizumab 
(Arms B and C)

To characterize the pharmacokinetics of paclitaxel when given in combination with 
atezolizumab and carboplatin (Arm A)

To characterize the pharmacokinetics of nab-paclitaxel (reported as total paclitaxel) when 
given in combination with carboplatin with and without atezolizumab (Arms B and C)
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


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#
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 cancerrelated symptoms, and 
functioning as assessed by the EORTC QLQ-C30 and LC13
Study Design
Description of Study
This is a randomized, Phase III, multicenter, open-label study (IMpower131) designed to 
evaluate the safety and efficacy of atezolizumab in combination with carboplatin ∀paclitaxel or 
with carboplatin ∀nab-paclitaxel compared with treatment with carboplatin ∀nab-paclitaxel in 
approximately 1025 chemotherapy-naive patients with Stage IV 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 1:1:1 ratio to receive one of the following 
treatment regimens.
Treatment Arm A:  Atezolizumab∀carboplatin∀paclitaxel (Induction: four or six 21-day 
cycles); atezolizumab (Maintenance: 21-day cycle)
Treatment Arm B:  Atezolizumab∀carboplatin∀nab-paclitaxel (Induction: four or six 21-day 
cycles); atezolizumab (Maintenance: 21-day cycle)
Treatment Arm C:  Carboplatin∀nab-paclitaxel (Induction: four or six 21-day cycles); best 
supportive care (Maintenance: 21-day cycle)
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 C) or loss of clinical benefit 
(Arms A and B) is documented. 
Following the induction phase, patients randomized to atezolizumab (Arms A and B) may 
continue treatment with atezolizumab beyond radiographic disease progression by 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 C) will be offered best supportive care provided they have non-progressive disease.
Treatment with chemotherapy must be discontinued in all patients who exhibit evidence of 
progressive disease by RECIST v1.1.
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 48 weeks 
following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, tumor assessments will be 
required every 9 weeks.  Patients will undergo tumor assessments until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who 
continue treatment with atezolizumab after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever occurs 


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first.  Patients who discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled 
tumor assessments until radiographic disease progression per RECIST v1.1 (or loss of clinical 
benefit for atezolizumab-treated patients who had continued treatment with atezolizumab after 
radiographic disease progression according to RECIST v1.1), withdrawal of consent, 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.
For Treatment Arms A and B only:
During treatment (induction or maintenance), patients who show evidence of clinical benefit will 
be permitted to continue atezolizumab after RECIST v1.1 for progressive disease are met if 
they meet all of the following criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values, [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in 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 study treatment atezolizumab at the time of initial progression
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 time 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 Arms A and B who are unable 
to undergo biopsy sample collection but who otherwise meet the criteria listed above may 
continue to receive atezolizumab.
Number of Patients
Approximately 310 sites globally will participate in the study and approximately 1025 patients 
will be randomized.
Target Population
Inclusion Criteria
Patients may be eligible if they have chemotherapy-naive, Stage IV, squamous NSCLC.
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 squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 
7th edition).
Patients with tumors of mixed histology (squamous and non-squamous) are eligible if 
the major histological component appears to be squamous.


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19/Protocol GO29437, Version 7

No prior treatment for Stage IV squamous NSCLC
Patients known to have 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 with unknown EGFR
mutation status do not require testing.
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 (i.e. crizotinib) appropriate for the treatment of NSCLC in patients having 
an ALK fusion oncogene.  Patients with unknown ALK mutation status do not require 
testing.

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.

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.

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 GO29437, 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, for 30 days after the last dose of nab-paclitaxel, or for 6 months after 
the last dose of 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, paclitaxel, and/or 
carboplatin.  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.  Men must refrain from 
donating sperm during the study and for 6 months after the last dose of nab-paclitaxel, 
paclitaxel, and/or carboplatin, whichever is latest.

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 trial 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 CT or magnetic resonance imaging 
(MRI) evaluation during screening and prior radiographic assessments

Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for 2 weeks prior to randomization

Leptomeningeal disease


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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 I 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 (BSA)
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)


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
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 positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative 
for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within 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 
render the patient at high risk from treatment complications

Patients with illnesses or conditions that interfere with their capacity to understand, follow 
and/or comply with study procedures
Exclusion Criteria Related to Medications

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.


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
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] 
Grade 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 paclitaxel or nab-paclitaxel

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria (paclitaxel and 
nab-paclitaxel)

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 240 PFS events have occurred in Arms B and C combined in the tGE population, 
approximately 499 PFS events have occurred in Arms B and C combined in the ITT population, 
and the last patient has been enrolled in the study.  The final PFS analysis is expected to occur 
approximately 30 months after the first patient is enrolled. 
With a sample size of 684 patients, approximately 477 OS events are expected to occur in Arms 
B and C combined in the ITT population for the final OS analysis.  The final OS analysis is 
expected to occur approximately 39 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 the following:

PFS, defined as the time from randomization to the first occurrence of the disease
progression as determined by the investigator using RECIST v1.1 or death from any cause, 
whichever occurs first in the tGE population and ITT population

OS, defined as the time from randomization to death from any cause in the ITT population
The secondary efficacy outcome measures for this study are the following:

OS in the tGE population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the TC2/3 or 
IC2/3 population and the TC1/2/3 or IC1/2/3 population

Objective response, defined as partial response (PR) or complete response (CR) as 
determined by the investigator according to RECIST v1.1 in the tGE population and ITT 
population

DOR, defined as the time interval from the 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 in the tGE population and 
ITT population

OS rates at 1 and 2 years for the tGE population and ITT 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 population and ITT population

Change from baseline in patient-reported lung cancer symptoms (cough, dyspnea, and 
chest pain) on the symptom severity score of the SILC scale in the tGE population and ITT 
population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the two 
atezolizumab-containing arms in the tGE population and the ITT 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 
study treatment 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:

Maximum observed serum atezolizumab concentration (Cmax) after infusion (Arms A and B)

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 (Arms A and B)

Plasma concentrations for carboplatin (Arms A, B, and C)

Plasma concentrations for paclitaxel (Arm A)

Plasma concentrations for nab-paclitaxel (Arms B and C)


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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 tumor-infiltrating immune cells 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 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 to patients who 
are randomized to Arms A and B.
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients who had 
already started switch maintenance treatment with erlotinib under previous protocol versions 
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 
investigational medicinal product (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curve (AUC) of 6 mg/mL/min on Day 1 of each 21-day cycle for four or 
six cycles during the induction phase

Paclitaxel (200 mg/m2 IV) will be administered on Day 1 of each 21-day cycle for four or 
six cycles during the induction phase.
Carboplatin and paclitaxel will be administered to patients randomized to Arm A.  Carboplatin 
and nab-paclitaxel will be administered to patients in Arms B and C.  
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 population and the ITT population.  OS will be 
analyzed in the ITT population. Treatment comparisons will be conducted sequentially by first 
comparing Arm B versus Arm C and then comparing Arm A versus Arm C.  For each 
comparison, 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. 
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 died at the time of analysis will be censored at the time of the last tumor 


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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 endpoints described above and for 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 each comparison (i.e., Arm B vs. Arm C, Arm A vs. Arm C) will 
be estimated using a stratified Cox regression model, respectively.  The 95% CI for the HR will 
be provided.
The hypothesis testing will be done in the order described below: 
Comparison of Arm B versus Arm C
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 the 
comparison of Arm B versus Arm C.
1. PFS in the tGE 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 population.
2. If the null hypothesis is rejected in the tGE population (Step 1), PFS in the ITT 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 PFS analysis in the ITT population (Step 2), OS 
in the ITT population will be tested at 0.022 (one sided).
b.
If the null hypothesis is rejected for PFS analysis in the ITT population (Step 2), OS in 
the ITT population will be tested at 0.025 (one sided).
Comparison of Arm A versus Arm C
If the difference in OS between Arm B and Arm C in the ITT population is statistically significant 
at an of 0.022 or 0.025 (Step 3), that same will become the overall one-sided type I error 
rate for the comparison of Arm A versus Arm C, with allocated to PFS and OS at the same 
3:22 ratio (see Figure 3 in Section 6.1).  If the difference in OS between Arm B and Arm C in the 
ITT population is not statistically significant, there will be no formal comparison of Arm A versus 
Arm C for the co-primary endpoints of PFS and OS.
1. If the difference in OS between Arm B and Arm C is statistically significant at 0.022 (one 
sided):
a. PFS in the tGE population will be tested at 0.00264 (one sided).  If the estimate of 
the HR is 1 and the one-sided p-value corresponding to the stratified log-rank test is 
0.00264, the null hypothesis will be rejected and it will be concluded that 
atezolizumab carboplatin paclitaxel prolongs the duration of PFS relative to control 
treatment in the tGE population.
b. If the null hypothesis is rejected in the tGE population (Step 1a), PFS in the ITT 
population will be tested at 0.00264 (one sided).
c. recycling from PFS to OS will be conducted as follows:

If the null hypothesis is not rejected in the ITT population (Step 1b), OS in the ITT 
population will be tested at 0.01936 (one sided).

If the null hypothesis is rejected in the ITT population (Step 1b), OS in the ITT 
population will be tested at 0.022 (one sided).  


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2. If the difference in OS between Arm B and Arm C is statistically significant at 0.025 (one 
sided):
a. PFS in the tGE 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 paclitaxel prolongs the duration of PFS relative to control 
treatment in the tGE population.
b. If the null hypothesis is rejected in the tGE population (Step 2a), PFS in the ITT 
population will be tested at 0.003 (one sided).
c. recycling from PFS to OS will be conducted as follows:

If the null hypothesis is not rejected in the ITT population (Step 2b), OS in the ITT 
population will be tested at 0.022 (one sided).

If the null hypothesis is rejected in the ITT population (Step 2b), OS in the ITT 
population will be tested at 0.025 (one sided).   
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 interactive 
voice/Web response system.
Results from an unstratified analysis will also be presented.  Kaplan-Meier methodology will be 
used to estimate median PFS and 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.
Determination of Sample Size
This study will randomize approximately 1025 patients, including approximately 513 patients in 
the tGE population, 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) for the comparison of Arm B 
versus Arm C.
The estimate of the number of events required to demonstrate efficacy with regard to PFS in the 
comparison of Arm B versus Arm C is based on the following assumptions:

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in the tGE 
population

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in the 
ITT population

97% 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 population

98% 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 population

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 B versus Arm C is based on the following assumptions:

One-sided significance level of 0.022 for the comparison of Arm B versus Arm C in the 
ITT population

86% power to detect an HR of 0.75, corresponding to an improvement in median OS from 
12 months to 16 months in the ITT population


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
One interim OS analysis performed at the time of the final PFS analysis, at which time 
approximately 76% 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 1025 patients in total will be enrolled into this study, 
with approximately 684 patients in each comparison (i.e., Arm B vs. Arm C, Arm A vs. Arm C).  
The final PFS analysis will be conducted when all of the following criteria have been met:  
approximately 240 PFS events have occurred in Arms B and C combined in the tGE population, 
approximately 499 PFS events have occurred in Arms B and C combined in the ITT population, 
and the last patient has been enrolled in the study.  The final PFS analysis is expected to occur 
approximately 30 months after the first patient is enrolled.  These numbers of events would 
allow for a minimum detectable difference corresponding to an HR of approximately 0.70 in the 
tGE population and approximately 0.75 in the ITT population.
With a sample size of 684 patients, approximately 477 OS events are expected to occur in Arms 
B and C combined in the ITT population for the final OS analysis.  The final OS analysis is 
expected to occur approximately 39 months after the first patient is enrolled.
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 (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 Institutional Review Boards (IRBs)/Ethics Committees (ECs).  
A detailed plan will be included in the iDMC Charter.
If approximately 365 OS events have occurred in Arms B and C combined in the ITT population 
at the time of the final PFS analysis (see criteria for final PFS analysis in Section 6.1), an interim 
OS analysis will be conducted for Arm B versus Arm C in the ITT population.  If there are 
significantly fewer than the expected 365 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 final PFS analysis and a second interim OS analysis will then be conducted after 
approximately 365 OS events have occurred.
The final OS analysis for the comparison of Arm B versus Arm C will be conducted when 
approximately 447 OS events have occurred in Arms B and C combined in the ITT population.  
This is expected to occur approximately 39 months after the first patient is enrolled.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
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
Euro QoL5 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
IC
tumor-infiltrating immune cell
ICH
International Council for Harmonisation


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Abbreviation
Definition
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 web/voice response system
LFT
liver function test
MP
Medicinal Product
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
NIMP
Non-Investigational Medicinal Product
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
SAP
Statistical Analysis Plan
SILC
Symptoms in Lung Cancer


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Abbreviation
Definition
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
TTF-1
thyroid transcription factor1
TTP
time to progression
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
Vss
volume of distribution at steady state


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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. 2014).  
NSCLC can be divided into two major histologic types:  adenocarcinoma and squamous 
cell carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for more than 
half of all NSCLC, while squamous cell histology accounts for approximately 25% 
(Langer et al. 2010).  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 


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10%40% of patients with adenocarcinoma NSCLC but are infrequently observed in 
squamous NSCLC (Herbst et al. 2008).  Similarly, the ALK fusion oncogene, recognized 
as a driver of lung tumorigenesis, is observed in approximately 7% of patients with 
adenocarcinoma but is very rare in the squamous histology (Herbst et al. 2008; Langer 
et al. 2010).  In addition, KRAS mutations are very rare in squamous NSCLC, while they 
can be observed in up to 30% of cases of adenocarcinoma NSCLC (Travis et al. 2011).
1.1.1
First-Line Treatment for Advanced NonSmall Cell Lung 
Cancer with an EGFR Mutation or ALK Rearrangement
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC characterized by alterations of 
driver oncogenes, including sensitizing EGFR mutations and ALK rearrangements.  
However, these mutations are more prevalent in adenocarcinoma NSCLC and are very 
rare in squamous NSCLC.  Randomized Phase III studies of gefitinib (IPASS), erlotinib 
(EURTAC), and afatinib (LUX-Lung3) showed significant improvement of 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 (XALKORI®) 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 [USPI]).  
Both EGFR tyrosine kinase inhibitors (TKIs) and crizotinib have been shown to be 
generally well tolerated.  
1.1.2
First-Line Treatment for 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 versus 5.7 months; hazard ratio [HR]0.77, 
95% CI: 0.66, 0.89). 
Recently, immune checkpoint inhibitors, including PD-L1/PD-1 blocking antibodies, have 
emerged as a new therapeutic option for first-line treatment of metastatic NSCLC.  Study 
KEYNOTE-024 was a Phase III, randomized, open-label study evaluating 
pembrolizumab given as monotherapy compared with platinum-based chemotherapy in 
patients who had previously untreated advanced NSCLC with PD-L1 expression on at 


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least 50% of tumor cells.  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
Platinum-Based Regimens for First-Line NSCLC
The globally recognized standard of care for patients with inoperable Stage IIIB and 
Stage IV NSCLC is platinum-based chemotherapy for 46 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 Maininis et al. 2011; National Comprehensive Cancer Network [NCCN] 2014).  
Agents that have been partnered with either cisplatin or carboplatin include the 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.
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; see Table 1).


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Table 1
Randomized Phase III Studies 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
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


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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
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
HRhazard ratio; NRnot reported; ORRobjective response rate; OSoverall survival; 
PFSprogression-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.
Several meta-analyses have compared the use of cisplatin and carboplatin as 
treatments for NSCLC.  In general, although the objective response rate was higher in 
patients treated with cisplatin than in those treated with carboplatin, the 1-year 
and overall survival rates were comparable.  When given in combination with a 
third-generation chemotherapy, cisplatin may result in longer survival than carboplatin 
(OR 30% vs. 24%, respectively; Hotta et al. 2004; Ardizzoni et al. 2007), but overall 
benefit was quite marginal and subgroup analyses including additional, more recent 
studies indicate that there may be no difference between the two agents 
(Jiang et al. 2007, Azzoli et al. 2007).
With regard to safety, cisplatin-based chemotherapy was associated with more severe 
nausea and vomiting and nephrotoxicity, while severe thrombocytopenia was more 
frequent during carboplatin-based chemotherapy (Hotta et al. 2004; 
Ardizzoni et al. 2007).  The risk of treatment-related deaths was greater in the cisplatin 
arm, but this increase was not statistically significant (Jiang et al. 2007).  
Data from a large randomized Phase III study demonstrated that patients with squamous 
NSCLC had inferior PFS and OS with the combination of pemetrexed∀cisplatin 
compared with gemcitabine∀cisplatin, as evidenced by the hazard ratios (HRs) for both 
endpoints (PFS: HR−1.36, p−0.002; OS: HR−1.23, p−0.05) (Scagliotti et al. 2008).  
The median duration of PFS was 4.4 months in those who received 
cisplatin∀pemetrexed versus 5.5 months in the cisplatin∀gemcitabine–treated patients.  
OS in the cisplatin∀pemetrexed group was 9.4 months versus 10.8 months in the 
cisplatin∀gemcitabine group.  In addition, maintenance therapy with pemetrexed 


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produced no improvement in PFS or OS when compared with placebo in patients with 
advanced NSCLC who achieved stable disease after 4 cycles of platinum-based doublet 
therapy (Ciuleanu et al. 2009).  One possible explanation for the differential benefit 
between squamous and non-squamous NSCLC with pemetrexed is the difference in the 
protein level of thymidylate synthase (TS), the primary target of pemetrexed.  Squamous 
NSCLC tumors have higher TS levels, which may account for the decreased response to 
pemetrexed (Ceppi et al. 2006).
Few studies have prospectively evaluated gemcitabine versus paclitaxel in patients with 
squamous NSCLC.  While both agents have activity in NSCLC (Treat et al. 2010), a 
retrospective analysis of data generated from a large randomized Phase III clinical study 
revealed significantly different efficacy results by tumor histology (Treat et al. 2010).  In 
this analysis, efficacy results were similar across three treatment regimens in patients 
with non-squamous NSCLC.  However, patients with squamous NSCLC who received 
paclitaxelcarboplatin (n61) had a median survival of 10.3 months (95% CI: 8.7, 12.0) 
compared with 6.6 months (95% CI: 5.1, 9.5) in patients who received 
gemcitabinecarboplatin (n67); the adjusted HR was 0.73 (95% CI: 0.50, 1.07), and 
the histology-by-treatment interaction p-value was 0.04.  Additionally, the overall 
response rate (45.9% vs. 25.4%) and median time to progression (5.7 months vs. 
4.3 months) was higher in patients who received paclitaxelcarboplatin versus 
gemcitabinecarboplatin.  From a safety perspective, the combination of gemcitabine 
and carboplatin was associated with significantly more Grade 34 hematologic toxicity 
but less sensory neuropathy than the paclitaxelcarboplatin combination.  In summary, 
the data from this analysis suggests that the combination of paclitaxelcarboplatin has a 
more favorable benefit–risk profile compared with gemcitabinecarboplatin in patients 
with squamous NSCLC.
A potential explanation for the difference in efficacy results by treatment regimen in 
patients with squamous NSCLC in this study may be related to RRM1 expression, which 
has been shown in both tumor cell lines and in clinical NSCLC samples to correlate with 
resistance to gemcitabine (Gong et al. 2012; Rosell et al. 2004; Bepler et al. 2004; 
Ceppi et al. 2006).  RRM1 mRNA expression levels have been shown to differ by tumor 
histology.  An evaluation of tissue specimens for RRM1 from 1104 patients with NSCLC 
(n678 adenocarcinoma, n426 squamous NSCLC) suggests that the great majority of 
patients with squamous NSCLC (87%) have high RRM1 mRNA expression and, 
subsequently, may derive little benefit from gemcitabine-containing chemotherapy 
(Gandara et al. 2010).
1.1.4
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 


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secondary endpoints of progression-free survival (PFS) and overall survival (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. 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 [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.  
1.1.5
Erlotinib Maintenance Therapy for Squamous 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 6 cycles.  
The guidelines also recommend stopping first-line cytotoxic chemotherapy at disease 
progression.  At study start, switch maintenance treatment with erlotinib in unselected 
patients 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 the sequential Tarceva unresectable NSCLC study (SATURN), which had
shown a PFS and OS benefit after the initiation of erlotinib after induction treatment in 
patients with non-progressive disease.  The median PFS in patients receiving 
maintenance therapy with erlotinib was statistically 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).  This 
Phase III study resulted in regulatory approval (U.S. Food and Drug Administration [FDA] 
and European Medicines Agency) for erlotinib as maintenance therapy of patients with 
locally advanced or metastatic NSCLC whose disease has not progressed after 4 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 


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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 randomized to receive maintenance erlotinib followed by chemotherapy or BSC 
upon disease progression compared with patients 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 (MPDL3280A)
Atezolizumab (MPDL3280A) 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.
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.


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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 that are summarized below include data from the following studies:

Study PCD4989g:  A Phase Ia, multicenter, first-in-human, open-label, 
dose-escalation study evaluating the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of 
biologic activity of atezolizumab administered as a single agent by IV infusion every 
3 weeks (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

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.


