Conditions: Carcinoma, Non-Small-Cell Lung
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1202
Healthy volunteers: no

Brief summary:
This randomized, open-label study evaluated the safety and efficacy of atezolizumab (an engineered anti-programmed death-ligand 1 \[PD-L1\] antibody) in combination with carboplatin+paclitaxel with or without bevacizumab compared with treatment with carboplatin+paclitaxel+bevacizumab in chemotherapy-naïve participants with Stage IV non-squamous NSCLC. Participants were randomized in a 1:1:1 ratio to Arm A (Atezolizumab+Carboplatin+Paclitaxel), Arm B (Atezolizumab+Carboplatin+Paclitaxel+Bevacizumab), or Arm C (Carboplatin+Paclitaxel+Bevacizumab).

Detailed description:

Arms:
arm 1: Participants received intravenous (IV) infusion of atezolizumab on Day 1 of each 21-day cycle followed by IV infusion of paclitaxel and carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first, during induction treatment phase. Participants received IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit. arm 2: Participants received IV infusion of atezolizumab and bevacizumab on Day 1 of each 21-day cycle followed by IV infusion of paclitaxel and carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first, during induction treatment phase. Participants received IV infusion of atezolizumab until loss of clinical benefit and bevacizumab until progressive disease, unacceptable toxicity, or death during maintenance treatment phase. arm 3: Participants received IV infusion of bevacizumab on Day 1 of each 21-day cycle followed by IV infusion of paclitaxel and carboplatin on Day 1 of each 21-day cycle for 4 or 6 cycles or loss of clinical benefit whichever occurs first, during induction treatment phase. Participants received IV infusion of bevacizumab during maintenance treatment phase until progressive disease, unacceptable toxicity, or death.

Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody intervention 2: Bevacizumab intervention 3: Carboplatin intervention 4: Paclitaxel
Intervention descriptions: intervention 1: Atezolizumab was administered as IV infusion at a dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle until loss of clinical benefit. intervention 2: Bevacizumab was administered as IV infusion at a dose of 15 milligrams per kilogram (mg/kg) on Day 1 of each 21-day cycle until progressive disease, unacceptable toxicity, or death. intervention 3: Carboplatin was administered at area under the concentration-time curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first. intervention 4: Paclitaxel was administered as IV infusion at a dose of 200 milligrams per square meter (mg/m\^2) on Day 1 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first.

Protocol document:
Prot_001.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol GO29436, Version 8
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (MPDL3280A, ANTI–PD-L1 
ANTIBODY) IN COMBINATION WITH 
CARBOPLATINPACLITAXEL WITH OR WITHOUT 
BEVACIZUMAB COMPARED WITH 
CARBOPLATINPACLITAXELBEVACIZUMAB IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH 
STAGE IV NON-SQUAMOUS NON–SMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29436
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-003207-30
IND NUMBER:
117296
NCT NUMBER:
NCT02366143
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
MEDICAL MONITOR:
, R.N.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  21 November 2014
DATES AMENDED:
Version 2:  29 March 2015
Version 3:  14 August 2015
Version 4:  11 November 2015
Version 5:  31 May 2016
Version 6:  1 March 2017
Version 7:  24 October 2018
Version 8:  See electronic date stamp below.
 
11-Feb-2020 22:50:26
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol GO29436, Version 8
PROTOCOL AMENDMENT, VERSION 8:
RATIONALE
Protocol GO29436 has been amended to include risks and management guidelines for 
atezolizumab, which align with the latest Atezolizumab Investigator's Brochure.  
Changes to the protocol, along with a rationale for each change, are summarized below.

A list of risks associated with atezolizumab have been included (Section 5.1.1).

To address a request by the French National Agency for the Safety of Medicines 
and Health Products (ANSM), the description of systemic immune activation has 
been replaced with descriptions for hemophagocytic lymphohistiocytosis and 
macrophage activation syndrome (Section 5.1.7 and Appendix 16).

Management guidelines for atezolizumab have been included in Appendix 16.  
Note: The management guidelines for infusion-related reactions associated with 
atezolizumab have been updated to include guidelines for cytokine-release 
syndrome (CRS) to align with the definition, grading, and management of CRS 
reflected in a recent publication (Lee et al. 2019).
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 .......................................................................................... 34
1.1
Background on Lung Cancer................................................. 34
1.1.1
First-Line Treatment for Advanced NonSmall 
Cell Lung Cancer with an EGFR Mutation or ALK 
Rearrangement...................................................................... 35
1.1.2
First-Line Treatment for Advanced NSCLC 
without an EGFR Mutation or ALK 
Rearrangement...................................................................... 35
1.1.3
AYDVWLQ and Vascular Endothelial Growth 
Factor .................................................................................... 39
1.1.3.1
Clinical Studies of Bevacizumab and Platinum-
Based Treatment in NSCLC .................................................. 39
1.1.4
Targeted Therapy for NSCLC................................................ 41
1.2
Background on Atezolizumab (MPDL3280A) ........................ 41
1.2.1
Summary of Nonclinical Studies............................................ 42
1.3
Clinical Experience with Atezolizumab .................................. 42
1.3.1
Ongoing Clinical Studies........................................................ 42
1.3.2
Clinical Safety........................................................................ 43
1.3.2.1
Single-Agent Clinical Safety in Patients with 
NSCLC in Study PCD4989g.................................................. 43
1.3.2.2
Single-Agent Clinical Safety in Patients with 
NSCLC in Study GO28753 (POPLAR) .................................. 45
1.3.2.3
Single-Agent Clinical Safety in Patients with 
NSCLC in Study GO28915 (OAK)......................................... 47
1.3.2.4
Clinical Safety in Combination with Bevacizumab 
or Platinum-Based Doublet Chemotherapy ........................... 47
1.3.3
Clinical Activity....................................................................... 49
1.3.3.1
Single-Agent Clinical Activity in Patients with 
NSCLC in Study PCD4989g.................................................. 49
1.3.3.2
Single-Agent Clinical Activity in Patients with 
NSCLC in Study GO28753 (POPLAR) .................................. 50


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1.3.3.3
Single-Agent Clinical Activity in Patients with 
NSCLC in Study GO28915 (OAK)......................................... 52
1.3.3.4
Clinical Efficacy in Combination with 
Platinum-Based Doublet Chemotherapy in 
Patients with NSCLC ............................................................. 53
1.3.4
Clinical Pharmacokinetics and Immunogenicity..................... 53
1.3.5
Rationale for Atezolizumab Dosage ...................................... 53
1.4
Study Rationale and Benefit-Risk Assessment...................... 54
1.4.1
Rationale for Testing Atezolizumab in 
Combination with Bevacizumab............................................. 55
1.4.2
Rationale for Testing Atezolizumab in 
Combination with Carboplatin/Paclitaxel................................ 56
2.
OBJECTIVES.............................................................................................. 57
2.1
Efficacy Objectives ................................................................ 58
2.1.1
Co-Primary Efficacy Objectives ............................................. 58
2.1.2
Secondary Efficacy Objectives .............................................. 58
2.2
Safety Objectives................................................................... 59
2.3
Pharmacokinetic Objectives .................................................. 59
2.4
Exploratory Objectives........................................................... 60
3.
STUDY DESIGN......................................................................................... 60
3.1
Description of the Study......................................................... 60
3.1.1
Independent Data Monitoring Committee .............................. 63
3.2
End of Study.......................................................................... 64
3.3
Rationale for Study Design.................................................... 64
3.3.1
Rationale for Testing Atezolizumab in Patients 
with PD-L1Unselected NSCLC............................................ 64
3.3.2
Rationale for Control Arm ...................................................... 65
3.3.3
Rationale for Open-Label Study ............................................ 66
3.3.4
Rationale for Progression-Free Survival and 
Overall Survival as Co-Primary Endpoints............................. 66
3.3.5
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment until Loss of Clinical 
Benefit ................................................................................... 67
3.3.6
Rationale for Patient-Reported 
Outcome Assessments.......................................................... 68


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3.3.7
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens and Evaluation of PD-L1 and 
T-Effector Gene Signature..................................................... 69
3.3.8
Rationale for Blood Sampling for Biomarkers........................ 69
3.3.9
Rationale for the Collection of Mandatory Tumor 
Specimens at Radiographic Progression............................... 70
3.4
Outcome Measures ............................................................... 70
3.4.1
Efficacy Outcome Measures.................................................. 70
3.4.1.1
Co-Primary Efficacy Outcome Measures............................... 70
3.4.1.2
Secondary Efficacy Outcome Measures................................ 70
3.4.2
Safety Outcome Measures .................................................... 71
3.4.3
Pharmacokinetic Outcome Measures.................................... 71
3.4.4
Exploratory Outcome Measures ............................................ 72
4.
MATERIALS AND METHODS .................................................................... 72
4.1
Patients.................................................................................. 72
4.1.1
Inclusion Criteria.................................................................... 72
4.1.2
Exclusion Criteria................................................................... 75
4.1.2.1
Cancer-Specific Exclusions ................................................... 75
4.1.2.2
General Medical Exclusions .................................................. 76
4.1.2.3
Exclusion Criteria Related to Medications ............................. 78
4.1.2.4
Exclusions Related to Bevacizumab...................................... 78
4.1.2.5
Exclusions Related to Chemotherapy.................................... 79
4.2
Method of Treatment Assignment and Blinding..................... 80
4.3
Study Treatment.................................................................... 80
4.3.1
Formulation, Packaging, and Handling.................................. 80
4.3.1.1
Atezolizumab (MPDL3280A) ................................................. 80
4.3.1.2
Carboplatin, Paclitaxel, and Bevacizumab............................. 80
4.3.2
Dosage, Administration, and Compliance.............................. 81
4.3.2.1
Atezolizumab......................................................................... 83
4.3.2.2
Bevacizumab, Carboplatin, and Paclitaxel............................. 84
4.3.3
Additional Required Medication............................................. 86
4.3.3.1
Prophylactic Measures for Carboplatin.................................. 86
4.3.3.2
Premedication for Paclitaxel .................................................. 86
4.3.4
Investigational Medicinal Product Accountability ................... 86


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4.3.5
Post-Study Access to Atezolizumab ...................................... 87
4.4
Concomitant Therapy ............................................................ 87
4.4.1
Permitted Therapy................................................................. 87
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 88
4.4.3
Prohibited Therapy ................................................................ 88
4.5
Study Assessments ............................................................... 89
4.5.1
Informed Consent Forms and Screening Log........................ 89
4.5.2
Medical History and Demographic Data ................................ 90
4.5.3
Physical Examinations........................................................... 90
4.5.4
Vital Signs.............................................................................. 90
4.5.5
Tumor and Response Evaluations......................................... 91
4.5.6
Laboratory Assessments and Biomarker 
Samples................................................................................. 93
4.5.7
Tumor Tissue Samples.......................................................... 94
4.5.7.1
Archival and Freshly Collected Tumor Tissue 
Samples for Screening .......................................................... 94
4.5.7.2
Tumor Samples at the Time of Radiographic 
Progression ........................................................................... 95
4.5.7.3
Tumor Samples at Other Timepoints..................................... 96
4.5.7.4
Use and Storage of Remaining Samples from 
Study-Related Procedures..................................................... 96
4.5.8
Anti-Therapeutic Antibody Testing......................................... 97
4.5.9
Electrocardiograms................................................................ 97
4.5.10
Patient-Reported Outcomes .................................................. 97
4.5.11
Samples for Roche Clinical Repository.................................. 99
4.5.11.1
Overview of the Roche Clinical Repository............................ 99
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 99
4.5.11.3
Sample Collection................................................................ 100
4.5.11.4
Confidentiality...................................................................... 100
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository ........................................................................... 101
4.5.11.6
Withdrawal from the Roche Clinical Repository................... 101
4.5.11.7
Monitoring and Oversight..................................................... 102


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4.5.12
Timing of Assessments........................................................ 102
4.5.12.1
Screening and Baseline Assessments ................................ 102
4.5.12.2
Assessments during Treatment........................................... 102
4.5.12.3
Assessments at Study Drug Discontinuation Visit ............... 103
4.5.12.4
Follow-Up Assessments ...................................................... 103
4.5.12.5
Assessments at Unplanned Visits ....................................... 105
4.6
Patient, Treatment, Study, and Site 
Discontinuation.................................................................... 105
4.6.1
Patient Discontinuation........................................................ 105
4.6.2
Study Treatment Discontinuation......................................... 105
4.6.3
Study and Site Discontinuation............................................ 107
5.
ASSESSMENT OF SAFETY..................................................................... 108
5.1
Safety Plan .......................................................................... 108
5.1.1
Risks Associated with Atezolizumab ................................... 108
5.1.2
Risks Associated with Bevacizumab ................................... 109
5.1.3
Risks Associated with Carboplatin....................................... 109
5.1.4
Risks Associated with Paclitaxel.......................................... 109
5.1.5
General Plan to Manage Safety Concerns .......................... 110
5.1.5.1
Monitoring............................................................................ 110
5.1.6
Dose Modification................................................................ 110
5.1.6.1
General Notes Regarding Dose Modification....................... 110
5.1.6.2
Atezolizumab Dose Modification.......................................... 111
5.1.7
Management of Atezolizumab-Specific Adverse 
Events.................................................................................. 111
5.1.8
Bevacizumab Dose Modification and 
Management of Specific Adverse Events ............................ 111
5.1.9
Carboplatin and Paclitaxel Dose Modification and 
Management of Specific Adverse Events ............................ 115
5.1.9.1
Hematologic Toxicity ........................................................... 116
5.1.9.2
Gastrointestinal Toxicity....................................................... 117
5.1.9.3
Hepatic Toxicity (Paclitaxel Only) ........................................ 118
5.1.9.4
Cardiovascular Toxicity (Paclitaxel Only)............................. 119
5.1.9.5
Neurologic Toxicity (Paclitaxel Only) ................................... 119


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5.1.9.6
Allergic Reaction/Hypersensitivity (Paclitaxel 
Only).................................................................................... 120
5.1.9.7
Other Toxicities.................................................................... 120
5.1.10
Potential Overlapping Toxicities .......................................... 121
5.2
Safety Parameters and Definitions ...................................... 121
5.2.1
Adverse Events ................................................................... 121
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 122
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 123
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 123
5.3.1
Adverse Event Reporting Period ......................................... 124
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.......................... 126
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 126
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................. 126
5.3.5.3
Persistent or Recurrent Adverse Events.............................. 127
5.3.5.4
Abnormal Laboratory Values ............................................... 127
5.3.5.5
Abnormal Vital Sign Values ................................................. 128
5.3.5.6
Abnormal Liver Function Tests............................................ 128
5.3.5.7
Deaths ................................................................................. 129
5.3.5.8
Preexisting Medical Conditions............................................ 129
5.3.5.9
Worsening of NSCLC .......................................................... 129
5.3.5.10
Hospitalization or Prolonged Hospitalization........................ 130
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........................................................ 131
5.4.1
Emergency Medical Contacts.............................................. 131


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5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 132
5.4.2.1
Events That Occur prior to Study Treatment 
Initiation ............................................................................... 132
5.4.2.2
Events That Occur after Study Treatment 
Initiation ............................................................................... 132
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............... 133
5.4.3.3
Abortions ............................................................................. 133
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 134
5.5
Follow-Up of Patients after Adverse Events ........................ 134
5.5.1
Investigator Follow-Up......................................................... 134
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............................................................... 135
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 135
6.1
Determination of Sample Size ............................................. 136
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............................................. 142
6.4.2.1
Progression-Free Survival and Overall Survival in 
Secondary Populations........................................................ 142
6.4.2.2
Objective Response Rate.................................................... 142
6.4.2.3
Duration of Response.......................................................... 142
6.4.2.4
Progression-Free Survival as Assessed by the 
Independent Review Facility................................................ 143
6.4.2.5
Overall Survival Rate at Landmark Timepoints.................... 143
6.4.2.6
Progression-Free Survival and Overall Survival in 
the Atezolizumab-Containing Arms ..................................... 143


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6.4.2.7
Patient-Reported Outcomes ................................................ 143
6.4.3
Handling of Missing Data..................................................... 144
6.5
Safety Analyses................................................................... 144
6.6
Pharmacokinetic Analyses................................................... 145
6.7
Exploratory Analyses........................................................... 145
6.7.1
Time to Response ............................................................... 145
6.7.2
Time in Response................................................................ 146
6.7.3
Objective Response Rate and Duration of 
Response by Independent Review Facility 
Assessment per RECIST v1.1............................................. 146
6.7.4
Objective Response Rate, Progression-Free 
Survival, and Duration of Responseper Modified 
RECIST ............................................................................... 146
6.7.5
Exploratory Analyses of Progression-Free 
Survival................................................................................ 146
6.7.5.1
Progression-Free Survival Rate at Landmark 
Timepoints........................................................................... 146
6.7.5.2
Non–Protocol-Specified Anti-Cancer Therapy..................... 146
6.7.5.3
Subgroup Analysis............................................................... 147
6.7.5.4
Sensitivity Analyses............................................................. 147
6.7.6
Exploratory Analyses of Overall Survival............................. 147
6.7.6.1
Loss to Follow-Up................................................................ 147
6.7.6.2
Subgroup Analysis............................................................... 147
6.7.6.3
Overall Survival Rate at Three-Year Landmark................... 148
6.7.6.4
Milestone Overall Survival Analysis..................................... 148
6.7.7
Exploratory Biomarker Analysis........................................... 148
6.7.8
EQ-5D-3L Health Status Data ............................................. 148
6.7.9
Patient-Reported Outcome Analyses .................................. 148
6.8
Interim Analyses .................................................................. 148
6.8.1
Planned Interim Analyses.................................................... 148
6.8.2
Optional Interim Analysis..................................................... 150
7.
DATA COLLECTION AND MANAGEMENT ............................................. 151
7.1
Data Quality Assurance....................................................... 151
7.2
Electronic Case Report Forms............................................. 151


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7.3
Electronic Patient-Reported Outcome Data......................... 152
7.4
Source Data Documentation................................................ 152
7.5
Use of Computerized Systems ............................................ 153
7.6
Retention of Records........................................................... 153
8.
ETHICAL CONSIDERATIONS.................................................................. 153
8.1
Compliance with Laws and Regulations .............................. 153
8.2
Informed Consent................................................................ 154
8.3
Institutional Review Board or Ethics Committee.................. 155
8.4
Confidentiality...................................................................... 155
8.5
Financial Disclosure ............................................................ 156
9.
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION........................................................................... 156
9.1
Study Documentation .......................................................... 156
9.2
Protocol Deviations.............................................................. 156
9.3
Site Inspections ................................................................... 156
9.4
Administrative Structure....................................................... 156
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 157
9.6
Protocol Amendments ......................................................... 158
10. REFERENCES ......................................................................................... 159
LIST OF TABLES
Table 1
Randomized Phase III Trials in Patients with Previously 
Untreated NonSmall Cell Lung Cancer ..................................... 37
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades................................................................ 44
Table 3
Study GO28753 (POPLAR):  Adverse Events Reported in at 
Least 10% of Patients................................................................. 46
Table 4
Adverse Events in Study GO28915 (OAK) with a Between-
Arm Difference in frequency of at least 5 Percentage Points...... 47
Table 5
Study GP28328:  All Reported Adverse Events.......................... 48


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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 
6-Month Progression-Free Survival Rates (per RECIST, 
Version 1.1)................................................................................. 50
Table 7
Efficacy Results in Study GO28753 (POPLAR):  
Intent-to-Treat Population ........................................................... 51
Table 8
Study GO28753 (POPLAR) Efficacy Results by Combination 
PD-L1 Diagnostic Subgroups with Complementary 
Comparison Subgroupings:  Intent-to-Treat Population.............. 52
Table 9
Study GO29436 Treatment Arms................................................ 61
Table 10
Suggested Premedication for Induction Treatment for 
All Treatment Arms ..................................................................... 82
Table 11
Treatment Regimen and Order of Administration for 
All Treatment Arms ..................................................................... 82
Table 12
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 83
Table 13
Vital Sign Measurements at Cycle 1 and All Subsequent 
Cycles ......................................................................................... 91
Table 14
Bevacizumab Dose Management for Adverse Events.............. 113
Table 15
Dosing Based on ANC and Febrile Neutropenia—Paclitaxel 
and Carboplatin......................................................................... 116
Table 16
Dosing Based on Nadir Platelet Count—Paclitaxel 
and Carboplatin......................................................................... 116
Table 17
Carboplatin and Paclitaxel Dose Modification Based on 
Gastrointestinal Toxicities in the Preceding Cycle .................... 118
Table 18
Dose Modifications for Paclitaxel for Hepatic Toxicity............... 119
Table 19
Paclitaxel Dose Modification for Neurologic Toxicity................. 120
Table 20
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 125
Table 21
Analysis Timing and Stopping Boundaries for Overall 
Survival in the ITT-WT Population:  Arm B vs Arm C................ 149
Table 22
Analysis Timing and Stopping Boundaries for Overall 
Survival in the ITT-WT Population:  Arm A vs Arm C................ 150
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 63
Figure 2
Criteria for Continuing Atezolizumab in Presence of 
Increased Radiographic Tumor Size (Atezolizumab Arms)....... 107
Figure 3
Progression-Free Survival and Overall Survival Analysis 
Hierarchy, Alpha Allocation, and Alpha Recycling .................... 136


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LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 167
Appendix 2
Schedule of Pharmacokinetic, Biomarker, and 
Anti-Therapeutic Antibody Assessments .................................. 174
Appendix 3
American Joint Committee on Cancer Non–Small Cell Lung 
Cancer Staging, 7th Edition ...................................................... 178
Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication ............................... 180
Appendix 5
Modified Response Evaluation Criteria in Solid Tumors ........... 191
Appendix 6
AntiPD-L1 Immunohistochemistry........................................... 198
Appendix 7
EORTC QLQ-C30..................................................................... 199
Appendix 8
EORTC QLQ-LC13................................................................... 201
Appendix 9
EQ-5D-3L.................................................................................. 202
Appendix 10
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 205
Appendix 11
Anaphylaxis Precautions........................................................... 206
Appendix 12
Preexisting Autoimmune Diseases ........................................... 207
Appendix 13
Symptoms in Lung Cancer........................................................ 208
Appendix 14
Patient Global Impression of Severity....................................... 211
Appendix 15
Additional Guidance on Chemotherapy Administration............. 212
Appendix 16
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 214


Atezolizumab—F. Hoffmann-La Roche Ltd
14/Protocol GO29436, Version 8
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (MPDL3280A, ANTI–PD-L1 
ANTIBODY) IN COMBINATION WITH 
CARBOPLATINPACLITAXEL WITH OR WITHOUT 
BEVACIZUMAB COMPARED WITH 
CARBOPLATINPACLITAXELBEVACIZUMAB IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH 
STAGE IV NON-SQUAMOUS NON–SMALL CELL 
LUNG CANCER
PROTOCOL NUMBER:
GO29436
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-003207-30
IND NUMBER:
117296
NCT NUMBER:
NCT02366143
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
MEDICAL MONITOR:
, R.N.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy to 
the Sponsor or their designee.