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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, melanoma, and renal cell carcinoma.  Safety data for NSCLC 
are also derived from Studies GO28625 (FIR), GO28915 (OAK), and GO28753 
(POPLAR).
Adverse Events
Of the 558 patients, 520 (93.2%) patients 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).  
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades
Adverse Event
All Grades
n (%)
All Grades 
Related
n (%)
Grade 34
n (%)
Grade 34 
Related
n (%)
Any adverse event
520 (93.2)
376 (67.4)
239 (42.8)
66 (11.8)
Fatigue
192 (34.4)
115 (20.6)
13 (2.3)
6 (1.1)
Decreased appetite
142 (25.4)
62 (11.1)
4 (0.7)
0 (0.0)
Nausea
136 (24.4)
65 (11.6)
5 (0.9)
2 (0.4)
Pyrexia
117 (21.0)
63 (11.3)
2 (0.4)
0 (0.0)
Constipation
116 (20.8)
8 (1.4)
2 (0.4)
0 (0.0)
Cough
113 (20.3)
11 (2.0)
1 (0.2)
1 (0.2)
Dyspnea
112 (20.1)
18 (3.2)
18 (3.2)
4 (0.7)
Diarrhea
110 (19.7)
53 (9.5)
2 (0.4)
1 (0.2)
Anemia
104 (18.6)
26 (4.7)
23 (4.1)
5 (0.9)
Vomiting
96 (17.2)
28 (5.0)
3 (0.5)
2 (0.4)
Asthenia
88 (15.8)
53 (9.5)
8 (1.4)
4 (0.7)
Back pain
85 (15.2)
9 (1.6)
8 (1.4)
1 (0.2)
Headache
83 (14.9)
32 (5.7)
2 (0.4)
1 (0.2)
Arthralgia
79 (14.2)
35 (6.3)
2 (0.4)
0 (0.0)
Pruritus
75 (13.4)
55 (9.9)
0 (0.0)
0 (0.0)
Rash
73 (13.1)
53 (9.5)
0 (0.0)
0 (0.0)
Abdominal pain
63 (11.3)
12 (2.2)
8 (1.4)
0 (0.0)
Insomnia
62 (11.1)
7 (1.3)
1 (0.2)
0 (0.0)
Peripheral edema
59 (10.6)
7 (1.3)


Chills
57 (10.2)
31 (5.6)
0 (0.0)
0 (0.0)
Note:  “” refers to missing Common Terminology Criteria grade.


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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 (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.
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 5.1.7.2. 
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 Study GO28753 (POPLAR) 
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 the 
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 at 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 an arm difference 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 in Arm A (atezolizumabbevacizumab), 36 in Arm B 
(atezolizumabbevacizumab and FOLFOX), 14 in Arm C (atezolizumabcarboplatin
and paclitaxel), 24 in Arm D (atezolizumabcarboplatin and pemetrexed), 20 in Arm E 
(atezolizumabcarboplatin and nab-paclitaxel), and 11 in Arm F (atezolizumabnab
paclitaxel).  The treatment combinations have been generally well tolerated.  No DLTs 
have been reported during the dose-escalation stage in any study arm.  Patients are 
being enrolled in safety and biopsy expansion cohorts in Arms A and B as well as in 
additional arms testing atezolizumab in combination with commonly used NSCLC 
chemotherapy doublets.  


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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 one or more adverse event.  The 
five most frequently reported events were consistent with the overall population and
included fatigue, nausea, diarrhea, decreased appetite, and pyrexia.  There were 
36 patients enrolled in Arm B, and 97% of patients reported at least one adverse event.  
The most frequently reported adverse events (20% of patients) included fatigue, 
pyrexia, peripheral neuropathy, neutropenia, anemia, diarrhea, decreased appetite, 
temperature intolerance, constipation, vomiting, and nausea.  
All patients who were enrolled in Arms C and D experienced an adverse event; 95% of 
patients who were enrolled in Arm E experienced an adverse event, and 83.3 % of 
patients enrolled in Arm F experienced an adverse event.  The adverse events 
commonly reported in 2 or more patients in Arms C, D, and E included anemia, 
decreased appetite, hypomagnesemia, nausea, neutropenia, constipation, vomiting, 
fatigue, rash, cough, and diarrhea.  Adverse events commonly reported in 2 or more 


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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)ased responses (i.e., RECIST, Version 1.1 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 additional details on clinical activity 
in all patients treated to date, regardless of tumor type.
1.3.3.1
Single-Agent Clinical Activity in Patients with NSCLC in 
Study PCD4989g
As of the clinical data cutoff of 2 December 2014, the efficacy evaluable population 
included 88 patients with locally advanced or metastatic NSCLC.  The median age was 
60.5 years (range 2484 years) and represented a heavily pre-treated patient population:  
97% of the patients had received 2 prior systemic therapies, and 77.3% had received 
4 prior systemic therapies.
Overall, responses were observed in 20 of 88 (22.7%) patients with NSCLC and 
included responses in patients with squamous and non-squamous NSCLC (4 in 
21 patients and 16 in 67 patients, respectively).  A total of 8 of the 20 responding 
patients have continued to respond at the time of the clinical data cutoff.
Table 6 displays the confirmed ORR, duration of confirmed 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 (IC) and tumor cells (TC) 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 additional details on 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 (per RECIST, Version 1.1)
PD-L1 IHC 
Expression 
Category
ORR by RECIST, 
Version 1.1
n 88
SD
(n/N)
PD
(n/N)
DOR (range 
in months)
6-month 
PFS 
% (95% CI)
TC3 or IC3
50.0% (11 of 22)
(95%CI: 28.22%, 
71.78%)
13.6%
(3/22)
31.8%
(7/22)
7.1625.26
50.0
(29.1, 70.9)
TC3 or IC2/3
37.5% (15 of 40)
(95% CI: 22.73%, 
54.2%)
12.5%
(5/40)
45.0%
(18/40)
7.1626.74+
44.9
(29.4, 60.3)
TC2/3 or IC2/3
33.3% (16 of 48)
(95%CI: 20.40%, 
48.41%)
22.9%
(11/48)
37.5%
(18/48)
7.1626.74+
41.6
(27.6, 55.5)
TC0/1/2 and 
IC0/1/2
15.5% (9 of 58)
(95%CI: 7.35%, 
27.42%)
37.9%
(22/58)
37.9%
(22/58)
7.1626.74+
41.1 
(28.4, 53.8)
TC0/1/2 and 
IC0/1
12.5% (5 of 40)
(95%CI: 4.19%, 
26.8%)
37.5%
(15/40)
40.0%
(16/40)
9.9224.74
42.3
(27, 57.7)
TC0/1 and IC0/1
12.5% (4 of 32)
(95% CI: 3.51%, 
28.99%)
43.8%
(14/32)
34.4%
(11/32)
9.9224.74
46.7
(29.3, 64.0)
DORduration of response; ICtumor-infiltrating immune cell; IHCimmunohistochemistry; 
NSCLCnonsmall cell lung cancer; ORRobjective response rate; PFSprogression-free 
survival; PRpartial response; SDstable disease; PD progressive disease; 
RECIST Response Evaluation Criteria in Solid Tumors; TCtumor cell.
Notes: This table is based on a data cutoff of 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 overall survival 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). 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 (see Table 7) (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 Subgroup 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.f
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 per RECIST v1.1.  Objective responses with atezolizumab were 
durable, with a median duration of 16.3 months (95% CI: 10.0 months, not estimable) in 
the atezolizumab arm compared with 6.2 months (95% CI: 4.9, 7.6 months) in the 
docetaxel arm (Rittmeyer et al. 2017).


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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 into Arms 
C, D, or E of the Phase Ib Study GP28328.  Patients who had received their first dose of 
atezolizumab by 10 November 2014 were evaluable for efficacy (n41).  Patients who 
were enrolled into Arms C, D, and E received 15 mg/kg atezolizumab administered Q3W
in combination with carboplatinpaclitaxel, carboplatinpemetrexed, and 
carboplatinnab-paclitaxel, respectively.  All patients had histologically or cytologically 
documented Stage IIIB, Stage IV or recurrent NSCLC and had not received prior 
chemotherapy for advanced disease.  The median age was 65 years, and 79% of 
patients had non-squamous histology.  The overall confirmed objective response rate 
per 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 
target trough concentration (Ctrough) was projected to be 6 mg/mL on the basis of several 


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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 
levels relative to the proposed 15-mg/kg atezolizumab Q3W level. 
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose or a dose adjusted for weight.  Therefore, a fixed dose 
of 1200 mg has been selected (equivalent to an average body weightbased dose 
of 15 mg/kg).  Selection of an every-21-day dosing interval is supported by this 
preliminary pharmacokinetics evaluation.
Refer to the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012).
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1. PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is sustained in 
states of chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008).  Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of 
T cells.  B7.1 is a molecule expressed on antigen-presenting cells and activated T cells.  
PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate 
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 tumor cells 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 GO29437 initiation, Study PCD4989g, a Phase Ia dose-escalation and 
expansion study of patients who were treated with atezolizumab as a single agent had 
the following clinical activity:  345 evaluable patients were dosed by 21 October 2013 
(data cutoff date as of 21 April 2014) with a minimum of 6 months of follow-up; 
62 patients experienced objective responses per RECIST v1.1 with an ORR of 18.0% 
(95% CI: 14.1%, 22.3%).  Objective responses were observed across a broad range of 
malignancies, including NSCLC, RCC, melanoma, and urothelial bladder cancer.  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/Paclitaxel or Carboplatin/nab-Paclitaxel
Platinum-based regimens remain the standard first-line option for patients with locally 
advanced or metastatic NSCLC that is not harboring EGFR mutations or ALK gene 
rearrangements.  However, the survival benefit conferred by cytotoxic chemotherapy has 
reached a plateau, with overall response rates of approximately 20% and 1-year survival 
ranging from 31% to 36% (Schiller et al. 2002), leaving considerable room for 
improvement in outcomes.  Tumor cell 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 ASCO 2014 (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 duration of response ranged from 24 weeks 
with nivolumab in combination with paclitaxelcarboplatin to 45 weeks with nivolumab in 
combination with gemcitabinecisplatin.  The 1-year OS for patients treated with 


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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 of nab-paclitaxelatezolizumab demonstrated 
significantly greater anti-tumor activity than either agent alone.
In light of these observations, Study GO29437 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 PFS and OS when used in combination
with carboplatinnab-paclitaxel compared with carboplatinnab-paclitaxel in patients 
with 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 6).
Study GO29437 will enroll patients with Stage IV squamous NSCLC who are naive to 
chemotherapy treatment and for whom the experimental arms 
(atezolizumabcarboplatinpaclitaxel and atezolizumabcarboplatinnab-paclitaxel) 
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 or have proven intolerance 
during or after treatment with an EGFR tyrosine kinase or 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 criteria (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 
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.


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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 platinum-based chemotherapy.  Patients will be fully 
informed of the risk of continuing study treatment in spite of apparent radiographic 
progression and investigators should make a careful assessment of the potential benefit 
of doing so, considering radiographic data, biopsy results, and the clinical status of 
the patient.
2.
OBJECTIVES
The following objectives will be assessed in chemotherapy-naive patients with Stage IV 
squamous NSCLC.  
2.1
EFFICACY OBJECTIVES
Unless otherwise specified, efficacy objectives will be analyzed for the following two 
treatment comparisons:

Atezolizumabcarboplatinnab-paclitaxel (Arm B) versus 
carboplatinnabpaclitaxel (Arm C)

Atezolizumabcarboplatinpaclitaxel (Arm A) versus carboplatinnabpaclitaxel 
(Arm C)
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 as measured by investigator-assessed 
PFS according to RECIST v1.1 in the tGE population and the ITT population

To evaluate the efficacy of atezolizumab as measured by OS in the ITT population
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 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 TC2/3 or IC2/3 population and the 
TC1/2/3 or IC1/2/3 population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
ORR according to RECIST v1.1 in the tGE population and the ITT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
duration of response (DOR) according to RECIST v1.1 in the tGE population and 
the ITT population

To evaluate the OS rate at 1 and 2 years in each treatment arm for the tGE
population and the ITT 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 population and the ITT 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 
population and the ITT population

To evaluate the efficacy of the treatment regimen of 
atezolizumabcarboplatinpaclitaxel versus 
atezolizumabcarboplatinnab-paclitaxel as measured by investigator-assessed 
PFS according to RECIST v1.1 and  OS in the tGE population and the ITT 
population
2.2
SAFETY OBJECTIVES
The safety objectives for this study are the following:

To evaluate the safety and tolerability of atezolizumab in each of the two treatment 
comparisons

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
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objectives for this study are the following:

To characterize the pharmacokinetics of atezolizumab when given in combination 
with carboplatinpaclitaxel (Arm A) or with carboplatinnab-paclitaxel (Arm B)

To characterize the pharmacokinetics of carboplatin when given in combination with 
paclitaxel and atezolizumab (Arm A) or withnab-paclitaxel with and without 
atezolizumab (Arms B and C)


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
To characterize the pharmacokinetics of paclitaxel when given in combination with 
atezolizumab and carboplatin (Arm A)

To characterize the pharmacokinetics of nab-paclitaxel (reported as total paclitaxel)
when given in combination with carboplatin with and without atezolizumab (Arms B 
and C)
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 (HRQoL), 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 (IMpower131) designed to 
evaluate the safety and efficacy of atezolizumab in combination with 
carboplatinpaclitaxel or with carboplatinnab-paclitaxel compared with treatment with 
carboplatinnab-paclitaxel in approximately 1025 chemotherapy-naive patients with 
Stage IV squamous NSCLC.  Figure 1 illustrates the study design.  The schedules of 
assessments are provided in Appendix 1 and Appendix 2.  
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 1:1:1 ratio to 
receive one of the following treatment regimens detailed in Table 9.


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Table 9
Treatment Arms in Study GO29437
Treatment Arm
Induction 
(Four or Six 21-day Cycles)
Maintenance 
(21-day Cycle)
A
Atezolizumab carboplatin paclitaxel
Atezolizumab
B
Atezolizumab carboplatin nab-paclitaxel
Atezolizumab
C
Carboplatin nab-paclitaxel
Best supportive care
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 C) or 
loss of clinical benefit (Arms A and B) is documented. 
Following the induction phase, patients randomized to atezolizumab (Arms A and B) 
may continue treatment with atezolizumab beyond radiographic disease progression by 
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 C) will be offered best 
supportive care provided they have non-progressive disease.
Treatment with chemotherapy must be discontinued in all patients who exhibit evidence 
of progressive disease by RECIST v1.1.
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 
48 weeks following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, tumor 
assessments will be required every 9 weeks.  Patients will undergo tumor assessments 
until radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who continue 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 per RECIST v1.1
(e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments 
until radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who had continued treatment with atezolizumab after 
radiographic disease progression according to RECIST v1.1), withdrawal of consent, 
study termination by Sponsor, or death, whichever occurs first, regardless of whether 
patients start a new anti-cancer therapy.


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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.
For Treatment Arms A and B Only
During treatment (induction or maintenance), patients who show evidence of clinical 
benefit will be permitted to continue atezolizumab after RECIST v1.1 for progressive 
disease are met if they meet all of the following criteria: 

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values, [e.g., 
new or worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Patients must provide written consent to acknowledge deferring other treatment 
options in favor of continuing atezolizumab at the time of initial progression
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 time 
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 Arms A and B who are unable to undergo 
biopsy sample collection but who otherwise meet the criteria listed above may continue 
to receive atezolizumab.


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Figure 1
Study Schema
Chemotherapy-Naive Patients with Stage IV Squamous NSCLC
(n=approximately 1025)
Arm A:
Atezolizumab (1200 mg IV Day 1)
+Carboplatin (AUC=6 IV Day 1)
+Paclitaxel (200 mg/m2 IV Day 1)
Arm B:
Atezolizumab (1200 mg IV Day 1)
+ Carboplatin (AUC=6 IV Day 1)
+nab-Paclitaxel (100 mg/m2 IV 
Days 1, 8, and 15)
Arm C:
Carboplatin (AUC=6 IV Day 1)
+nab-Paclitaxel (100 mg/m2 IV 
Days 1, 8, and 15)
Treat until 
Loss of Clinical Benefit
Treat until 
Disease Progression, per RECIST v 1.1
Survival Follow-Up
1:1:1 Randomization
Stratification Factors:
•
Sex
•
Liver metastases
•
PD-L1 expression (by central 
testing for PD-L1 status)
Induction Treatment:  Four or Six 21-Day Cycles
Maintenance Treatment:  21-Day Cycles
Arm A:
Atezolizumab (1200 mg IV)
Arm B:
Atezolizumab (1200 mg IV)
Arm C:
Best Supportive Care
No Crossover Permitted
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.
Note:  In Arm A, patients with Asian race/ethnicity receive paclitaxel at a dose of 175 mg/m2
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.


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The Sponsor will remain blinded to the efficacy results until the final PFS analysis for the 
primary comparisons (i.e., Arm A vs. Arm C, Arm B vs. Arm C).  All summaries and 
analyses by treatment arm for the iDMC review will be prepared by an external 
independent Data Coordinating Center (iDCC).  Following the safety reviews, 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. 
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 a median survival duration of approximately 
89 months (Stinchcombe et al. 2008).  Approved therapies are associated with 
significant toxicities (e.g., neuropathy, febrile neutropenia, myelosuppression, and 
alopecia) that negatively 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.


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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).
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 or 
bevacizumab, this study will evaluate atezolizumab in combination with platinum-based 
chemotherapy.  Tumor-cell 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 NSCLC.  Patients enrolled into the experimental Arm B 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.  Because the effects of corticosteroids on T-cell proliferation have the 
potential to ablate early atezolizumab-mediated anti-tumor immune activity, it is 
recommended that dexamethasone doses be minimized to the extent that is clinically 
feasible in patients treated with atezolizumab.  Therefore, the backbone treatment of 
carboplatin nab-paclitaxel in combination with atezolizumab is considered optimal to 
minimize the prolonged requirement for systemic corticosteroids, and it follows that 
carboplatin nab-paclitaxel would be a logical comparator.  
In the Phase III study conducted by Socinski et al. (2012) comparing 
carboplatinpaclitaxel to carboplatinnab-paclitaxel, no statistically significant 
differences in PFS or OS was seen in patients with squamous histology.  Therefore, the 
control group of carboplatinnab-paclitaxel is considered a suitable comparator for the 


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experimental arm of carboplatinpaclitaxel 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.
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 randomized to Arm C, which could pose a significant burden to 
patients. Furthermore, because of the potential for pseudoprogression in patients 
randomized to atezolizumab-containing arms, a blinded study would require the option 
that all patients continue treatment until loss of clinical benefit regardless of whether they 
were receiving atezolizumab. In the absence of pseudoprogression, this could then 
delay subsequent treatment with approved therapies for NSCLC in patients assigned to 
any treatment arm, as well as increase the complexity of treatment decisions.
Adequate steps have been taken to ensure the validity of data in an open-label study 
design. This includes performing a sensitivity analysis to demonstrate the robustness of 
the 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 only be performed 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, with a stratified 
HR of 0.73 (95% CI: 0.53, 0.99).  PFS in the ITT population was similar between both 
treatment arms:  HR of 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 either of the 
experimental arms after the disease progression will not be permitted, with the aim of 


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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 of 0.65 in the 
ITT and of 0.55 in the biomarkerselected tGE population), and study assessments that 
will allow a robust evaluation of benefit-risk assessment (using standard RECIST to 
define progression with fixed assessment intervals that are identical in all treatment arms 
and a robust definition of PFS and prospectively defined methods to assess, quantify, 
and analyze PFS, including sensitivity analyses).
New treatment modalities, such as targeted therapies and immunotherapy, are emerging 
as highly effective regimens that are providing improvements in patient outcomes far 
beyond what was achieved before (Ellis et al. 2014).  In particular, immunotherapy has 
been correlated/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 arms to remain on atezolizumab after apparent radiographic 
progression, provided the benefit-risk ratio is judged to be favorable.  Patients should be 
discontinued for unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as determined by the investigator after an integrated assessment of 
radiographic data and clinical status (see Section 3.1).
3.3.6
Rationale for Patient-Reported Outcome Assessments
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on HRQoL (Hyde and 
Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).  This is especially true for 
studies that use PFS as the primary endpoint, where it is important to better understand 
in what regard the delay in disease progression is meaningful to patients.


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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, squamous NSCLC in the first-line setting.
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 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 tumor-infiltrating immune cells was reported to be 
associated with expression of a 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).  
On the basis of an analysis of independent cohorts of patients with NSCLC, it is 


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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 
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.


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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 the following:

PFS, defined as the time from randomization to the first occurrence of the disease 
progression as determined by the investigator according to RECIST v1.1 or death 
from any cause, whichever occurs first in the tGE population and ITT population

OS, defined as the time from randomization to death from any cause, in the ITT 
population
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are the following:

OS in the tGE population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
TC2/3 or IC2/3 population and the TC1/2/3 or IC1/2/3 population

Objective response, defined as PR or CR as determined by the investigator 
according to RECIST v1.1 in the tGE population and ITT population

DOR, defined as the time interval from the first occurrence of a documented 
objective response to the time of disease progression as determined by the 
investigator according to RECIST v1.1, or death from any cause, whichever occurs 
first in the tGE population and ITT population

OS rates at 1 and 2 years for the tGE population and the ITT 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 population and ITT
population

Change from baseline in patient-reported lung cancer symptoms (cough, dyspnea, 
and chest pain) on the symptom severity score of the SILC scale in the tGE 
population and ITT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
two atezolizumab-containing arms in the tGE population and the ITT 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 study treatment administration

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters


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3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are the following:

Maximum observed serum atezolizumab concentration (Cmax) after infusion 
(Arms A and B)

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 (Arms A and B)

Plasma concentrations for carboplatin (Arms A, B, and C)

Plasma concentrations for paclitaxel (Arm A)

Plasma concentrations for nab-paclitaxel (Arms B and C)
See Appendix 2 for specific sample collection times.
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 tumor-infiltrating immune cells 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 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 10)


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
Histologically or cytologically confirmed, Stage IV squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging 
system, 7th edition; Detterbeck et al. 2009; see Appendix 3)
Patients with tumors of mixed histology (squamous and non-squamous) are 
eligible if the major histological component appears to be squamous.

No prior treatment for Stage IV squamous NSCLC

Patients known to have 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 with 
unknown EGFR mutation status do not require testing.

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 (i.e., crizotinib) appropriate for the treatment of 
NSCLC in patients having an ALK fusion oncogene.  Patients with unknown 
ALK mutation status do not require testing.

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.

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.

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.


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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

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, for 30 days after the last dose of nab-paclitaxel, 
or for 6 months after the last dose of 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 


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after the last dose of nab-paclitaxel, paclitaxel, and/or carboplatin.  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.  Men must 
refrain from donating sperm during the study and for 6 months after the last dose of 
nab-paclitaxel, paclitaxel, and/or carboplatin, whichever is latest.

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 trial 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 following criteria 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

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.


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
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 12 for 
a more comprehensive list of autoimmune diseases)
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, or lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions:
Rash must cover less than 10% of body surface area (BSA).
Disease is well controlled at baseline and only requires 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)


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
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.

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 render the patient at high risk from treatment 
complications


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
Patients with illnesses or conditions that interfere with their capacity to understand, 
follow and/or comply with study procedures
4.1.2.3
Exclusion Criteria Related to Medications

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.

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 paclitaxel or nab-paclitaxel

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 (paclitaxel and 
nab-paclitaxel)

Known history of severe hypersensitivity reactions to products containing 
Cremophor® EL (e.g., cyclosporin for injection concentrate and teniposide for 
injection concentrate)


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.
After written informed consent has been obtained and eligibility has been established, 
the study site will enter demographic and baseline characteristics in the interactive 
voice/Web response system (IxRS).  For patients who are eligible for enrollment, the 
study site will obtain the patient’s randomization number and treatment assignment from 
the IxRS.  The number of cycles of induction treatment (four or six) will be determined by 
the investigator and documented prior to randomization.
Randomization to one of the three treatment arms will occur in a 1:1:1 ratio.  
Permuted-block randomization will be applied to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified by the following criteria:

Sex (male vs. female)

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.
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, Paclitaxel, and nab-Paclitaxel
Carboplatin and paclitaxel 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 and paclitaxel will be provided by Roche or its designee. 
For information on the formulation, packaging, and handling of carboplatin, paclitaxel, 
and nab-paclitaxel, see the prescribing information for each drug.


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4.3.1.3
Erlotinib
Switch maintenance to erlotinib is no longer permitted.  However, patients who had 
already started switch maintenance treatment with erlotinib under previous protocol 
versions 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.  For information 
on the formulation and packaging and handling of erlotinib, see the prescribing 
information.
4.3.2
Dosage, Administration, and Compliance
The induction phase of the study will consist of four or six cycles of chemotherapy; 
atezolizumab, paclitaxel, 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 drug administration is as follows:
Arm A:  Atezolizumab paclitaxel carboplatin
Arm B:  Atezolizumab nab-paclitaxel carboplatin
Arm C:  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 
prespecified number of induction chemotherapy cycles.  Additional guidance is provided 
in Appendix 15.
Patients who experience no further clinical benefit (for patients enrolled into Arms A or B, 
see Section 3.1 for definition) or disease progression (for patients enrolled into Arm C) 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 who are 
randomized to Arms A and B will begin maintenance therapy with atezolizumab.  
Patients randomized to Arm C will receive best supportive care until disease progression.  
During treatment (induction or maintenance), patients randomized to Arms A or B who 
show evidence of clinical benefit will be permitted to continue atezolizumab after 
RECIST v1.1 criteria 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.  Table 10 lists the 
suggested premedication for induction treatment for patients randomized to Arm A and 
Table 11 lists the suggested infusion times for treatment administration during the 
induction and maintenance phases.  


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Chemotherapy infusion times may be adapted in accordance with local standard of care 
in lieu of the suggested infusion times specified in Table 11 and Section 4.3.2.2.  
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.
Table 10 Suggested Premedication for Induction Treatment for Arm A
Premedication
Dose/Route
Timing
Before paclitaxel 
treatment in Arm A
Dexamethasone
20 mg PO
12 and 6 hours before 
paclitaxel (or per standard of 
care at treating institution)
Diphenhydramine 
(or equivalent)
50 mg IV
30–60 minutes before 
paclitaxel
Cimetidine (or 
ranitidine) (or 
equivalent)
300 mg 
(or 50 mg) IV 
(or equivalent)
30–60 minutes before 
paclitaxel
IVintravenous; PO oral.
Note:  Prophylactic anti-emetics and hydration should be administered as per the local 
standard of care and manufacturer’s instruction. 


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Table 11 Treatment Regimen and Order of Administration for 
All Treatment Arms
Agent
(1) Atezolizumab
(2) Paclitaxel OR nab-Paclitaxel
(3) Carboplatin
Dose and 
administration 
route
1200 mg IV
Paclitaxel
200 mg/m 2 IVa
nab-Paclitaxel b
100 mg/m2 IV
AUC 6 IV e
Infusion rate
Over 60 (15) min 
(for the first 
infusion); 
30 (10) min for 
subsequent 
infusions if 
tolerated
Over 180 
minutes c
Over 30 
minutes d
Over 
approximately 
1530 min e
Frequency
Day 1 of every 21 days (and Days 8 and 15 for nab-paclitaxel)
Induction 
Phase
(four or six
Cycles)
A
x
x
x
B
x
x
x
C
x
x
Maintenance 
Phase
A
x
B
x
C
AUCarea under the concentrationtime curve; IVintravenous.
a Patients of Asian race/ethnicity: 175 mg/m2 IV
b On Days 8 and 15, nab-paclitaxel will be administered alone over 30 minutes.
c See Section 4.3.2.2 for more details on paclitaxel dosing.
d See Section 4.3.2.2 for more details on nab-paclitaxel dosing.
e See Section 4.3.2.2 for details on dose calculation of carboplatin.
Guidelines for dose modification and treatment interruption or discontinuation for 
carboplatin, paclitaxel, and nab-paclitaxel are provided in Section 5.1.7, Section 5.1.9, 
and Section 5.1.10.
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 12.


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Table 12 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) every 15 (5) minutes
during the infusion if clinically indicated or 
patient experienced symptoms during the 
previous infusion. 
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) 30 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 5.1.7.1, 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
Paclitaxel, nab-Paclitaxel, and Carboplatin
Paclitaxel
In general, paclitaxel will be administered intravenously at a dose of 200 mg/m2 over 
3 hours followed by carboplatin. Patients of Asian race/ethnicity will have a lower 
starting dose of paclitaxel at 175 mg/m2 intravenously over 3 hours. The lower starting 
dose of paclitaxel is based on a higher overall incidence of hematologic toxicities in 
patients from Asian countries compared with those from non-Asian countries, as
observed during safety review of this study by the iDMC. The term "Asian race/ethnicity"
refers to a pan-ethnic/racial group that includes diverse populations who either live or 
have ancestral origins in East Asia, Southeast Asia, or South Asia. The applicability of 
such term in a particular patient will be at the discretion of the treating investigator and 
should be based on the patient’s clinical characteristics and country of origin.
Paclitaxel Injection must be diluted prior to infusion.  Paclitaxel should be diluted in 0.9% 
Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 
0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2 mg/mL. 
Contact of the undiluted concentrate with plasticized PVC equipment or devices used to 
prepare solutions for infusion is not recommended.  Paclitaxel should be administered 
through an in-line filter with a microporous membrane not greater than 0.22 m.  Use of 
filter devices such as IVEX-2® filters, which incorporate short inlet and outlet PVC-coated 
tubing, has not resulted in significant leaching of bis(2-ethylhexyl)phthalate (DEHP).
Sites should follow their institutional standard of care for determining the paclitaxel dose
adjustments in the event of patient weight changes.  For paclitaxel infusion, exceptions 
to the infusion time of 3 hours will be allowed for sites that have an institutional policy of 
infusing paclitaxel more quickly (over 90 minutes) or more slowly (up to 4 hours for 
the first infusion).
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 intravenous 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 prescribing information for nab-paclitaxel for more information.


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Carboplatin
Carboplatin should be administered by IV infusion, immediately after the completion of 
paclitaxel or nab-paclitaxel administration, over 1530 minutes to achieve an initial target 
area under the concentrationtime curve (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.
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.


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Refer to the FDA’s communication regarding carboplatin dosing using the following URL 
for more details:
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/
ucm228974.htm.
4.3.2.3
Erlotinib
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients 
who had already started switch maintenance treatment with erlotinib under previous 
protocol versions 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 erlotinib prescribing information.  
4.3.3
Additional Required Medication
4.3.3.1
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. 
4.3.3.2
Premedication for Paclitaxel
All patients should be premedicated prior to paclitaxel administration to prevent severe 
hypersensitivity reactions.  Prior to receiving paclitaxel, all patients will receive either the 
institutional standard of care or the following premedication: 

Dexamethasone 20 mg orally approximately 12 hours prior and 6 hours prior to the 
paclitaxel infusion
Patients may be treated with dexamethasone 1020 mg IV within 1 hour prior to 
paclitaxel infusion if the patient did not take the oral dexamethasone.

Diphenhydramine 50 mg IV (or equivalent) 3060 minutes prior to paclitaxel infusion

Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 3060 minutes prior to 
paclitaxel infusion 
Because the effects of corticosteroids on T-cell proliferation have the potential to ablate 
early atezolizumab-mediated anti-tumor immune activity, it is recommended that 
dexamethasone doses be minimized to the extent that is clinically feasible.  For example, 
if Cycle 1 is tolerated without apparent hypersensitivity reaction, a reduction in 
dexamethasone premedication dose should be considered for subsequent cycles if 
permitted by institutional standard of care.
4.3.4
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 or an IMP.  IMPs required for completion of this study will be provided by the 


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Sponsor if required by local health authority regulations.  The Sponsor or 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.
4.3.5
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 erlotinib is no longer permitted.  However, patients who 
had already started treatment with erlotinib under previous protocol versions may be 
allowed to continue treatment with erlotinib upon discussion of the risks, the potential 
benefits, and alternative treatment options with the investigator.  Investigators should 
follow the dosage and administration instructions in the prescribing information for 
erlotinib.  
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2-receptor antagonist, as per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local practice).  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 11). 
All concomitant medications must be recorded on the appropriate Concomitant 
Medications electronic Case Report Form (eCRF).  Erlotinib use will be recorded on a 
separate Erlotinib Administration eCRF.
4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations where 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered first by the treating physician.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the treating physician except in the case of patients for 


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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 and Appendix 2.
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient.
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.


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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 per RECIST v.1.1 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.
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).
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.


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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 13.
For all sites in Argentina, pulse oximetry to measure hypoxia will be performed at every 
visit.  These data will not be recorded.
Table 13 Vital Sign Measurements at Cycle 1 and All Subsequent Cycles
Cycle 1
Treatment Arm
Timepoints
Arms A and B

Within 60 minutes prior to atezolizumab infusion

During (every 15 [5] minutes) the atezolizumab
infusion and within 30 (10) minutes after 
atezolizumab infusion if clinically indicated

Within 30 (10) minutes after carboplatin infusion
Arm C

Within 60 minutes prior to nab-paclitaxel infusion

Within 30 (10) minutes after carboplatin infusion
Subsequent Cycles
Treatment Arm
Timepoints
Arms A and B

Within 60 minutes prior to atezolizumab infusion

During (every 15 [5] minutes) the atezolizumab
infusion and within 30 (10) minutes after 
atezolizumab infusion if clinically indicated or 
symptoms occurred during prior infusion
Arm C

Within 60 minutes prior to nab-paclitaxel infusion

During infusion if clinically indicated or symptoms 
occurred during prior infusion

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 12.
4.5.5
Tumor and Response Evaluations
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRIs of the chest and abdomen.  A CT or MRI scan of the pelvis is 
required at screening and as clinically indicated or as per local standard of care at 
subsequent response evaluations.  A spiral CT scan of the chest may be obtained but is 
not a requirement.


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A CT (with contrast if not contraindicated) or MRI scan of the head must be done at 
screening to exclude CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.  
Patients with active or untreated CNS metastases are not eligible for the study 
(see Section 4.1.2.1).
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for 
a full-contrast diagnostic CT scan.
Bone scans and CT scans of the neck should also be performed if clinically indicated.  At 
the investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days of Cycle 1, Day 1 may be used rather than repeating tests.  All known 
sites of disease must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Patients with a history of irradiated brain metastases at screening are 
not required to undergo imaging brain scans at subsequent tumor evaluations, unless 
scans are clinically indicated.  The same radiographic procedure used to assess disease 
sites at screening should be used throughout the study (e.g., the same contrast protocol 
for CT scans).  Response will be assessed by the investigator according to RECIST v1.1 
and modified RECIST.  Tumor assessments will be performed according to RECIST v1.1 
and modified RECIST for atezolizumab-containing treatment arms (Arms A and B) and 
only according to RECIST v1.1 for carboplatin nab-paclitaxel treatment arm (Arm C).  
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, after completion of the Week 48 tumor assessment, every 
9 weeks (7 days), regardless of treatment delays until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for patients assigned to 
atezolizumab who continue treatment 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 per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue 
scheduled tumor assessments until radiographic disease progression per RECIST v1.1 
(or loss of clinical benefit for atezolizumab-treated patients who had continued treatment
with atezolizumab after radiographic disease progression according to RECIST v1.1), 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.


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Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 will continue scheduled tumor assessments until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first.  Patients who are treated with 
atezolizumab who continue to experience clinical benefit, despite evidence of 
radiographic progression, will continue tumor assessments as per the schedule listed 
above.  
Scans will be submitted to an IRF.
4.5.6
Laboratory Assessments and Biomarker Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, total bilirubin, 
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin)

Coagulation (aPTT or INR)

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed 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, 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.  The 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.


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
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.
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 assay

Blood samples for PK assessments will be obtained according to the schedule 
in Appendix 2.  
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.

At selected sites, a subset of 20 patients in each arm will undergo the additional 
PK assessments for carboplatin and paclitaxel (Arm A) and carboplatin and 
nab-paclitaxel (Arms B and C). 
Plasma carboplatin, paclitaxel, and nab-paclitaxel (reported as total paclitaxel) 
concentrations will be assayed using validated methods.

Biomarker assays in blood samples
Blood samples will be obtained for biomarker evaluation (including but not 
limited to biomarkers that are related to NSCLC or tumor immune biology) from 
all eligible patients according to the schedule in Appendix 2.  Samples will be 
processed to obtain 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 all those outlined 
below, provided there is a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method:

Core-needle 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 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.


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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 start of the next anti-cancer 
treatment, whichever is sooner).
Acceptable samples include:

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. Food and Drug Administration; 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 and 
Appendix 2 for the schedule).  The immunogenicity evaluation will utilize a risk-based 
immunogenicity strategy (Rosenberg and Worobec 2004; Koren et al. 2008) to 
characterize ATA responses to atezolizumab in support of the clinical development 
program.  This tiered strategy may include an assessment of whether detected 
ATA responses correlate with relevant clinical endpoints.  Implementation of ATA 
characterization assays will depend on the safety profile and clinical immunogenicity 
data.
4.5.9
Electrocardiograms
Twelve-lead ECG is required at screening and as clinically indicated.  ECGs should be 
obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.10
Patient-Reported Outcomes
PRO data will be collected via the EORTC QLQ-C30, 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, 


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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 7) is a validated and reliable self-report measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999) that consists of 30 questions that assess 
five aspects of patient functioning (physical, emotional, role, cognitive, and social), three 
symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties).  Scale scores can be obtained for the multi-item scales.  The EORTC 
QLQ-C30 module takes approximately 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 continue treatment after radiographic 
disease progression according to RECIST v1.1).  
The EORTC QLQ-LC13 (see Appendix 8) module incorporates one multiple-item scale 
to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, 
dysphagia, peripheral neuropathy, alopecia, and hemoptysis.  The EORTC QLQ-LC13 
module takes approximately 15 minutes to complete.  This questionnaire will be 
completed on the ePRO tablet at each scheduled 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 continue 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 
self-report measure of lung cancer symptoms. It measures severity of cough, dyspnea, 
and chest pain with a symptom severity score. This questionnaire will be completed 
using an ePRO device at the patient’s home on a weekly basis, then during survival 
follow-up every month for 6 months following disease progression (or loss of clinical 
benefit for atezolizumab-treated patients who continue treatment after radiographic 
disease progression according to RECIST v1.1).  


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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 9).  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 for at 3 months 
and 6 months following disease progression (or loss of clinical benefit for 
atezolizumab-treated patients who continue treatment after radiographic disease 
progression according to RECIST v1.1).  
The 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 per 
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 exempted from completing all ePRO assessments.
4.5.11
Samples for Roche Clinical Repository
4.5.11.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.


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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)
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).


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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.
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.


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The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research.
4.5.11.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  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 GO29437 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 
GO29437.
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.
4.5.12
Timing of Assessments
4.5.12.1
Screening and Baseline Assessments
Screening tests and evaluations will be performed within 28 days prior to Cycle 1, Day 1.  
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 28 days prior to Cycle 1, Day 1, may be used; such tests do not need 
to be repeated for screening. 
See Appendix 1 for the schedule of screening assessments and Appendix 2 for the 
schedule of PK, ATA, and biomarker sampling.


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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 C who had started erlotinib switch maintenance 
after the induction phase (allowed under previous protocol versions), will continue with 
cycle visits as outlined in Appendix 1 for the maintenance phase until erlotinib treatment 
termination, disease progression, withdrawal of consent, death, or study termination by 
the Sponsor, whichever occurs first. 
Patients who are randomized to Arm C 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 per 
RECIST v1.1 (or loss of clinical benefit for patients who continue treatment with 
atezolizumab after disease progression according to RECIST v1.1 for Arms A and B 
only), withdrawal of consent, death, or study termination by the Sponsor, whichever 
occurs first.  Patients who discontinue treatment for reasons other than radiographic 
disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will 
continue scheduled tumor assessments until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who had 
continued treatment with atezolizumab beyond radiographic disease progression per 
RECIST v1.1), withdrawal of consent, death, or study termination by Sponsor, whichever 
occurs first.


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The following assessments may be performed 96 hours before Day 1 of each cycle:  

ECOG performance status

Limited physical examination

Local laboratory tests
Screening assessments performed 96 hours before Cycle 1, Day 1, are not required to 
be repeated for Cycle 1 Day 1.
Local hematology tests must be performed prior to nab-paclitaxel infusions also on 
Day 8 and Day 15.
See Appendix 1 for the schedule of assessments performed during the treatment period 
and Appendix 2 for the schedule of PK, pharmacodynamic, ATA, and biomarker 
sampling.
4.5.12.3
Assessments at Study Drug Discontinuation Visit
When a patient discontinues all study treatment (including erlotinib switch maintenance 
for patients randomized to Arm C who receive erlotinib switch maintenance allowed 
under previous versions of this protocol) regardless of the reason for discontinuation, the 
patient will be asked to return to the clinic within 30 days after the treatment for a study 
drug discontinuation visit.  The visit at which the decision is made to discontinue 
treatment (e.g., loss of clinical benefit is confirmed) may be used as the study-drug 
discontinuation visit. The treatment discontinuation visit for patients in Arm C 
who receive best supportive care will take place when patients discontinue best 
supportive care.
See Appendix 1 and Appendix 2 for the schedule of follow-up assessments.
4.5.12.4
Follow-Up Assessments
After the study drug discontinuation visit, adverse events should be followed as outlined 
in Section 5.3.1.
For patients who discontinue study treatment (including chemotherapy induction and
erlotinib switch maintenance for patients who are randomized to Arm C and receive 
erlotinib switch maintenance allowed under previous protocol versions) for any reason 
other than radiographic disease progression per RECIST v1.1, tumor assessments 
should continue at the same frequency as would have been followed had the patient 
remained on study treatment until radiographic disease progression (or loss of clinical 
benefit for patients treated with atezolizumab 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 per RECIST v1.1 should continue tumor assessments according to the 


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protocol schedule of response assessments until radiographic disease progression per 
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 who continue treatment after disease progression 
according to RECIST v1.1] 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 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 
per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who had
continued treatment with atezolizumab after radiographic disease progression according 
to RECIST v1.1) 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 and Appendix 2 for the schedule of follow-up assessments.
4.5.12.5
Assessments at Unplanned Visits
Assessments for unscheduled visits related to a patient’s underlying NSCLC, study drug, 
or adverse event should be performed as clinically indicated and entered into 
Unscheduled Visit eCRFs.


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4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status

Intolerable toxicity related to atezolizumab, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Intolerable toxicity related to other components of study treatment

If one component of study treatment is discontinued permanently due to tolerability 
concerns, the patient may continue with other components of study treatment until 
disease progression (or loss of clinical benefit for atezolizumab-treated patients who 
continue treatment after disease progression according to RECIST v1.1) if agreed 
upon by the investigator and patient

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another nonprotocol-specified anti-cancer therapy (see Section 4.4.3)

Pregnancy


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
Radiographic disease progression per 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 
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.


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Figure 2
Criteria for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size (Atezolizumab Arms)
Radiographic Progression according to RECIST v 1.1.
Patients Must Provide the Following:
•
Signed Informed Consent Form(s)
•
Tissue Biopsy Unless Not Clinically Feasible
Atezolizumab May Be Continued, Provided All of the Following 
Criteria Are Met:
•Evidence of Clinical Benefit, as Assessed by the Investigator
•No Signs/Symptoms Indicating Unequivocal Disease Progression
•No Decline in ECOG PS Attributed to Disease Progression
•No Tumor Growth at Critical Sites
Continue Treatment Until Evidence of 
Loss of Clinical Benefit
Survival Follow-Up
Atezolizumab-Treated Patients Only
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
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory


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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 Section 4.1.1 and 
Section 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 switch maintenance for patients randomized to Arm C who receive erlotinib 
switch maintenance allowed under previous versions of this protocol) 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 switch maintenance 
for patients who are randomized to Arm C who receive erlotinib switch maintenance 
allowed under previous protocol versions) 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 
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.