Atezolizumab—F. Hoffmann-La Roche Ltd
15/Protocol GO29436, Version 8
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF
ATEZOLIZUMAB (MPDL3280A, ANTI–PD-L1 ANTIBODY) IN 
COMBINATION WITH CARBOPLATIN PACLITAXEL WITH OR 
WITHOUT BEVACIZUMAB COMPARED WITH 
CARBOPLATIN PACLITAXEL BEVACIZUMAB IN 
CHEMOTHERAPY-NAIVE PATIENTS WITH STAGE IV 
NON-SQUAMOUS NON–SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO29436
VERSION NUMBER:
8
EUDRACT NUMBER:
2014-003207-30
IND NUMBER:
117296
NCT NUMBER:
NCT02366143
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
PHASE:
III
INDICATION:
Non-squamous nonsmall cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
Unless otherwise specified, efficacy objectives will be analyzed for the following two treatment 
comparisons:

Atezolizumabcarboplatinpaclitaxelbevacizumab (Arm B) versus 
carboplatinpaclitaxelbevacizumab (Arm C)

Atezolizumabcarboplatinpaclitaxel (Arm A) versus carboplatinpaclitaxelbevacizumab 
(Arm C)
The term “wild type” (WT) refers to randomized patients who do not have a sensitizing EGFR
mutation or ALK translocation.
The term “tumor gene expression” (tGE) refers to randomized patients with a defined level of 
expression of a PD-L1 and T-effector gene signature in tumor tissue, as analyzed through use 
of a centrally performed RNA-based assay.
Some efficacy endpoints will be analyzed in a population of randomized patients with a defined 
level of PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as analyzed through 
use of a centrally performed IHC test.
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 RECIST v1.1 in the tGE-WT population and 
the ITT-WT population

To evaluate the efficacy of atezolizumab as measured by overall survival (OS) in the 
ITT-WT population


Atezolizumab—F. Hoffmann-La Roche Ltd
16/Protocol GO29436, Version 8
The secondary efficacy objectives for this study are the following:

To evaluate the efficacy of atezolizumab as measured by OS in the tGE-WT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed PFS 
according to RECIST v1.1 and OS in the TC2/3 or IC2/3 WT population and the TC1/2/3 or 
IC1/2/3 WT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed PFS 
according to RECIST v1.1 and OS in the tGE population and the ITT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed objective 
response rate (ORR) according to RECIST v1.1 in the tGE-WT population and the ITT-WT 
population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed duration of 
response (DOR) according to RECIST v1.1 in the tGE-WT population and the ITT-WT 
population

To evaluate the efficacy of atezolizumab as measured by an Independent Review Facility 
(IRF)-assessed PFS according to RECIST v1.1 in the tGE-WT population and the ITT-WT 
population

To evaluate the OS rate at 1 and 2 years in each treatment arm for the tGE-WT population 
and the ITT-WT population

To compare the efficacy of the two atezolizumab-containing arms, Arm A versus Arm B,
as measured by investigator-assessed PFS according to RECIST v1.1 and by OS in the 
tGE-WT population and the ITT-WT population

To determine the impact of atezolizumab as measured by time to deterioration (TTD) in 
patient-reported lung cancer symptoms of cough, dyspnea (single-item and multi-item 
subscales), chest pain, or arm/shoulder pain, using the European Organisation for the 
Research and Treatment of Cancer (EORTC) Quality-of-Life QuestionnaireCore 30 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) in the tGE-WT 
population and the ITT-WT population

To determine the impact of atezolizumab as measured by change in 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 for the tGE-WT population 
and the ITT-WT 
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 and paclitaxel with and without bevacizumab (Arms A and B)

To characterize the pharmacokinetics of carboplatin when given in combination with 
paclitaxel with and without atezolizumab and/or bevacizumab (Arms A, B, and C)

To characterize the pharmacokinetics of paclitaxel when given in combination with 
carboplatin with and without atezolizumab and/or bevacizumab (Arms A, B, and C)

To characterize the pharmacokinetics of bevacizumab when given in combination with 
carboplatin and paclitaxel with and without atezolizumab (Arms B and C)


Atezolizumab—F. Hoffmann-La Roche Ltd
17/Protocol GO29436, Version 8
Exploratory Objectives
The exploratory objectives for this study are the following:

To evaluate the efficacy of atezolizumab as measured by investigator-assessed time to 
response (TTR) and time-in-response (TIR) according to RECIST v1.1

To evaluate ORR and DOR according to RECIST v1.1 as assessed by the IRF

To evaluate investigator-assessed ORR, PFS, and DOR according to modified RECIST for 
the atezolizumab-containing treatment arms

To evaluate PFS at 6 months and at 1 year in each treatment arm

To evaluate the OS rate at 3 years in each treatment arm

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue and blood and their association with disease status, mechanisms 
of resistance, and/or response to study treatment

To evaluate the utility of biopsy at the time of apparent disease progression to distinguish 
apparent increases in tumor volume related to the immunomodulatory activity of 
atezolizumab (i.e., pseudoprogression/tumor-immune infiltration) from true disease 
progression

To evaluate and compare patient’s health status as assessed by the EuroQoL 
5 Dimensions 3-Level (EQ-5D-3L) questionnaire to generate utility scores for use in 
economic models for reimbursement

To determine the impact of atezolizumab as measured by change from baseline in 
patient-reported outcomes of health-related quality of life, lung cancerrelated symptoms, 
and functioning as assessed by the EORTC QLQ-C30 and QLQ-LC13 
Study Design
Description of Study
This is a randomized, Phase III, multicenter, open-label study (IMpower150) designed to 
evaluate the safety and efficacy of atezolizumab in combination with carboplatin paclitaxel with 
or without bevacizumab compared with treatment with carboplatin paclitaxel bevacizumab in 
approximately 1200 chemotherapy-naive patients with Stage IV non-squamous nonsmall cell 
lung cancer (NSCLC).
Tumor specimens will be prospectively tested for PD-L1 expression by a central laboratory. 
Eligible patients will be stratified by sex (male vs. female), presence of liver metastases at 
baseline (yes vs. no), and by PD-L1 tumor expression by IHC (TC3 and any IC vs. TC0/1/2 and 
IC2/3 vs. TC0/1/2 and IC0/1).  Patients will be 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 cycles)

Treatment Arm B:  Atezolizumabcarboplatinpaclitaxelbevacizumab (Induction: four or 
six 21-day cycles); atezolizumabbevacizumab (Maintenance: 21-day cycles)

Treatment Arm C:  Carboplatinpaclitaxelbevacizumab (Induction: four or six 21-day 
cycles); bevacizumab (Maintenance: 21-day cycles)
The number of cycles of induction treatment (four or six) will be at the discretion of the 
investigator and will be determined and documented prior to randomization.  Induction treatment 
will be administered on a 21-day cycle until the following occur (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 will continue treatment with maintenance therapy.  
Patients who are randomized to Arms B and C will continue treatment with bevacizumab until 
progressive disease, unacceptable toxicity, or death.  Patients who are randomized to Arm A or 
B may continue treatment with atezolizumab beyond radiographic progression according to 


Atezolizumab—F. Hoffmann-La Roche Ltd
18/Protocol GO29436, Version 8
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).  
Treatment with chemotherapy (Arms A, B, and C) and bevacizumab (Arms B and C) must be 
discontinued in all patients who exhibit evidence of progressive disease.
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 48 weeks
following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, tumor assessment will be 
required every 9 weeks.  Patients will undergo tumor assessments until radiographic disease 
progression 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.  Patients who discontinue treatment for reasons other than radiographic disease 
progression (e.g., toxicity) will continue scheduled tumor assessments until radiographic 
disease progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated 
patients who had continued 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.
A secondary endpoint of this study is IRF-assessed PFS according to RECIST v1.1.  An IRF will 
therefore conduct an independent review of the responses of all patients, including a blinded 
review of computed tomography (CT) scans.  All primary imaging data used for tumor 
assessment will be collected by the Sponsor to enable centralized, independent review of 
response endpoints.  These reviews will be performed prior to the final efficacy analyses.
For Treatment Arms A and B Only
At any point during treatment, patients receiving atezolizumab 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 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 270 sites globally will participate in the study, and approximately 1200 patients 
will be randomized.


Atezolizumab—F. Hoffmann-La Roche Ltd
19/Protocol GO29436, Version 8
Target Population
Inclusion Criteria
Patients may be eligible if they have chemotherapy-naive, Stage IV, non-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 non-squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 7th 
edition).
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible 
if the major histological component appears to be non-squamous.

No prior treatment for Stage IV non-squamous NSCLC
Patients with a sensitizing mutation in the 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 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 EGFR and/or ALK status require test results at screening.  ALK
and/or EGFR may be assessed locally or at a central laboratory.

Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or 
chemoradiotherapy with curative intent for non-metastatic disease must have experienced a 
treatment-free interval of at least 6 months from randomization since the last chemotherapy, 
radiotherapy, or chemoradiotherapy.

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.


Atezolizumab—F. Hoffmann-La Roche Ltd
20/Protocol GO29436, Version 8

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. 

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 and/or 6 months after the last dose of bevacizumab or paclitaxel, 
whichever is later).  Women must refrain from donating eggs during this same period.  
Highly effective contraceptive 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, vasectomized partner (on the understanding that this is the only 
one partner during the whole study duration), and sexual abstinence.


Atezolizumab—F. Hoffmann-La Roche Ltd
21/Protocol GO29436, Version 8

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 bevacizumab, carboplatin, or paclitaxel.  Male patients 
should not donate sperm during this study and for at least 6 months after the last dose of 
bevacizumab, carboplatin, or paclitaxel.

Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drug.  The same rules are valid for male
patients involved in this clinical study if they have a partner of childbirth potential.  Male 
patients must always use a condom.

Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug
Exclusion Criteria
Patients who meet any of the criteria below will be excluded from study entry.
Cancer-Specific Exclusions

Active or untreated CNS metastases as determined by 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 PD-1 or anti-PD-L1 antibodies but were not eligible are excluded)


Atezolizumab—F. Hoffmann-La Roche Ltd
22/Protocol GO29436, Version 8
General Medical Exclusions

Women who are pregnant, lactating, or intending to become pregnant during the study

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study.
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)

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.


Atezolizumab—F. Hoffmann-La Roche Ltd
23/Protocol GO29436, Version 8

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months 
prior to randomization, unstable arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or left ventricular ejection fraction 50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate.

Major surgical procedure other than for diagnosis within 28 days prior to randomization or 
anticipation of need for a major surgical procedure during the course of the study

Prior allogeneic bone marrow transplantation or solid organ transplant

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
renders the patient at high risk from treatment complications

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 3 weeks prior to 
initiation of study treatment; the following exceptions are allowed:
TKIs approved for treatment of NSCLC discontinued 7 days prior to randomization; 
the baseline scan must be obtained after discontinuation of prior TKIs.

Treatment with any other investigational agent with therapeutic intent within 28 days prior to 
randomization

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, antiPD-1, 
and antiPD-L1 therapeutic antibodies
Patients who have had prior antiCTLA-4 treatment may be enrolled, provided the 
following requirements are met:
–
Last dose of antiCTLA-4 at least 6 weeks prior to randomization
–
No history of severe immune-mediated adverse effects from antiCTLA-4 (National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
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.


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Exclusions Related to Bevacizumab

Inadequately controlled hypertension (defined as systolic blood pressure 150 mmHg 
and/or diastolic blood pressure 100 mmHg)
Anti-hypertensive therapy to achieve these parameters is allowable.

Prior history of hypertensive crisis or hypertensive encephalopathy

Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to randomization

History of hemoptysis (one-half teaspoon of bright red blood per episode) within 1 month 
prior to randomization

Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation)

Current or recent (within 10 days of randomization) use of aspirin (325 mg/day) or 
treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol

Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic purposes that has not been stable for 2 weeks prior to randomization
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or 
aPTT is within therapeutic limits (according to the medical standard of the enrolling 
institution) and the patient has been on a stable dose of anticoagulants for at least 
2 weeks prior to randomization.
Prophylactic anticoagulation for the patency of venous access devices is allowed, 
provided the activity of the agent results in an INR 1.5ULN and aPTT is within 
normal limits within 14 days prior to randomization.
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is 
permitted.

Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to the first dose of bevacizumab

History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 
6 months prior to randomization

Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, 
parenteral nutrition, or tube feeding 

Evidence of abdominal free air not explained by paracentesis or recent surgical procedure

Serious, non-healing wound, active ulcer, or untreated bone fracture

Proteinuria, as demonstrated by urine dipstick or 1.0 g of protein in a 24-hour urine 
collection
All patients with 2protein on dipstick urinalysis at baseline must undergo a 24-hour 
urine collection and must demonstrate 1 g of protein in 24 hours.

Known sensitivity to any component of bevacizumab

Clear tumor infiltration into the thoracic great vessels is seen on imaging

Clear cavitation of pulmonary lesions is seen on imaging
Exclusions Related to Chemotherapy

Known history of severe allergic reactions to platinum-containing compounds or mannitol

Known sensitivity to any component of paclitaxel

Grade 2 peripheral neuropathy as defined by NCI CTCAE v4.0 (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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Length of Study
The final PFS analysis will be conducted when both of the following criteria have been met:  
approximately 516 PFS events have occurred in Arms B and C combined in the ITT-WT 
population and the last patient has been enrolled in the study.  The final PFS analysis is 
expected to occur approximately 29 months after the first patient is enrolled.  At the time of 
the final PFS analysis, it is expected that approximately 249 events will have occurred in the 
tGE-WT population.
With a sample size of 720 patients, approximately 507 OS events are expected to occur in 
Arms B and C combined in the ITT-WT population for the final OS analysis.  The final OS 
analysis is expected to occur approximately 40 months after the first patient is enrolled.  This 
number of events corresponds to a minimum detectable difference in HR of approximately 0.83 
in the ITT-WT population
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.
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 disease progression 
as determined by the investigator using RECIST v1.1 or death from any cause, whichever 
occurs first in the tGE-WT population and the ITT-WT population

OS, defined as the time from randomization to death from any cause in the ITT-WT 
population
The secondary efficacy outcome measures for this study are the following:

OS in the tGE-WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the TC2/3 or 
IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the tGE 
population and the ITT population

Objective response, defined as partial response (PR) or complete response (CR) as 
determined by the investigator according to RECIST v1.1 1 in the tGE-WT population and 
the ITT-WT population

DOR, defined as the time interval from first occurrence of a documented objective response 
to the time of disease progression as determined by the investigator using RECIST v1.1 or 
death from any cause, whichever occurs first 1 in the tGE-WT population and the ITT-WT 
population

PFS, defined as the time from randomization to the first occurrence of disease progression 
as determined by the IRF using RECIST v1.1 or death from any cause, whichever occurs 
first 1 in the tGE-WT population and the ITT-WT population

OS rates at 1 and 2 years 1 in the tGE-WT population and the ITT-WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the two 
atezolizumab-containing arms in the tGE-WT population and the ITT-WT population

TTD in patient-reported lung cancer symptoms, defined as time from randomization to 
deterioration (10-point change) on each of the EORTC QLQ-C30 and EORTC QLQ-LC13 
symptom subscales in the tGE-WT population and the ITT-WT population

Change from baseline in patient-reported lung cancer symptoms (chest pain, dyspnea, and 
cough) on the symptom severity score of the Symptoms in Lung Cancer scale in the 
tGE-WT population and the ITT-WT population


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Safety Outcome Measures
The safety outcome measures for this study are the following:

Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v4.0

Changes in vital signs, physical findings, and clinical laboratory results during and following 
atezolizumab administration

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are the following:

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 (Arms A, B, and C) 

Bevacizumab Cmax and Cmin (Arms B and C)
Exploratory Outcome Measures
The exploratory outcome measures for this study are:

TTR, defined as the time from randomization to first occurrence of a documented objective 
response as determined by the investigator according to RECIST v1.1

Time in response (TIR), defined as 1 day for non-responders and defined the same as DOR 
for responders, as determined by the investigator according to RECIST v1.1

Objective response and DOR, as determined by the IRF according to RECIST v1.1

Objective response, PFS, and DOR, in the two atezolizumab-containing arms, as 
determined by the investigator according to modified RECIST (Arms A and B)

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)
Atezolizumab (1200 mg IV) will be administered on Day 1 of each 21–day cycle.  Atezolizumab 
will be administered to patients who are randomized to Arms A and B.
Comparator
Bevacizumab (15 mg/kg IV) will be administered on Day 1 of each 21-day cycle for four or 
six cycles during the induction phase and during the maintenance phase.
Bevacizumab will be administered to patients randomized to Arms B and C.


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Non-Investigational Medicinal Products

Carboplatin will be administered by IV infusion to achieve an initial target area under the 
concentrationtime 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 in in all treatment arms.  
Statistical Methods
Primary Analysis
The co-primary efficacy endpoints are PFS as assessed by the investigator using RECIST v1.1, 
and OS.  The primary endpoint of PFS will be analyzed in the tGE-WT population and in the 
ITT-WT population, and the primary endpoint of OS will be analyzed in the ITT-WT population.  
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 date 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 A vs. Arm C, Arm B 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 
() will be allocated to PFS in the tGE-WT population, PFS in the ITT-WT population, and OS in 
the ITT-WT population in a 3:3:19 ratio for comparison of Arm B versus Arm C
1.
PFS in the tGE-WT population will be tested at 0.003 (one sided).  If the estimate of the 
HR is <1 and the one-sided p-value corresponding to the stratified log-rank test is 0.003, 
the null hypothesis will be rejected, and it will be concluded that 
atezolizumab carboplatin paclitaxel bevacizumab prolongs the duration of PFS relative 
to the control arm in the tGE-WT population.
2.
PFS in the ITT-WT population will be tested at 0.003 (one sided).
3.
recycling from PFS to OS will be conducted as follows:
a.
If the PFS result is not statistically significant in either the tGE-WT population or the 
ITT-WT population, OS in the ITT-WT population will be tested at 0.019 (one sided).
b.
If the PFS result is only statistically significant in the tGE-WT population or the ITT-WT 
population, OS in the ITT-WT population will be tested at 0.022 (one sided).
c.
If the PFS result is statistically significant in both the tGE-WT population and the 
ITT-WT population, OS in the ITT-WT 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-WT population is statistically 
significant at an of 0.019, 0.022, or 0.025 (Step 3 above), 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 
in the tGE-WT population, PFS in the ITT-WT population, and OS in the ITT-WT population at 
the same 3:3:19 ratio.  If the difference in OS between Arm B and Arm C in the ITT-WT 
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.