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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 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 Paclitaxel
Paclitaxel is known to cause myelosuppression, alopecia, peripheral neuropathy, 
myalgia, arthralgia, nausea, and vomiting.  Less commonly reported adverse events are 
hypersensitivity reactions, infections, bleeding, diarrhea, mucositis, liver function test 
(LFT) elevations, injection site reactions, and cardiovascular effects such as hypotension, 
bradycardia, hypertension, arrhythmias, other ECG abnormalities, syncope, and venous 
thrombosis.
For more details regarding the safety profile of paclitaxel, refer to the prescribing 
information for paclitaxel.
5.1.4
Risks Associated with nab-Paclitaxel
In clinical studies and post-marketing experience, 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 


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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.
For more details regarding the safety profile of nab-paclitaxel, refer to the prescribing 
information for nab-paclitaxel.
5.1.5
Risks Associated with Erlotinib
Switch maintenance therapy with erlotinib is no longer permitted, except for patients who 
have already started treatment with erlotinib allowed under previous protocol versions.  
These patients may continue to receive erlotinib upon discussion of the risks, potential 
benefits, and alternative treatment options with the investigator.  The most commonly 
reported adverse drug reactions associated with erlotinib were rash and diarrhea.  Most 
adverse events 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.
5.1.6
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 and Appendix 2 for the list and timing of study assessments).
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.
All serious adverse events and protocol-defined events of special interest 
(see Section 5.2.2 and Section 5.2.3) will be reported in an expedited fashion.  In 
addition, the iDMC and Medical Monitor will review and evaluate observed adverse 
events on a regular basis.




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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 11 for precautions for anaphylaxis.
Refer to Section 5.1.10.5 and Table 22 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 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/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 paclitaxel are allowed as described in the 
following sections.
5.1.9.1
Hematologic Toxicity
At the start of each cycle, the ANC must be 1500 cells/L and the platelet count must 
be 100,000/L.  Treatment may be delayed for up to 63 days from the last dose to 
allow sufficient time for recovery.  Growth factors may be used in lieu of a dose reduction 
for neutropenic fever or Grade 4 neutropenia in accordance with ASCO and NCCN 
guidelines (Smith et al. 2006; NCCN 2014).  Upon recovery, dose adjustments at the 
start of a subsequent cycle will be based on the lowest platelet and neutrophil values 
from the previous cycle (see Table 14 and Table 15).
Table 14 Dosing Based on ANC and Febrile Neutropenia—Paclitaxel and 
Carboplatin
Dose of Paclitaxel and Carboplatin
ANC (Day 1 of Each Cycle)
1500 cells/L
1500 cells/L
Febrile neutropenia
(regardless of duration)
0
Paclitaxel 150 mg/m2
Carboplatin AUC 4.5
ANCabsolute neutrophil count; AUCarea under the concentrationtime curve.
Table 15 summarizes dose modifications based on platelet count.


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Table 15 Dosing Based on Nadir Platelet Count—Paclitaxel and 
Carboplatin
Nadir of Last Course
Dose of Paclitaxel and Carboplatin
Platelets (Day 1 of Each Cycle)
100,000/L
100,000/L
25,000/L or 
50,000/L with bleeding 
or requiring transfusion
0
Paclitaxel 150 mg/m2
CarboplatinAUC 4.5
AUCarea under the concentrationtime curve.
All dose reductions for the first episode of neutropenic fever or thrombocytopenia 
(platelet count 25,000/L or 50,000 cells/L with bleeding or that requires transfusion) 
are permanent.  If a second episode of neutropenic fever or thrombocytopenia requiring 
dose reduction occurs, another 25% dose reduction of carboplatin and paclitaxel is 
recommended.  Patients who require a third dose reduction will immediately discontinue 
chemotherapy.
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.
Treatment should be delayed for up to 3 weeks until the Day 1 ANC is 1500 cells/L 
and the platelet count is 100,000/L.  However, if the counts have not recovered within 
3 weeks, the patient’s chemotherapy will be dose reduced, withheld until adequate 
neutrophil recovery, or discontinued, according to physician judgment and local standard 
practice.  If chemotherapy is withheld longer than 63 days from the last dose, all 
chemotherapy should be discontinued. 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity. 
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment schedule will then proceed in the usual 
sequence.
No dose reductions will be made for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines.


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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 16 provides the relevant dose adjustments for 
gastrointestinal toxicities.
Table 16 Carboplatin and Paclitaxel Dose Modification Based on 
Gastrointestinal Toxicities in the Preceding Cycle
Toxicity
Adjusted 
Carboplatin Dose 
as % of Previous 
Dose a
Adjusted Paclitaxel
Dose as % of 
Previous Dose
Diarrhea
Grade 3 or 4 b
75%
75%
Oral mucositis/stomatitis
Grade 3 or 4
75%
75%
Nausea/vomiting
Grade 3 or 4
75%
75%
AUCarea under the concentrationtime curve.
a If deemed appropriate by the treating physician, adjust carboplatin dose to the specified 
percentage of the previous AUC.
b And per investigator discretion.
Nausea and/or vomiting should be controlled with adequate anti-emetics.  If Grade 3 or 
4 nausea/vomiting occurs despite the use of anti-emetics, the dose should be reduced 
by 25% for the next course.  If tolerated, the dose should be increased back to 100% 
as soon as possible.
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 resolved to a Grade 1 or 0 in 3 weeks, the patient’s 
chemotherapy will be discontinued.  If acute Grade 3 oral mucositis occurs at any time, a 
75% dose should be given when the oral mucositis has resolved to a Grade 1 or 0.  This 
is a permanent dose reduction.
5.1.9.3
Hepatic Toxicity (Paclitaxel Only)
No dose adjustment is required in patients with mild hepatic impairment.  For patients 
who develop hepatic toxicity, paclitaxel dose should be withheld until LFTs resolve to 
Grade1 prior to subsequent dosing.  If paclitaxel is withheld because of hepatic toxicity, 
carboplatin should also be withheld and administered when the paclitaxel is resumed.  
The recommendations for paclitaxel dose reduction based on elevated LFTs are 
provided in Table 17.


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Table 17 Dose Modifications for Paclitaxel for Hepatic Toxicity
SGOT (AST) 
Levels
Bilirubin Levels
Paclitaxel Reduction from 
Starting Dose
10ULN
AND
1.25ULN
No change
10ULN
AND
1.26–2.0ULN
25%
10ULN
AND
2.01–5.0ULN
50%
10ULN
OR
5.0ULN
Discontinue paclitaxel a
ULNupper limit of normal.
Note:  Recommendations for paclitaxel dose adjustments are extrapolated from 
dose adjustments for patients with hepatic impairment at baseline.
a Patients with AST 10ULN or bilirubin 5.0ULN were excluded from clinical 
studies for lung cancer.
If paclitaxel is withheld, hepatic values must recover to Grade 1 within 3 weeks or the 
patient’s paclitaxel treatment will be discontinued.  No dose reductions for carboplatin 
will be made for hepatic toxicity.
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.
5.1.9.4
Cardiovascular Toxicity (Paclitaxel Only)
Cardiac rhythm disturbances have occurred infrequently in patients treated with 
paclitaxel in clinical studies; however, most patients were asymptomatic, and cardiac 
monitoring is not required.  Transient asymptomatic bradycardia has been noted in as 
many as 29% of patients.  More significant atrioventricular block has rarely been noted.  
Cardiac events should be managed as follows:

Asymptomatic bradycardia:  no treatment required

Symptomatic arrhythmia during infusion:  Stop paclitaxel infusion, manage 
arrhythmia according to standard practice.  Paclitaxel treatment will be discontinued. 

Chest pain and/or symptomatic hypotension (90/60 mmHg or requires fluid 
replacement):  Stop paclitaxel infusion.  Perform an ECG.  Give IV 
diphenphydramine and dexamethasone if hypersensitivity is considered.  
Also consider epinephrine or bronchodilators if chest pain is not thought to 
be cardiac.  Paclitaxel treatment will be discontinued, and cardiovascular support 
should be given as appropriate.  If appropriate, the advice of a cardiologist should 
also be sought.


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5.1.9.5
Neurologic Toxicity (Paclitaxel Only)
The dose of paclitaxel should be modified as follows for sensory neuropathy. 
Table 18 Paclitaxel Dose Modification for Neurologic Toxicity
Toxicity
Paclitaxel Dose Modification
Grade 0
None
Grade 1
None
Grade 2
Withhold treatment until patient recovers to Grade 1 
toxicity, then resume treatment at a 25% reduction.
Grade 3 or worse
Withhold treatment until patient recovers to Grade 1 
toxicity, then resume treatment at a 50% reduction.
Dose modifications made for neurotoxicity are permanent.  If recovery to Grade 1 toxicity 
does not occur within 3 weeks, the patient’s paclitaxel treatment will be discontinued.
5.1.9.6
Allergic Reaction/Hypersensitivity (Paclitaxel Only)
CAUTION:  Patients who had a mild to moderate hypersensitivity reaction have been 
successfully rechallenged, but the administration of prophylactic medication (see below) 
and intensive monitoring of vital signs is recommended.

Mild symptoms:  Complete paclitaxel infusion.  Supervise at bedside.  No treatment 
required.

Moderate symptoms:  Stop paclitaxel infusion.  Give IV diphenhydramine 2550 mg 
and IV dexamethasone 10 mg.  Resume paclitaxel infusion after recovery of 
symptoms at a low rate, 20 mL/hr for 15 minutes, then 40 mL/hr for 15 minutes, then 
if no further symptoms, at full-dose rate until infusion is complete.  If symptoms recur, 
stop paclitaxel infusion.  Paclitaxel treatment will be discontinued.

Severe life-threatening symptoms:  Stop paclitaxel infusion.  Give IV 
diphenhydramine and dexamethasone as above.  Add epinephrine or 
bronchodilators if indicated.  Paclitaxel treatment will be discontinued.
Moderate or severe hypersensitivity reactions should be recorded as an adverse event.
5.1.9.7
Other Toxicities
For any Grade 3 or 4 toxicities not mentioned above, carboplatin or paclitaxel should be 
withheld until the patient recovers completely or to Grade 1 toxicity.  The treatment 
should then be resumed at 75% dose (permanent dose reduction) for Grade 3 toxicities 
and 50% of dose (permanent dose reduction) for Grade 4 toxicities.  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.
For guidelines on the dosing of other study drugs when carboplatin or paclitaxel are
withheld, see Section 5.1.7.1.


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5.1.10
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 drugs 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/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.
5.1.10.1
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 platelet 
count 50,000/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 according to the criteria in Table 19.  
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 with applicable 
reductions according to criteria in Table 19.  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 


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recovered to permissible levels.  When dosing resumes, the carboplatin and 
nab-paclitaxel doses should be permanently reduced as outlined in Table 19.
Table 19 nab-Paclitaxel and Carboplatin Permanent Dose Reductions 
Based on Nadir Absolute Neutrophil Count and Platelets
Hematologic Toxicity
Occurrence
Weekly 
nab-Paclitaxel 
Dose (mg/m2)
Every-3-Week 
Carboplatin Dose 
(AUC mgmin/mL)
Neutropenic fever (nadir ANC
500 cells/L with fever 38°C)
OR
Delay of next scheduled dose by
7 days for nadir 
ANC 1500 cells/L
OR
Nadir ANC500/L for 7 days
First
75
4.5
Second
50
3
Third
Discontinue treatment
Nadir platelet count 50,000/L
First
75
4.5
Second
Discontinue treatment
ANCabsolute neutrophil count; AUCarea under the concentrationtime curve.
5.1.10.2
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 20 provides the relevant dose adjustments for 
gastrointestinal toxicities.


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Table 20 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.
Nausea and/or vomiting should be controlled with adequate anti-emetics.  If Grade 3 or 4 
nausea/vomiting occurs in spite 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 20 for additional details on dose reductions.  Dose reductions 
listed are permanent.
5.1.10.3
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 21) when 
peripheral neuropathy recovers to Grade 1 or completely resolves. 


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Table 21 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.
5.1.10.4
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.
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.
5.1.10.5
Pulmonary Events and Pneumonitis:  Atezolizumab with 
nab-Paclitaxel, or nab-Paclitaxel with or without Atezolizumab
Note:  When atezolizumab is administered without nab-paclitaxel, refer to the 
Atezolizumab Investigator’s Brochure for management of pulmonary events, including 
pneumonitis. 


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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 or 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 22 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.
After ruling out an infectious etiology, IV high-dose 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 22 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 22 Management Guidelines for Pneumonitis:  Atezolizumab with 
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, IVIg, 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.
5.1.10.6
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 23) 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 23 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. 
5.1.11
Erlotinib Dose Modification and Management of Specific 
Adverse Events
For patients who had already started switch maintenance therapy with erlotinib allowed 
under previous versions of this protocol, refer to the prescribing information for erlotinib
for further details regarding erlotinib dose modifications for adverse event management.
5.1.12
Potential Overlapping Toxicities
To date, on the basis of safety data from Study GP28328, the risk of overlapping 
toxicities between atezolizumab, carboplatin, and paclitaxel or 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 
Section 5.1.7.1 to Section 5.1.10, 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
Hypoxia or dyspnea Grade3
Colitis
Endocrinopathies:  diabetes mellitus, pancreatitis, or adrenal insufficiency
Vasculitis
Hepatitis
Transaminitis:  Grade2 (AST or ALT3ULN and bilirubin2ULN) OR 
AST/ALT10ULN
Systemic lupus erythematosus
Guillain-Barré syndrome
Skin reactions:  vitiligo, pemphigoid


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
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response system (SIRS), 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 erlotinib switch maintenance 
for patients randomized to Arm C who received switch maintenance with erlotinib under 
previous protocol versions) 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 erlotinib switch maintenance for patients 
randomized to Arm C who received switch maintenance with erlotinib under previous 
protocol versions) or until initiation of new systemic anti-cancer therapy after the last 


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dose of study treatment, whichever occurs first.  Instructions for reporting adverse 
events that occur after the adverse event reporting period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?”
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  Table 24 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 24 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) rather than individual signs and symptoms 
should be recorded on the Adverse Event eCRF (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated 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).  The iDMC will 
monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
During survival follow-up, deaths attributed to progression of NSCLC should be recorded 
on the Study Discontinuation eCRF. 


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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 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
5.3.5.12
Patient-Reported Outcome Data
Adverse 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 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 
erlotinib switch maintenance for patients who were randomized to Arm C who received
switch maintenance with erlotinib under previous protocol versions) or until initiation of 
new systemic anti-cancer therapy after the last dose of study treatment, whichever 


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occurs first.  All other adverse events, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study treatment (inclusive of erlotinib switch 
maintenance for patients who are randomized to Arm C who received switch 
maintenance with erlotinib under previous protocol versions) 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 30 days after the last dose of nab-paclitaxel or 6 months after 
the last dose of 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 


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6 months after the last dose of nab-paclitaxel, 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), 
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 


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serious adverse events considered to be related to study drug or study-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed 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.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following as a reference:

Atezolizumab Investigator's Brochure

Tarceva(erlotinib) Summary of Product Characteristics (SmPC)/Local Label

Abraxane® (nab-paclitaxel) Summary of Product Characteristics (SmPC)/Local
Label
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 randomized Phase III, multicenter, open-label study designed to evaluate the 
safety and efficacy of atezolizumab in combination with either carboplatinpaclitaxel 
or carboplatinnab-paclitaxel as compared with treatment with 
carboplatinnab-paclitaxel in approximately 1025 patients with Stage IV squamous 
NSCLC in the first-line setting. 
Efficacy analyses will be performed in one or more populations (tGE, ITT, TC2/3 or IC2/3, 
or TC1/2/3 or IC1/2/3), with patients grouped according to the treatment assigned at 
randomization, regardless of whether they received any assigned study treatment.
Safety analyses will be performed on all randomized patients who received any amount 
of any components of protocol treatments, with patients grouped according to whether 
any full or partial dose of atezolizumab was received.  Specifically, for patients 
randomized to Arm C, if atezolizumab was received by mistake, the patients will be 
grouped with Arm B for safety analyses.
6.1
DETERMINATION OF SAMPLE SIZE
The primary endpoint of PFS will be analyzed in the tGE population and in the ITT 
population, and the primary endpoint of OS will be analyzed in the ITT population.  
Treatment comparisons will be tested by first comparing Arm B versus Arm C and then 
comparing Arm A versus Arm C as shown in the in the -spending algorithm (see 
Figure 3).  For each comparison, analyses will be conducted according to the
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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) for the comparison of 
Arm B versus Arm C.
The estimate of the number of events required to demonstrate efficacy with regard to 
PFS in the comparison of Arm B versus Arm C is based on the following assumptions:

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in 
the tGE population

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in 
the ITT population

97% 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 population

98% 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 population

No interim analysis 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 B versus Arm C is based on the following assumptions:

One-sided significance level of 0.022 for the comparison of Arm B versus Arm C in 
the ITT population

86% power to detect an HR of 0.75, corresponding to an improvement in median 
OS from 12 months to 16 months in the ITT population

One interim OS analysis performed at the time of the final PFS analysis, at which 
time approximately 76% 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
The estimate of the number of events required to demonstrate efficacy with regard to 
PFS and OS in the comparison of Arm A versus Arm C is based on assumptions similar 
to those outlined above for Arm B versus Arm C.
With these assumptions, approximately 1025 patients in total will be enrolled into this 
study, with approximately 684 patients in each comparison (i.e., Arm B vs. Arm C, Arm A 
vs. Arm C).  The final PFS analysis will be conducted when all of the following criteria 
have been met:  approximately 240 PFS events have occurred in Arms B and C 
combined in the tGE population, approximately 499 PFS events have occurred in 
Arms B and C combined in the ITT population, and the last patient has been enrolled in 
the study.  The final PFS analysis is expected to occur approximately 30 months after 
the first patient is enrolled.  These numbers of events would allow for a minimum 


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detectable difference corresponding to an HR of approximately 0.70 in the tGE 
population and approximately 0.75 in the ITT population.
With a sample size of 684 patients, approximately 477 OS events are expected to occur 
in Arms B and C combined in the ITT population for the final OS analysis.  The final OS 
analysis is expected to occur approximately 39 months after the first patient is enrolled.  
This number of events would allow for a minimum detectable difference corresponding to 
an HR of 0.83 in the ITT 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 and the ITT population.  Major protocol deviations, including major deviations 
with regard to inclusion/exclusion criteria, will be reported and summarized by treatment 
arm for the ITT 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 population and the ITT 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 treatments. 
6.4
EFFICACY ANALYSES
6.4.1
Co-Primary Efficacy Endpoints
The co-primary efficacy endpoints are PFS, as assessed by the investigator according to
RECIST v1.1, and OS.  PFS will be analyzed in the tGE population and the ITT 
population.  OS will be analyzed in the ITT 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 died 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 




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b.
If the null hypothesis is rejected for PFS analysis in the ITT population (Step 2),
OS in the ITT population will be tested at 0.025 (one sided).
Comparison of Arm A versus Arm C
If the difference in OS between Arm B and Arm C in the ITT population is statistically 
significant at an of 0.022 or 0.025 (Step 3), that same will become the overall 
one-sided type I error rate for the comparison of Arm A versus Arm C, with allocated 
to PFS and OS at the same 3:22 ratio (see Figure 3 in Section 6.1). If the difference in 
OS between Arm B and Arm C in the ITT population is not statistically significant, there 
will be no formal comparison of Arm A versus Arm C for the co-primary endpoints of 
PFS and OS.
1.
If the difference in OS between Arm B and Arm C is statistically significant at
0.022 (one sided):
a.
PFS in the tGE population will be tested at 0.00264 (one sided).  If the
estimate of the HR is 1 and the one-sided p-value corresponding to the
stratified log-rank test is 0.00264, the null hypothesis will be rejected and it will
be concluded that atezolizumabcarboplatinpaclitaxel prolongs the duration of
PFS relative to control treatment in the tGE population.
b.
If the null hypothesis is rejected in the tGE population (Step 1a), PFS in the ITT
population will be tested at 0.00264 (one sided).
c.
recycling from PFS to OS will be conducted as follows:

If the null hypothesis is not rejected in the ITT population (Step 1b), OS in
the ITT population will be tested at 0.01936 (one sided).

If the null hypothesis is rejected in the ITT population (Step 1b), OS in the
ITT population will be tested at 0.022 (one sided).
2.
If the difference in OS between Arm B and Arm C is statistically significant at
0.025 (one sided):
a.
PFS in the tGE 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paclitaxel prolongs the duration of PFS relative
to control treatment in the tGE population.
b.
If the null hypothesis is rejected in the tGE population (Step 2a), PFS in the ITT
population will be tested at 0.003 (one sided).
c.
recycling from PFS to OS will be conducted as follows:

If the null hypothesis is not rejected in the ITT population (Step 2b), OS in
the ITT population will be tested at 0.022 (one sided).

If the null hypothesis is rejected in the ITT population (Step 2b), OS in the
ITT population will be tested at 0.025 (one sided).


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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 population and the TC1/2/3 or IC1/2/3 
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 population, the TC2/3 or IC2/3 population, and the 
TC1/2/3 or IC1/2/3 population, through use of the same methods described for the 
primary OS analysis (see Section 6.4.1).  
6.4.2.2
Objective Response Rate
An objective response is defined as either an unconfirmed CR or a PR, as determined 
by the investigator according to 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 population and the ITT 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 described in Section 6.4.1.
6.4.2.3
Duration of Response
DOR will be analyzed in the tGE population and in the ITT population.  DOR will be 
assessed in patients who had an objective response as determined by the investigator 
according to 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 the 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.  


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DOR is based on a non-randomized subset of patients (specifically, patients who 
achieved an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between treatment arms will be made for 
descriptive purposes.  The methodologies detailed for the PFS analysis will be used for 
the DOR analysis.
6.4.2.4
Overall Survival Rate at Landmark Timepoints
OS rate at 1 and 2 years will be analyzed in the tGE population and the ITT 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 Greenwood’s formula.  The 95% CI for the difference in OS rates between the two 
treatment arms will be estimated using the normal approximation method.
6.4.2.5
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 population 
and the ITT 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 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.


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For OS, data for patients who are not reported as having died will be analyzed as 
censored observations on the date they were last known to be alive.  If no post-baseline 
data are available, OS will be censored at the date of randomization plus 1 day. 
For DOR, data for patients who have not progressed and who have not died at the time 
of analysis will be censored at the time of the last tumor assessment date.  If no tumor 
assessments were performed after 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 when they completed an assessment.  If no 
post-baseline assessment is performed, data for patients will be censored at 
randomization date plus 1 day.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety-evaluable population, which is defined 
as all randomized patients who receive any amount of any components of protocol 
treatments.  Patients will be allocated according to whether any full or partial dose of 
atezolizumab was received.  Specifically for patients randomized to Arm C, if 
atezolizumab was received by mistake, patients will be grouped under Arm B in the 
safety analyses.
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.


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6.6
PHARMACOKINETIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 2.  Atezolizumab 
serum concentration data (Cmin and Cmax) will be tabulated and summarized.  Descriptive 
statistics will include means, medians, ranges, and standard deviations, as appropriate.
Plasma concentrations of carboplatin, paclitaxel, and nab-paclitaxel (reported as total 
paclitaxel) will be collected in this study as outlined in Appendix 2.  The concentrations of 
carboplatin, paclitaxel, and nab-paclitaxel (reported as total 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 rate at various timepoints (e.g., 6 months and at 1 year after randomization)
will be estimated by the Kaplan-Meier methodology for each treatment arm, with 95% 
CIs calculated using Greenwood’s formula.  The 95% CIs for the difference in PFS rates 
between the two treatment arms (i.e., Arm A vs. Arm C and Arm B vs. Arm C) 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 for the comparisons between the two treatment arms (i.e., Arm A vs. 
Arm C and Arm B vs. Arm C) 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 receipt of nonprotocol-specified anti-cancer therapy.
6.7.1.3
Subgroup Analysis
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG 
performance status, 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 for the comparisons between two treatment arms (i.e., Arm A vs.
Arm C and Arm B vs. Arm C) (Lewis and Clarke 2001).


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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 all treatment arms.  Statistical 
methodologies that are analogous to those used in the primary analysis of PFS as 
specified in Section 6.4.1 will be used for this sensitivity analysis.
6.7.2
Exploratory Analyses of Overall Survival
6.7.2.1
Loss to Follow-up
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  If 5% of patients are lost to follow-up for OS in either 
treatment arm, a sensitivity analysis will be performed for the comparisons between two 
treatment arms (i.e., Arm A vs. Arm C and Arm B vs. Arm C) 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 between two treatment arms 
(i.e., Arm A vs. Arm C and Arm B vs. Arm C) (Lewis and Clarke 2001).
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.
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 


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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 365 OS events have occurred in Arms B and C combined in the ITT 
population at the time of the final PFS analysis (see criteria for final PFS analysis in 
Section 6.1), an interim OS analysis will be conducted for Arm B versus Arm C in the ITT 
population.  If there are significantly fewer than the expected 365 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 final PFS analysis and a second interim OS 
analysis will then be conducted after approximately 365 OS events have occurred.




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Table 26 Analysis Timing and Stopping Boundaries for Overall Survival 
in the ITT Population:  Arm A vs. Arm C
A.  Boundaries if difference in OS between Arm B and Arm C in the ITT population 
was statistically significant at 0.022.
Analysis Timing
Stopping Boundary:  HR (p-value)
If 0.01936
If 0.022
Interim OS analysis
HR0.775
(p0.0075)
HR0.780
(p0.0088)
Final OS analysis
HR0.824
(p0.0171)
HR0.828
(p0.0194)
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.
B.  Boundaries if difference in OS between Arm B and Arm C in the ITT population 
was statistically significant at 0.025.
Analysis Timing
Stopping Boundary:  HR (p-value)
If 0.022
If 0.025
Interim OS analysis
HR0.780
(p0.0088)
HR0.785
(p0.0104)
Final OS analysis
HR0.828
(p0.0194)
HR0.832
(p0.0219)
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 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 


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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.
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 


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data transfers will occur from the centralized database at the vendor to the database at 
the Sponsor.
Once the study is complete, the ePRO data, audit trail, and study and system 
documentation will be archived.  The Sponsor will receive all data entered by patients on 
the e-diary and tablet device and all the 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 


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acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, the name of the 
person making the change, and the date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final 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.


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The Informed Consent Form will contain a separate section that addresses the use of 
remaining samples for optional exploratory research.  The investigator or authorized 
designee will explain to each patient the objectives of the exploratory research.  Patients 
will be told that they are free to refuse to participate and may withdraw their specimens 
at any time and for any reason during the storage period.  A separate, specific signature 
will be required to document a patient's agreement to allow any remaining specimens to 
be used for exploratory research.  Patients who decline to participate will not provide a 
separate signature.
The Informed Consent Form will also contain the following additional signature pages:

A signature page for patients receiving atezolizumab who wish, if approved by the 
treating physician, to continue treatment beyond initial radiographic disease 
progression per RECIST v1.1 and meet criteria specified in Section 4.6.2.  This 
separate consent is to be signed after initial radiographic disease progression per 
RECIST v1.1 has occurred and patients have discussed other available treatment 
options and the potential risks of continuing treatment.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (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 


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processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the 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.  


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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor or a 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 310 sites globally will participate in the study and approximately 
1025 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.
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 


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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
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Appendix 1
Schedule of Assessments
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up 
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months 
after Disease 
Progression or Loss 
of Clinical Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Informed consent 
x
Tumor tissue specimen for PD-L1 testing 
(15 FFPE slides required; blocks preferred) c
Fresh or archival tissue can be used
x
Demographic data
x
Medical history and baseline conditions
x
NSCLC cancer history 
x
Vital signs d
x
x
x
x
Weight
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examination e
x
x
x
ECOG performance status
x
x
x
x
12-Lead ECG
x
x f
x f
x f
Hematology g
x
x
x
x
Serum chemistry h
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol GO29437, Version 7
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up 
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months 
after Disease 
Progression or Loss 
of Clinical Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Coagulation test (aPTT or INR)
x
x
Pregnancy test (women of childbearing-potential 
ONLY)
x i
x j
x j
x j
x y
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 paclitaxel
Arm B: Atezolizumab carboplatin nab-paclitaxel
Arm C: Carboplatin nab-paclitaxel)
x n
Maintenance treatment administration
Arm A: Atezolizumab
Arm B: Atezolizumab
Arm C: Best supportive care o
x n
Tumor response assessment
x p
x q
x q
x r
Serum sample for ATA assessment 
x
x
x
120 (30) days 


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol GO29437, Version 7
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up 
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months 
after Disease 
Progression or Loss 
of Clinical Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
(atezolizumab-treated patients only) s
after last dose
Serum sample for PK sampling
(atezolizumab-treated patients only) s
x
x
x
120 (30) days 
after last dose
Carboplatin, paclitaxel, and nab-paclitaxel PK 
sampling as applicable (20 patients per arm) s
x
Blood samples for PD biomarkers s
x
x
x
x
120 (30) days 
after last dose
Optional blood for DNA extraction 
(RCR only) s, t
x
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab-treated 
patients only)
At time of radiographic progression
Tumor biopsy 
At time of radiographic progressionu
Optional tumor biopsy at other timepoints 
(RCR only)
Any time during study treatment or during survival follow-up
Adverse events v
x
x
x
x v


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol GO29437, Version 7
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up 
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months 
after Disease 
Progression or Loss 
of Clinical Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Concomitant medications
From 7 days 
before 
screening
x
x
x
Patient-reported outcomes w
x w
x w
x w
Survival and anti-cancer therapy follow-up x
x
ATAanti-therapeutic antibody; BSCbest supportive care; ECOGEastern Cooperative Oncology Group; EORTCEuropean Organization for 
Research and Treatment of Cancer; 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; ICF Informed Consent Form; IVintravenous; QLQ-LC13Lung Cancer module; 
NSCLCnonsmall cell lung cancer; PDpharmacodynamic; PD-L1programmed deathligand 1; PGISPatient Global Impression of Severity; 
PKpharmacokinetic; QLQ-C30Quality-of-Life Questionnaire Core 30; SILCSymptoms in Lung Cancer; EQ-5D-3 Level version; 
TSHthyroid-stimulating hormone.
Note:  For patients who are randomized to Arm C who receive erlotinib switch maintenance allowed under previous protocol versions, patients will 
continue with cycle visits at the same frequency as those patients randomized to Arms A and B until disease progression, withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first.
a Assessments should be performed before study drug infusion unless otherwise noted. 
b Except for Cycle 1, Day 1, which must be performed within 5 days after the patient is randomized. 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.  
Screening assessments performed 96 hours before Cycle 1, Day 1, do not need to be repeated for Cycle 1 Day 1.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol GO29437, Version 7
c If a representative FFPE tumor specimen in paraffin block (preferred) or 15 (or more) unstained, freshly cut, serial sections on slides from an FFPE 
tumor specimen are not available for PD-L1 testing, contact the Medical Monitor to discuss to determine if the patient may participate in the study.  
Fine-needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or cell smears), brushing, cell 
pellets from pleural effusion, and lavage samples are NOT acceptable.  For core needle biopsy specimens, at least three cores should be 
submitted for evaluation.  Retrieval of archival tumor sample may occur outside the 28-day screening period prior to enrollment.  See 
Section 4.5.7.1 and the inclusion criteria in Section 4.1.1. 
d Vital signs include pulse rate, respiratory rate, blood pressures, and temperature.  Vital signs should be recorded as described in Section 4.5.4.  
For all sites in Argentina, pulse oximetry will be performed at every visit; these data will not be recorded.
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 5.1.10.1 (Table 19) for dose modifications due to hematological toxicities.
h Serum chemistry includes BUN, 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 5.1.10.6 (Table 23) for dose modifications 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, free T3, free T4) collected at Cycle 1, Day 1, and every fourth cycle thereafter.  Total T3 to 
be tested only at sites where free T3 testing cannot be performed.
l
All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study. 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, paclitaxel, and nab-paclitaxel, study drug will be administered according to the local prescribing 
information, including premedication with steroids (see Section 4.3.2).


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol GO29437, Version 7
o Only patients who are already receiving switch maintenance therapy with erlotinib, permitted under previous protocol versions, may be allowed to 
remain on treatment with erlotinib after discussion of the risks, potential benefits, and alternative treatment options with the investigator.
p 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.
q Perform every 6 weeks (7 days) (approximately every two cycles) for 48 weeks following Cycle 1, Day 1, and then, after completion of the 
Week 48 tumor assessment, every 9 weeks (7 days) 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.
r
If a patient discontinues study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration, tumor assessments will continue at the same frequency as would have been followed if the patient had remained on study treatment 
until radiographic disease progression (loss of clinical benefit for patients treated with atezolizumab who continue treatment after disease 
progression according to RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if patient 
starts another anti-cancer therapy after study treatment discontinuation.
s See Appendix 2 for the detailed schedule.
t
The optional RCR whole blood sample requires an additional informed consent and can be collected at any time during the course of the study.
u Mandatory tumor biopsy at radiographic disease progression, if clinically feasible, within 40 days of radiographic progression or prior to start of the 
next anti-cancer therapy, whichever occurs is sooner.
v All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study treatment (inclusive of erlotinib switch maintenance for patients who are randomized to Arm C who receive switch maintenance 
allowed under previous protocol versions) or initiation of new systemic anti-cancer therapy after last dose of study treatment.  All other adverse 
events, regardless of relationship to study drug, will be reported until 30 days after the last dose of study treatment (inclusive of erlotinib switch 
maintenance for patients who are randomized to Arm C who receive switch maintenance allowed under previous protocol versions) or initiation of 
new systemic anti-cancer therapy after last dose of study treatment.  After this period, , all deaths should continue to be reported.  In addition, the 
Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that is believed to 
be related to prior exposure to study treatment (see Section 5.6).


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol GO29437, Version 7
w 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 using an ePRO device at the patient’s 
home on a weekly basis.  During survival follow-up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L will be completed at 3 and 6 
months following disease progression.  The SILC would be completed monthly during survival follow-up for 6 months following disease progression 
or 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 per 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 in the ePRO device or who are deemed by the investigator 
incapable of inputting their ePRO assessment after undergoing appropriate training are exempt from all ePRO assessments.
x 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. 
y For Argentina sites only: A urine pregnancy test is required monthly until 6 months after the last dose of study treatment.


Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol GO29437, Version 7
Appendix 2
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Therapeutic Antibody Assessments
Study Visit
Time
Arm A 
(Atezolizumab 
Carboplatin 
Paclitaxel)
Arm B
(Atezolizumab 
Carboplatin 
nab-Paclitaxel)
Arm C
(Carboplatin 
nab-Paclitaxel)
Screening
N/A

Biomarkers b

Biomarkers b

Biomarkers b
Cycle 1, Day 1e
Predose 
(same day as 
treatment 
administration) 

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Carboplatin 
pharmacokinetics a

Paclitaxel 
pharmacokinetics a

Biomarkers d

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

Atezolizumab 
pharmacokinetics
510 min before the 
end of paclitaxel 
infusion a

Paclitaxel 
pharmacokinetics a
1 hour after the end 
of paclitaxel 
infusion a

Paclitaxel 
pharmacokinetics a
510 min before the 
end of nab-paclitaxel 
infusion a

nab-Paclitaxel 
pharmacokinetics a

nab-Paclitaxel 
pharmacokinetics a
1 hour after the 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

Carboplatin 
pharmacokinetics a
1 hour after the end 
of carboplatin 
infusion a

Carboplatin 
pharmacokinetics a

Carboplatin 
pharmacokinetics a

Carboplatin 
pharmacokinetics a
Cycle 2, Day 1 
(3 days)
Predose 
(same day as 
treatment 
administration)

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Biomarkers d


Appendix 2
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and ATA Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol GO29437, Version 7
Study Visit
Time
Arm A 
(Atezolizumab 
Carboplatin 
Paclitaxel)
Arm B
(Atezolizumab 
Carboplatin 
nab-Paclitaxel)
Arm C
(Carboplatin 
nab-Paclitaxel)
Cycle 3, Day 1 
(3 days)
Predose 
(same day as 
treatment 
administration)

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Carboplatin 
pharmacokinetics a

Paclitaxel 
pharmacokinetics a

Biomarkers d

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Carboplatin 
pharmacokinetics a

nab-Paclitaxel 
pharmacokinetics a

Biomarkers d

Biomarkers d

Carboplatin 
pharmacokinetics a

nab-Paclitaxel 
pharmacokinetics a

Biomarkers d
30 min (10 min) 
after end of 
atezolizumab 
infusion

Atezolizumab 
pharmacokinetics

Atezolizumab 
pharmacokinetics
510 min before the 
end of paclitaxel 
infusion a

Paclitaxel 
pharmacokinetics a
1 hour after the end 
of paclitaxel infusion a

Paclitaxel 
pharmacokinetics a
510 min before the 
end of nab-paclitaxel 
infusion a

nab-Paclitaxel 
pharmacokinetics a

nab-Paclitaxel 
pharmacokinetics a
1 hour after the 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

Carboplatin 
pharmacokinetics a
1 hour after the end 
of carboplatin 
infusion a

Carboplatin 
pharmacokinetics a

Carboplatin 
pharmacokinetics a

Carboplatin 
pharmacokinetics a
Cycles 4, 8, 
and 16, Day 1 
(3 days)
Predose 
(same day as 
treatment 
administration)

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Biomarkers d
After Cycle 16, 
every eighth 
cycle, Day 1 
(3 days)
Predose 
(same day as 
treatment 
administration)

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Biomarkers d


Appendix 2
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and ATA Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol GO29437, Version 7
Study Visit
Time
Arm A 
(Atezolizumab 
Carboplatin 
Paclitaxel)
Arm B
(Atezolizumab 
Carboplatin 
nab-Paclitaxel)
Arm C
(Carboplatin 
nab-Paclitaxel)
At time of fresh 
biopsy 
(on-treatment, 
or at 
progression, 
including during 
follow-up)
At visit

Biomarkers d

Biomarkers d

Biomarkers d
Treatment 
discontinuation 
visit
At visit

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Biomarkers d
120 30 days 
after last dose 
of atezolizumab
At visit

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Biomarkers d
Any time point 
during study 
(RCR consent 
required)

Optional RCR 
blood (DNA 
extraction) c

Optional RCR blood 
(DNA extraction) c
Optional RCR blood 
(DNA extraction) c
ATAanti-therapeutic antibody; PKpharmacokinetic; RCRRoche Clinical Repository.
Note:  Serum PK samples for atezolizumab and plasma PK samples for carboplatin, paclitaxel, 
and nab-paclitaxel.
a Twenty patients in each treatment arm will undergo the additional PK assessments for 
carboplatin, paclitaxel, and nab-paclitaxel, where applicable.
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
174/Protocol GO29437, Version 7
Appendix 3
American Joint Committee on Cancer 
NonSmall Cell Lung Cancer Staging, 7th Edition


Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol GO29437, Version 7
Appendix 3
American Joint Committee on Cancer 
NonSmall Cell Lung Cancer Staging, 7th Edition (cont.)
Reference:  Lung. In: Edge S, Byrd DR, Compton CC, et al., editors. AJCC cancer staging 
Manual, Seventh Edition. Chicago: Springer, 2010:267–70.


Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol GO29437, Version 7
Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows.
a.
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of:

10 mm by 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 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:22847.
2
For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


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


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Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).
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.
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 


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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.
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 


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Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b.
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
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.


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


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


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


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


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


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


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment.
Modified Response Evaluation Criteria in Solid Tumors (RECIST) is derived from 
RECIST, Version 1.1 (v1.1) conventions3 and immune-related response criteria4 (irRC).  
When not otherwise specified, RECIST v1.1 conventions will apply.
Modified RECIST and RECIST v1.1:  Summary of Changes
RECIST v1.1
Modified RECIST
New lesions after baseline
Define progression
New measurable lesions are 
added into the total tumor 
burden and followed.
Non-target lesions
May contribute to the 
designation of overall 
progression
Contribute only in the 
assessment of a complete 
response
Radiographic progression
First instance of 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease
Determined only on the basis 
of measurable disease
RECIST Response Evaluation Criteria in Solid Tumors.
A.
DEFINITIONS OF MEASURABLE/NON-MEASURABLE LESIONS
All measurable and non-measurable lesions should be assessed at Screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
performed, as clinically indicated for suspicion of progression.  
                                           
3
Eisenhauer et al. Eur J Cancer 2009;45: 22847; Topalian et al. N Engl J Med
2012;366:244354; and Wolchok et al., Clin Can Res 2009;15:741220.
4
Wolchok et al. Clin Can Res 2009;15:741220; Nishino et al. J Immunother Can 2014;2:17; 
Nishino et al. Clin Can Res 2013;19:393643.


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


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


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


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


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
B.3
RESPONSE CRITERIA
Timepoint Response
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
Complete Response (CR):  Disappearance of all target and non-target lesions.  Lymph 
nodes that shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
Note: the appearance of new measurable lesions is factored into the overall tumor 
burden, but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
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 


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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
those gave a sum of 80 mm, the patient will be assigned PD status, regardless of the 
contribution of the missing lesion.
Table 1  Modified RECIST Timepoint Response Definitions
% Change in Sum of the Diameters a
Non-Target Lesion 
Response 
Assessment
Overall Modified RECIST 
Timepoint Response
100% from baseline b
CR
CR
100% from baseline b
Non-CR or not all 
evaluated
PR
30% from baseline
Any
PR
30% to 20%
Any
SD
Not all evaluated
Any
NE
20%from nadir SLD
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; RECIST Response Evaluation Criteria in Solid Tumors; SDstable disease; 
SLDsum of the longest diameter.
a Percent change in sum of the diameters (including measurable new lesions when 
present).
b When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met, 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 6
AntiPD-L1 Immunohistochemistry
OVERVIEW
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody 
Immunohistochemistry (IHC) assay will be used to determine 
programmed death-ligand 1 (PD-L1) IHC status.  The antiPD-L1 (SP142) rabbit 
monoclonal antibody IHC assay is currently being developed by Ventana Medical 
Systems as a companion diagnostic to atezolizumab.  For Study GO29437, 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 (TCs) and tumor-infiltrating immune cells (ICs).
Details of the criteria for PD-L1 diagnostic assessment are described in the IDI 
document.


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Appendix 7
EORTC QLQ-C30


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 7
EORTC QLQ-C30 (cont.)


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Appendix 8
EORTC QLQ-LC13




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Appendix 9
EQ-5D-3L (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 9
EQ-5D-3L (cont.)