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Depending on the outcome of the PFS testing of Arm A vs. Arm C in the tGE-WT and ITT-WT 
populations, the from these two PFS comparisons will be recycled back to the OS comparison 
in the ITT-WT population for Arm A vs. Arm C.
1.
If the difference in OS between Arm B and Arm C is statistically significant at 0.019 
(one sided):
a.
PFS in the tGE-WT population will be tested at 0.00228 (one sided).  If the estimate 
of the HR is <1 and the one-sided p-value corresponding to the stratified log-rank test 
is 0.00228, the null hypothesis will be rejected, and it will be concluded that 
atezolizumab carboplatin paclitaxel prolongs the duration of PFS relative to the 
control arm in the tGE-WT population.
b.
PFS in the ITT-WT population will be tested at 0.00228 (one sided
c.
recycling from PFS to OS will be conducted as follows:

If the PFS result is not statistically significant in either the tGE-WT population or 
the ITT-WT population, OS in the ITT-WT population will be tested at 0.01444 
(one sided)

If the PFS result is only statistically significant in the tGE-WT population or the 
ITT-WT population, OS in the ITT-WT population will be tested at 0.01672 
(one sided)

If the PFS result is statistically significant in both the tGE-WT population and the 
ITT-WT population, OS in the ITT-WT population will be tested at 0.019 
(one sided).
2.
If the difference in OS between Arm B and Arm C is statistically significant at 0.022 
(one sided):
a.
PFS in the tGE-WT 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 the 
control arm in the tGE-WT population.
b.
PFS in the ITT-WT population will be tested at 0.00264 (one sided
c.
recycling from PFS to OS will be conducted as follows:

If the PFS result is not statistically significant in either the tGE-WT population or 
the ITT-WT population, OS in the ITT-WT population will be tested at 0.01672 
(one sided)

If the PFS result is only statistically significant in the tGE-WT population or the 
ITT-WT population, OS in the ITT-WT population will be tested at 0.01936 
(one sided)

If the PFS result is statistically significant in both the tGE-WT population and the 
ITT-WT population, OS in the ITT-WT population will be tested at 0.022 
(one sided).
3.
If the difference in OS between Arm B and Arm C is statistically significant at 0.025 
(one sided):
a.
PFS in the tGE-WT population will be tested at 0.003 (one sided).  If the estimate of 
the HR is <1 and the one-sided p-value corresponding to the stratified log-rank test 
is 0.003, the null hypothesis will be rejected, and it will be concluded that 
atezolizumab carboplatin paclitaxel prolongs the duration of PFS relative to the 
control arm in the tGE-WT population.
b.
PFS in the ITT-WT population will be tested at 0.003(one sided
c.
recycling from PFS to OS will be conducted as follows:

If the PFS result is not statistically significant in either the tGE-WT population or 
the ITT-WT population, OS in the ITT-WT population will be tested at 0.019 
(one sided)


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
If the PFS result is only statistically significant in the tGE-WT population or the 
ITT-WT population, OS in the ITT-WT population will be tested at 0.022
(one sided)

If the PFS result is statistically significant in both the tGE-WT population and the 
ITT-WT population, OS in the ITT-WT 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 IxRS.
Results from an unstratified analysis will also be presented.  Kaplan-Meier methodology will be 
used to estimate the median PFS and the median OS for each treatment arm, and a 
Kaplan-Meier curve will be constructed to provide a visual description of the difference between 
treatment arms.  The Brookmeyer-Crowley methodology will be used to construct the 95% CI
for the median PFS and the median OS for each treatment arm.
Determination of Sample Size
This study will enroll approximately 1200 patients.  The ITT-WT population will include 
approximately 1080 patients, assuming a 10% prevalence for sensitizing EGFR mutations or 
ALK translocations.  The tGE-WT population will include approximately 540 patients, assuming 
a 50% prevalence with the chosen tGE cutoff.
The sample size of this study is based on the number of events required to demonstrate 
efficacy with regard to both PFS and OS (co-primary endpoints).
The estimate of the number of events required to demonstrate efficacy with regard to PFS in the 
comparison of Arm 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-WT population

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in the 
ITT-WT population

98% power to detect an HR of 0.55, corresponding to an improvement in median PFS from 
6 months to 10.9 months in the tGE-WT population

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-WT 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 0.019 for the comparison of Arm B versus Arm C in the 
ITT-WT population

87% power to detect an HR of 0.75, corresponding to an improvement in median OS from 
12 months to 16 months in the ITT-WT population

One interim OS analysis performed at the time of the final PFS analysis, at which time 
approximately 73% 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 1200 patients in total will be enrolled into this study,
with approximately 720 patients in each comparison (i.e., Arm B vs. Arm C and Arm A vs. 
Arm C) in the ITT-WT population.  The final PFS analysis will be conducted when both of the 


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following criteria have been met:  approximately 516 PFS events have occurred in Arms B 
and C combined in the ITT-WT population and the last patient has been enrolled in the study.  
The final PFS analysis is expected to occur approximately 29 months after the first patient is 
enrolled.  At the time of the final PFS analysis, it is expected that approximately 249 events will 
have occurred in the tGE-WT population.  These numbers of events would allow for a minimum 
detectable difference corresponding to an HR of approximately 0.70 in the tGE-WT population 
and 0.78 in the ITT-WT population.
With a sample size of 720 patients, approximately 507 OS events are expected to occur in 
Arms B and C combined in the ITT-WT population for the final OS analysis.  The final OS 
analysis is expected to occur approximately 40 months after the first patient is enrolled.  This 
number of events corresponds to a minimum detectable difference in HR of approximately 0.83 
in the ITT-WT population
Interim Analyses
There will be 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 370 OS events have occurred in Arms B and C combined in the ITT-WT 
population at the time of the final PFS analysis, an interim OS analysis will be conducted for 
Arm B versus Arm C in the ITT-WT population.  If there are significantly fewer than the expected 
370 OS events at the time of the final PFS analysis, a nominal of 0.01% (negligible impact on 
overall type I error rate) will be spent on the OS analysis at the time of the final PFS analysis 
and a second interim OS analysis will then be conducted after approximately 370 OS events 
have occurred.
The final OS analysis for the comparison of Arm B versus Arm C will be conducted when 
approximately 507 OS events have occurred in Arms B and C combined in the ITT-WT 
population.  This is expected to occur approximately 40 months after the first patient is enrolled.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ASCO
American Society of Clinical Oncology
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
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NGS
next-generation sequencing
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PD1
programmed death1
PDL1
programmed deathligand 1
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
SILC
Symptoms in Lung Cancer
TC
tumor cell


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Abbreviation
Definition
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
UBC
urothelial bladder cancer
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. 2011). 
NSCLC can be divided into two major histologic types:  adenocarcinoma and squamous 
cell carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for more than 
half of all NSCLC, while squamous cell histology accounts for approximately 25% 
(Langer et al. 2010).  The remaining cases of NSCLC are represented by large cell 
carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated 
histology.
The overall 5-year survival rate for advanced disease is 2%4%, depending on 
geographic location (Cetin et al. 2011).  Poor prognostic factors for survival in patients 
with NSCLC include advanced stage of disease at the time of initial diagnosis, poor 
performance status, and a history of unintentional weight loss.  More than half of the 
patients with NSCLC are diagnosed with distant disease, which directly contributes to 
poor survival prospects.
There are recognized differences in disease characteristics between adenocarcinoma and 
squamous NSCLC.  First, squamous tumors commonly present in the central airways and 
typically remain localized in the bronchial epithelium (Hirsch et al. 2008), whereas 
non-squamous tumors are more commonly located in the lung parenchyma distal to the 
central airways.  Evaluation of NSCLC tumor tissue will reveal cytological differences 
between the squamous cell type (keratinization, intracellular bridges, and central necrosis) 
and adenocarcinoma (glandular architecture).  In cases where the tumor sample is poorly 
differentiated or there is limited tissue available, immunohistochemical markers may 
support the histologic diagnosis.  Thyroid transcription factor1 (TTF-1) is infrequently 
expressed in squamous cells and strongly expressed in adenocarcinoma.  In contrast, p63, 
CK5/6, and 34E12 are strongly expressed in squamous cell carcinoma and less 
frequently in adenocarcinoma (Travis et al. 2011).
Genetic changes that have prognostic and/or predictive significance in NSCLC include 
mutations in the EGFR, the rearrangement in the ALK genes, and mutations in the 
KRAS gene.  The rates of these mutations differ between squamous cell carcinoma and 
adenocarcinoma.  For example, EGFR kinase domain mutations have been reported in 
10%40% of patients with adenocarcinoma NSCLC but are infrequently observed in 


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


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taxanes (paclitaxel, docetaxel), vinorelbine, gemcitabine, and pemetrexed.  
Combinations of these drugs with platinum analogs are superior to single-agent 
therapy and have been shown to prolong survival (Azzoli et al. 2009).  
The Eastern Cooperative Oncology Group (ECOG) conducted a Phase III study 
(Study E1594) to compare four commonly used platinum-based doublets in patients with 
Stage IIIB/IV NSCLC who had not previously received chemotherapy 
(Schiller et al. 2002).  Gemcitabine cisplatin, docetaxelcisplatin, 
and paclitaxelcarboplatin were compared with paclitaxelcisplatin.  No significant 
clinical advantage of any one of the chemotherapy regimens over the others was 
observed; the median survival rates of the four treatment arms were approximately the 
same:  approximately 8 months.  The regimen of paclitaxelcarboplatin was chosen 
as the reference regimen for ECOG’s future studies because of its more favorable 
toxicity profile. 
Despite modest gains, the benefit conferred by platinum-based chemotherapy 
regimens appears to have reached a plateau in ORR (approximately 15%25%) and 
median survival (711 months).  Pemetrexed (ALIMTA® U.S. Package Insert) has 
recently demonstrated activity in the first-line setting where patients with 
non-squamous carcinoma had improved survival when treated with cisplatin and 
pemetrexed compared with those treated with cisplatin and gemcitabine 
(11.8 vs. 10.4 months; p0.005) (Scagliotti et al. 2008).  In addition, cisplatin and 
pemetrexed was associated with better tolerability and safety and necessitated less 
supportive care.  More recently, the addition of bevacizumab to carboplatin and 
paclitaxel in patients with non-squamous NSCLC resulted in an increase in response 
rate from 15% to 35% and an increase in median overall survival (OS) from 10 to 
12 months (see Table 1). 
Recently, immune checkpoint inhibitors, including PD-L1/PD-1 blocking antibodies, have
emerged as a new therapeutic option for first-line treatment of metastatic NSCLC.  
Study KEYNOTE-024 was a Phase III, randomized, open-label study evaluating 
pembrolizumab given as monotherapy compared with platinum-based chemotherapy in 
patients who had previously untreated advanced NSCLC with PD-L1 expression on at 
least 50% of tumor cells.  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 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.


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


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


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1.1.3
AVASTINand Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor 
and a key regulator of physiological angiogenesis.  It is also implicated in pathological 
angiogenesis such as that associated with tumor growth.  Increased levels of VEGF 
have been found in most tumors examined to date, including tumors of the lung where, 
in addition, overexpression is associated with a poorer prognosis (Giatromanolaki 2001; 
Brattstrom et al. 2004).
AVASTIN® (bevacizumab) is a recombinant humanized monoclonal antibody to VEGF that 
recognizes all isoforms of VEGF.  It may exert a direct anti-angiogenic effect by binding to 
and clearing VEGF from the tumor environment.  Additional anti-tumor activity may be on 
tumor vasculature, interstitial pressure, and blood vessel permeability, providing for 
enhanced chemotherapy delivery to tumor cells (Jain 2001).
Bevacizumab has been tested in Phase II and III studies in a variety of solid tumors 
in combination with chemotherapy.  Bevacizumab is registered in over 40 countries 
worldwide for the first-line treatment of metastatic colorectal cancer (CRC) 
in combination with chemotherapy, as second-line CRC treatment, and first-line 
treatment of advanced NSCLC, metastatic breast cancer, advanced renal cell carcinoma 
(RCC), ovarian cancer, and glioblastoma (Reck and Crino 2009).
1.1.3.1
Clinical Studies of Bevacizumab and Platinum-Based 
Treatment in NSCLC
Two Phase III studies have demonstrated the benefit of bevacizumab in combination 
with platinum-based chemotherapy as first-line treatment of patients with unresectable, 
advanced, metastatic or recurrent non-squamous NSCLC. 
Efficacy
The first study, conducted by the ECOG (Study E4599) was an open-label, randomized, 
Phase III study comparing the regimen of 15 mg/kg bevacizumab every 3 weeks (Q3W) 
in combination with carboplatin and paclitaxel versus carboplatin and paclitaxel alone as 
first-line treatment of patients with advanced non-squamous NSCLC.  The Phase III 
study was based on a randomized Phase II study in patients with recurrent or advanced 
NSCLC that evaluated carboplatin and paclitaxel (up to six cycles) with or without 
bevacizumab (7.5 or 15 mg/kg) and found that the combination of bevacizumab 
15 mg/kg with carboplatin/paclitaxel for up to six cycles followed by maintenance 
bevacizumab until disease progression resulted in increased response rates 
(31.5% vs. 18.8%) and prolonged time to progression (TTP) (7.4 vs. 4.2 months; 
p0.023) compared with chemotherapy alone (Johnson et al. 2004).  There was also a 
non-significant improvement in OS (17.7 vs. 14.9 months) (Johnson et al. 2004).  
A higher incidence of bleeding was noted in the bevacizumab-treated patients. Severe 
pulmonary hemorrhage, which was observed in 6 patients (9.1%) and led to 4 fatalities, 
was more common in patients with squamous cell histology, tumor necrosis, and 


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cavitation, and central tumors (Johnson et al. 2004).  On the basis of the results of this 
Phase II study, patients with squamous cell histology were excluded from this and other 
studies utilizing bevacizumab in NSCLC.  In Study E4599, patients who received 
six cycles of bevacizumab plus chemotherapy without disease progression continued on 
single-agent bevacizumab until progression.  A total of 878 patients were enrolled.  
Median OS was 12.3 months versus 10.3 months (HR0.79; p0.003); PFS was 
6.2 months versus 4.5 months (HR0.66; p0.001), and the response rate was 35% 
(133 of 381) versus 15% (59 of 392) (p0.001) for patients treated with bevacizumab 
versus chemotherapy alone (Sandler et al. 2006). 
The second study (BO17704 or AVAiL) was a randomized, double-blind, multicenter, 
two-stage, Phase III study of bevacizumab in combination with cisplatin and gemcitabine 
versus placebo, cisplatin, and gemcitabine as first-line treatment in patients with 
advanced or recurrent non-squamous NSCLC.  A total of 1043 patients were 
randomized.  Bevacizumab-based therapy until disease progression reduced the risk of 
disease progression.  Bevacizumab at a dose level of 7.5 mg/kg resulted in an HR for 
PFS of 0.75 (median PFS, 6.7 vs. 6.1 months; p0.003), and bevacizumab at a dose 
level of 15 mg/kg resulted in an HR of 0.82 (median 6.5 months vs. 6.1 months, p0.03).  
These results were maintained with a longer follow-up.  OS was a secondary endpoint, 
and the PFS benefit did not translate into a significant OS benefit.  Nevertheless, median 
OS in all treatment arms of the study exceeded 13 months (Reck et al. 2009; 
Reck et al. 2010). 
Safety
In the initial Phase II and III clinical studies, four potential bevacizumab-associated 
safety signals were identified:  hypertension, proteinuria, thromboembolic events (TEs), 
and hemorrhage.  Additional completed Phase II and III studies of bevacizumab and 
spontaneous reports have further defined the safety profile of this agent.  
Bevacizumab-associated adverse events identified in Phase III studies include 
congestive heart failure (primarily in metastatic breast cancer), gastrointestinal 
perforations, wound-healing complications, and arterial TEs.  Reversible posterior 
leukoencephalopathy syndrome and fistula have also been reported infrequently.  
Further details on the safety profile of bevacizumab are available in the 
Bevacizumab Investigator’s Brochure. 
In summary, platinum-based regimens remain the standard first-line option for most 
patients with locally advanced and metastatic NSCLC not harboring an activating EGFR
mutation or ALK gene rearrangement.  In particular, for newly diagnosed 
advanced-stage non-squamous NSCLC, the current standard-of-care is a platinum 
doublet with either cisplatin or carboplatin and a taxane or pemetrexed, with or without 
bevacizumab.  However, these regimens are associated with substantial toxicities (such 
as febrile neutropenia, myelosuppression, nausea, alopecia, nephropathy, and 
neuropathy) and are generally poorly tolerated by elderly and poor performance status 


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patients.  Therefore, novel therapies that deliver an improved therapeutic index are 
urgently needed for non-squamous NSCLC.
1.1.4
Targeted Therapy for NSCLC
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC (mainly non-squamous histology) 
characterized by alterations of driver oncogenes, including sensitizing EGFR mutations 
and ALK rearrangement.  Randomized Phase III studies of gefitinib (IPASS), erlotinib 
(EURTAC), and afatinib (LUX-LUNG 3) showed significant improvement of PFS and 
objective response rate (ORR) compared with platinum doublet chemotherapy 
(Fukuoka et al. 2011; Rosell et al. 2012; Sequist et al. 2013).  Similarly, the ALK 
inhibitors crizotinib and ceritinib have demonstrated efficacy in patients with NSCLC
positive for ALK rearrangement as defined by fluorescence in situ hybridization 
(Crino et al. 2011; Camidge et al. 2012; Shaw et al. 2012; Shaw and Engelman 2014; 
XALKORI® U.S. Package Insert; ZYKADIAU.S. Package Insert).
Despite progress with new targeted treatments and new chemotherapy combinations, 
survival rates for advanced disease remain low and acquired resistance to targeted 
agents is a major clinical problem.  Therefore, alternative treatment options that yield 
durable responses and enhance OS remain an important focus of research.  Against this 
background, immunotherapeutic agents, such as cancer vaccines and antibodies that 
modulate immune cell activity, offer an alternative treatment approach that could 
potentially improve the prognosis of patients with this disease.
1.2
BACKGROUND ON ATEZOLIZUMAB (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 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 locally 
advanced or metastatic urothelial carcinoma after prior chemotherapy.


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1.2.1
Summary of Nonclinical Studies
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab.
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid 
in projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical studies in patients.
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.3
CLINICAL EXPERIENCE WITH ATEZOLIZUMAB
1.3.1
Ongoing Clinical Studies
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  The single-agent safety 
and efficacy data available to date 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 
Q3Wto 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


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


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


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Immune-Mediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
atezolizumab clinical program.  These include potential dermatologic, hepatic, endocrine, 
gastrointestinal, and respiratory events.  
Refer to the Atezolizumab Investigator’s Brochure for details on immune-mediated 
adverse events that were observed in patients treated with atezolizumab.  Guidelines for 
the management of immune-mediated adverse events are described in Section 5.1.7.
1.3.2.2
Single-Agent Clinical Safety in Patients with NSCLC in 
Study GO28753 (POPLAR)
As of the 1 December 2015 data cutoff date, the Phase II POPLAR study (GO28753) 
included data from 277 safety-evaluable patients treated with either atezolizumab as a 
fixed dose of 1200 mg IV every three weeks (Q3W) (n142) or docetaxel 75 mg/m2 IV 
Q3W (n135).  The frequency of patients in the POPLAR study who reported an 
adverse event regardless of attribution was 95.8% for the atezolizumab arm and 96.3% 
for the docetaxel arm.  A higher frequency of Grade3or 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.


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1.3.2.3
Single-Agent Clinical Safety in Patients with NSCLC in 
Study GO28915 (OAK)
As of the 7 July 2016 data cutoff date for the primary analysis, the Phase III Study 
GO28915 (OAK) included data from 609 patients treated with atezolizumab as a fixed 
dose of 1200 mg IV Q3W and 578 patients treated with docetaxel 75 mg/m2 IV Q3W.  
The frequency of patients who reported any adverse event regardless of attribution was
94.1% for the atezolizumab arm and 96.0% for the docetaxel arm.  A higher frequency of 
Grade 3 or 4 adverse events was observed among patients in the docetaxel arm 
(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
Stomatitis
3.9%
3.1%
11.2%
10.9%
Febrile neutropenia
0.2%
10.7%
Dysgeusia
3%
10%
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 


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Arm F (atezolizumabnab-paclitaxel).  The treatment combinations have been generally 
well tolerated.  No DLTs have been reported during the dose-escalation stage in any 
study arm.  Patients are being enrolled in safety and biopsy expansion cohorts in Arms A 
and B as well as in additional arms testing atezolizumab in combination with commonly 
used NSCLC chemotherapy doublets.  
A total of 141 of 144 patients (97.9%) reported at least one adverse event while 
receiving study drug.  The majority of these events were Grade 2 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.  


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All patients who were enrolled in Arms C and D experienced an adverse event; 95% of 
patients who were enrolled in Arm E experienced an adverse event, and 83.3% of 
patients enrolled in Arm F experienced an adverse event.  The adverse events 
commonly reported in 2 or more patients in Arms C, D, and E included anemia, 
decreased appetite, hypomagnesemia, nausea, neutropenia, constipation, vomiting, 
fatigue, rash, cough, and diarrhea.  Adverse events commonly reported in 2 or more 
patients in Arm F included dermatitis, upper respiratory infection, alopecia, peripheral 
sensory neuropathy, fever, constipation, neutrophil count decreased, anemia, diarrhea, 
headache, nausea, and fatigue.
1.3.3
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)-based responses (i.e., RECIST, 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 updated details on clinical activity 
in all patients treated to date, regardless of tumor type.
1.3.3.1
Single-Agent Clinical Activity in Patients with NSCLC in 
Study PCD4989g
As of the clinical data cutoff of 2 December 2014, the efficacy evaluable population 
included 88 patients with locally advanced or metastatic NSCLC.  The median age was 
60.5 years (range 2484 years) and represented a heavily pre-treated patient population:  
97% of the patients had received 2 prior systemic therapies, and 77.3% 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 (ICs) and tumor cells (TCs) for PD-L1 expression on baseline tumor tissue from 
NSCLC patients have been performed. Higher ORRs were associated with higher PD-L1 
expression (TC3 or IC3).
Refer to the Atezolizumab Investigator’s Brochure for updated details on clinical activity 
in patients with NSCLC treated to date.




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duration of 14.3 months (95% CI: 11.6, 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 Subgroups with Complementary Comparison 
Subgroupings:  Intent-to-Treat Population
Population
HR (95% CI)
Total No. of Patients
(Atezolizumab/
Docetaxel)
OS
PFS
ITT
0.69 (0.52, 0.92)
0.92 (0.71, 1.20)
287 (144/143)
TC3 or IC3
0.45 (0.22, 1.95)
0.60 (0.32, 1.13)
47 (24/23)
TC2/3 or IC2/3
0.50 (0.31, 0.80)
0.71 (0.47, 1.08)
105 (50/55)
TC1/2/3 or IC1/2/3
0.59 (0.41, 0.83)
0.86 (0.63, 1.16)
195 (93/102)
TC0 and IC0
0.88 (0.55, 1.42)
1.06 (0.68, 1.67)
92 (51/41)
HRhazard ratio; ICtumor-infiltrating immune cell; ITTintent to treat; OSoverall 
survival; PFSprogression-free survival; TCtumor cell.
Notes:  The data cutoff date is 1 December 2015.
The HRs are stratified for the ITT population and unstratified for the PD-L1 
expression subgroups.
In summary, the data from Study GO28753 (POPLAR) show that atezolizumab provides 
survival benefit compared with docetaxel in previously treated patients with NSCLC.
1.3.3.3
Single-Agent Clinical Activity in Patients with NSCLC in Study 
GO28915 (OAK)
The co-primary endpoints of the 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 in Arms C, 
D, or E of the Phase Ib Study GP28328.  Patients who had received their first dose of 
atezolizumab by 10 November 2014 were evaluable for efficacy (n41).  Patients who 
were enrolled in Arms C, D, and E received 15 mg/kg atezolizumab administered Q3W
in combination with carboplatinpaclitaxel, carboplatinpemetrexed, and 
carboplatinnab-paclitaxel, respectively.  All patients had histologically or cytologically 
documented Stage IIIB, Stage IV, or recurrent NSCLC and had not received prior 
chemotherapy for advanced disease.  The median age was 65 years and 79% of 
patients had non-squamous histology.  The overall confirmed ORR 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. 