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Appendix 10
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead


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Appendix 11
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
203/Protocol GO29437, Version 7
Appendix 12
Preexisting Autoimmune Diseases
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias 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 13
Symptoms in Lung Cancer


Atezolizumab—F. Hoffmann-La Roche Ltd
205/Protocol GO29437, Version 7
Appendix 13
Symptoms in Lung Cancer (cont.)


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Appendix 13
Symptoms in Lung Cancer (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 14
Patient Global Impression of Severity


Atezolizumab—F. Hoffmann-La Roche Ltd
208/Protocol GO29437, Version 7
Appendix 15
Additional Guidance on Chemotherapy Administration
For the purposes of this protocol, the Sponsor defines a chemotherapy cycle as the 
administration of at least one chemotherapy component for at least one time 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 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


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209/Protocol GO29437, Version 7
Appendix 15
Additional Guidance on Chemotherapy Administration (cont.)
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, the remaining components should be 
delayed until the next cycle and the chemotherapy induction cycle considered not done 
(Arm A), or 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 (Arms B and C).
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.

SAP_001.pdf: 
 
Official Title: 
 
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTI-PD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATIN +PACLITAXEL OR 
ATEZOLIZUMAB IN COMBINATION WITH CARBOPLATIN+NAB-
PACLITAXEL VERSUS CARBOPLATIN+NAB-PACLITAXEL IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV SQUAMOUS 
NON-SMALL CELL LUNG CANCER 
NCT Number: 
NCT02367794 
Document Date: 
SAP Version 3: 11-January-2018 
 
 
 


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
1/Statistical Analysis Plan GO29437, Version 3
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATINPACLITAXEL OR 
ATEZOLIZUMAB IN COMBINATION WITH 
CARBOPLATINNAB-PACLITAXEL VERSUS 
CARBOPLATINNAB-PACLITAXEL IN CHEMOTHERAPYNAÏVE
PATIENTS WITH STAGE IV SQUAMOUS NONSMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29437
STUDY DRUG:
Atezolizumab (RO5541267)
VERSION NUMBER:
3
IND NUMBER:
117296
EUDRACT NUMBER:
2014-003208-59
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
19 May 2017
DATES AMENDED
Version 2: 26 September 2017
Version 3: See electronic date stamp below.
Name                                                             Reason for Signing                              Date and Time
(UTC)
1 -Jan-2018 
:
:
Company Signatory
Name                                                             Reason for Signing                              Date and Time
(UTC)
11-Jan-2018 07:27:08
Company Signatory


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan GO29437, Version 3
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE
The following changes have been made in Statistical Analysis Plan (SAP) GO29437, 
Version 3:
1.
Per modification plan in Appendix 4 of SAP GO29437, Version 2 for primary 
analysis, Statistical Analysis Plan (SAP) GO29437, Version 2 has been amended to 
reflect the final statistical testing strategy prior to study database lock and unblinding.  
In SAP GO29437, Version 2, based on recently available data from Study GO29436 
that are external to Study GO29437. 
–
The primary analysis of progression-free survival (PFS) was planned to be 
conducted hierarchically:  first, in patients with high expression of the T-effector 
(Teff) gene signature (Teff-high, previously referred to as tGE) and,
subsequently, in the intent-to-treat (ITT) population (Section 2.3).  Based on 
recently available data from Study GO29436 suggest that the treatment effect 
on PFS is observed in the ITT population, thus in accord with the modification 
scenarios, the primary analysis of PFS in SAP GO29437, Version 3 will be 
conducted in the ITT population directly, i.e., testing of PFS in the Teff-high 
population has been removed from the primary testing hierarchy.
–
Recent external data from Study GO29436 also suggest that the treatment 
effect on overall survival (OS) may be delayed such that an accurate 
assessment of the magnitude of the effect will take longer than initially expected.  
Thus, a second OS interim analysis with spending has been added for when 
approximately 410 OS events have occurred in Arm B and Arm C combined.  
The previously planned initial interim analysis at the time of primary PFS 
analysis will still be conducted but with a nominal spent (Section 2.4.2).
2.
Based on recent data from Study GO29436, the patient-reported outcomes (PRO) 
time to deterioration (TTD) analysis was modified to form a composite symptom 
endpoint rather than assessing each individual symptom.  PRO responder analyses 
were also added to help interpret the results from the change from baseline 
analyses.
This amendment represents cumulative changes to the original analysis plan.  Additional 
minor changes have been made to improve clarity and consistency.


Atezolizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan GO29437, Version 3
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT  RATIONALE............................ 2
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 8
2.2
Outcome Measures ................................................................. 8
2.2.1
Primary Efficacy 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 ..................................................................... 13
2.4.1
Primary Analysis Timing for PFS........................................... 13
2.4.2
Interim and Final Analysis Timing for OS............................... 14
3.
STUDY CONDUCT..................................................................................... 17
3.1
Randomization Issues ........................................................... 17
3.2
Independent Review Facility.................................................. 17
3.3
Data Monitoring ..................................................................... 17
4.
STATISTICAL METHODS .......................................................................... 18
4.1
Analysis Populations ............................................................. 18
4.1.1
Randomized Population /ITT Population ............................... 18
4.1.2
Pharmacokinetic Evaluable Population ................................. 18
4.1.3
Safety Population .................................................................. 19
4.2
Analysis of Study Conduct..................................................... 19
4.3
Analysis of Treatment Group Comparability .......................... 19
4.4
Efficacy Analysis.................................................................... 19
4.4.1
Primary Efficacy Endpoint...................................................... 19
4.4.2
Secondary Efficacy Endpoints............................................... 22
4.4.2.1
PFS and OS in Teff Populations............................................ 22
4.4.2.2
PFS and OS in PD-L1 Populations........................................ 22


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4/Statistical Analysis Plan GO29437, Version 3
4.4.2.3
Objective Response Rate...................................................... 22
4.4.2.4
Duration of Response............................................................ 22
4.4.2.5
OS Rate at 1- and 2-Year Landmark Timepoints................... 22
4.4.2.6
Investigator-Assessed PFS and OS Comparison 
between Atezolizumab-Containing Arms............................... 23
4.4.2.7
Patient-Reported Outcomes .................................................. 23
4.4.3
Exploratory Efficacy Endpoints.............................................. 24
4.4.3.1
Progression-Free Survival Rates at 6 Months and 
1 Year.................................................................................... 24
4.4.3.2
Overall Survival Rate at 3 Years............................................ 24
4.4.3.3
EQ-5D-3L Health Status Data ............................................... 24
4.4.3.4
Additional Patient-Reported Outcome Analyses.................... 25
4.4.4
Sensitivity Analyses............................................................... 25
4.4.4.1
Missing Tumor Assessment................................................... 25
4.4.4.2
Non-Proportional Hazard....................................................... 26
4.4.4.3
Loss to Follow-Up.................................................................. 27
4.4.4.4
Progression-Free Survival by Independent 
Review Facility....................................................................... 27
4.4.5
Subgroup Analyses ............................................................... 27
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 28
4.6
Safety Analyses..................................................................... 28
4.6.1
Exposure of Study Medication............................................... 28
4.6.2
Adverse Events ..................................................................... 29
4.6.3
Laboratory Data..................................................................... 29
4.6.4
Vital Signs.............................................................................. 29
4.6.5
Anti-Drug Antibody ................................................................ 29
4.7
Missing Data.......................................................................... 29
5.
REFERENCES ........................................................................................... 30


Atezolizumab—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan GO29437, Version 3
LIST OF TABLES
Table 1
Primary Analysis for Progression-Free Survival for Arm B
versus Arm C Comparison.......................................................... 14
Table 2
Analysis for Overall Survival for the Comparison of Arm B
versus Arm C .............................................................................. 15
Table 3
Analysis Timing and Stopping Boundary for Overall Survival 
in the Intent-to-Treat Population for the Comparison of Arm B
versus Arm C .............................................................................. 15
Table 4
Analysis Timing and Stopping Boundary for Overall Survival 
in the Intent-to-Treat Population for the Comparison of Arm A
versus Arm C .............................................................................. 16
Table 5
Significance Level (one-sided) for Comparison of Arm A
versus Arm C .............................................................................. 21
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 7
Figure 2
Progression-Free Survival and Overall Survival Analysis 
Hierarchy, Allocation, and Recycling .................................... 11
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 31
Appendix 2
Schedule of Assessments........................................................... 46
Appendix 3
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Drug Antibody Assessments......................................... 53


Atezolizumab—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan GO29437, Version 3
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study GO29437 (IMpower131), “A Phase III, Open-label, 
Multicenter, Randomized Study Evaluating the Efficacy and Safety of Atezolizumab 
(MPDL3280A, AntiPD-L1 Antibody) in Combination with CarboplatinPaclitaxel or 
Atezolizumab in Combination with CarboplatinNab-Paclitaxel versus 
CarboplatinNab-Paclitaxel in ChemotherapyNaïve Patients with Stage IV 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 
safety and efficacy of atezolizumab in combination with carboplatinpaclitaxel or with 
carboplatinnab-paclitaxel as compared with treatment with carboplatinnab-paclitaxel
in approximately 1025 chemotherapynaïve patients with Stage IV 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 1:1:1 ratio to one of the following treatment 
regimens:

Treatment Arm A: Atezolizumabcarboplatinpaclitaxel (induction: four or six 
21-day cycles); atezolizumab (maintenance: 21-day cycles)

Treatment Arm B: Atezolizumabcarboplatinnab-paclitaxel (induction: four or six
21-day cycles); atezolizumab (maintenance: 21-day cycles)

Treatment Arm C: Carboplatinnab-paclitaxel (induction: four or six 21-day cycles); 
best supportive care
Patients who were randomized to Arms A or Arm B may continue treatment with 
atezolizumab beyond radiographic disease progression by Response Evaluation Criteria 
in Solid Tumors, Version 1.1 (RECIST v1.1) provided they were 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 


Atezolizumab—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan GO29437, Version 3
[if available], and clinical status).  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 v1.1Response Evaluation Criteria in 
Solid Tumors, Version 1.1.
Note:  In Arm A, patients with Asian race/ethnicity receive paclitaxel at a dose of 175 mg/m2
(Protocol Amendment v6 dated 1 March 2017).
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 
Chemotherapy-Naive Patients with Stage IV Squamous NSCLC
(n=approximately 1025)
Arm A:
Atezolizumab (1200 mg IV Day 1)
+Carboplatin (AUC=6 IV Day 1)
+Paclitaxel (200 mg/m2 IV Day 1)
Arm B:
Atezolizumab (1200 mg IV Day 1)
+ Carboplatin (AUC=6 IV Day 1)
+nab-Paclitaxel (100 mg/m2 IV 
Days 1, 8, and 15)
Arm C:
Carboplatin (AUC=6 IV Day 1)
+nab-Paclitaxel (100 mg/m2 IV 
Days 1, 8, and 15)
Treat until 
Loss of Clinical Benefit
Treat until 
Disease Progression, per RECIST v 1.1
Survival Follow-Up
1:1:1 Randomization
Stratification Factors:
•
Sex
•
Liver metastases
•
PD-L1 expression (by central 
testing for PD-L1 status)
Induction Treatment:  Four or Six 21-Day Cycles
Maintenance Treatment:  21-Day Cycles
Arm A:
Atezolizumab (1200 mg IV)
Arm B:
Atezolizumab (1200 mg IV)
Arm C:
Best Supportive Care
No Crossover Permitted


Atezolizumab—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan GO29437, Version 3
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) continue scheduled tumor assessments until radiographic disease 
progression per RECIST v1.1 or loss of clinical benefit (for atezolizumab-treated patients 
who continue treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, study termination by Sponsor, or death, whichever 
occurs first, regardless of whether patients start a new anti-cancer therapy.
The co-primary efficacy endpoints are progression-free survival (PFS), as assessed by 
the investigator using RECIST v1.1, and overall survival (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 (the intent-to-treat [ITT] population).  See Section 4.1 for details on analysis 
populations.
There are no interim analyses planned for PFS. Two interim analyses are 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 endpoints are PFS, as assessed by the investigator using 
RECIST v1.1, and OS.

PFS is defined as the time between the date of randomization and the date of first 
documented disease progression or death, whichever occurs first, in the 
ITT population.

OS is defined as the time between the date of randomization and date of death from 
any cause in the ITT population.
2.2.2
Secondary Efficacy Measures
The secondary efficacy outcome measures for this study are:

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
PD-L1 IHC populations defined as TC2/3 or IC2/3 and TC1/2/3 or IC1/2/3 using the 
SP142 assay


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9/Statistical Analysis Plan GO29437, Version 3

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
biomarker populations defined by expression of a T-effector (Teff) gene signature in 
tumor tissue, as described in Section 4.4.5 (previously referred to as tGE)

Objective response, defined as either complete response (CR) or partial response 
(PR) as determined by the investigator according to RECIST v1.1 in the 
ITT population

Duration of response (DOR), defined for patients with 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, in the ITT population

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 for the
ITT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
two atezolizumab-containing arms in the ITT population

Time to deterioration (TTD) in patient-reported lung cancer symptoms, defined as 
time from randomization to deterioration (10-point change) on each of the European 
Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life
Questionnaire Core 30 (QLQ-30) and supplemental lung cancer module
(EORTC QLQ-LC13) symptom subscales (cough, dyspnea [single item], dyspnea 
[multi-item subscale], chest pain, and arm/shoulder pain) in the ITT 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 in the ITT population
2.2.3
Exploratory Efficacy Measures
The exploratory efficacy measures for this study are:

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

Utility scores of the Euro QoL5 Dimensions 3-Level Version (EQ-5D-3L)


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10/Statistical Analysis Plan GO29437, Version 3

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
2.2.4
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are:

Maximum observed serum atezolizumab concentration (Cmax) after infusion (Arms A
and B)

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 (Arms A and B)

Plasma concentrations for carboplatin (Arms A, B, and C)

Plasma concentrations for paclitaxel (Arm A)

Plasma concentrations for nab-paclitaxel (Arms B and C)
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, physical findings, 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 (PD), safety, and efficacy parameters
2.3
DETERMINATION OF SAMPLE SIZE
This study will randomize approximately 1025 patients.
To control the overall type I error rate for the one-sided test at 0.025 for the primary 
comparison of atezolizumabcarboplatinnab-paclitaxel (Arm B) against the control 
arm of carboplatinnab-paclitaxel (Arm C), a one-sided of 0.003 and a one-sided of
0.022 are allocated to PFS and OS, respectively.  The primary comparison of PFS will 
be tested at a one-sided level of 0.003 in the ITT population.  The primary comparison 
of OS will be tested in the ITT population at the allocated together with the recycled 
from the PFS analysis if the PFS comparison is statistically significant.
If OS in the ITT population is statistically significant between the comparison of Arm B 
versus Arm C, PFS in the ITT population and OS in the ITT population for the primary 
comparison of atezolizumabcarboplatinpaclitaxel (Arm A) against the control arm 
(Arm C) will be tested with the same level of split with the ratio of 3:22 between the 






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The estimates of the number of events required to demonstrate efficacy with regard to 
PFS in the comparison of Am B versus Arm C are based on the following assumptions:

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in 
the ITT population

98% 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 population

No interim analysis for PFS

Dropout rate of 5% per 12 months
The estimates of the number of events required with regard to OS in the comparison of 
Am B versus Arm C are based on the following assumptions:

One-sided significance level of 0.022 for the comparison of Arm B versus Arm C in 
the ITT population

86% power to detect an HR of 0.75, corresponding to an improvement in median 
OS from 12 months to 16 months in the ITT population

First OS interim analysis performed at approximately 53% event-patient ratio (EPR) 
with nominal spent (one sided 0.0001), a second OS interim analysis 
performed at approximately 60% EPR or approximately 86% of the total OS events 
required for the final analysis using the Lan-DeMets approximation to the 
O’Brien-Fleming boundary for group sequential design

Dropout rate of 5% per 24 months
The estimates of the number of events required to demonstrate efficacy with regard to 
PFS and OS in the comparison of Arm A versus Arm C are based on assumptions 
similar to those outlined above for Arm B versus Arm C.
With these assumptions, approximately 1025 patients in total will be randomized into this 
study, with approximately 684 patients in each comparison (i.e., Arm A vs. Arm C, Arm B
vs. Arm C).
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 for the primary comparison of Arm B versus Arm C will be 
conducted when approximately 365 OS events in the ITT population have occurred in 
Arm B and Arm C combined, which is when the first planned interim analysis of OS as 
described in Section 2.4.2 will be conducted.  It is expected that there will be 
approximately 499 PFS events in the ITT population in Arm B and Arm C combined at 
this timepoint.  These numbers of events correspond to a minimum detectable difference 
(MDD) in HR of approximately 0.78 in the ITT population.  It is projected that an 
observed HR of 0.78 or lower will result in a statistically significant difference between 
treatment arms in the ITT population in this analysis.  The PFS primary analysis is 


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expected to occur approximately 30 months after the first patient is randomized based 
on the study assumptions and the projected accrual rate.
Table 1
Primary Analysis for Progression-Free Survival for Arm B versus 
Arm C Comparison
Population
Analysis Timing 
(Months from FPI)
No. of Events 
(Event Ratio, %)
MDD in Hazard Ratio
Power, %
ITT
30
499 (73)
0.78
98
FPI first patient in; ITT intent-to-treat; MDD minimum detectable difference.
The PFS analysis between Arm A and Arm C will be performed at the same time as the 
Arm B and Arm C comparison.  However, the statistical significance will be claimed in 
accordance with the testing strategy in Figure 2 depending on the recycled to the 
comparison of Arm A versus Arm C.
2.4.2
Interim and Final Analysis Timing for OS
There are two interim analyses planned for the co-primary endpoint of OS.
The first OS interim analysis for the primary comparison of Arm B versus Arm C will be 
conducted when approximately 365 OS events in the ITT population have occurred in 
Arm B and Arm C combined, with nominal spent (one sided 0.0001) on the 
comparison.  At the time of the first OS interim analysis, the final PFS analysis will be 
conducted by the Sponsor. 
The second OS interim analysis for the primary comparison of Arm B versus Arm C will 
be conducted when approximately 410 OS events in the ITT population have occurred in 
Arm B and Arm C combined.  This number of events corresponds to a MDD in HR of 
approximately 0.80 in the ITT population.  The OS second interim analysis is expected to 
occur approximately 33 months after the first patient is randomized.
The final OS analysis for the primary comparison of Arm B versus Arm C will be 
conducted when there are approximately 477 OS events in the ITT population in Arm B
and Arm C combined. This number of events corresponds to a MDD in HR of 
approximately 0.83 in the ITT population.  The OS final analysis is expected to occur 
approximately 39 months after the first patient is randomized.
The expected analysis timing for the OS interim and final analyses for the comparison of 
Arm B versus Arm C is shown in Table 2.


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Table 2
Analysis for Overall Survival for the Comparison of Arm B versus 
Arm C
Type of Analysis
Analysis Timing
ITT Population
Months from 
FPI
Percentage 
Information, %
No. of Events 
(Event Ratio, %)
Power, %a
OS first interim 
analysis
30
76
365 (53)
18
OS second interim 
analysis
33
86
410 (60)
76
OS final analysis
39
100
477 (70)
86
FPIfirst patient in; ITT intent-to-treat; OSoverall survival.
a Power is calculated using one-sided of 0.022.
The stopping boundaries for the second interim and final OS analyses will be calculated 
using the Lan-DeMets approximation to the O’Brien-Fleming boundary.  The stopping 
boundaries for the comparison of Arm B versus Arm C in the ITT population, assuming 
the specified observed number of events at each analysis (365, 410, and 477, 
respectively), are shown in Table 3.  The p-value will be used to claim crossing of the 
boundaries.  For example, if approximately 410 events have occurred at the time of the 
OS second interim analysis in the ITT population for Arm B and Arm C combined, 
statistical significance of the OS endpoint in the ITT population will be declared for 
Arm B if one-sided p 0.0156 when PFS has claimed significance in the ITT population.
Table 3
Analysis Timing and Stopping Boundary for Overall Survival in 
the Intent-to-Treat Population for the Comparison of Arm B
versus Arm C
Analysis Timing
Stopping Boundary in HR (p-value)
If 0.022a
If 0.025b
OS first interim 
analysis
HR0.682
(p-value≤0.0001)
HR0.683 
(p-value0.0001)
OS second interim 
analysis
HR0.804 
(p-value0.0134)
HR0.808 
(p-value0.0156)
OS final analysis
HR0.826
(p-value0.0182)
HR0.830
(p-value0.0206)
HRhazard ratio; OSoverall survival.
a.
When the PFS result is not statistically significant in the ITT population for Arm B vs Arm C 
comparison. 
b.
When the PFS result is statistically significant in the ITT population for Arm B vs Arm C 
comparison
Note:  and p-value are one-sided.
The OS analysis between Arm A and Arm C will be performed at the same time as the 
Arm B versus Arm C comparison.  However, the statistical significance will be claimed in 


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accordance with the testing strategy in Figure 2 depending on the recycled to the 
comparison of Arm A versus Arm C.  If the difference in OS between Arm B and Arm C
in the ITT population is statistically significant at an one-sided of 0.022 or 0.025, that 
same will become the overall one-sided type I error rate for the comparison of Arm A
versus Arm C, as described in Section 2.3.  The stopping boundaries for the interim and 
final OS analyses for the comparison of Arm A versus Arm C in the ITT population, 
assuming the specified observed number of events at each analysis (365, 410, and 477, 
respectively), are provided for the two scenarios (0.022 or 0.025) in Table 4.
Table 4
Analysis Timing and Stopping Boundary for Overall Survival in 
the Intent-to-Treat Population for the Comparison of Arm A
versus Arm C
A. OS tested for statistically significant at 0.022 in the ITT population for Arm B vs. 
Arm C Comparison
Analysis Timing
Stopping Boundary in HR (p-value)
If 0.01936a
If 0.022b
OS first interim 
analysis
HR0.682 
(p-value0.0001)
HR0.682 
(p-value0.0001)
OS second interim 
analysis
HR0.799 
(p-value0.0116)
HR0.804 
(p-value0.0134)
OS final analysis
HR0.822 
(p-value0.0160)
HR0.826 
(p-value0.0182)
ITTintent to treat; HRhazard ratio; OSoverall survival.
a.
When the PFS result is not statistically significant in the ITT population for Arm A vs Arm C 
comparison. 
b.
When the PFS result is statistically significant in the ITT population for Arm A vs Arm C 
comparison
Note:  and p-value are one-sided.