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The target trough concentration (Ctrough) was projected to be 6 g/mL on the basis of 
several assumptions, including the following:  1) 95% tumor-receptor saturation is 
needed for efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 
based on tissue distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, 
pharmacokinetics, and immunogenicity data. Anti-tumor activity has been observed 
across doses from 1 mg/kg to 20 mg/kg. The MTD of atezolizumab was not 
reached, and no DLTs have been observed at any dose in Study PCD4989g. Currently 
available PK and ATA data suggest that the 15-mg/kg atezolizumab Q3W regimen 
(or fixed-dose equivalent) for Phase II and Phase III studies would be sufficient to both 
maintain Ctrough 6 g/mL and further safeguard against both interpatient variability and 
the potential effect of ATAs that could lead to subtherapeutic levels of atezolizumab 
relative to the 10-mg/kg atezolizumab Q3W regimen (or fixed-dose equivalent).  
From inspection of available observed Ctrough data, moving further to the 20-mg/kg 
atezolizumab Q3W regimen does not appear to be warranted to maintain targeted Ctrough 
relative to the proposed 15-mg/kg atezolizumab Q3W level. 
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose or a dose adjusted for weight.  Therefore, a fixed dose 
of 1200 mg has been selected (equivalent to an average body weightbased dose of 
15 mg/kg).  Selection of an every-21-day dosing interval is supported by this preliminary 
pharmacokinetics evaluation.
Refer to the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012).
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1.  PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is sustained in 
states of chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008). Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of 
T cells.  B7.1 is a molecule expressed on antigen-presenting cells and activated T cells.  
PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate 
down-regulation 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 GO29436 initiation, Study PCD4989g, a Phase Ia dose-escalation and 
expansion study of patients treated with atezolizumab as a single agent, had the 
following clinical activity:  345 evaluable patients were dosed by 21 October 2013 (data 
cutoff date as of 21 April 2014) with a minimum of 6 months of follow-up; 62 patients 
experienced objective responses per RECIST v1.1 with an ORR of 18.0% 
(95% CI: 14.1%, 22.3%).  Objective responses were observed across a broad range 
of malignancies, including NSCLC, RCC, melanoma, and UBC.  In 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 Bevacizumab
Bevacizumab is a recombinant, humanized therapeutic antibody directed against VEGF.  
In addition to promoting tumor angiogenesis, there is increasing evidence that VEGF 
plays a role in cancer immune evasion through several different mechanisms.  For 
example, experiments with activated endothelial cells suggested that in the tumor 
microenvironment, VEGF may reduce lymphocyte adhesion to vessel walls, thus 
contributing to decreased immune cell recruitment to the tumor site 
(Bouzin and Feron 2007).  Some immunosuppressive activities of VEGF can be 
reversed by inhibition of VEGF signaling.  Thus, mice exposed to pathophysiologic levels 
of VEGF exhibited impaired dendritic cell function, which could be restored by blockade 
of VEGFR2 (Huang et al. 2007).  In a murine melanoma model, VEGF blockade 
synergized with adoptive immunotherapy, as evidenced by improved anti-tumor activity, 
prolonged survival, and increased trafficking of T cells into tumors (Shrimali et al. 2010).  
Synergistic effects have also been observed in a clinical study combining an 
immunomodulatory antibody (antiCTLA-4; ipilimumab) and bevacizumab:  
Hodi et al. (2010) described increased T-cell trafficking in post-treatment biopsies, as 
well as marked increases in central memory cells in peripheral blood in the majority of 
patients.  Therefore, combined treatment with PD-L1 and bevacizumab may augment 
the anti-tumor immune response, resulting in improved and more durable clinical benefit.


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1.4.2
Rationale for Testing Atezolizumab in Combination with 
Carboplatin/Paclitaxel
Platinum-based regimens remain the standard first-line option for patients with locally 
advanced or metastatic NSCLC not harboring EGFR mutations or ALK gene 
rearrangements.  However, the survival benefit conferred by cytotoxic chemotherapy has 
reached a plateau, with overall response rates of approximately 20% and 1-year survival 
ranging 31%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 American Society of Clinical Oncology 
(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 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.
In light of these observations, Study GO29436 is designed to evaluate whether the 
anti-tumor effect seen in atezolizumab-treated patients would translate into statistically 
significant and clinically relevant improvement in PFS and OS when used in combination 
with carboplatinpaclitaxel with or without bevacizumab compared with 
carboplatinpaclitaxelbevacizumab in patients with non-squamous NSCLC.  This 
study will allow for the evaluation of the efficacy of atezolizumab in both the ITT 
population, as well as in patients with PD-L1selected tumors (defined by expression of 


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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 GO29436 will enroll patients with Stage IV non-squamous NSCLC who 
are naive to chemotherapy treatment and for whom the experimental arms 
(atezolizumabcarboplatinpaclitaxel and 
atezolizumabcarboplatinpaclitaxelbevacizumab) 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 (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.
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 with or without 
bevacizumab.  Patients will be fully informed of the risk of continuing study treatment in 
spite of apparent radiographic progression, and investigators should make a careful 
assessment of the potential benefit of doing so, considering radiographic data, biopsy 
results, and the clinical status of the patient.
2.
OBJECTIVES
The following objectives will be assessed in chemotherapy-naive patients with Stage IV 
non-squamous NSCLC.


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2.1
EFFICACY OBJECTIVES
Unless otherwise specified, efficacy objectives will be analyzed for the following two 
treatment comparisons:

Atezolizumabcarboplatinpaclitaxelbevacizumab (Arm B) versus 
carboplatinpaclitaxelbevacizumab (Arm C)

Atezolizumabcarboplatinpaclitaxel (Arm A) versus 
carboplatinpaclitaxelbevacizumab (Arm C)
The term “wild type” (WT) refers to randomized patients who do not have a sensitizing 
EGFR mutation or ALK translocation.
The term “tumor gene expression” (tGE) refers to randomized patients with a defined 
level of expression of a PD-L1 and T-effector gene signature in tumor tissue, as 
analyzed through use of a centrally performed RNA-based assay.
Some efficacy endpoints will be analyzed in a population of randomized patients with a 
defined level of PD-L1 expression on TCs and ICs, as analyzed through use of a 
centrally performed IHC test.
2.1.1
Co-Primary Efficacy Objectives
The co-primary objectives of this study are the following:

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
PFS according to RECIST v1.1 in the tGE-WT population and the ITT-WT 
population

To evaluate the efficacy of atezolizumab as measured by OS in the ITT-WT 
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-WT
population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
PFS according to RECIST v1.1 and OS in the TC2/3 or IC2/3 WT population and 
the TC1/2/3 or IC1/2/3 WT population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
PFS according to RECIST v1.1 and OS in the tGE population and the ITT
population

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
ORR according to RECIST v1.1 in the tGE-WT population and the ITT-WT 
population


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
To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
duration of response (DOR) according to RECIST v1.1 in the tGE-WT population 
and the ITT-WT population

To evaluate the efficacy of atezolizumab as measured by an Independent Review 
Facility (IRF)-assessed PFS according to RECIST v1.1 in the tGE-WT population 
and the ITT-WT population

To evaluate the OS rate at 1 and 2 years in each treatment arm for the tGE-WT 
population and the ITT-WT population

To compare the efficacy of the two atezolizumab-containing arms, Arm A versus 
Arm B, as measured by investigator-assessed PFS according to RECIST v1.1 and 
by OS in the tGE-WT population and the ITT-WT population

To determine the impact of atezolizumab as measured by time to deterioration (TTD) 
in patient-reported lung cancer symptoms of cough, dyspnea (single-item and 
multi-item subscales), chest pain, or arm/shoulder pain, using the European 
Organisation for the Research and Treatment of Cancer (EORTC) Quality-of-Life 
QuestionnaireCore 30 (QLQ-C30) and the supplemental lung cancer module
(QLQ-LC13) in the tGE-WT population and the ITT-WT population

To determine the impact of atezolizumab as measured by change from baseline
(i.e., improvement or deterioration based upon presenting symptomatology) in 
patient-reported lung cancer symptom (chest pain, dyspnea, and cough) score using 
the Symptoms in Lung Cancer (SILC) scale symptom severity score for the tGE-WT 
population and the ITT-WT population
2.2
SAFETY OBJECTIVES
The safety objectives for this study are the following:

To evaluate the safety and tolerability of atezolizumab 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 PK objectives for this study are the following:

To characterize the pharmacokinetics of atezolizumab when given in combination 
with carboplatinandpaclitaxel with and without bevacizumab (Arms A and B)

To characterize the pharmacokinetics of carboplatin when given in combination with 
paclitaxel with and without atezolizumab and/or bevacizumab (Arms A, B, and C)

To characterize the pharmacokinetics of paclitaxel when given in combination with
carboplatin with and without atezolizumab and/ or bevacizumab (Arms A, B, and C)

To characterize the pharmacokinetics of bevacizumab when given in combination 
with carboplatin and paclitaxel with and without atezolizumab (Arms B and C)


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2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are the following:

To evaluate the efficacy of atezolizumab as measured by investigator-assessed 
time to response (TTR) and time-in-response (TIR) according to RECIST v1.1

To evaluate ORR and DOR  according to RECIST v1.1 as assessed by the IRF

To evaluate investigator-assessed ORR, PFS, and DOR, according to modified 
RECIST for the atezolizumab-containing treatment arms

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 (IMpower150) designed to 
evaluate the safety and efficacy of atezolizumab in combination with 
carboplatinpaclitaxel with or without bevacizumab compared with treatment with 
carboplatinpaclitaxelbevacizumab in approximately 1200 chemotherapy-naive 
patients with Stage IV non-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).  Patients will be randomized in a 
1:1:1 ratio to receive one of the following treatment regimens as shown in Table 9.


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Table 9
Study GO29436 Treatment Arms
Treatment 
Arm
Induction 
(Four or Six 21-Day Cycles)
Maintenance 
(21-Day Cycles)
A
Atezolizumabcarboplatinpaclitaxel
Atezolizumab
B
Atezolizumabcarboplatinpaclitaxel
bevacizumab
Atezolizumabbevacizumab 
C
Carboplatinpaclitaxelbevacizumab
Bevacizumab
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 occur (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 will continue treatment with maintenance therapy 
as per Table 9.  Patients who are randomized to Arms B and C will continue treatment 
with bevacizumab until progressive disease, unacceptable toxicity, or death.  Patients 
who are randomized to Arm A or B may continue treatment with atezolizumab beyond 
radiographic 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).  
Treatment with chemotherapy (Arms A, B, and C) and bevacizumab (Arms B and C) 
must be discontinued in all patients who exhibit evidence of disease progression
according to RECIST v1.1.
Patients will undergo tumor assessments at baseline and every 6 weeks for the first 
48 weeks following Cycle 1, Day 1, regardless of dose delays.  After 48 weeks, tumor 
assessment will be required every 9 weeks.  Patients will undergo tumor assessments 
until radiographic disease progression 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.  Patients who discontinue 
treatment for reasons other than radiographic disease progression according to
RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor 
assessments until radiographic disease progression 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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A secondary endpoint of this study is IRF-assessed PFS according to RECIST v1.1.  
An IRF will therefore conduct an independent review of the responses of all patients, 
including a blinded review of CT scans.  All primary imaging data used for tumor 
assessment will be collected by the Sponsor to enable centralized, independent review 
of response endpoints. These reviews will be performed prior to the final efficacy 
analyses.
For Treatment Arms A and B Only
At any point during treatment, patients receiving atezolizumab 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 Non-Squamous NSCLC
(n=approximately 1200)
Arm A:
Atezolizumab (1200 mg IV)
+ Carboplatin (AUC=6 IV)
+Paclitaxel (200 mg/m2 IV)
Arm B:
Atezolizumab (1200 mg IV)
+ Carboplatin (AUC=6 IV)
+Paclitaxel (200 mg/m2 IV)
+Bevacizumab (15 mg/kg IV)
Arm C:
Carboplatin (AUC=6 IV)
+Paclitaxel (200 mg/m2 IV)
+Bevacizumab (15 mg/kg IV)
Treat with  Atezolizumab 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:  Every 21 Days
Arm A:
Atezolizumab (1200 mg IV)
Arm B:
Atezolizumab (1200 mg IV)
+ Bevacizumab (15 mg/kg IV)
Arm C:
Bevacizumab (15 mg /kgIV)
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. 
Patients of 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).  In addition, 
the iDMC will review safety data once 12 patients have been enrolled into each 
treatment arm and have received treatment for two cycles.  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 and 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 data review, the iDMC will 
provide a recommendation as to whether the study may continue, whether amendment(s) 
to the protocol should be implemented, or whether the study should be stopped.  
The final decision will rest with the Sponsor.
Members of the iDMC will be external to the Sponsor and will follow a separate iDMC 
Charter that outlines their roles and responsibilities, as well as a detailed monitoring plan. 
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 


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(12.6 vs. 9.7 months; HR0.73; 95% CI: 0.53, 0.99, p0.04) versus docetaxel 
(Fehrenbacher et al. 2016).  In the Phase III Study GO28915 (OAK) which investigated 
the efficacy and safety of atezolizumab compared with docetaxel in patients with 
previously treated locally advanced or metastatic NSCLC, OS was significantly 
prolonged with atezolizumab (median OS 13.8 months vs 9.6 months, HR0.73;
95% CI 0.62,0.87, p=0.0003).  In patients with squamous and non-squamous disease, 
OS was 8.9 versus 7.7 months (HR0.73; 95% CI: 0.54, 0.98), and 15.6 versus 
11.2 months (HR0.73; 95% CI: 0.60, 0.89), respectively, in the atezolizumab arm 
compared with the docetaxel arm (Rittmeyer et al. 2017).
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, with or without bevacizumab.  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
Standard-of-care first-line treatment for advanced stage non-squamous NSCLC is a 
platinum doublet with either cisplatin or carboplatin and a taxane or pemetrexed, with or 
without bevacizumab.  In this study, all patients in the experimental arms will receive, at 
minimum, the platinum doublet of carboplatin with paclitaxel with atezolizumab.  The 
control group will receive the combination of carboplatinpaclitaxelbevacizumab.  This 
control group is recognized as a standard of care for the first-line treatment of NSCLC 
based on the results of the ECOG 4599 study, which showed a significant improvement 
in OS (12.3 months vs. 10.3 months [HR0.80; p0.003]), PFS (6.4 months vs. 
4.8 months [HR0.65; p0.0001]), and response rate (35% [133 of 381 patients] vs. 15% 
[59 of 392 patients]; p0.001) in patients treated with bevacizumab Q3W in combination 
with carboplatin/paclitaxel compared with carboplatin/paclitaxel alone.  
In addition, as opposed to the platinum-doublet regimen with pemetrexed induction 
followed by pemetrexed maintenance, the platinum-doublet with bevacizumab does not 
require the use of corticosteroids during bevacizumab maintenance.  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paclitaxelbevacizumab in combination with atezolizumab is considered 


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optimal to minimize the prolonged requirement for systemic corticosteroids, and it follows 
that carboplatinpaclitaxelbevacizumab would be a logical comparator.  This control 
group will be instrumental in assessing the relative benefit and safety of atezolizumab in 
combination with carboplatinpaclitaxel with and without bevacizumab 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:  Given 
the known toxicities associated with bevacizumab therapy, patients assigned to 
bevacizumab-containing arms (Arms B and C), as well as physicians, may be capable of 
identifying treatment assignment in a blinded study. In addition, a blinded study would 
require prolonged administration of placebo during the maintenance phase, which could 
pose a significant burden to patients. Furthermore, because of the potential for 
pseudoprogression in patients randomized to atezolizumab-containing arms, a blinded 
study would require the option that all patients continue treatment until loss of clinical 
benefit regardless of whether they were receiving atezolizumab. In the absence of 
pseudoprogression, this could then delay subsequent treatment with approved therapies 
for NSCLC in patients assigned to any treatment arm, as well as increase the complexity 
of treatment decisions.
Adequate steps have been taken to ensure the validity of data in an open-label study 
design. This includes performing a supportive analysis of efficacy on the basis of 
determined progression by an IRF, performing a sensitivity analysis to demonstrate the 
robustness of the primary endpoint, defining progression using established response 
evaluation criteria (RECIST v1.1), performing tumor assessments at the same frequency 
in all arms, adhering to protocol-defined schedules, and determining the strategy for the 
final analysis of the primary endpoint prior to database lock for the primary efficacy 
analyses, including predefined methods for handling missing data and censoring 
rules. Efficacy analyses will be performed only at the prespecified analysis timepoints in 
the protocol.
3.3.4
Rationale for Progression-Free Survival and Overall Survival 
as Co-Primary Endpoints
Investigator-assessed PFS (which will be supported by an IRF-assessed PFS analysis, 
one of the secondary endpoints of the study) 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).  


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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 
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 risk-benefit 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:  full IRF assessment to support the analysis of the co-primary 
endpoint, a substantial target magnitude of benefit (target HR0.65 in the ITT-WT and 
0.55 in the  tGE-WT population), and study assessments that will allow a robust 
evaluation of risk-benefit (standard RECIST to define progression with fixed assessment 
intervals that are identical in all treatment arms and a robust definition of PFS and 
prospectively defined methods to assess, quantify, and analyze PFS, including 
sensitivity analyses).
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). 


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In addition, while a co-primary endpoint measure of efficacy (PFS) comparing the 
atezolizumab-containing treatment arms with carboplatinpaclitaxelbevacizumab will 
be using RECIST v1.1, exploratory analyses of PFS, ORR, and DOR, using modified 
RECIST (see Section 2.4) will be performed for patients randomized to receive 
atezolizumab.  Modified RECIST allows for the incorporation of new lesions into the 
calculation of total tumor burden after baseline.  Tumor assessments will be performed 
according to RECIST v1.1 and modified RECIST for patients in the atezolizumab-
containing treatment arms (Arms A and B) and only according to RECIST v1.1 for 
patients in the control arm (Arm C).
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 a primary endpoint, where it is important 
to better understand in what regard the delay in disease progression is meaningful 
to patients.
Chest pain, dyspnea, and cough have been regarded as the most frequent and clinically 
relevant disease-related symptoms experienced by patients with NSCLC.  The BR.21 
study (erlotinib vs. best supportive care in second- or third-line NSCLC) demonstrated 
that longer TTD in the pain, dyspnea, and cough scales of the EORTC QLQ-C30 and 
EORTC QLQ-LC13 was consistent with superior PFS, OS, and quality-of-life benefits in 
the erlotinib arm compared with the placebo arm (Aaronson et al. 1993; 
Bergman et al. 1994; Bezjak et al. 2006).  Patients in the afatinib LUX-Lung 3 first-line 
study also reported significant delay of TTD in lung cancer symptoms (chest pain, 
dyspnea, and cough) as measured by the EORTC QLQ-C30 and EORTC QLQ-LC13 
(Yang et al. 2013).  In this study, the validated EORTC QLQ-C30 and EORTC 
QLQ-LC13 will be used to assess HRQoL and symptom severity. 
In addition, the SILC scale will be used to assess the effect/impact of atezolizumab on 
TTD of specific lung cancer symptoms (chest pain, dyspnea, and cough) in patients with 
Stage IV, non-squamous NSCLC in the first-line setting.
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.


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3.3.7
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens and Evaluation of PD-L1 and T-Effector 
Gene Signature
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) (Spiegel et al. 2015), GO28754 (BIRCH) (Besse et al. 2015), GO28753 
(POPLAR) (Fehrenbacher et al. 2016), and GO28915 (OAK) (Rittmeyer et al. 2017). 
In addition, POPLAR data suggest that higher expression of genes related to PD-L1 and
T-effector biology in tumor tissue is associated with improved efficacy of atezolizumab 
compared with docetaxel (Fehrenbacher et al. 2016). Similar observations have been 
reported for other PD-L1 or PD-1 inhibitors (Higgs et al. 2015; Muro et al. 2015; Seiwert 
et al. 2015). Furthermore, expression of PD-L1 on ICs was reported to be associated 
with expression of a T-effector gene signature, therefore representing a preexisting 
immunity (Fehrenbacher et al. 2016).
In this study, archival and/or fresh tumor specimens will be prospectively tested for 
PD-L1 expression by a central laboratory during the screening period.  Patients will be 
stratified by PD-L1 expression.  The primary analysis of this study will evaluate the 
efficacy of atezolizumab in the ITT population, as well as in patients with a defined level 
of expression of a PD-L1 and T-effector gene signature (tGE population).  Both 
populations will exclude patients with a sensitizing EGFR mutation or ALK translocation.  
On the basis of an analysis of independent cohorts of patients with NSCLC, it is 
estimated that the primary tGE cutoff for this study will identify a population 
corresponding to approximately 50% of the first-line NSCLC patient population.
In addition to the assessment of PD-L1 status and T-effector gene signature status, 
other exploratory markers, such as potential predictive and prognostic markers related to 
the clinical benefit of atezolizumab, tumor immunobiology, mechanisms of resistance, or 
tumor type, may also be analyzed. DNA and/or RNA extraction and analysis may be 
performed to enable identification of somatic mutations by use of 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. 


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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 
analysis may be performed to enable identification of somatic mutations, by use of NGS, 
that are associated with disease progression or acquired resistance to atezolizumab and 
to increase understanding of disease pathobiology.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
3.4.1.1
Co-Primary Efficacy Outcome Measures
The co-primary efficacy outcome measures for this study are the following:

PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator according to RECIST v1.1 or death 
from any cause, whichever occurs first in the tGE-WT population and the ITT-WT 
population

OS, defined as the time from randomization to death from any cause in the ITT-WT 
population
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are the following:

OS in the tGE-WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
TC2/3 or IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
tGE population and the ITT population


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
Objective response, defined as partial response (PR) or complete response (CR) as 
determined by the investigator according to RECIST v1.1 in the tGE-WT population 
and the ITT-WT population

DOR, defined as the time interval from first occurrence of a documented objective 
response to the time of disease progression as determined by the investigator 
according to RECIST v1.1 or death from any cause, whichever occurs first in the 
tGE-WT population and the ITT-WT population

PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the IRF according to RECIST v1.1 or death from any 
cause, whichever occurs first, in the tGE-WT population and the ITT-WT population

OS rates at 1 and 2 years for the tGE-WT population and the ITT-WT population

PFS, as determined by the investigator according to RECIST v1.1, and OS in the 
two atezolizumab-containing arms in the tGE-WT population and the ITT-WT 
population 

TTD in patient-reported lung cancer symptoms, defined as time from randomization 
to deterioration (10-point change) on each of the EORTC QLQ-C30 and EORTC 
QLQ-LC13 symptom subscales in the tGE-WT population and the ITT-WT 
population

Change from baseline in patient-reported lung cancer symptoms (chest pain, 
dyspnea, and cough) on the symptom severity score of the SILC scale for the 
tGE-WT population and the ITT-WT population
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are the following:

Incidence, nature, and severity of adverse events graded according to the 
NCI CTCAE v4.0

Changes in vital signs, physical findings, and clinical laboratory results during and 
following atezolizumab administration

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are the following:

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 (Arms A, B, and C) 

Bevacizumab Cmax and Cmin (Arms B and C)


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See Appendix 2 for specific sample collection times.
3.4.4
Exploratory Outcome Measures
The exploratory outcome measures for this study are:

TTR, defined as the time from randomization to first occurrence of a documented 
objective response as determined by the investigator according to RECIST v1.1

Time in response (TIR), defined as 1 day for non-responders and defined the same 
as DOR for responders, as determined by the investigator according to 
RECIST v1.1

Objective response and DOR, as determined by the IRF according to RECIST v1.1

Objective response, PFS, and DOR, in the two atezolizumab-containing arms, as 
determined by the investigator according to modified RECIST (Arms A and B)

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, 
non-squamous NSCLC.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Male or female, 18 years of age or older

ECOG performance status of 0 or 1 (see Appendix 10)


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
Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the 
Union Internationale contre le Cancer/American Joint Committee on Cancer staging 
system, 7th edition; Detterbeck et al. 2009; see Appendix 3)
Patients with tumors of mixed histology (i.e., squamous and non-squamous) are 
eligible if the major histological component appears to be non-squamous.

No prior treatment for Stage IV non-squamous NSCLC
Patients with a sensitizing mutation in the EGFR gene must have experienced 
disease progression (during or after treatment) or intolerance to treatment with 
one or more EGFR TKIs, such as erlotinib, gefitinib, or another EGFR TKI
appropriate for the treatment of EGFR-mutant NSCLC.  
Patients with 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 EGFR and/or ALK status require test results at 
screening.  ALK and/or EGFR may be assessed locally or at a central 
laboratory.

Patients who have received prior neo-adjuvant, adjuvant chemotherapy, 
radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease 
must have experienced a treatment-free interval of at least 6 months from 
randomization since the last chemotherapy, radiotherapy, or chemoradiotherapy.

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 


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patient may still be eligible, upon discussion with the Medical Monitor.  This 
specimen must be accompanied by the associated pathology report.
Fine-needle aspiration (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or cell smears), brushing, cell pellet 
specimens (e.g., from pleural effusion, and lavage samples) are not acceptable.  
Tumor tissue from bone metastases that is subject to decalcification is not 
acceptable.  
For core needle biopsy specimens, preferably at least three cores embedded in 
a single paraffin block, should be submitted for evaluation.

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions can only be considered as measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of disease. 

Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to randomization:
–
ANC 1500 cells/L without granulocyte colony-stimulating factor support
–
Lymphocyte count 500/L
–
Platelet count 100,000/L without transfusion 
–
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
–
INR or aPTT 1.5upper limit of normal (ULN)
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
–
AST, ALT, and alkaline phosphatase 2.5ULN, with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase 
5ULN.
–
Serum bilirubin1.25ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN 
may be enrolled.
–
Serum creatinine 1.5ULN

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 and/or 6 months after the last dose of 
bevacizumab or paclitaxel, whichever is later).  Women must refrain from donating 
eggs during this same period.  Highly effective contraceptive methods include:  
combined (estrogen and progestogen containing) hormonal contraception, 
progestogen-only hormonal contraception associated with inhibition of ovulation 


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together with another additional barrier method always containing a spermicide, 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral 
tubal occlusion, vasectomized partner (on the understanding that this is the only one 
partner during the whole study duration), and sexual abstinence.  

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 bevacizumab, carboplatin, or 
paclitaxel.  Male patients should not donate sperm during this study and for at least 
6 months after the last dose of bevacizumab, carboplatin, or paclitaxel.

Oral contraception should always be combined with an additional contraceptive 
method because of a potential interaction with the study drug.  The same rules are 
valid for male patients involved in this clinical study if they have a partner of 
childbearing potential.  Male patients must always use a condom.

Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug
4.1.2
Exclusion Criteria
Patients who meet any of the criteria below will be excluded from study entry.
4.1.2.1
Cancer-Specific Exclusions

Active or untreated CNS metastases as determined by CT or MRI evaluation during 
screening and prior radiographic assessments

Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 2 weeks prior to randomization

Leptomeningeal disease

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, 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 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 3 months prior to randomization, unstable arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or left ventricular ejection fraction 50% must be on 
a stable medical regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist if appropriate.

Major surgical procedure other than for diagnosis within 28 days prior to 
randomization or anticipation of need for a major surgical procedure during the 
course of the study

Prior allogeneic bone marrow transplantation or solid organ transplant

Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or renders the patient at high risk from treatment 
complications


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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

Treatment with any approved anti-cancer therapy, including hormonal therapy, 
within 3 weeks 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 Grade 3 or 4)

Treatment with systemic immunostimulatory agents (including but not limited to 
interferons, 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.
4.1.2.4
Exclusions Related to Bevacizumab

Inadequately controlled hypertension (defined as systolic blood pressure
150 mmHg and/or diastolic blood pressure 100 mmHg)
Anti-hypertensive therapy to achieve these parameters is allowable.

Prior history of hypertensive crisis or hypertensive encephalopathy

Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to randomization


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
History of hemoptysis (one-half teaspoon of bright red blood per episode) within 
1 month prior to randomization

Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation)

Current or recent (within 10 days of randomization) use of aspirin (325 mg/day) or 
treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol

Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic purposes that has not been stable for 2 weeks prior to randomization
The use of full-dose oral or parenteral anticoagulants is permitted as long as 
the INR or aPTT is within therapeutic limits (according to the medical standard 
of the enrolling institution) and the patient has been on a stable dose of 
anticoagulants for at least 2 weeks prior to randomization.
Prophylactic anticoagulation for the patency of venous access devices is 
allowed, provided the activity of the agent results in an INR1.5ULN and 
aPTT is within normal limits within 14 days prior to randomization.
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) 
is permitted.

Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 days prior to the first dose of bevacizumab

History of abdominal or tracheosphageal fistula or gastrointestinal perforation within 
6 months prior to randomization

Clinical signs of gastrointestinal obstruction or requirement for routine parenteral 
hydration, parenteral nutrition, or tube feeding 

Evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure

Serious, non-healing wound, active ulcer, or untreated bone fracture

Proteinuria, as demonstrated by urine dipstick or 1.0 g of protein in a 24-hour urine 
collection
All patients with 2protein on dipstick urinalysis at baseline must undergo a 
24-hour urine collection and must demonstrate 1 g of protein in 24 hours.

Known sensitivity to any component of bevacizumab

Clear tumor infiltration into the thoracic great vessels is seen on imaging

Clear cavitation of pulmonary lesions is seen on imaging
4.1.2.5
Exclusions Related to Chemotherapy

Known history of severe allergic reactions to platinum-containing compounds or 
mannitol

Known sensitivity to any component of paclitaxel

Grade2 peripheral neuropathy as defined by NCI CTCAE v4.0 (paclitaxel)


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
Known history of severe hypersensitivity reactions to products containing 
Cremophor® EL (e.g., cyclosporin for injection concentrate and teniposide for 
injection concentrate)
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING

This is an open-label study.

After written informed consent has been obtained and eligibility has been 
established, the study site will enter demographic and baseline characteristics in the 
interactive voice/Web response system (IxRS/IWRS).  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 Atezolizumab Investigator’s Brochure.
Atezolizumab (MPDL3280A) will be supplied by the Sponsor.
4.3.1.2
Carboplatin, Paclitaxel, and Bevacizumab
Carboplatin, paclitaxel, and bevacizumab will be used in commercially available 
formulations.  For information on the formulation, packaging, and handling of carboplatin, 
paclitaxel, and bevacizumab, see the local prescribing information for each drug.


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4.3.2
Dosage, Administration, and Compliance
The induction phase of the study will consist of four or six cycles of chemotherapy, each 
cycle being 21 days in duration.  On Day 1 of each cycle, all eligible patients will receive 
drug infusions in the following order:
Arm A:  Atezolizumab paclitaxel carboplatin
Arm B:  Atezolizumab bevacizumab paclitaxel carboplatin
Arm C:  Bevacizumab 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.  Cycles in which no chemotherapy is 
given do not count toward the total number of induction chemotherapy cycles.  Additional 
guidance in the event of chemotherapy interruption and reintroduction is provided in 
Appendix 15.
Patients who experience no further clinical benefit (for patients enrolled into Arm 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 fourth or sixth-cycle induction phase, patients will begin 
maintenance therapy (atezolizumab in Arm A; atezolizumabbevacizumab in Arm B; 
bevacizumab in Arm C). 
During treatment (induction or maintenance), patients in Arms A and B who show 
evidence of clinical benefit will be permitted to continue atezolizumab after RECIST v1.1 
for progressive disease are met if they meet all criteria listed in Section 3.1.  Treatment 
with chemotherapy (Arms A, B, and C) and bevacizumab (Arms B and C) must be 
discontinued.
Patients should receive anti-emetic medications 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, and Table 11 lists 
the suggested infusion times for treatment administration during the induction and 
maintenance phases.  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 5.1.6.1 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.


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Table 10 Suggested Premedication for Induction Treatment for 
All Treatment Arms
Premedication
Dose/Route
Timing
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. 
Table 11 Treatment Regimen and Order of Administration for 
All Treatment Arms 
Agent
(1) Atezolizumab
(2) Bevacizumab
(3) Paclitaxel
(4) 
Carboplatin
Dose and 
administration 
route
1200 mg IV
15 mg/kg IV
200 mg/m2 IV a
AUC 6 IV b
Infusion rate
Over 60 (15) min 
(for the first 
infusion); 
30 (10) min for 
subsequent 
infusions if tolerated
Over 90 (15) min (for 
the first infusion); 
shortening to 
60 (10) then 
30 (10) min for 
subsequent infusions 
if tolerated 
Over 3 hours c
Over 
approximately 
1530 min
Frequency
Day 1 of every 21 days
Induction 
Phase
(Four or Six
Cycles)
A
x
x
x
B
x
x
x
x
C
x
x
x
Maintenance
Phase
A
x
B
x
x
C
x
AUCarea under the concentrationtime curve; IVintravenous.
a Patients of Asian race/ethnicity: 175 mg/m2 IV.
b See Section 4.3.2.2 for details on dose calculation of carboplatin.
c See Section 4.3.2.2 for more details on paclitaxel infusion times.


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Guidelines for dose modification and treatment interruption or discontinuation for 
carboplatin, paclitaxel, and bevacizumab are provided in Sections 5.1.6.1, 5.1.8, 
and 5.1.9.
4.3.2.1
Atezolizumab
Patients randomized to atezolizumab will receive 1200 mg of atezolizumab administered 
by IV infusion every 21 days in a monitored setting where there is immediate access to 
trained personnel and adequate equipment/medicine to manage potentially serious 
reactions.  
Atezolizumab infusions will be administered per the instructions outlined in Table 12.
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.


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Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are 
provided in Sections 5.1.6.2 and 5.1.7.
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, 
and administration.
4.3.2.2
Bevacizumab, Carboplatin, and Paclitaxel
Bevacizumab
Bevacizumab will be administered at a dose of 15 mg/kg on Day 1 of each 21-day cycle.  
The initial dose of bevacizumab will be based on the patient’s weight at screening and 
will remain the same throughout the study unless the patient’s weight changes by 10%.
Bevacizumab will be diluted in 0.9% sodium chloride injection, USP, to a total volume of 
100 mL.  For patients weighing more than 110 kg, please refer to AVASTIN Pharmacy 
Manual for this protocol for the infusion preparation. The initial dose will be delivered 
over 9015 minutes.  If the first infusion is tolerated without any infusion-associated 
adverse events (i.e., fever and/or chills), the second infusion may be delivered over 
6010 minutes.  If the 60-minute infusion is well tolerated, all subsequent infusions may 
be delivered over 3010 minutes.  Bevacizumab infusions may be slowed or interrupted 
for patients experiencing infusion-associated symptoms.  If infusion-related symptoms 
occur, patients should be treated according to best medical practice, and patients will be 
monitored until adequate resolution of signs and symptoms.
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 


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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 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).
Carboplatin
Carboplatin should be administered by IV infusion, immediately after the completion of 
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) 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 on the basis of 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.  On the basis of the Calvert formula described in the 
carboplatin label, the maximum doses can be calculated as follows:
Maximum carboplatin dose (mg)target AUC (mg min/mL)(GFR25 mL/min)


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The maximum dose is based on a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function. No higher estimated GFR values should be used.
For a target AUC6, the maximum dose is 6150900 mg. 
For a target AUC5, the maximum dose is 5150750 mg. 
For a target AUC4, the maximum dose is 4150600 mg.
Refer to the FDA’s communication regarding carboplatin dosing using the following URL 
for more details: 
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm 
228974.htm.
4.3.3 
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 investigational medicinal products (IMPs) for this study are atezolizumab and 
bevacizumab.  IMPs required for completion of this study will be provided by the 
Sponsor if required by local health authority regulations.  The Sponsor or appointed 
designee will supply other medicinal products in accordance with local regulations.


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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)

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.


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
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
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2-receptor antagonist per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local practice).  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
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).
4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations where 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered first by the treating physician.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the treating physician except in the case of patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance) (see also Section 4.4.3).
Systemic corticosteroids are recommended, with caution at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with 
atezolizumab therapy.  Guidelines for the management of immune-mediated adverse 
events are described in Section 5.1.7. 
4.4.3
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment, depending on the anti-cancer agent (see Section 4.1.2), and 
during study treatment until disease progression is documented and patient has 
discontinued study treatment.  This includes, but is not limited to, chemotherapy, 


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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 because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, their use for patients in the study is allowed at the discretion of the 
investigator, provided that there are no known interactions with any study treatment.  
As noted above, herbal therapies intended for the treatment of cancer are prohibited.
4.5
STUDY ASSESSMENTS 
Flowcharts of scheduled study assessments are provided in Appendix 1 and Appendix 2.
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient.
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Patients who are treated with atezolizumab and who show apparent radiographic 
progression per RECIST v1.1at a tumor response evaluation and are eligible and willing 
to continue treatment with atezolizumab must sign consent at that time to have a biopsy 


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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).  For patients not previously tested for tumor mutational status, testing will be 
required at screening.  For these patients, testing can either be performed locally or 
submitted for central evaluation during the screening period.  If EGFR mutations or ALK
status testing is not performed locally, additional tumor sections may be required for 
central evaluation of the mutational status of these genes.  Please review tissue 
requirements for central evaluation in the central laboratory instruction manual.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified 
at baseline should be recorded on the General Medical History and Baseline
Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of temperature, pulse rate, respiratory rate, and 
systolic and diastolic blood pressures.
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.


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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 bevacizumab 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 if symptoms occurred during prior 
infusion
Arm C

Within 60 minutes prior to bevacizumab infusion

During the bevacizumab infusion if clinically indicated or 
if symptoms occurred during the prior infusions

Within 30 (10) minutes after carboplatin infusion if 
clinically indicated or if symptoms occurred during the 
prior infusion
For patients in the atezolizumab arm, also refer to Section 4.3.2.1.
4.5.5
Tumor and Response Evaluations
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRIs of the chest and abdomen.  A CT or MRI scan of the pelvis is
required at screening and as clinically indicated or as per local standard of care at 
subsequent response evaluations.  A spiral CT scan of the chest may be obtained but is 
not a requirement.
A CT (with contrast if not contraindicated) or MRI scan of the head must be done at 
screening to exclude CNS metastasis.  An MRI scan of the brain is required to confirm or 
refute the diagnosis of CNS metastases at baseline in the event of an equivocal scan.  
Patients with active or untreated CNS metastases are not eligible for the study 
(see Section 4.1.2.1).


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If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for 
a full-contrast diagnostic CT scan.
Bone scans and CT scans of the neck should also be performed if clinically indicated.  
At the investigator’s discretion, other methods of assessment of measurable disease as 
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 patients in the atezolizumab-containing treatment arms (Arms 
A and B) and only according to RECIST v1.1 for patients in the control 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 every 9 weeks (7 days) after the completion of the Week 48 
tumor assessment, regardless of treatment delays, until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients 
who had continued treatment after radiographic disease progression according to 
RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, 
whichever occurs first. Patients who discontinue treatment for reasons other than
radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration) will continue scheduled tumor assessments until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients 
who had continued treatment with atezolizumab after radiographic disease progression 
according to RECIST v1.1), withdrawal of consent, death, or study termination by 
Sponsor, whichever occurs first.
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.


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Patients treated with atezolizumab continuing to experience clinical benefit, despite 
evidence of radiographic progression, will continue tumor assessments as per the 
schedule listed above.  
Scans will be submitted for central review 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 will be tested only at sites where free T3 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.  HBV DNA test 
must be negative.

HCV serology: hepatitis C virus antibody (anti-HCV)
HCV RNA test must be performed prior to randomization if the patient tests 
positive for anti-HCV.

HIV testing

All patients will be tested for HIV prior to inclusion into the study, and HIV-positive 
patients will be excluded from the clinical study.
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 


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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- and bevacizumab-treated patients)
Serum samples will be assayed for the presence of ATAs to atezolizumab and 
bevacizumab with use of validated immunoassays.  Accompanying PK samples 
will be collected at the same timepoints (See Appendix 2).

PK assays
Blood samples for PK assessments will be obtained according to the schedule 
in Appendix 2.
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.
At selected sites, a subset of 20 patients in each arm will undergo additional PK 
assessments for carboplatin, paclitaxel, and bevacizumab (bevacizumab in 
Arms B and C only).  
Serum samples will be assayed for bevacizumab concentration with use of 
a validated immunoassay.
Plasma carboplatin and 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).  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 RCR any 
leftover material from the above sample collection will be stored and used for 
exploratory analyses as indicated in Section 4.5.11.  For patients who consent to 
RCR optional future research on their whole blood samples collected at screening 
but are determined to be ineligible for study participation, these samples and their 
derivatives (e.g., DNA, RNA, protein) may be used for future development of 
biomarker and/or diagnostic tests as indicated in Section 4.5.11.
4.5.7
Tumor Tissue Samples
4.5.7.1
Archival and Freshly Collected Tumor Tissue Samples 
for Screening
Representative tumor specimens in paraffin blocks (preferred) or 15 (or more) freshly cut, 
serial unstained sections, with an associated pathology report, must be submitted at 
screening for determination of PD-L1 status prior to study randomization.  If fewer than 


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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), next-generation sequencing (NGS), 
and/or other methods.
Tumor tissue should be of good quality based on total and viable tumor content 
(sites will be informed if the quality of the submitted specimen is inadequate to determine 
tumor PD-L1 status). 
An archival tumor specimen should be submitted if available.  If an archival specimen is 
not available, the patient may still be eligible, with the assumption that the patient is 
willing to consent to and undergo a pre-treatment biopsy or resection of the tumor.  
For freshly collected biopsy specimens, acceptable samples include those outlined 
below, provided there is a minimum of 50 viable 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 a cell suspension and/or cell smears), brushing, cell pellets (e.g., from pleural 
effusion), and lavage samples are not acceptable.
Tumor tissue from bone metastases that is subject to decalcification is not acceptable.
For archival samples, the remaining tumor tissue block for all patients enrolled will be 
returned to the site upon request or 18 months after final closure of the study database, 
whichever is sooner.  Tissue samples from patients who are deemed ineligible to enroll 
in the study will be returned no later than 6 weeks after eligibility determination.
ALK and/or EGFR status may be assessed locally or at a central lab if unknown.
4.5.7.2
Tumor Samples at the Time of Radiographic Progression
Patients in all treatment arms will undergo a mandatory tumor biopsy to obtain a tumor 
sample, unless not clinically feasible, at the time of radiographic disease progression 
(within 40 days of radiographic progression or prior to the start of the next anti-cancer 
treatment, whichever is sooner).


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Acceptable samples include the following:

Core-needle biopsies for deep tumor tissue; at least three cores, embedded into a 
single paraffin block, should be submitted for evaluation.

Excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions

Tumor tissue resection
The status of immune-related and tumor typerelated, and other exploratory biomarkers 
(including, but not limited to, T-cell markers and non-inherited biomarkers identified 
through NGS on extracted DNA and/or RNA) in tumor tissue samples may be evaluated. 
NGS may be performed by Foundation Medicine. If performed by Foundation Medicine, 
the investigator can obtain results from the samples collected at the time of disease 
progression in the form of an NGS report, which is available upon request directly from 
Foundation Medicine. The investigator may share and discuss the results with the 
patient, unless the patient chooses otherwise. The Foundation Medicine NGS assay 
has not been cleared or approved by the U.S. FDA; results from these investigational 
tests should not be used to guide future treatment decisions.
4.5.7.3
Tumor Samples at Other Timepoints
If a patient undergoes a medically indicated procedure (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) any time during the course of the study 
that has the likelihood of yielding tumor tissue, any remaining samples or a portion of the 
sample not necessary for medical diagnosis (leftover tumor tissue) may be obtained 
for exploratory analysis.
Patients with additional tissue samples from procedures performed at different times 
during the course of their study participation (during treatment and during survival 
follow-up) who have signed the Roche Clinical Repository (RCR) optional consent will be 
requested (but not required) to also submit these optional fresh samples for central 
testing.  Tumor tissue samples collected at the time of clinical events (e.g., clinical 
response) are preferred.  Tissue samples obtained at multiple times for individual 
patients will greatly contribute to an improved understanding of the dynamics of PD-L1 
expression and relationship with intervening anti-cancer therapy.
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.