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B. OS tested for statistically significant at 0.025 in the ITT population for Arm B vs.
Arm C Comparison
Analysis Timing
Stopping Boundary in HR (p-value)
If 0.022a
If 0.025b
OS first interim 
analysis
HR0.682 
(p-value0.0001)
HR0.683 
(p-value0.0001)
OS second interim 
analysis
HR0.804 
(p-value0.0134)
HR0.808 
(p-value0.0156)
OS final analysis
HR0.826 
(p-value0.0182)
HR0.830 
(p-value0.0206)
ITTintent to treat; HRhazard ratio; OSoverall survival.
a. When the PFS result is not statistically significant in the ITT population for Arm A vs Arm C 
comparison. 
b. When the PFS result is statistically significant in the ITT population for Arm A vs Arm C 
comparison
Note:  and p-value are one-sided.
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Randomization to the treatment and control arms will occur in a 1:1:1 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)

PD-L1 expression by IHC (TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 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 will be used for sensitivity analyses.
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 the first 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.


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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 GO29437
for the purposes of a regulatory filing.
4.1
ANALYSIS POPULATIONS
4.1.1
Randomized Population/ITT Population
The randomized population or ITT population is defined as all randomized patients, 
regardless of whether the patient received the assigned treatment.
The Teff (-0.91) population is defined  as ITT patients with Teff signature score-0.91 in 
baseline tumor tissues.  The Teff (-1.91) population is defined as ITT patients with a Teff 
signature score1.91. The Teff signature score captures the gene expression of PD-L1 
(CD274), CXCL9, and interferon-gamma relative to a reference gene using RNA isolated 
from the patient’s formalinfixed paraffin-embedded tumor tissue, as measured on a 
Roche Molecular System Cobas 4800 platform.
The PD-L1 TC2/3 or IC2/3 population is defined as ITT patients with PD-L1 TC2/3 or 
IC2/3 expression in baseline tumor tissue.  Similarly, the PD-L1 TC1/2/3 or IC1/2/3 
population is defined as ITT patients with PD-L1 TC1/2/3 or IC1/2/3 expression in 
baseline tumor tissue.
The primary analyses of PFS and all OS analyses will be performed on the ITT 
population.  Patients are grouped according to the treatment assigned at randomization, 
regardless of whether they received any assigned study drug.
Objective response rate (ORR) will be analyzed for patients in the ITT population who 
have measurable disease as assessed by investigator at baseline.  DOR will be 
assessed in patients in the ITT population who have an objective response and 
measurable disease as assessed by investigator at baseline. TTD analyses will be 
conducted in the ITT population. Change from baseline analysis in PROs will be 
performed for patients in the ITT 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, paclitaxel, or nab-paclitaxel and who have evaluable 
PK samples.


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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 amount of atezolizumab was received, including when 
atezolizumab was received in error.  Specifically for patients randomized to Arm C, if 
atezolizumab was received in error in addition to Arm C treatment, then the patients will 
be grouped to Arm B 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 discontinuation from the study will be 
summarized overall and by treatment arm for the ITT population.  Study treatment 
administration and reasons for discontinuation from study treatment will be summarized 
for the safety population.
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 populations.  
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 per 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 


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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 ITT population can be 
phrased in terms of the survival functions SA(t) or SB(t) for the atezolizumab arms (Arms 
A or B, respectively) and SC(t) for the control arm (Arm C):
H0: SA(t)SC(t) versus H1: SA(t) SC(t)
or H0:  SB(t)SC(t) versus H1:  SB(t)SC(t)
The HRs, λA/λC and λB/λC where λA, λB, and λC represent the hazard of having a PD event
or death in Arm A, Arm B, and Arm C, 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 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 
and IC0/1).  The stratification factors will be those used during randomization as 
recorded in the interactive web/voice response system (IxRS) per the request of the 
U.S. Food and Drug Administration.  The analyses based on stratification factors as 
recorded on the electronic Case Report Form (CRF) may also be provided if the 
discrepancy between IxRS and CRF recorded strata is substantial. Results from an 
unstratified analysis will also be provided.
Treatment comparisons will be conducted by first comparing Arm B versus Arm C and 
then comparing Arm A versus Arm C based on a stratified log-rank test in the ITT 
population for the PFS and OS endpoints.  For each comparison, analyses will be 
conducted according to an analysis hierarchy and an spending algorithm to control for 
the type I error rate (see Figure 2 in Section 2.3) and to account for interim analyses
(see Section 2.4.2).
To control the overall type I error rate for the one-sided test at 0.025, the hypothesis 
testing for the comparison of Arm B versus Arm C will be done at the specified 
significance levels in the order described below:
1.
PFS in the ITT 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 
the control arm in the ITT population.
2.
recycling from PFS to OS will be conducted as follows:
a)
If PFS result is not statistically significant in the ITT population, then OS in the
ITT population will be tested at 0.022 (one-sided).


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b)
If PFS result is statistically significant in the ITT population, then OS in the 
ITT population will be tested at 0.025 (one-sided).
If the difference in OS between Arm B and Arm C in the ITT population is statistically 
significant, the comparison of Arm A versus Arm C will be statistically tested at the same 
significance level, with allocated to PFS and OS endpoints at the same 3:22 ratio (see 
Figure 2 in Section 2.3).  Depending on the outcome of the PFS testing of Arm A versus 
Arm C in the ITT population, the from the PFS comparison will be recycled back to the 
OS comparison in the ITT population for Arm A versus Arm C.  The significance levels at 
which the PFS and OS will be tested for the comparison of Arm A versus Arm C are 
shown in Table 5 for all scenarios.
Table 5
Significance Level (one-sided) for Comparison of Arm A versus 
Arm C
Arm B vs. Arm C
Arm A vs. Arm C
level at which the OS is 
tested statistically significant in 
the ITT population
level at which the PFS 
will be tested in the ITT 
population
level at which the OS will be 
tested in the ITT population
0.022
0.00264
0.01936, if the PFS result is 
not statistically significant in 
the ITT population
0.022, if the PFS result is 
statistically significant in the 
ITT population
0.025
0.003
0.022, if the PFS result is not 
statistically significant in the 
ITT population
0.025, if the PFS result is 
statistically significant in the 
ITT population
ITTintent-to-treat; OSoverall survival; PFSprogression-free survival.
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 Teff Populations
PFS, as determined by the investigator according to RECIST v1.1, and OS in the Teff 
(formerly referred to as tGE) populations, will be analyzed using the same methods as 
described in Section 4.4.1.
4.4.2.2
PFS and OS in PD-L1 Populations
PFS, as determined by the investigator according to RECIST v1.1, and OS in the PD-L1
TC2/3 or IC2/3 and TC1/2/3 or IC1/2/3 populations will be analyzed using the same 
methods as described in Section 4.4.1.
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 as determined by the investigator using RECIST v1.1.  
Patients not meeting these criteria, including those without any post-baseline 
assessment, will be considered non-responders.  Confirmation of response according to 
RECIST is not required, but for exploratory purposes, ORR with confirmation may be 
reported.  The analysis population for ORR will be the ITT population with measurable 
disease at baseline, i.e., patients with at least one measureable lesion as assessed by 
the investigator using RECIST v1.1.  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 
estimated using KM methodology.  Comparisons between treatment arms will be made 
using the stratified and unstratified log-rank test for descriptive purposes only.
4.4.2.5
OS Rate at 1- and 2-Year Landmark Timepoints
The OS rate at 1- and 2-year landmark time points after randomization in the ITT 
population will be estimated for each treatment arm using KM methodology, along with 
95% CI calculated with the standard error derived from Greenwood’s formula.  The 95% 
CI for the difference in OS rates between the two treatment arms will be estimated using 


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the normal approximation method, with standard errors computed using Greenwood’s 
method.
4.4.2.6
Investigator-Assessed PFS and OS Comparison between 
Atezolizumab-Containing Arms
The comparison between atezolizumab-containing arms, i.e., Arm A and Arm B, will also
be made using the investigator-assessed PFS per RECIST v1.1 and OS endpoints.
4.4.2.7
Patient-Reported Outcomes
Through the SILC scale, the EORTC QLQ-C30, and the EORTC QLQ-LC13, lung 
cancer symptom data will be collected for symptoms commonly associated with cancer 
treatments and on disease and treatment impact on patient 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.
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 a10-point increase above 
baseline in any of the listed symptom scores, whichever occurs first (cough, chest pain, 
and dyspnea multi-item scale).  Confirmed clinically meaningful symptom deterioration 
will need to be held for the original symptom; a10-point increase above baseline in a 
symptom score (i.e. cough) must be held for at least two consecutive assessments (i.e. 
cough for two 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).


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TTD analyses will be performed for the ITT population and will include all data collected 
through disease progression and survival follow-up.  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 the 
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 population with a baseline and a 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.
The analyses per SILC scale may not be included in the CSR for this study.
4.4.3
Exploratory Efficacy Endpoints
4.4.3.1
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.
4.4.3.2
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.
4.4.3.3
EQ-5D-3L Health Status Data
Health status is assessed by the EQ-5D-3L.  Data from the EQ-5D-3L questionnaire will 
be collected to generate HRQoL and utility scores for use in economic models for 
reimbursement.
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 


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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 
Clinical Study Report (CSR) for this study.
4.4.3.4
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 
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 one or more assessments scheduled immediately prior to the date of 
disease progression per RECIST v1.1 or the data cutoff in any treatment arm, the 
following two sensitivity analyses will be performed:

Patients who missed two or more scheduled assessments immediately prior to the 
date of disease progression per RECIST v1.1 or the data cutoff 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 the data cutoff 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 4.4.1 will be used for this sensitivity analysis.


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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 (i.e., Arm A vs. Arm C, Arm B vs. Arm C) 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.
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 will be discounted according to a range of possible effects on OS of the 
subsequent NPT after treatment switching occurred (e.g., 10%, 20%, and 30%).

Rank preserving structural failure time provides an estimate of the OS time for the 
control group had NPT not occurred (Robins and Tsiatis 1991).  It estimates OS
measured from the time of NPT by applying an estimate of the benefit of the NPT.  
The total OS time (sum of time to NPT and the estimated survival time after NPT 
started) will then be analyzed using the same methodology as for the primary 
analysis of OS.

The inverse probability of censoring weighting method censors patients at the start 
of NPT and uses patients in the control arm to create weights that represent how 
NPT-treatedlike a nonNPT-treated patient is (Robins and Finkelstein 2000).
These time-varying weights are included 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 could be conducted to assess a potential 
delayed clinical effect for the treatment group.
Milestone OS Analysis
To assess the effect of long-term survival and delayed clinical effects, a milestone 
OS analysis may be conducted (Chen 2015).  The milestone timepoint(s) will be chosen 
such that the patients included in the analysis will achieve a certain percentage of 
patient-event ratio.
The milestone OS analysis may be conducted only when the milestone duration has 
elapsed from the time the last patient entered the study, using the same methods as 
those specified for the primary OS analysis.


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Restricted Mean Survival Time
The restricted mean survival time (RMST) may be computed for OS using the area 
under the curve from baseline to several timepoints.  RMST may be computed for each 
treatment arm and the difference with its 95% CI will be displayed.
Weighted Log-Rank Analysis
Where the delayed clinical effect is10% of the median survival time of the control arm, 
an analysis of OS may be performed using the weighted log-rank test (Fleming and
Harrington 1991) that weight more on late events to account for the delayed clinical 
effect (Fine et al. 2007).
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 will be performed for the comparisons between two 
treatment arms (i.e., Arm A vs. Arm C, Arm B vs. Arm C) in which patients who are lost 
to follow-up may be considered as having died at the last date they were known to be 
alive.
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 will be examined as 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.; 
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 as determined 
by the SP263 assay may also be performed)

Teff populations with the corresponding complementary biomarker populations 
defined by the Teff cutoff values of 0.91, and 1.91

Intended cycles during induction phase (4 cycles vs. 6 cycles)


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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 two treatment 
arms (i.e., Arm A vs. Arm C, Arm B vs. Arm C) 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 SDs, as 
appropriate.
Plasma concentrations of carboplatin, paclitaxel, and nab-paclitaxel will be collected in 
this study as outlined in Appendix 3.  The concentrations of carboplatin, paclitaxel, 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.
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with response to study drug, including efficacy and/or 
safety.  The tumor biomarkers include but are not limited to PD-L1 and CD8, as defined 
by IHC, quantitative reverse transcriptasepolymerase chain reaction, or other methods.  
In addition, predictive, prognostic and PD exploratory biomarkers in archival and/or fresh 
tumor tissue and/or blood will 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.
4.6
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 C, 
if atezolizumab was received in error in addition to Arm C treatment, the patients will be 
grouped to Arm B for the safety analyses.
4.6.1
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.


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4.6.2
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 
according to the NCI CTCAE v4.0.  Treatment-emergent adverse events will be 
summarized by mapped term, appropriate thesaurus level, NCI CTCAE grade, and 
treatment arm.  Multiple occurrences of the same event will be counted once at the 
maximum grade.  Adverse events, common adverse events (defined as adverse events 
that occur in10% of patients), 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 led 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.
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, deaths reported during the follow-up period 
after treatment completion/discontinuation, and causes of death will be summarized by 
treatment arm.
4.6.3
Laboratory Data
Laboratory data will be summarized over time by treatment arm.  Change from baseline 
and values outside the normal ranges may be summarized.  In addition, selected 
laboratory data will be classified according to NCI CTCAE and will be summarized by 
grade. Highest NCI CTCAE grade post-baseline will also be reported and shift tables 
from baseline to worst value during the study post-baseline will be presented.
4.6.4
Vital Signs
Changes in selected vital signs will be summarized by treatment arm and by change 
over time including change from baseline.
4.6.5
Anti-Drug Antibody 
Serum levels and incidence of ADAs against atezolizumab will be summarized.  
The analyses of pharmacokinetics, key efficacy, and safety by ADA status will be 
conducted to explore the potential impact of immunogenicity as appropriate.
4.7
MISSING DATA
Please refer to Section 4.4.1 and Section 4.4.2 for methods of handling missing data for 
the primary and secondary efficacy endpoints.


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5.
REFERENCES
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:djv156.
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual. 3rd 
ed. Brussels: European Organisation for Research and Treatment of Cancer, 2001.
Fine GD. Consequences of delayed treatment effects on analysis of time-to-event 
endpoints. Ther Innov Regul Sci 2007;41:5359.
Fleming TR, Harrington DP. Counting processes and survival analysis. New York: John 
Wiley & Sons, 1991.
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:147980.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:13944.
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Commun Stat Theory Methods 
1991;20:260931.
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in 
an AIDS clinical trial with inverse probability of censoring weighted (IPCW) 
log-rank tests. Biometrics 2000;56:77988.


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Appendix 1 Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
ATEZOLIZUMAB (MPDL3280A, ANTIPD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATIN PACLITAXEL OR 
ATEZOLIZUMAB IN COMBINATION WITH 
CARBOPLATIN NAB-PACLITAXEL VERSUS 
CARBOPLATIN NAB-PACLITAXEL IN CHEMOTHERAPYNAIVE
PATIENTS WITH STAGE IV SQUAMOUS NONSMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29437
VERSION NUMBER:
6
EUDRACT NUMBER:
2014-003208-59
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
PHASE:
III
INDICATION:
Squamous nonsmall cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Unless otherwise specified, efficacy objectives will be analyzed for the following two treatment 
comparisons:

Atezolizumabcarboplatinnab-paclitaxel (Arm B) versus
carboplatinnabpaclitaxel (Arm C)

Atezolizumabcarboplatinpaclitaxel (Arm A) versus
carboplatinnabpaclitaxel (Arm C)
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 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 population and the intent-to-treat (ITT) population
To evaluate the efficacy of atezolizumab as measured by overall survival (OS) in the ITT 
population


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Appendix 1 Protocol Synopsis (cont.)
The secondary efficacy objectives for this study are the following:
To evaluate the efficacy of atezolizumab as measured by OS in the tGE 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 population and the TC1/2/3 or IC1/2/3 population 
To evaluate the efficacy of atezolizumab as measured by investigator-assessed objective 
response rate (ORR) according to RECIST v1.1 in the tGE population and the ITT population
To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response (DOR) according to RECIST v1.1 in the tGE population and the ITT population
To evaluate the OS rate at 1 and 2 years in each treatment arm for the tGE population and the 
ITT population n
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 (QLQ-C30) and the 
supplemental lung cancer module (QLQ-LC13) in the tGE population and the ITT 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 population and the ITT population
To evaluate the efficacy of the treatment regimen of atezolizumabcarboplatinpaclitaxel 
versus atezolizumabcarboplatinnab-paclitaxel as measured by investigator-assessed PFS 
according to RECIST v1.1 and OS in the tGE population and the ITT population
Safety Objectives
The safety objectives for this study are the following:

To evaluate the safety and tolerability of atezolizumab in each of the two treatment 
comparisons

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paclitaxel (Arm A) or with carboplatinnab-paclitaxel (Arm B)

To characterize the pharmacokinetics of carboplatin when given in combination with 
paclitaxel and atezolizumab (Arm A) or with nab-paclitaxel with and without atezolizumab 
(Arms B and C)

To characterize the pharmacokinetics of paclitaxel when given in combination with 
atezolizumab and carboplatin (Arm A)

To characterize the pharmacokinetics of nab-paclitaxel (reported as total paclitaxel) when 
given in combination with carboplatin with and without atezolizumab (Arms B and C)
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


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Appendix 1 Protocol Synopsis (cont.)

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 LC13
Study Design
Description of Study
This is a randomized, Phase III, multicenter, open-label study (IMpower131) designed to 
evaluate the safety and efficacy of atezolizumab in combination with carboplatinpaclitaxel or 
with carboplatinnab-paclitaxel compared with treatment with carboplatin nab-paclitaxel in 
approximately 1025 chemotherapynaive patients with Stage IV 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 1:1:1 ratio to receive one of the following 
treatment regimens.
Treatment Arm A:  Atezolizumabcarboplatinpaclitaxel (Induction: four or six 21-day 
cycles); atezolizumab (Maintenance: 21-day cycle)
Treatment Arm B:  Atezolizumabcarboplatinnab-paclitaxel (Induction: four or six 21-day 
cycles); atezolizumab (Maintenance: 21-day cycle)
Treatment Arm C:  Carboplatinnab-paclitaxel (Induction: four or six 21-day cycles); best 
supportive care (Maintenance: 21-day cycle)
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 C) or loss of clinical benefit 
(Arms A and B) is documented. 
Following the induction phase, patients randomized to atezolizumab (Arms A and B) may 
continue treatment with atezolizumab beyond radiographic disease progression by 
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 C) will be offered best supportive care provided they have 
non-progressive disease.
Treatment with chemotherapy must be discontinued in all patients who exhibit evidence of 
progressive disease by RECIST v1.1.


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Appendix 1 Protocol Synopsis (cont.)
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 assessments will be 
required every 9 weeks.  Patients will undergo tumor assessments until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who 
continue 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 per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled 
tumor assessments until radiographic disease progression per RECIST v1.1 (or loss of clinical 
benefit for atezolizumab-treated patients who had continued treatment with atezolizumab after 
radiographic disease progression according to RECIST v1.1), withdrawal of consent, 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.
For Treatment Arms A and B only:
During treatment (induction or maintenance), patients who show evidence of clinical benefit will 
be permitted to continue atezolizumab after RECIST v1.1 for progressive disease are met if 
they meet all of the following criteria:

Evidence of clinical benefit as assessed by the investigator

Absence of symptoms and signs (including worsening of laboratory values, [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in 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 study treatment atezolizumab at the time of initial progression
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 time 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 Arms A and B who are unable 
to undergo biopsy sample collection but who otherwise meet the criteria listed above may 
continue to receive atezolizumab.
Number of Patients
Approximately 310 sites globally will participate in the study and approximately 1025 patients 
will be randomized.
Target Population
Inclusion Criteria
Patients may be eligible if they have chemotherapynaive, Stage IV, squamous NSCLC.
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


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Appendix 1 Protocol Synopsis (cont.)

Histologically or cytologically confirmed, Stage IV squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 
7th edition).
Patients with tumors of mixed histology (squamous and non-squamous) are eligible if 
the major histological component appears to be squamous.

No prior treatment for Stage IV squamous NSCLC
Patients known to have a sensitizing mutation in the epidermal growth factor receptor
(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 with unknown EGFR mutation status do not require 
testing.
Patients known to have an anaplastic lymphoma kinase (ALK) fusion oncogene must 
have experienced disease progression (during or after treatment) or intolerance to 
treatment with one or more ALK inhibitors (i.e. crizotinib) appropriate for the treatment 
of NSCLC in patients having an ALK fusion oncogene.  Patients with unknown 
ALK mutation status do not require testing.

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.

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 central nervous system 
(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.  


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36/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)

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

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, for 30 days after the last dose of nab-paclitaxel, or for 6 months after 
the last dose of 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, 
paclitaxel, and/or carboplatin.  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.  Men must refrain 
from donating sperm during the study and for 6 months after the last dose of nab-paclitaxel, 
paclitaxel, and/or carboplatin, whichever is latest.