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
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 and bevacizumab 
(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
A 12-lead ECG is required at screening and as clinically indicated.  ECGs should be 
obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.10
Patient-Reported Outcomes
PRO data will be collected via the EORTC QLQ-C30, the EORTC QLQ-LC13, SILC, 
PGIS, and EQ-5D-3L to more fully characterize the clinical profile of atezolizumab.
The questionnaires will be translated as required in the local language.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires scheduled for administration during a clinic visit will be completed in their 
entirety by the patient prior to the performance of non-PRO assessments and the 
administration of study treatment. 
Patients will use an electronic PRO (ePRO) device to capture PRO data.  The ePRO 
device and/or instructions for completing the PRO questionnaires electronically will be 
provided by the investigator staff.  The data will be transmitted via a prespecified 
transmission method (e.g., web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the Internet.


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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 study visit during study treatment 
and during survival follow-up at 3 months and 6 months following disease progression 
(or loss of clinical benefit for atezolizumab-treated patients who had continued treatment 
with atezolizumab after radiographic disease progression according to RECIST v1.1). 
The EORTC QLQ-LC13 (see Appendix 8) module incorporates one multiple-item scale 
to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, 
dysphagia, peripheral neuropathy, alopecia, and hemoptysis.  The EORTC QLQ-LC13 
module takes approximately 15 minutes to complete.  This questionnaire will be 
completed on the ePRO tablet at each scheduled study visit during study treatment and 
during survival follow-up at 3 months and 6 months following disease (or loss of clinical 
benefit for atezolizumab-treated patients who had continued treatment with atezolizumab
after radiographic disease progression according to RECIST v1.1).
The 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 
validated self-report measure of lung cancer symptoms. It measures severity of cough, 
dyspnea, and chest pain with a symptom severity score. This questionnaire will be 
completed using an ePRO device at the patient’s home on a weekly basis, then during 
survival follow-up every month for 6 months following disease progression (or loss of 
clinical benefit for atezolizumab-treated patients who had continued treatment with 
atezolizumab after radiographic disease progression according to RECIST v1.1).
The EQ-5D-3L is a generic, preference-based health utility measure with questions 
about mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that is 
used to build a composite of the patient’s health status (see Appendix 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 study visit during study treatment and during 
survival follow-up for at 3 months and 6 months following disease progression (or loss of 
clinical benefit for atezolizumab-treated patients who had continued treatment with 
atezolizumab after radiographic disease progression according to RECIST v1.1). 
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 
study visit during study treatment. The PGIS is not required during survival follow-up.


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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 exempt from all ePRO assessments.
4.5.11
Samples for Roche Clinical Repository
4.5.11.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB/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.


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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).
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.


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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.
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant’s death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.11.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the study is ongoing, must enter the date of withdrawal on the RCR 
Research Sample Withdrawal of Informed Consent eCRF.  A patient's withdrawal from 
Study GO29436 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 GO29436.


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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.
4.5.12.2
Assessments during Treatment
All visits must occur 3 days from the scheduled date unless otherwise noted 
(see Appendix 1). All assessments will be performed on the day of the specified visit 
unless a time window is specified.  Assessments scheduled on the day of study 
treatment administration (Day 1) of each cycle should be performed prior to study 
treatment infusion unless otherwise noted.
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing continuing on a 21-day schedule.  If treatment was postponed 
for fewer than 3 days, the patient can resume the original schedule.
After completion of the induction phase one of three cycles may be delayed by 1 week 
(28 days instead of 21 days for one cycle) to allow for vacations/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 because 
of toxicity, refer to Section 5.1.


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Tumor assessments should occur every 6 weeks (7 days) for 48 weeks following 
Cycle 1, Day 1 and every 9 weeks (7 days) after completion of the Week 48 tumor 
assessment, regardless of treatment delays, until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated 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) should continue scheduled tumor assessments until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients 
who had continued treatment with atezolizumab after radiographic disease progression 
according to RECIST v1.1), withdrawal of consent, death, or study termination by 
Sponsor, whichever occurs first.
The following assessments may be performed 96 hours before Day 1 of each cycle: 

ECOG performance status

Limited physical examination

Local laboratory tests

Screening assessments performed 96 hours before Cycle 1, Day 1 are not 
required to be repeated for Cycle 1, Day 1.

See Appendix 1 for the schedule of assessments performed during the treatment 
period and Appendix 2 for the schedule of PK, pharmacodynamic, ATA, 
and biomarker sampling.
4.5.12.3
Assessments at Study Drug Discontinuation Visit
When a patient discontinues all study treatment, regardless of the reason 
for discontinuation, the patient will be asked to return to the clinic within 30 days 
after the treatment for a study drug discontinuation visit.  The visit at which the 
decision is made to discontinue treatment (e.g., loss of clinical benefit is confirmed 
[atezolizumab-treated patients] or disease progression occurs) may be used as the 
study drug discontinuation visit.
See Appendix 1 and Appendix 2 for the schedule of follow-up assessments.
4.5.12.4
Follow-Up Assessments
After the study drug discontinuation visit, adverse events should be followed as outlined 
in Section 5.3.1.
For patients who discontinue study treatment for any reason other than radiographic 
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 per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who had continued treatment with atezolizumab after 


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radiographic disease progression according to RECIST v1.1), withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first.
Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 should continue tumor assessments according to the 
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 PROs (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 had continued treatment with atezolizumab after 
radiographic 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 disease progression
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, death, or study termination by the Sponsor whichever 
occurs first).
Adverse events will be followed as described in Appendix 16.
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.


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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.
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 because of 
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 had continued treatment with atezolizumab after 
disease progression according to RECIST v1.1) if agreed upon by the investigator 
and patient.

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another nonprotocol-specified anti-cancer therapy (see Section 4.4.3)

Pregnancy

Radiographic disease progression per RECIST v1.1 


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Exception for atezolizumab treatment:  patients randomized to atezolizumab 
treatment will be permitted to continue atezolizumab after RECIST v1.1 criteria for 
progressive disease are met if they meet all of the following criteria (see Figure 2 for 
the schematic representation):
–
Evidence of clinical benefit as assessed by the investigator
–
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease
–
No decline in ECOG performance status 
–
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be readily managed and stabilized by protocol-allowed 
medical interventions prior to repeat dosing
–
Patients must provide written consent to acknowledge deferring any standard 
treatment options that may exist in favor of continuing atezolizumab treatment 
at the time of initial progression.
–
A mandatory biopsy sample collection, unless not clinically feasible as 
assessed by the investigators, at the site of local or metastatic progression
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 




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The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
The following information is based on results from nonclinical and clinical studies and 
published data on similar molecules.
5.1
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (see Sections 4.1.1
and 4.1.2) and close monitoring (as indicated below and in Section 5.1.5).  
See Section 5.3 (Methods and Timing for Capturing and Assessing Safety Parameters) 
for complete details regarding safety reporting for this study.
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
All serious adverse events and adverse events of special interest will be recorded during 
the study and for up to 90 days after the last dose of study treatment or initiation of new 
systemic anti-cancer therapy after the last dose of study treatment, whichever occurs 
first.  All other adverse events will be recorded during the study and for up to 30 days 
after the last dose of study treatment or initiation of new systemic anti-cancer therapy 
after the last dose of study treatment, whichever occurs first.
After the adverse event reporting period, all deaths should continue to be reported.  In 
addition, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event or adverse event of special interest that is believed to be related to prior 
exposure to study treatment (see Section 5.6).  The potential safety issues anticipated in 
this trial, as well as measures intended to avoid or minimize such toxicities, are outlined 
in the following sections.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, 


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nephritis, and myositis.  Immune-mediated reactions may involve any organ system 
and may lead to hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome.  Refer to Appendix 16 of the protocol and Section 6 of the Atezolizumab 
Investigator's Brochure for a detailed description of anticipated safety risks for 
atezolizumab.
5.1.2
Risks Associated with Bevacizumab
Serious side effects associated with bevacizumab include gastrointestinal perforations, 
surgery and wound healing complications, hemorrhage (severe or fatal hemorrhage 
including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, 
pulmonary hemorrhage, epistaxis, and vaginal bleeding), non-gastrointestinal fistula 
formation, arterial thromboembolic events (including cerebral infarction, transient 
ischemic attacks, myocardial infarction, angina), and hypertension.  
For more details regarding the safety profile of bevacizumab, refer to the prescribing 
information for bevacizumab.  
5.1.3
Risks Associated with Carboplatin
Carboplatin is known to cause bone marrow suppression, including myelosuppression, 
anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is considered to 
be moderately emetogenic.  Patients will be monitored for carboplatin-related 
adverse events.
For more details regarding the safety profile of carboplatin, refer to the prescribing 
information for carboplatin.
5.1.4
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.


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5.1.5
General Plan to Manage Safety Concerns
5.1.5.1
Monitoring
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events defined and graded according to NCI CTCAE v4.0.  Patients 
will be assessed for safety (including laboratory values) according to the schedule in 
Appendix 1.  Laboratory values must be reviewed prior to each infusion.
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts 
(see Appendix 1 for the list and timing of study assessments).
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.
All serious adverse events and protocol-defined events of special interest 
(see Sections 5.2.2 and 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.
Patients will be followed for adverse events (including deaths, serious adverse events, 
and adverse events of special interest) during and after the adverse event reporting 
period as described in Sections 5.3.1, 5.3.5.7, 5.5, and 5.6.
5.1.6
Dose Modification
5.1.6.1
General Notes Regarding Dose Modification
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF. 
The severity of adverse events will be graded according to the NCI CTCAE v4.0 
grading system.

For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator 
feels it is appropriate.  For example, if a patient has Grade 1 asthenia at baseline 
that increases to Grade 2 during treatment, this will be considered a shift of one 
grade and treated as Grade 1 toxicity for dose-modification purposes.

When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed.

If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
component of the study treatment (i.e., atezolizumab, bevacizumab, carboplatin, or 
paclitaxel) and the dose of that component is delayed or modified in accordance 
with the guidelines below, other components may be administered if there is no 
contraindication.


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
When treatment is temporarily interrupted because of toxicity caused by 
bevacizumab, atezolizumab, carboplatin and/or paclitaxel (if applicable), 
the treatment cycles will be restarted such that the atezolizumab and bevacizumab
(if applicable) infusions remain synchronized and aligned with the chemotherapy 
schedule.

If, in the opinion of the investigator, toxicity is considered to be due solely to 
one chemotherapy drug, the dose of the other chemotherapy drug does not 
require modification.
The investigator may use discretion in modifying or accelerating the dose modification 
guidelines described below depending on the severity of toxicity and an assessment of 
the risk versus benefit for the patient, with the goal of maximizing patient compliance and 
access to supportive care.
5.1.6.2 
Atezolizumab Dose Modification
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment with atezolizumab for up to 105 days beyond the last dose if 
they experience an adverse event that requires a dose to be withheld. If atezolizumab is 
withheld because of adverse events for more than 105 days beyond the last dose, then 
the patient will be discontinued from atezolizumab treatment and will be followed for 
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.
5.1.7 
Management of Atezolizumab-Specific Adverse Events 
Refer to Appendix 16 for details on management of atezolizumab-specific adverse 
events.  Refer to Appendix 11 for precautions for anaphylaxis.
5.1.8 
Bevacizumab Dose Modification and Management of
Specific Adverse Events
No reductions in bevacizumab dose are allowed in this study.  Criteria for treatment
modification and guidelines for the management of toxicities are summarized in Table 14. 
If adverse events occur that necessitate withholding bevacizumab, the dose will remain 
unchanged once treatment resumes.
Temporary suspension of bevacizumab must occur if a patient experiences a serious 
adverse event or a Grade 3 or 4 non-serious adverse event assessed by the investigator


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as related to bevacizumab.  If the event resolves to Grade 1, bevacizumab may be 
restarted at the same dose level.  If bevacizumab is delayed because of toxicity for 
42 days beyond when the next dose should have been given, the patient must be 
permanently discontinued from bevacizumab.  
The appropriate interval between the last dose of bevacizumab and major surgery is 
unknown.  Because bevacizumab has a half-life of approximately 21 days, elective 
surgery should be delayed whenever possible, but if necessary, bevacizumab should be 
withheld for 28 days prior to the procedure.  Re-initiation of bevacizumab following 
surgery should not occur for 28 days and until wounds have fully healed.  Re-initiation 
of bevacizumab after surgery requires documented approval from the Medical Monitor.
Infusion of bevacizumab should be interrupted in patients who develop dyspnea 
or clinically significant hypotension.  Patients who experience an NCI CTCAE Grade 3 or 
4 allergic reaction/hypersensitivity, adult respiratory distress syndrome, or 
bronchospasm (regardless of grade) will be discontinued from bevacizumab treatment.  
If possible, a sample for ATA assessment will be collected at the time of discontinuation.
Bevacizumab infusion should be slowed to 50% or interrupted for patients who 
experience any infusion-associated symptoms not specified above.  If the infusion is 
interrupted, it may be resumed at 50% of the rate prior to the reaction after the 
patient’s symptoms have adequately resolved and increased in 50% increments up to 
the full rate if well tolerated.  Infusions may be restarted at the full rate during the 
next cycle.
All patients receiving bevacizumab should have their baseline scans reviewed with a 
radiologist at the investigational site. 
If the patient is found to have the features of cavitation and/or tumor invasion of thoracic 
vessels at baseline, the subsequent scans should also be reviewed and the decision to 
withdraw patients from bevacizumab should be based on the appearances of the scan. 

If the high-risk features are still apparent on the later scans, the investigator should
consider withdrawing the patient from bevacizumab

If the high-risk features are no longer visible on post-baseline scans, the investigator 
should make a benefit-risk assessment in consultation with a radiologist whether or 
not to continue treatment with bevacizumab

If the patient did not have features of cavitation or tumor invasion of thoracic vessels 
at baseline, but develops cavitation during treatment, the investigator should make a 
benefit-risk assessment in consultation with a radiologist whether or not to continue 
treatment with bevacizumab.
For guidelines on the dosing of other study drugs when bevacizumab is withheld, 
see Section 5.1.6.1.


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Table 14 Bevacizumab Dose Management for Adverse Events
Event
Action to Be Taken
Hypertension 
Grade 1 (asymptomatic, 
transient [24 hr] blood 
pressure increase by 
20 mmHg (diastolic) or to 
150/100 mmHg if 
previously within normal 
limits)
No bevacizumab dose modifications
Grade 2 (recurrent or 
persistent [24 hr] or 
symptomatic increase by 
20 mmHg (diastolic) or to 
150/100 mmHg if 
previously within normal 
limits)
Withhold bevacizumab.  Start antihypertensive therapy.  Once 
blood pressure is 150/100 mmHg, patient may continue 
bevacizumab therapy.
Grade 3
Requires more than one antihypertensive drug or more intensive 
therapy than previously:  If not controlled to 150/100 mmHg with 
medication, discontinue bevacizumab.
Grade 4 (including 
hypertensive 
encephalopathy)
Discontinue bevacizumab. 
Hemorrhage 
Grade 1 or 2 non-pulmonary 
or non-CNS events
No bevacizumab modifications
Grade 3 non-pulmonary or 
non-brain or non-spinal cord 
hemorrhage
Withhold bevacizumab until all of the following criteria are met:
The bleeding has resolved and hemoglobin is stable.
There is no bleeding diathesis that would increase the risk of 
therapy.
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence.
Patients who experience a repeat Grade 3 hemorrhagic event will 
be discontinued from bevacizumab.
Grade 4 non-pulmonary or 
non-brain or non-spinal cord 
hemorrhage
Discontinue bevacizumab.


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Table 14 Bevacizumab Dose Management for Adverse Events (cont.)
Event
Action to Be Taken
Hemorrhage (cont.)
Grade 1 pulmonary or brain 
or spinal cord hemorrhage
Withhold bevacizumab until all of the following criteria are met:
The bleeding has resolved and hemoglobin is stable.
There is no bleeding diathesis that would increase the risk of 
therapy.
There is no anatomic or pathologic condition that significantly 
increases the risk of hemorrhage recurrence.
Grade 2, 3, or 4 pulmonary 
or brain or spinal cord 
hemorrhage
Discontinue bevacizumab.
Venous thromboembolic event 
Grade 1 or 2
No bevacizumab modifications.
Grade 3 or 
asymptomatic Grade 4
If the planned duration of full-dose anticoagulation is 2 weeks, 
bevacizumab should be withheld until the full-dose anticoagulation 
period is over.  If the planned duration of full-dose anticoagulation 
is 2 weeks, bevacizumab may be resumed after 2 weeks of 
full-dose anticoagulation if all of the following criteria are met:
The patient must have an in-range INR (usually between 2 
and 3) if on warfarin; LMWH, warfarin, or other anticoagulant 
dosing must be stable prior to restarting study treatment.  
The patient must not have had a Grade 3 or 4 hemorrhagic 
event while on anticoagulation.
Symptomatic Grade 4
Discontinue bevacizumab.
Arterial thromboembolic event
(new onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial thromboembolic event)
Any grade
Discontinue bevacizumab.
Congestive heart failure
(left ventricular systolic dysfunction)
Grade 1 or 2
No bevacizumab modifications.
Grade 3
Withhold bevacizumab until resolution to Grade 1.
Grade 4
Discontinue bevacizumab.
Proteinuria
Grade 1 (urine dipstick 1or 
urine collection 0.15 to 1.0 
g/24 hr)
No bevacizumab modifications
Grade 2 (urine dipstick 2to 
3or urine collection 1.0 
to 
3.5 g/24 hr)
For 2 dipstick, may administer bevacizumab and obtain 24-hour 
urine prior to next dose.
For 3 dipstick, obtain 24-hour urine prior to administration of 
bevacizumab.
Withhold bevacizumab for proteinuria 2 g/24 hr and resume 
when proteinuria is 2 g/24 hr.a


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Table 14 Bevacizumab Dose Management for Adverse Events (cont.)
Event
Action to Be Taken
Proteinuria (cont.)
Grade 3 
(urine dipstick 4or urine 
collection 3.5 g/24 hr) 
Withhold bevacizumab.  Resume when proteinuria is 2 g/24 hr. a
Grade 4 
(nephrotic syndrome)
Discontinue bevacizumab.
GI perforation
Any grade
Discontinue bevacizumab.
Fistula
Any grade 
tracheoesophageal fistula
Discontinue bevacizumab.
Grade 4 fistula (other than 
tracheoesophageal)
Discontinue bevacizumab.
Bowel obstruction
Grade 1
Continue patient on study for partial obstruction not requiring 
medical intervention.
Grade 2
Discontinue bevacizumab.
Wound dehiscence
Any grade
(requiring medical or 
surgical therapy)
Discontinue bevacizumab.
Reversible posterior leukoencephalopathy
Any grade
(confirmed by MRI)
Discontinue bevacizumab.
GIgastrointestinal; LMWHlow molecular weight heparin.
a All proteinuria values are from 24-hour urine collection.
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 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 


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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/L and the platelet count must 
be 100,000 cells/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 15 and Table 16).
Table 15 Dosing Based on ANC and Febrile Neutropenia—Paclitaxel 
and Carboplatin
Dose of Paclitaxel and Carboplatin
ANC (Day 1 of each cycle)
1500/L
1500/L
Febrile neutropenia
(regardless of duration)
0
Paclitaxel 150 mg/m2
Carboplatin AUC 4.5
AUCarea under the concentrationtime curve.
Table 16 summarizes dose modifications based on platelet count.
Table 16 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.


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All dose reductions for the first episode of neutropenic fever or thrombocytopenia 
(platelet count 25,000 or 50,000 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/L and the 
platelet count is 100,000/L.  However, if the counts have not recovered in 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.
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 17 provides the relevant dose adjustments for 
gastrointestinal toxicities.


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Table 17 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 a
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 cleared 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 is completely cleared.  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 liver function 
tests are provided in Table 18. 


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Table 18 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.
5.1.9.5
Neurologic Toxicity (Paclitaxel Only)
The dose of paclitaxel should be modified as follows for sensory neuropathy. 


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Table 19 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 5.1.6.1.


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5.1.10
Potential Overlapping Toxicities 
The risk of overlapping toxicities between atezolizumab, bevacizumab, carboplatin, and 
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 bevacizumab and 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, Section 5.1.8, Section 5.1.9, and Appendix 16 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 1/2 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 5.1.6.2).  Exceptions require Medical Monitor approval.  Prompt 
symptomatic management is appropriate for mild immune-mediated adverse events.  
In severe cases, 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


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
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.

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 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see
Section 5.4.2 for reporting instructions). Adverse events of special interest for this study 
include the following:

Confirmed treatment-emergent autoimmune conditions:
– 
Pneumonitis
– 
Hypoxia or dyspnea Grade  3
– 
Colitis
– 
Endocrinopathies: diabetes mellitus, pancreatitis, or adrenal insufficiency
– 
Vasculitis
– 
Hepatitis
– 
Transaminitis: Grade 2 (AST or ALT 3ULN and bilirubin 2ULN) OR
AST/ALT 10ULN
– 
Systemic lupus erythematosus
– 
Guillain-Barré syndrome
– 
Skin reactions: vitiligo, pemphigoid

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response system, or infusion-reaction syndromes

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by
Hy’s law (see Section 5.3.5.6)

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5.7.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity
(see Section 5.3.3), and causality (see Section 5.3.4).


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5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, 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 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 or initiation of new systemic 
anti-cancer therapy after the last 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 20 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 20 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating “yes” or “no” 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event


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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
For all adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.


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5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity) of the event will be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, the 
most extreme intensity should also be recorded on the Adverse Event eCRF.  If the 
event becomes serious, it should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning that the event became serious; see Section 5.4.2 for 
reporting instructions).  The Adverse Event eCRF should be updated by changing the 
event from “non-serious” to “serious,” providing the date that the event became serious, 
and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it is a change from baseline and meets any of 
the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”).  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.”


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


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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 
StudyDiscontinuation 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 
only on the StudyDiscontinuation eCRF. 
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.


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5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration or 
to perform an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.

Hospitalization due solely to progression of the underlying cancer 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Adverse Events Associated with an Overdose or Error in 
Drug Administration
Study overdose is the accidental or intentional use of a drug in an amount higher than 
the dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Study Drug Administration eCRF.  
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 


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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

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:
, R.N. (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 


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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 Treatment 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 Treatment Initiation
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment or initiation of 
new systemic anti-cancer therapy after the last dose of study treatment, whichever 
occurs first.  All other adverse events, regardless of relationship to study treatment, will 
be reported until 30 days after the last dose of study treatment or initiation of new 
systemic anti-cancer therapy after the last dose of study treatment, whichever 
occurs first.
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 and/or 6 months after the last dose of bevacizumab or paclitaxel, 
whichever is later.  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 


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learning of the pregnancy), either by faxing or by scanning and emailing the form with 
use of the fax number or e-mail address provided to investigators..  Pregnancy should 
not be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
6 months after the last dose of bevacizumab, paclitaxel, 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 
e-mail address provided to investigators.  Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient 
exposed to study treatment.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An 
investigator who is contacted by the male patient or his pregnant partner may provide 
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 
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5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or study-related procedures 
until a final outcome can be reported.
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.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Atezolizumab Investigator’s Brochure

AVASTIN (bevacizumab) Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor safety data during the study.  An aggregate report of any clinically 
relevant imbalances that do not favor the test product will be submitted to health 
authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a randomized, Phase III, global, multicenter, open-label study designed to 
evaluate the safety and efficacy of atezolizumab in combination with 
carboplatinpaclitaxel with and without bevacizumab compared with treatment with 
carboplatinpaclitaxelbevacizumab in approximately 1200 patients with Stage IV 
non-squamous NSCLC in the first-line setting.
Efficacy analyses will be performed in one or more populations (tGE-WT, ITT-WT, tGE, 
ITT, TC2/3 or IC2/3 WT, or TC1/2/3 or IC1/2/3 WT) with patients grouped according to 
the treatment assigned at randomization, regardless of whether they received any 
assigned study treatment
Safety analyses will be performed on all randomized patients who received any amount 
of any components of protocol treatment, 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 would be 
grouped under Arm B for safety analyses.




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This study will enroll approximately 1200 patients.  The ITT-WT population will include 
approximately 1080 patients, assuming a 10% prevalence for sensitizing EGFR
mutations or ALK translocations.  The tGE-WT population will include approximately 
540 patients, assuming a 50% prevalence with the chosen tGE cutoff.
The sample size of this study is based on the number of events required to demonstrate 
efficacy with regard to both PFS and OS (co-primary endpoints) 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-WT population

One-sided significance level of 0.003 for the comparison of Arm B versus Arm C in 
the ITT-WT population

98% power to detect an HR of 0.55, corresponding to an improvement in median 
PFS from 6 months to 10.9 months in the tGE-WT population

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-WT 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 0.019 for the comparison of Arm B versus Arm C in 
the ITT-WT population

87% power to detect an HR of 0.75, corresponding to an improvement in median 
OS from 12 months to 16 months in the ITT-WT population

One interim OS analysis performed at the time of the final PFS analysis, at which 
time approximately 73% 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.


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With these assumptions, approximately 1200 patients in total will be enrolled into this 
study, with approximately 720 patients in each comparison (i.e., Arm B vs. Arm C and
Arm A vs. Arm C) in the ITT-WT population.  The final PFS analysis will be conducted 
when both of the following criteria have been met:  approximately 516 PFS events have 
occurred in Arms B and C combined in the ITT-WT population and the last patient has 
been enrolled in the study.  The final PFS analysis is expected to occur approximately 
29 months after the first patient is enrolled.  At the time of the final PFS analysis, it is 
expected that approximately 249 events will have occurred in the tGE-WT population.  
These numbers of events would allow for a minimum detectable difference 
corresponding to an HR of approximately 0.70 in the tGE-WT population and 0.78 in the 
ITT-WT population.
With a sample size of 720 patients, approximately 507 OS events are expected to occur 
in Arms B and C combined in the ITT-WT population for the final OS analysis.  The final 
OS analysis is expected to occur approximately 40 months after the first patient is 
enrolled.  This number of events corresponds to a minimum detectable difference in HR 
of approximately 0.83 in the ITT-WT population.
6.2
SUMMARIES OF CONDUCT OF STUDY
Study enrollment, study drug administration, reasons for discontinuation from the study 
drug, and reasons for study termination will be summarized by treatment arm for the tGE
population, the tGE-WT population, the ITT population, and the ITT-WT population.  
Major protocol deviations, including major deviations with regard to inclusion/exclusion 
criteria, will be reported and summarized by treatment arm for the ITT-WT population.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG performance status), will be summarized by treatment arms 
for each population (tGE-WT and ITT-WT).  Descriptive statistics (mean, median, 
standard deviation, and range) will be presented for continuous data, and frequencies 
and percentages will be presented for categorical data.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of protocol treatment.
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-WT population and the ITT-WT 
population.  OS will be analyzed in the ITT-WT population.  The timing of the final PFS 
and OS analyses is described in Section 6.1.  At least one interim OS analysis will be 
performed (see Section 6.8.1).


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PFS is defined as the time between the date of randomization and the date of first 
documented disease progression or death, whichever occurs first.  Patients who have 
not experienced disease progression or 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 date 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 and 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 stratification factors will be those used during randomization (i.e., sex [male vs. 
female], presence of liver metastases at baseline [yes vs. no], and PD-L1 tumor 
expression by IHC [TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1]), as 
recorded in the IxRS.
Results from an unstratified analysis will also be presented.  Kaplan-Meier methodology 
will be used to estimate the median PFS and the median OS for each treatment arm, 
and a Kaplan-Meier curve will be constructed to provide a visual description of the 
difference between treatment arms.  The Brookmeyer-Crowley methodology will be used 
to construct the 95% CI for the median PFS and the median OS for each treatment arm 
(Brookmeyer and Crowley 1982).
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 (see Figure 3 in Section 6.1) and to account for an interim analysis 
(see Section 6.8.1).  
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 () will be allocated to PFS in the tGE-WT population, PFS in the ITT-WT
population, and OS in the ITT-WT population in a 3:3:19 ratio for comparison of Arm B 
versus Arm C


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1.
PFS in the tGE-WT population will be tested at 0.003 (one sided). If the estimate 
of the HR is <1 and the one-sided p-value corresponding to the stratified log-rank 
test is0.003, the null hypothesis will be rejected, and it will be concluded that 
atezolizumabcarboplatinpaclitaxelbevacizumab prolongs the duration of PFS 
relative to the control arm in the tGE-WT population. 
2.
PFS in the ITT-WT population will be tested at 0.003 (one sided).
3.
recycling from PFS to OS will be conducted as follows: 
a.
If the PFS result is not statistically significant in either the tGE-WT population or 
the ITT-WT population, OS in the ITT-WT population will be tested at 0.019 
(one sided).
b.
If the PFS result is only statistically significant in the tGE-WT population or the 
ITT-WT population, OS in the ITT-WT population will be tested at 0.022 
(one sided).
c.
If the PFS result is statistically significant in both the tGE-WT population and 
the ITT-WT population, OS in the ITT-WT 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-WT population is statistically 
significant at an of 0.019, 0.022, or 0.025 (Step 3 above), 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 in the tGE-WT population, PFS in the ITT-WT population, and OS in 
the ITT-WT population at the same 3:3:19 ratio (see Figure 3 in Section 6.1).  If the 
difference in OS between Arm B and Arm C in the ITT-WT 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.
Depending on the outcome of the PFS testing of Arm A vs. Arm C in the tGE-WT and 
ITT-WT populations, the from these two PFS comparisons will be recycled back to the 
OS comparison in the ITT-WT population for Arm A vs. Arm C.
1.
If the difference in OS between Arm B and Arm C is statistically significant at 
0.019 (one sided): 
a.
PFS in the tGE-WT population will be tested at 0.00228 (one sided). If the 
estimate of the HR is <1 and the one-sided p-value corresponding to the 
stratified log-rank test is0.00228, the null hypothesis will be rejected, and it 
will be concluded that atezolizumabcarboplatinpaclitaxel prolongs the 
duration of PFS relative to the control arm in the tGE-WT population.
b.
PFS in the ITT-WT population will be tested at 0.00228 (one sided)


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c.
recycling from PFS to OS will be conducted as follows:

If the PFS result is not statistically significant in either the tGE-WT 
population or the ITT-WT population, OS in the ITT-WT population will be 
tested at 0.01444 (one sided).

If the PFS result is only statistically significant in the tGE-WT population or 
the ITT-WT population, OS in the ITT-WT population will be tested at 
0.01672 (one sided).

If the PFS result is statistically significant in both the tGE-WT population 
and the ITT-WT population, OS in the ITT-WT population will be tested at 
0.019 (one sided).
2.
If the difference in OS between Arm B and Arm C is statistically significant at 
0.022 (one sided): 
a.
PFS in the tGE-WT 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 the control arm in the tGE-WT population.
b.
PFS in the ITT-WT population will be tested at 0.00264 (one sided).
c.
recycling from PFS to OS will be conducted as follows:

If the PFS result is not statistically significant in either the tGE-WT 
population or the ITT-WT population, OS in the ITT-WT population will be 
tested at 0.01672 (one sided).

If the PFS result is only statistically significant in the tGE-WT population or
the ITT-WT population, OS in the ITT-WT population will be tested at 
0.01936 (one sided).

If the PFS result is statistically significant in both the tGE-WT population 
and the ITT-WT population, OS in the ITT-WT population will be tested at 
0.022 (one sided).
3.
If the difference in OS between Arm B and Arm C is statistically significant at 
0.025 (one sided): 
a.
PFS in the tGE-WT population will be tested at 0.003 (one sided). If the 
estimate of the HR is <1 and the one-sided p-value corresponding to the 
stratified log-rank test is0.003, the null hypothesis will be rejected, and it will 
be concluded that atezolizumabcarboplatinpaclitaxel prolongs the duration 
of PFS relative to the control arm in the tGE-WT population.
b.
PFS in the ITT-WT population will be tested at 0.003 (one sided).
c.
recycling from PFS to OS will be conducted as follows:

If the PFS result is not statistically significant in either the tGE-WT 
population or the ITT-WT population, OS in the ITT-WT population will be 
tested at 0.019 (one sided).


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
If the PFS result is only statistically significant in the tGE-WT population or 
the ITT-WT population, OS in the ITT-WT population will be tested at 
0.022 (one sided).

If the PFS result is statistically significant in both the tGE-WT population 
and the ITT-WT population, OS in the ITT-WT population will be tested at 
0.025 (one sided).
6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Progression-Free Survival and Overall Survival in Secondary
Populations
PFS will be analyzed in the TC2/3 or IC2/3 WT population, the TC1/2/3 or IC1/2/3 WT 
population, the tGE population, and the ITT population, through use of the same 
methods described for the primary PFS analysis (see Section 6.4.1).  
OS will be analyzed in the tGE-WT population, the TC2/3 or IC2/3 WT population, the 
TC1/2/3 or IC1/2/3 WT population, the tGE population, and the ITT population, through 
use of the same methods described for the primary OS analysis (see Section 6.4.1).  
If the difference in OS between Arm A and Arm C in the ITT-WT population is statistically 
significant, a comparison of Arm B versus Arm C and a comparison of Arm A versus 
Arm C will be conducted in the tGE population and the ITT population.  The allocation 
will follow the same -spending algorithm and allocation ratio described for analysis of 
the co-primary efficacy endpoints (see Section 6.4.1).
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 achieved an objective response.  
ORR will be analyzed in the tGE-WT population and the ITT-WT population.  Patients 
must have measurable disease at baseline to be included in the analysis.  An estimate 
of ORR and its 95% CI will be calculated using the Clopper-Pearson method for each 
treatment arm.  CIs for the difference in ORRs between the two treatment arms will be 
determined using the normal approximation to the binomial distribution.  The ORR will be 
compared between the two treatment arms using the stratified Mantel-Haenszel test.  
The stratification factors of this analysis will be the same as those described in 
Section 6.4.1.
6.4.2.3
Duration of Response
DOR will be analyzed in the tGE-WT population and the ITT-WT population.  DOR will 
be assessed in patients who achieved an objective response as determined by the 
investigator according to RECIST v1.1.  DOR is defined as the time interval from the 


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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.  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
Progression-Free Survival as Assessed by the 
Independent Review Facility
To support the primary analysis of investigator-assessed PFS, the analysis of PFS as 
assessed by the IRF will be performed in the tGE-WT population and the ITT-WT 
population.  The methodologies outlined for the primary analysis of PFS per the 
investigator will be used for the analyses of PFS based on IRF assessment.
6.4.2.5
Overall Survival Rate at Landmark Timepoints
OS rate at 1 and 2 years will be analyzed in the tGE-WT population and the ITT-WT 
population.  The OS rates at 1 and 2 years will be estimated using Kaplan-Meier
methodology for each treatment arm, along with 95% CIs calculated using the standard 
error derived from 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.
6.4.2.6
Progression-Free Survival and Overall Survival in the 
Atezolizumab-Containing Arms
PFS and OS analyses will be performed in the tGE-WT population and the ITT-WT 
population through use of the same methods described for the primary PFS and OS 
analyses (see Section 6.4.1.)
6.4.2.7
Patient-Reported Outcomes
TTD in lung cancer symptoms as determined by EORTC and change from baseline in 
lung cancer symptoms as determined by SILC will be analyzed in the tGE-WT 
population and the ITT-WT population.
TTD with use of the 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.  
The linear transformation gives each individual symptom subscale a possible score of 
0 to 100.  IA 10-point change in the symptoms subscale score is perceived by patients 


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as clinically significant (Osoba et al. 1998).  Patients will be censored at the last time 
when they completed an assessment if they have not deteriorated.  If no post-baseline 
assessment is performed, patients will be censored at the randomization date plus 1 day.  
TTD with use of the EORTC scale will be analyzed through use of the same methods 
described for the PFS analysis (See Section 6.4.1).
Change from baseline per SILC scale will be analyzed in patients with a baseline and a 
post-baseline PRO assessment.
Further details regarding all PRO analyses will be described in the Statistical Analysis 
Plan (SAP).
6.4.3
Handling of Missing Data 
For PFS, patients without a date of disease progression will be analyzed as censored 
observations on the date of the last tumor assessment.  If no post-baseline tumor 
assessment is available, PFS will be censored at the date of randomization plus 1 day.  
Data for patients with a PFS event who missed two or more scheduled assessments 
immediately prior to the PFS event will be handled as described in the sensitivity 
analysis in Section 6.7.5.4.
For objective response, patients without any post-baseline assessment will be 
considered non-responders.
For OS, 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, patients who have not progressed and who have not died at the time of 
analysis will be censored at the time of the last tumor assessment date.  If no tumor 
assessments were performed after the date of the first occurrence of a CR or PR, DOR 
will be censored at the date of the first occurrence of a complete or partial response plus 
1 day.
For TTD using EORTC, patients who have not deteriorated at the time of analysis will be 
censored at the last time they completed an assessment.  If no post-baseline 
assessment is performed, patients will be censored at the randomization date plus 1 day.
6.5
SAFETY ANALYSES
Safety analyses will include all treated patients, defined as randomized patients who 
received any amount of any component of study treatment.  Safety data will be 
summarized by treatment arm for treated patients in a primary safety-evaluable 
population consisting of the ITT-WT population and/or the tGE-WT population 
(depending on the results of the primary endpoint analyses).  Safety data will 
also be summarized by treatment arm for treated patients not included in the primary 


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safety-evaluable population.  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, patients who were randomized to Arm C but received
atezolizumab in error 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.
6.6
PHARMACOKINETIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 2.  Atezolizumab and 
bevacizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, and standard 
deviations, as appropriate.
Plasma concentrations of carboplatin and paclitaxel will be collected in this study as 
outlined in Appendix 2.  The concentrations of carboplatin and paclitaxel will be 
summarized using descriptive statistics as described above.
Additional PK analyses will be conducted, as appropriate, based on the availability 
of data.
6.7
EXPLORATORY ANALYSES
6.7.1
Time to Response
TTR will be assessed in patients who had an objective response as determined by the 
investigator according to RECIST v1.1.  TTR is defined as the time between the date of 
randomization and the date of first occurrence of a CR or PR (whichever status is 
recorded first).  No censoring observation will occur by definition. TTR is based on a 


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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.  TTR will 
be analyzed through use of the same methods described for the primary PFS analysis 
(see Section 6.4.1).
6.7.2
Time in Response
The two treatment arms will be compared with respect to time in response (TIR).  
Non-responders will be considered as having an event and TIR will be defined as 1 day; 
for responders, TIR will be same as DOR.  TIR will be analyzed through use of the same 
methods described for the primary PFS analysis (see Section 6.4.1).
6.7.3
Objective Response Rate and Duration of Response by 
Independent Review Facility Assessment per RECIST v1.1
The methodologies outlined for the primary and secondary efficacy endpoint analyses 
will be used for the analyses of ORR and DOR based on IRF assessment.
6.7.4
Objective Response Rate, Progression-Free Survival, and
Duration of Response per Modified RECIST
Analyses using modified RECIST (see Appendix 5) for ORR, PFS, and DOR, as 
determined by the investigator will also be conducted (Arms A and B only).  
Comparisons between the two experimental arms (i.e., Arm A vs. B) will be made.  
The methods outlined for the primary and secondary efficacy endpoint analyses will be 
used for these analyses. 
6.7.5
Exploratory Analyses of Progression-Free Survival
6.7.5.1
Progression-Free Survival Rate at Landmark Timepoints
The PFS rates (e.g., at 6 months and at 1-year after randomization) will be estimated 
using Kaplan-Meier methodology for each treatment arm, along with 95% CIs calculated 
using Greenwood’s formula.  The 95% 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.  
6.7.5.2
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 two treatment arms (i.e., Arm A vs. Arm C
and Arm B vs. Arm C) in which data from 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.


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6.7.5.3
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).
6.7.5.4
Sensitivity Analyses
Sensitivity analyses will be performed to evaluate the potential impact of missing 
scheduled tumor assessments on the primary analysis of PFS, as determined by the 
investigator using a PFS event imputation rule.  The following two imputation rules will 
be considered: 

If a patient missed two or more scheduled tumor assessments immediately prior to 
the date of the PFS event according to RECIST v1.1, the patient will be censored at 
the last tumor assessment prior to the first of these missed visits.

If a patient missed two or more tumor assessments scheduled immediately prior to 
the date of the PFS event according to RECIST v1.1, the patient will be counted as 
having progressed on the date of the first of these missing assessments.
The imputation rule will be applied to patients in all treatment arms.  Statistical 
methodologies analogous to those used in the primary analysis of PFS as specified in 
Section 6.4.1 will be used for this sensitivity analysis.
6.7.6
Exploratory Analyses of Overall Survival 
6.7.6.1
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.
6.7.6.2
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).


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6.7.6.3
Overall Survival Rate at Three-Year Landmark
The methodologies for landmark OS analysis outlined in Section 6.4.2.5 will be used.
6.7.6.4
Milestone Overall Survival Analysis
To assess the effect of long-term survival and delayed clinical effects, a milestone OS 
analysis will be conducted (Chen 2015).  The milestone OS is an OS endpoint with 
cross-sectional assessment at a pre-specified timepoint.  The milestone OS analysis will 
be performed using the same methods as those specified for the primary OS analysis 
and the specific definition of milestone will be documented in the SAP.
6.7.7
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.
6.7.8
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.
6.7.9
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 Analyses
There will be 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 370 OS events have occurred in Arms B and C combined in the ITT-WT 
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 


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ITT-WT population. If there are significantly fewer than the expected 370 OS events at 
the time of the final PFS analysis, a nominal of 0.01% (negligible impact on overall 
type I error rate) will be spent on the OS analysis at the time of the final PFS analysis
and a second interim OS analysis will then be conducted after approximately 370 OS 
events have occurred.
The final OS analysis for the comparison of Arm B versus Arm C will be conducted when 
approximately 507 OS events have occurred in Arms B and C combined in the ITT-WT 
population.  This is expected to occur approximately 40 months after the first patient is 
enrolled.
Stopping boundaries for the interim and final OS analyses will be computed through use 
of the Lan-DeMets approximation to the O’Brien-Fleming boundary.  The stopping 
boundaries for the interim and final OS analyses for the comparison of Arm B versus 
Arm C in the ITT-WT population, assuming the specified observed number of events 
(370 and 507, respectively), are provided in Table 21.
Table 21 Analysis Timing and Stopping Boundaries for Overall Survival in 
the ITT-WT Population: Arm B vs Arm C
Analysis Timing
Stopping Boundary:  HR (p-value)
If 0.019
If 0.022
If 0.025
Interim OS analysis
HR0.770
(p0.0064)
HR0.776
(p0.0073)
HR0.781
(p0.0087)
Final OS analysis 
HR0.829
(p0.0172)
HR0.833
(p0.0198)
HR0.837
(p0.0224)
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.
If the difference in OS between Arm B and Arm C in the ITT-WT population is 
statistically significant at an of 0.019, 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 6.4.1.  Stopping boundaries for the interim and final OS analyses 
will be computed through use of the Lan-DeMets approximation to the O’Brien Fleming 
boundary.  The stopping boundaries for the interim and final OS analyses for the 
comparison of Arm A versus Arm C in the ITT-WT population, assuming the specified 
observed number of events (370 and 507, respectively), are provided for the three
scenarios (0.019, 0.022, or 0.025) in Table 22.