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 trial 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.


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37/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)
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 (CT) or 
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments

Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for2 weeks prior to randomization

Leptomeningeal disease

Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to randomization.  
Patients should be recovered from the effects of radiation.  There is no required 
minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for 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


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38/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)

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 I 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 (BSA)
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 positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative 
for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within the 3 months
prior to randomization, unstable arrhythmias, or unstable angina


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39/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)
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 
render the patient at high risk from treatment complications

Patients with illnesses or conditions that interfere with their capacity to understand, follow 
and/or comply with study procedures
Exclusion Criteria Related to Medications

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cytotoxic T-lymphocyte-associated protein 4 (antiCTLA-4) at least 6 
weeks prior to randomization
No history of severe immune-mediated adverse effects from antiCTLA-4 (National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
Grade 3 and 4)

Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
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


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40/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)

Known sensitivity to any component of paclitaxel or nab-paclitaxel

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria (paclitaxel and 
nab-paclitaxel)

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 240 PFS events have occurred in Arms B and C combined in the tGE population, 
approximately 499 PFS events have occurred in Arms B and C combined in the ITT population, 
and the last patient has been enrolled in the study.  The final PFS analysis is expected to occur 
approximately 30 months after the first patient is enrolled. 
With a sample size of 684 patients, approximately 477 OS events are expected to occur in Arms 
B and C combined in the ITT population for the final OS analysis.  The final OS analysis is 
expected to occur approximately 39 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 
are undergoing survival follow-up may be enrolled into an extension study or a 
non-interventional study.
Outcome Measures
Efficacy Outcome Measures
The co-primary efficacy outcome measures for this study are the following:

PFS, defined as the time from randomization to the first occurrence of the disease
progression as determined by the investigator using RECIST v1.1 or death from any cause, 
whichever occurs first in the tGE population and ITT population

OS, defined as the time from randomization to death from any cause in the ITT population
The secondary efficacy outcome measures for this study are the following:

OS in the tGE population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the TC2/3 or 
IC2/3 population and the TC1/2/3 or IC1/2/3 population

Objective response, defined as partial response (PR) or complete response (CR) as 
determined by the investigator according to RECIST v1.1 in the tGE population and 
ITT population

DOR, defined as the time interval from the 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 in the tGE population and 
ITT population

OS rates at 1 and 2 years for the tGE population and ITT 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 population and ITT population

Change from baseline in patient-reported lung cancer symptoms (cough, dyspnea, and 
chest pain) on the symptom severity score of the SILC scale in the tGE population and ITT 
population


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41/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)

PFS, as determined by the investigator according to RECIST v1.1, and OS in the two 
atezolizumab-containing arms in the tGE population and the ITT 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 
study treatment 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:

Maximum observed serum atezolizumab concentration (Cmax) after infusion (Arms A and B)

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 (Arms A and B)

Plasma concentrations for carboplatin (Arms A, B, and C)

Plasma concentrations for paclitaxel (Arm A)

Plasma concentrations for nab-paclitaxel (Arms B and C)
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 tumor-infiltrating immune cells 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 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 to patients who 
are randomized to Arms A and B.
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients who had 
already started switch maintenance treatment with erlotinib under previous protocol versions 
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


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42/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)
.
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 
investigational medicinal product (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curve (AUC) of 6 mg/mL/min on Day 1 of each 21-day cycle for four or 
six cycles during the induction phase

Paclitaxel (200 mg/m2 IV) will be administered on Day 1 of each 21-day cycle for four or 
six cycles during the induction phase.
Carboplatin and paclitaxel will be administered to patients randomized to Arm A.  Carboplatin 
and nab-paclitaxel will be administered to patients in Arms B and C.
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 population and the ITT population.  OS will be 
analyzed in the ITT population.  Treatment comparisons will be conducted sequentially by first 
comparing Arm B versus Arm C and then comparing Arm A versus Arm C.  For each 
comparison, 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.
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 died 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 endpoints described above and for 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 each comparison (i.e., Arm B vs. Arm C, Arm A 
vs. Arm C) will be estimated using a stratified Cox regression model, respectively.  The 95% CI 
for the HR will be provided.
The hypothesis testing will be done in the order described below: 
Comparison of Arm B versus Arm C
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 the 
comparison of Arm B versus Arm C.


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43/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)
1. PFS in the tGE 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 population.
2. If the null hypothesis is rejected in the tGE population (Step 1), PFS in the ITT 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 PFS analysis in the ITT population (Step 2), OS 
in the ITT population will be tested at 0.022 (one-sided).
b.
If the null hypothesis is rejected for PFS analysis in the ITT population (Step 2), OS in 
the ITT population will be tested at 0.025 (one-sided).
Comparison of Arm A versus Arm C
If the difference in OS between Arm B and Arm C in the ITT population is statistically significant 
at an of 0.022 or 0.025 (Step 3), that same will become the overall one-sided type I error 
rate for the comparison of Arm A versus Arm C, with allocated to PFS and OS at the same 
3:22 ratio (see Figure 3 in Section 6.1).  If the difference in OS between Arm B and Arm C in the 
ITT population is not statistically significant, there will be no formal comparison of Arm A versus 
Arm C for the co-primary endpoints of PFS and OS.
1. If the difference in OS between Arm B and Arm C is statistically significant at 0.022 (one 
sided):
a. PFS in the tGE population will be tested at 0.00264 (one sided).  If the estimate of 
the HR is 1 and the one-sided p-value corresponding to the stratified log-rank test is 
0.00264, the null hypothesis will be rejected and it will be concluded that 
atezolizumabcarboplatinpaclitaxel prolongs the duration of PFS relative to control 
treatment in the tGE population.
b. If the null hypothesis is rejected in the tGE population (Step 1a), PFS in the 
ITT population will be tested at 0.00264 (one sided).
c. recycling from PFS to OS will be conducted as follows:

If the null hypothesis is not rejected in the ITT population (Step 1b), OS in the ITT 
population will be tested at 0.01936 (one sided).

If the null hypothesis is rejected in the ITT population (Step 1b), OS in the 
ITT population will be tested at 0.022 (one sided).
2. If the difference in OS between Arm B and Arm C is statistically significant at 0.025 (one 
sided):
a. PFS in the tGE 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paclitaxel prolongs the duration of PFS relative to control 
treatment in the tGE population.
b. If the null hypothesis is rejected in the tGE population (Step 2a), PFS in the 
ITT population will be tested at 0.003 (one sided).
c. recycling from PFS to OS will be conducted as follows:

If the null hypothesis is not rejected in the ITT population (Step 2b), OS in the ITT 
population will be tested at 0.022 (one sided).

If the null hypothesis is rejected in the ITT population (Step 2b), OS in the 
ITT population will be tested at 0.025 (one sided).


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44/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)
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 interactive 
voice/web response system.
Results from an unstratified analysis will also be presented.  Kaplan-Meier methodology will be 
used to estimate median PFS and 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.
Determination of Sample Size
This study will randomize approximately 1025 patients, including approximately 513 patients in 
the tGE population, 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) for the comparison of Arm B
versus Arm C.
The estimate of the number of events required to demonstrate efficacy with regard to PFS in the 
comparison of Arm B versus Arm C is based on the following assumptions:

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in the tGE 
population

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in the 
ITT population

97% 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 population

98% 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 population

No interim analyses for PFS

Dropout rate of 5% per 12 months
The estimates of the number of events required to demonstrate efficacy with regard to OS in the 
comparison of Arm B versus Arm C is based on the following assumptions:

One-sided significance level of 0.022 for the comparison of Arm B versus Arm C in the 
ITT population

86% power to detect an HR of 0.75, corresponding to an improvement in median OS from 
12 months to 16 months in the ITT population

One interim OS analysis performed at the time of the final PFS analysis, at which time 
approximately 76% 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 1025 patients in total will be enrolled into this study, 
with approximately 684 patients in each comparison (i.e., Arm B vs. Arm C, Arm A vs. Arm C).  
The final PFS analysis will be conducted when all of the following criteria have been met:  
approximately 240 PFS events have occurred in Arms B and C combined in the tGE population, 
approximately 499 PFS events have occurred in Arms B and C combined in the ITT population, 
and the last patient has been enrolled in the study.  The final PFS analysis is expected to occur 
approximately 30 months after the first patient is enrolled.  These numbers of events would 
allow for a minimum detectable difference corresponding to an HR of approximately 0.70 in the 
tGE population and approximately 0.75 in the ITT population.


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45/Statistical Analysis Plan GO29437, Version 3
Appendix 1 Protocol Synopsis (cont.)
With a sample size of 684 patients, approximately 477 OS events are expected to occur in Arms 
B and C combined in the ITT population for the final OS analysis.  The final OS analysis is 
expected to occur approximately 39 months after the first patient is enrolled.
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/Ethics Committees.  A detailed
plan will be included in the iDMC Charter.
If approximately 365 OS events have occurred in Arms B and C combined in the ITT population 
at the time of the final PFS analysis (see criteria for final PFS analysis in Section 6.1), an interim 
OS analysis will be conducted for Arm B versus Arm C in the ITT population.  If there are 
significantly fewer than the expected 365 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 final PFS analysis and a second interim OS analysis will then be conducted after 
approximately 365 OS events have occurred.
The final OS analysis for the comparison of Arm B versus Arm C will be conducted when 
approximately 447 OS events have occurred in Arms B and C combined in the ITT population.  
This is expected to occur approximately 39 months after the first patient is enrolled.


Atezolizumab—F. Hoffmann-La Roche Ltd
46/Statistical Analysis Plan GO29437, Version 3
Appendix 2 Schedule of Assessments
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Informed consent 
x
Tumor tissue specimen for PD-L1 testing 
(15 FFPE slides required; blocks preferred) c
Fresh or archival tissue can be used
x
Demographic data
x
Medical history and baseline conditions
x
NSCLC cancer history 
x
Vital signs d
x
x
x
x
Weight
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examination e
x
x
x
ECOG performance status
x
x
x
x
12-Lead ECG
x
x f
x f
x f
Hematology g
x
x
x
x


Appendix 2 Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan GO29437, Version 3
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Serum chemistry h
x
x
x
x
Coagulation test (aPTT or INR)
x
x
Pregnancy test (women of childbearing-potential 
ONLY)
x i
x j
x j
x j
x y
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paclitaxel
Arm B: Atezolizumabcarboplatinnab-paclitaxel
Arm C: Carboplatinnab-paclitaxel)
x n
Maintenance treatment administration
Arm A: Atezolizumab
Arm B: Atezolizumab
Arm C: Best supportive care o
x n
Tumor response assessment
x p
x q
x q
x r
Serum sample for ATA assessment 
x
x
x
120 (30) days after 


Appendix 2 Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
48/Statistical Analysis Plan GO29437, Version 3
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
(atezolizumab-treated patients only) s
last dose
Serum sample for PK sampling
(atezolizumab-treated patients only) s
x
x
x
120 (30) days after 
last dose
Carboplatin, paclitaxel, and nab-paclitaxel PK 
sampling as applicable (20 patients per arm) s
x
Blood samples for PD biomarkers s
x
x
x
x
120 (30) days after 
last dose
Optional blood for DNA extraction 
(RCR only) s, t
x
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab-treated 
patients only)
At time of radiographic progression
Tumor biopsy 
At time of radiographic progressionu
Optional tumor biopsy at other timepoints 
(RCR only)
Any time during study treatment or during survival follow-up
Adverse events v
x
x
x
x v
Concomitant medications
From 7 days 
before 
screening
x
x
x
Patient-reported outcomes w
x w
x w
x w


Appendix 2 Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan GO29437, Version 3
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation
Visit
Survival Follow-Up
Days –28
to –1
Induction Phase
(Cycles 1 to 4 
or 6)
Maintenance 
Phase
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months after 
Disease Progression 
or Loss of Clinical 
Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Survival and anti-cancer therapy follow-up x
x
ATAanti-therapeutic antibody; BSCbest supportive care; 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; ICFInformed Consent 
Form; IVintravenous; QLQ-LC13Lung Cancer module; NSCLCnonsmall cell lung cancer; PDpharmacodynamic; PD-L1programmed 
deathligand 1; PGISPatient Global Impression of Severity; PKpharmacokinetic; QLQ-C30Quality-of-Life Questionnaire Core 30; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors Version 1.1 ;SILCSymptoms in Lung Cancer; EQ-5D-3 Level version; 
TSHthyroid-stimulating hormone.
Note:  For patients who are randomized to Arm C who receive erlotinib switch maintenance allowed under previous protocol versions, patients will 
continue with cycle visits at the same frequency as those patients randomized to Arms A and B until disease progression, withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first.
a Assessments should be performed before study drug infusion unless otherwise noted.
b Except for Cycle 1, Day 1, which must be performed within 5 days after the patient is randomized.  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 GO29437.  Screening assessments performed96 hours before Cycle 1, Day 1, do not need to be repeated for Cycle 1 Day 1.


Appendix 2 Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
50/Statistical Analysis Plan GO29437, Version 3
c If a representative FFPE tumor specimen in paraffin block (preferred) or 15 (or more) unstained, freshly cut, serial sections on slides from an FFPE 
tumor specimen are not available for PD-L1 testing, contact the Medical Monitor to discuss to determine if the patient may participate in the study.  
Fine-needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or cell smears), brushing, cell 
pellets from pleural effusion, and lavage samples are NOT acceptable.  For core needle biopsy specimens, at least three cores should be 
submitted for evaluation.  Retrieval of archival tumor sample may occur outside the 28-day screening period prior to enrollment.  See Section 
4.5.7.1 and the inclusion criteria in Section 4.1.1 of Protocol GO29437.
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 GO29437 sites in Argentina, pulse oximetry will be performed at every visit; these data will not be recorded.
e Symptom-directed physical examinations; see Section 4.5.3 of Protocol GO29437 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 5.1.10.1 of Protocol GO29437 for dose modifications due to hematological 
toxicities.
h Serum chemistry includes BUN, 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 5.1.10.6 of Protocol GO29437 for dose modifications 
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, free T3, free T4) collected at Cycle 1, Day 1, and every fourth cycle thereafter.  Total T3 to 
be tested only at sites where free T3 testing cannot be performed.
l
All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical study.  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, paclitaxel, and nab-paclitaxel, study drug will be administered according to the local prescribing 
information, including premedication with steroids (see Section 4.3.2 of Protocol GO29437).
o Only patients who are already receiving switch maintenance therapy with erlotinib, permitted under previous protocol versions, may be allowed to 
remain on treatment with erlotinib after discussion of the risks, potential benefits, and alternative treatment options with the investigator.
p 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 


Appendix 2 Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
51/Statistical Analysis Plan GO29437, Version 3
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 GO29437 for details.
q Perform every 6 weeks (7 days) (approximately every two cycles) for 48 weeks following Cycle 1, Day 1, and then, after completion of the 
Week 48 tumor assessment, every 9 weeks (7 days) 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 GO29437 for details.
r
If a patient discontinues study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration, tumor assessments will continue at the same frequency as would have been followed if the patient had remained on study treatment 
until radiographic disease progression (loss of clinical benefit for patients treated with atezolizumab who continue treatment after disease 
progression according to RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if patient 
starts another anticancer therapy after study treatment discontinuation.
s See Appendix 2 of Protocol GO29437 for the detailed schedule.
t
The optional RCR whole blood sample requires an additional informed consent and can be collected at any time during the course of the study.
u Mandatory tumor biopsy at radiographic disease progression, if clinically feasible, within 40 days of radiographic progression or prior to start of the 
next anti-cancer therapy, whichever occurs is sooner.
v All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study treatment (inclusive of erlotinib switch maintenance for patients who are randomized to Arm C who receive switch maintenance 
allowed under previous protocol versions) or initiation of new systemic anti-cancer therapy after last dose of study treatment.  All other adverse 
events, regardless of relationship to study drug, will be reported until 30 days after the last dose of study treatment (inclusive of erlotinib switch 
maintenance for patients who are randomized to Arm C who receive switch maintenance allowed under previous protocol versions) or initiation of 
new systemic anti-cancer therapy after last dose of study treatment.  After this period, all deaths should continue to be reported.  In addition, the 
Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that is believed to 
be related to prior exposure to study treatment (see Section 5.6 of protocol GO29437).
w 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 using an ePRO device at the patient’s 
home on a weekly basis.  During survival follow-up, the EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-3L will be completed at 3 and 
6 months following disease progression.  The SILC would be completed monthly during survival follow-up for 6 months following disease
progression or 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 per 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 


Appendix 2 Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
52/Statistical Analysis Plan GO29437, Version 3
patient leaves the investigational site. Patients whose native language is not available in the ePRO device or who are deemed by the investigator 
incapable of inputting their ePRO assessment after undergoing appropriate training are exempt from all ePRO assessments.
x 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.
y For Argentina sites only: A urine pregnancy test is required monthly until 6 months after the last dose of study treatment.


Atezolizumab—F. Hoffmann-La Roche Ltd
53/Statistical Analysis Plan GO29437, Version 3
Appendix 3 Schedule of Pharmacokinetic, Pharmacodynamic, 
Biomarker, and Anti-Drug Antibody Assessments
Study Visit
Time
Arm A 
(Atezolizumab
Carboplatin
Paclitaxel)
Arm B
(Atezolizumab
Carboplatin
Nab-Paclitaxel)
Arm C
(Carboplatin
Nab-Paclitaxel)
Screening
N/A
Biomarkers b
Biomarkers b
Biomarkers b
Cycle 1, 
Day 1e
Predose 
(same day as 
treatment 
administration) 
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Carboplatin 
pharmacokinetics a
Paclitaxel 
pharmacokinetics a
Biomarkers d
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
Atezolizumab 
pharmacokinetics
510 min before 
the end of 
paclitaxel infusion
a
Paclitaxel 
pharmacokinetics a
1 hour after the 
end of paclitaxel 
infusion a
Paclitaxel 
pharmacokinetics a
510 min before 
the end of 
nab-paclitaxel 
infusion a
Nab-Paclitaxel
pharmacokinetics a
Nab-Paclitaxel
pharmacokinetics a
1 hour after the 
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
Carboplatin 
pharmacokinetics a
1 hour after the 
end of carboplatin 
infusion a
Carboplatin 
pharmacokinetics a
Carboplatin 
pharmacokinetics a
Carboplatin 
pharmacokinetics a
Cycle 2, 
Day 1
(3 days)
Predose 
(same day as 
treatment 
administration)
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Biomarkers d


Appendix 3 Schedule of Pharmacokinetic, Pharmacodynamic, 
Biomarker, and Anti-Drug Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
54/Statistical Analysis Plan GO29437, Version 3
Study Visit
Time
Arm A 
(Atezolizumab
Carboplatin
Paclitaxel)
Arm B
(Atezolizumab
Carboplatin
Nab-Paclitaxel)
Arm C
(Carboplatin
Nab-Paclitaxel)
Cycle 3, Day 1
(3 days)
Predose 
(same day as 
treatment 
administration)
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Carboplatin 
pharmacokinetics a
Paclitaxel 
pharmacokinetics a
Biomarkers d
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Carboplatin 
pharmacokinetics a
Nab-Paclitaxel
pharmacokinetics a
Biomarkers d
Biomarkers d
Carboplatin 
pharmacokinetics a
Nab-Paclitaxel
pharmacokinetics a
Biomarkers d
30 min (10 min) 
after end of 
atezolizumab 
infusion
Atezolizumab 
pharmacokinetics
Atezolizumab 
pharmacokinetics
510 min before 
the end of 
paclitaxel infusion 
a
Paclitaxel 
pharmacokinetics a
1 hour after the 
end of paclitaxel 
infusion a
Paclitaxel 
pharmacokinetics a
510 min before 
the end of 
nab-paclitaxel 
infusion a
Nab-Paclitaxel
pharmacokinetics a
Nab-Paclitaxel
pharmacokinetics a
1 hour after the 
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
Carboplatin 
pharmacokinetics a
1 hour after the 
end of carboplatin 
infusion a
Carboplatin 
pharmacokinetics a
Carboplatin 
pharmacokinetics a
Carboplatin 
pharmacokinetics a
Cycles 4, 8, 
and 16, Day 1
(3 days)
Predose 
(same day as 
treatment 
administration)
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Biomarkers d


Appendix 3 Schedule of Pharmacokinetic, Pharmacodynamic, 
Biomarker, and Anti-Drug Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
55/Statistical Analysis Plan GO29437, Version 3
Study Visit
Time
Arm A 
(Atezolizumab
Carboplatin
Paclitaxel)
Arm B
(Atezolizumab
Carboplatin
Nab-Paclitaxel)
Arm C
(Carboplatin
Nab-Paclitaxel)
After Cycle 16, 
every eighth 
cycle, Day 1 
(3 days)
Predose 
(same day as 
treatment 
administration)
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
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
Biomarkers d
Treatment 
discontinuation 
visit
At visit
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Biomarkers d
12030 days
after last dose 
of 
atezolizumab
At visit
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Biomarkers d
Any time point 
during study 
(RCR consent 
required)
Optional RCR 
blood (DNA 
extraction) c
Optional RCR 
blood (DNA 
extraction) c
Optional RCR 
blood (DNA 
extraction) c
ATAanti-therapeutic antibody; PKpharmacokinetic; RCRRoche Clinical Repository.
Note:  Serum PK samples for atezolizumab and plasma PK samples for carboplatin, 
paclitaxel, and nab-paclitaxel.
a Twenty patients in each treatment arm will undergo the additional PK assessments for 
carboplatin, paclitaxel, and nab-paclitaxel, where applicable.
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.