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Table 22 Analysis Timing and Stopping Boundaries for Overall Survival in 
the ITT-WT Population: Arm A vs Arm C
A. Boundaries if difference in OS between Arm B and Arm C in the ITT-WT population 
was statistically significant at 0.019.
Analysis Timing
Stopping Boundary: HR (p-value)
If 0.01444
If 0.01672
If 0.019
Interim OS analysis
HR0.760
(p0.0042)
HR0.766
(p0.0051)
HR0.770
(p0.006)
Final OS analysis
HR0.821
(p0.0132)
HR0.825
(p0.0152)
HR0.829
(p0.0172)
B. Boundaries if difference in OS between Arm B and Arm C in the ITT-WT population 
was statistically significant at 0.022.
Analysis Timing
Stopping Boundary: HR (p-value)
If 0.01672
If 0.01936
If 0.022
Interim OS analysis
HR0.766
(p0.0051)
HR0.771
(p0.0062)
HR0.776
(p0.0073)
Final OS analysis
HR0.825
(p0.0152)
HR0.829
(p0.0175)
HR0.833
(p0.0198)
C. Boundaries if difference in OS between Arm B and Arm C in the ITT-WT population 
was statistically significant at 0.025.
Analysis Timing
Stopping Boundary: HR (p-value)
If 0.019
If 0.022
If 0.025
Interim OS analysis
HR0.770
(p0.006)
HR0.776
(p0.0073)
HR0.781
(p0.0087)
Final OS analysis
HR0.829
(p0.0172)
HR0.833
(p0.0198)
HR0.837
(p0.0224)
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 the 
boundaries.
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.


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The interim analysis will be conducted by an external statistical group and reviewed by 
the iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified 
in the iDMC charter. 
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the Statistical Analysis Plan 
(SAP), and the SAP will be submitted to relevant health authorities at least 2 months 
prior to the conduct of the interim analysis.  The iDMC charter will document potential 
recommendations the iDMC can make to the Sponsor as a result of the analysis 
(e.g., stop the study for positive efficacy, stop the study for futility), and the iDMC charter 
will also be made available to relevant health authorities.
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.


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7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected electronically through use of electronic devices 
provided by an ePRO vendor.  The electronic device is designed for entry of data in a 
way that is attributable, secure, and accurate, in compliance with U.S. FDA regulations 
for electronic records (21 Code of Federal Regulations, Part 11).  The data will be 
transmitted to a centralized database at the ePRO vendor.  The data from the ePRO 
devices are available for view access only via secure access to a Web portal provided 
by the ePRO vendor.  Only identified and trained users may view the data, and their 
actions become part of the audit trail.  The Sponsor will have view access only.  Regular 
data transfers will occur from the centralized database at the vendor to the database at 
the Sponsor.
Once the study is complete, the ePRO data, audit trail, and study and system 
documentation will be archived.  The Sponsor will receive all data entered by patients on 
the e-diary and tablet device and all study documentation.
Details regarding patient reported data and the electronic device are available in the 
Study Reference Manual.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.


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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, the name of the 
person making the change, and the date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final 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).


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  
If applicable, it will be provided in a certified translation of the local language.  
The Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor’s sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the “Consent Forms”) before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining samples for optional exploratory research.  The investigator or authorized 
designee will explain to each patient the objectives of the exploratory research.  Patients 
will be told that they are free to refuse to participate and may withdraw their specimens 
at any time and for any reason during the storage period.  A separate, specific signature 
will be required to document a patient’s agreement to allow any remaining specimens to 
be used for exploratory research.  Patients who decline to participate will not provide a 
separate signature.
The Informed Consent Form will also contain the following additional signature pages:

A signature page for patients receiving atezolizumab who wish, if approved by the 
treating physician, to continue treatment beyond initial radiographic disease 
progression 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.


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A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
156/Protocol GO29436, Version 8
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
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 270 sites globally will participate in the study, and approximately 
1200 patients will be randomized.


Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol GO29436, Version 8
Randomization will occur through an IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests and PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The 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.


Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol GO29436, Version 8
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Atezolizumab—F. Hoffmann-La Roche Ltd
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10.
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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 
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
ALK and/or EGFR assessment if status is 
unknown (may be done locally or centrally)
x
Demographic data
x
Medical history and baseline conditions
x
NSCLC cancer history 
x
Vital signs d
x
x d
x d
x d
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 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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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 
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 x
TSH, free T3, free T4k
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 paclitaxel 
bevacizumab
Arm C: Carboplatin paclitaxel bevacizumab
x n
Maintenance treatment administration
Arm A:  Atezolizumab
Arm B:  Atezolizumab bevacizumab
Arm C:  Bevacizumab
x n
Tumor response assessment
x o
x p
x p
x q


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol GO29436, Version 8
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 
Every 3 Months 
after Disease 
Progression or 
Loss of Clinical 
Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Serum sample for atezolizumab ATA assessment 
(atezolizumab patients only) r
x
x
x
120 (30) days 
after last dose of 
atezolizumab
Serum sample for PK sampling (atezolizumab-
treated patients only) r
x
x
x
120 (30) days 
after last dose of 
atezolizumab
Carboplatin, paclitaxel, and bevacizumab 
(Arms B and C) PK sampling (20 patients per 
arm) r
x
x
Bevacizumab ATA and PK sampling 
(Arms B and C patients) r
x
x
Blood samples for PD biomarkers r
x
x
x
x
120 (30) days 
after last dose of 
atezolizumab
Optional blood for DNA extraction (RCR only) r, s
x
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab-treated 
patients)
At time of radiographic progression
Tumor biopsy
At time of radiographic progression y


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol GO29436, Version 8
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 
Every 3 Months 
after Disease 
Progression or 
Loss of Clinical 
Benefit
Every 21 days
(3 Days) b
Every 21 days
(3 Days) 
Optional tumor biopsy at other timepoints (RCR 
only)
Any time during study treatment or during survival follow-up
Adverse events
x
x
x
x t
x t
Concomitant medications
x u
x
x
x
Patient-reported outcomes (EORTC QLQ-C30, 
EORTC QLQ-LC13, SILC, PGIS, and 
EQ-5D-3L) v
x v
x v
x v
Survival and anti-cancer therapy follow-up 
x w
ATAanti-therapeutic antibody; CT computed tomography; ECOGEastern Cooperative Oncology Group; EORTCEuropean 
Organization for Research and Treatment of Cancer; ePRO electronic Patient-Reported Outcome; EQ-5D-3L Euro QoL5 Dimensions 
3-Level Version; FFPEformalin fixed paraffin embedded; HBcAb hepatitis B core antibody; HBVhepatitis B virus; HCVhepatitis C 
virus; IVintravenous; LC13Lung Cancer module; MRImagnetic resonance imaging; NSCLCnonsmall cell lung cancer; 
PDpharmacodynamic; PGISPatient Global Impression of Severity; PKpharmacokinetic; QLQ-C30Quality-of-Life Questionnaire 
Core 30; RCRRoche Clinical Repository; SILCSymptoms in Lung Cancer; TSHthyroid-stimulating hormone.
a Assessments should be performed before study drug infusion unless otherwise noted. 
b Cycle 1, Day 1 must be performed within 5 days after the patient is randomized.  Screening assessments performed 96 hours before 
Cycle 1 Day 1 are not required to be repeated for Cycle 1 Day 1.  In addition, ECOG performance status, limited physical examination, 
and local laboratory tests may be performed 96 hours before Day 1 of each cycle as specified in Section 4.5.12.2.  


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol GO29436, Version 8
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 is 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 a cell 
suspension and/or cell smears), brushing, cell pellets from pleural effusion, and lavage samples are NOT acceptable.  For core needle 
biopsy specimens, at least three cores should be submitted for evaluation.  Retrieval of archival tumor sample can occur outside the 
28-day screening period prior to enrollment. Section 4.5.7.1 and 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 and 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.
h Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2, calcium, 
phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.
i
Serum pregnancy test within 14 days before Cycle 1, Day 1.
j
Urine pregnancy tests; if a urine pregnancy test 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 will be tested only at sites where free T3 is not 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 until disease progression per RECIST v1.1 or loss of clinical benefit.  For bevacizumab, 
carboplatin, and 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
172/Protocol GO29436, Version 8
o CT scans (with oral/IV contrast unless contraindicated) or MRI of the chest and abdomen.  A CT or MRI scan of the pelvis is required 
at screening and as clinically indicated or as per local standard of care at subsequent response evaluations.  A CT (with contrast) or 
MRI scan of the head must be done at screening to evaluate CNS metastasis in all patients.  See Section 4.5.5 for details.
p Perform every 6 weeks (7 days) (approximately every two cycles) for 48 weeks following Cycle 1, Day 1 and then every 9 weeks 
(7 days) thereafter after completion of the Week 48 tumor assessment, regardless of treatment delays, until radiographic disease 
progression (or loss of clinical benefit  for patients assigned to atezolizumab who had continued treatment with atezolizumab after 
radiographic disease progression according to RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, 
whichever occurs first.  See Section 4.5.5 for details.
q If a patient discontinues study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, 
symptomatic deterioration), tumor assessments will continue at the same frequency as would have been followed if the patient had 
remained on study treatment until radiographic disease progression (or loss of clinical benefit for patients treated with atezolizumab 
who had continued treatment with atezolizumab after radiographic disease progression according to RECIST v1.1), withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first, even if patient starts another anti-cancer therapy after 
study treatment discontinuation.
r
See Appendix 2 for the detailed schedule.
s The optional RCR whole blood sample requires an additional informed consent and the sample can be collected at any time during the 
course of the study.
t
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 or initiation of new non-protocol 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 or initiation of new non-protocol systemic anti-cancer therapy after the last dose of study 
treatment, whichever occurs first.  After this period, all deaths will be reported.  In addition, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event or adverse event of special interest that is believed to be related to prior 
exposure to study treatment (see Section 5.6).
u From 7 days before screening.


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol GO29436, Version 8
v EORTC QLQ-C30, EORTC QLQ-LC13, PGIS, and EQ-5D-3L questionnaires will be completed by the patients on the ePRO tablet at 
each scheduled study visit prior to administration of study drug and prior to any other study assessment(s).  SILC will be completed 
using an electronic device at the patient’s home on a weekly basis.  During survival follow-up, the EORTC QLQ-C30, EORTC 
QLQ-LC13, and EQ-5D-3L will be completed at 3 and 6 months following disease progression (or loss of clinical benefit for 
atezolizumab-treated patients).  The SILC will be completed monthly during survival follow-up for 6 months following disease 
progression (or loss of clinical benefit for atezolizumab-treated patients who had continued treatment with atezolizumab after 
radiographic 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 on 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.
w Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits every 3 months or more 
frequently until death, loss to follow-up, or study termination by the Sponsor, whichever occurs first.  All patients will be periodically 
contacted for survival and new anti-cancer therapy information unless the patient requests to be withdrawn from follow-up (this request 
must be documented in the source documents and signed by the investigator).  If the patient withdraws from the study, study staff may 
use a public information source (e.g., county records) when permissible, to obtain information about survival status only.
x For Argentina sites only: A urine pregnancy test is required monthly until 6 months after the last dose of study treatment
y Mandatory biopsy, if clinically feasible, within 40 days of radiographic progression or prior to the start of the next anti-cancer therapy, 
whichever is sooner (see Section 4.5.7.2).


Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol GO29436, Version 8
Appendix 2
Schedule of Pharmacokinetic, Biomarker,
and Anti-Therapeutic Antibody Assessments
Study Visit
Time
Arm A
(Atezolizumab
Carboplatin
Paclitaxel)
Arm B
(Atezolizumab
Carboplatin
Paclitaxel
Bevacizumab)
Arm C
(Carboplatin
Paclitaxel
Bevacizumab)
Screening
N/A
Biomarkers b
Biomarkers b
Biomarkers b
Cycle 1, 
Day 1 f
Pre-dose 
(same day as 
treatment 
administration) 
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Carboplatin 
pharmacokinetics a
Paclitaxel 
pharmacokinetics a
Biomarkers d
Atezolizumab ATA
Atezolizumab 
pharmacokinetics
Carboplatin 
pharmacokinetics a
Paclitaxel 
pharmacokinetics a
Bevacizumab 
pharmacokinetics
Bevacizumab ATA
Biomarkers d
Carboplatin 
pharmacokineticsa
Paclitaxel 
pharmacokineticsa
Bevacizumab 
pharmacokinetics
Bevacizumab ATA
Biomarkers d
30 min 
(10 min) 
after end of 
atezolizumab
infusion
Atezolizumab 
pharmacokinetic
Atezolizumab 
pharmacokinetics
30 min (10 
min) after end 
of 
bevacizumab 
infusion a
Bevacizumab 
pharmacokineticsa
Bevacizumab 
pharmacokineticsa
510 min 
before the end 
of carboplatin 
infusion a
Carboplatin 
pharmacokinetics a
Carboplatin 
pharmacokineticsa
Carboplatin 
pharmacokineticsa
1 hr after end 
of carboplatin 
infusion a
Carboplatin 
pharmacokinetics a
Carboplatin 
pharmacokineticsa
Carboplatin 
pharmacokineticsa
510 min 
before the end 
of paclitaxel 
infusion a
Paclitaxel 
pharmacokinetics a
Paclitaxel 
pharmacokineticsa
Paclitaxel 
pharmacokineticsa
1 hr after end 
of paclitaxel 
infusion a
Paclitaxel 
pharmacokinetics a
Paclitaxel 
pharmacokineticsa
Paclitaxel 
pharmacokineticsa


Appendix 2
Schedule of Pharmacokinetic, Biomarker, 
and Anti-Therapeutic Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol GO29436, Version 8
Study Visit
Time
Arm A
(Atezolizumab
Carboplatin
Paclitaxel)
Arm B
(Atezolizumab
Carboplatin
Paclitaxel
Bevacizumab)
Arm C
(Carboplatin
Paclitaxel
Bevacizumab)
Cycle 2, 
Day 1 
(3 days)
Pre-dose 
(same day as 
treatment 
administration)

Atezolizumab 
ATA

Atezolizumab 
pharmacokinetics

Biomarkers d 

Atezolizumab 
ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

Biomarkers d
Cycle 3, 
Day 1 
(3 days)
Pre-dose 
(same day as 
treatment 
administration)

Atezolizumab 
ATA

Atezolizumab 
pharmacokinetics

Carboplatin 
pharmacokinetics
a

Paclitaxel 
pharmacokinetics
a

Biomarkers d
Atezolizumab ATA

Atezolizumab 
pharmacokinetics

Carboplatin 
pharmacokineticsa

Paclitaxel 
pharmacokineticsa

Bevacizumab 
pharmacokinetics

Bevacizumab ATA

Biomarkers d
Carboplatin 
pharmacokineticsa
Paclitaxel 
pharmacokineticsa
Bevacizumab 
pharmacokinetics
Bevacizumab ATA
Biomarkers d
30 min 
(10 min) 
after end of 
atezolizumab
infusion

Atezolizumab 
pharmacokinetic

Atezolizumab 
pharmacokinetics
30 min 
(10 min) after 
end of 
bevacizumab 
infusion a

Bevacizumab 
pharmacokinetics a
Bevacizumab 
pharmacokineticsa
510 min 
before the end 
of carboplatin 
infusion a

Carboplatin 
pharmacokineticsa

Carboplatin 
pharmacokineticsa
Carboplatin 
pharmacokineticsa


Appendix 2
Schedule of Pharmacokinetic, Biomarker, 
and Anti-Therapeutic Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol GO29436, Version 8
Study Visit
Time
Arm A
(Atezolizumab
Carboplatin
Paclitaxel)
Arm B
(Atezolizumab
Carboplatin
Paclitaxel
Bevacizumab)
Arm C
(Carboplatin
Paclitaxel
Bevacizumab)
Cycle 3, 
Day 1 
(3 days)
(cont.)
1 hr after end 
of carboplatin 
infusion a

Carboplatin 
pharmacokineticsa

Carboplatin 
pharmacokineticsa
Carboplatin 
pharmacokineticsa
510 min 
before the end 
of paclitaxel 
infusion a

Paclitaxel 
pharmacokineticsa

Paclitaxel 
pharmacokineticsa
Paclitaxel 
pharmacokineticsa
1 hr after end 
of paclitaxel 
infusion a

Paclitaxel 
pharmacokinetic a

Paclitaxel 
pharmacokineticsa
Paclitaxel 
pharmacokineticsa
Cycles 4, 8, 
and 16,
Day 1 
(3 days)
Pre-dose 
(same day as 
treatment 
administration)

Atezolizumab 
ATA

Atezolizumab 
pharmacokinetics

Biomarkers d 

Atezolizumab 
ATA

Atezolizumab 
pharmacokinetic

Biomarkers d 
Biomarkers d
After 
Cycle 16 
and every 
eighth cycle, 
Day 1 
(3 days)
Pre-dose 
(same day as 
treatment 
administration)

Atezolizumab 
ATA

Atezolizumab 
pharmacokinetics

Biomarkers d

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


Appendix 2
Schedule of Pharmacokinetic, Biomarker, 
and Anti-Therapeutic Antibody Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol GO29436, Version 8
Study Visit
Time
Arm A
(Atezolizumab
Carboplatin
Paclitaxel)
Arm B
(Atezolizumab
Carboplatin
Paclitaxel
Bevacizumab)
Arm C
(Carboplatin
Paclitaxel
Bevacizumab)
Treatment 
discontinuation 
visit
At visit
Atezolizumab 
ATA
Atezolizumab 
pharmacokinetics
Biomarkers d

Atezolizumab 
ATA

Atezolizumab 
pharmacokinetics

Bevacizumab 
pharmacokineticse

Bevacizumab 
ATAe

Biomarkers d
Bevacizumab 
pharmacokineticse
Bevacizumab 
ATAe
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.
Notes:  Serum PK samples for atezolizumab and bevacizumab; plasma PK samples for 
carboplatin, and paclitaxel.
All patients in Arm B and C will undergo the additional ATA and PK assessments for 
bevacizumab at Cycle 1 pre-dose, Cycle 3 pre-dose, and at the time of bevacizumab 
discontinuation.
a At selected centers, 20 patients in each treatment arm will undergo additional PK assessments 
for carboplatin, paclitaxel, and bevacizumab where applicable.
b Whole blood for biomarkers.
c The optional RCR blood sample (for DNA extraction) requires an additional informed consent 
and the sample can be collected at any time during the course of the study.
d Plasma and serum for biomarkers.
e Bevacizumab PK and ATA are required at time of bevacizumab discontinuation.
f
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
178/Protocol GO29436, Version 8
Appendix 3
American Joint Committee on Cancer
NonSmall Cell Lung Cancer Staging, 7th Edition


Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol GO29436, Version 8
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
180/Protocol GO29436, Version 8
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol GO29436, Version 8
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.


Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol GO29436, Version 8
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 


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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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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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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

PD:  unequivocal progression of existing non-target lesions


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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 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 


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


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


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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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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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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 


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


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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 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 


Atezolizumab—F. Hoffmann-La Roche Ltd
197/Protocol GO29436, Version 8
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 (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 
GO29436, the antiPD-L1 (SP142) IHC assay will be used for investigational purposes 
only.
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody is intended for 
laboratory use in the semi-quantitative immunohistochemical assessment of the PD-L1 
protein in formalin-fixed, paraffin-embedded nonsmall cell lung carcinoma (NSCLC) 
tissue stained on a Ventana BenchMark ULTRA automated slide stainer.  It is indicated 
as an aid in the selection of patients with NSCLC with locally advanced or metastatic 
disease who might benefit from treatment with atezolizumab.
This assay is for investigational use only.  The performance characteristics of this 
product have not been established.
DEVICE DESCRIPTION
The Ventana antiPD-L1 (SP142) rabbit monoclonal primary antibody is a pre-dilute, 
ready-to-use antibody product optimized for use with the Ventana Medical Systems 
OptiView DAB IHC Detection Kit and the OptiView Amplification Kit on Ventana Medical 
Systems automated BenchMark ULTRA platforms.  One 5-mL dispenser of antiPD-L1 
(SP142) rabbit monoclonal primary antibody contains approximately 36 g of rabbit 
monoclonal antibody directed against the PD-L1 protein and contains sufficient reagent 
for 50 tests.  The reagents and the IHC procedure are optimized for use on the 
BenchMark ULTRA automated slide stainer, utilizing Ventana System Software (VSS).
SCORING SYSTEM
PD-L1 staining with antiPD-L1 (SP142) rabbit monoclonal primary antibody in NSCLC 
can be observed in both tumor cells and tumor-infiltrating immune cells.
Details of the criteria for PD-L1 diagnostic assessment are described in the IDI 
document.


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Appendix 7
EORTC QLQ-C30


Atezolizumab—F. Hoffmann-La Roche Ltd
200/Protocol GO29436, Version 8
Appendix 7
EORTC QLQ-C30 (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
201/Protocol GO29436, Version 8
Appendix 8
EORTC QLQ-LC13


Atezolizumab—F. Hoffmann-La Roche Ltd
202/Protocol GO29436, Version 8
Appendix 9
EQ-5D-3L


Atezolizumab—F. Hoffmann-La Roche Ltd
203/Protocol GO29436, Version 8
Appendix 9
EQ-5D-3L (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
204/Protocol GO29436, Version 8
Appendix 9
EQ-5D-3L (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
205/Protocol GO29436, Version 8
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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206/Protocol GO29436, Version 8
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


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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 over autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune thrombocytopenic 
purpura
Behcet’s disease
Bullous pemphigold
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating polyneuropathy
Chung-Strauss syndrome
Crohn’s disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia
Epidermolysis bullosa 
acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis 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


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Appendix 13
Symptoms in Lung Cancer


Atezolizumab—F. Hoffmann-La Roche Ltd
209/Protocol GO29436, Version 8
Appendix 13
Symptoms in Lung Cancer (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
210/Protocol GO29436, Version 8
Appendix 13
Symptoms in Lung Cancer (cont.)


Atezolizumab—F. Hoffmann-La Roche Ltd
211/Protocol GO29436, Version 8
Appendix 14
Patient Global Impression of Severity




Atezolizumab—F. Hoffmann-La Roche Ltd
213/Protocol GO29436, Version 8
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.
If it is anticipated that a component of study treatment cannot be administered, it is 
recommended to delay all study treatment for up to 2 weeks.  However, if it is anticipated 
that chemotherapy will be delayed by more than 2 weeks, then atezolizumab should be 
a given without chemotherapy, which will be delayed until the next cycle, provided there 
is no contraindication.
eCRF Data Entry for Recording Interruption and Re-Introduction of 
Chemotherapy
Because of the complex nature and possible permutations of such dosage interruptions 
and reintroductions, site personnel should contact the Monitor, and the Monitor will 
instruct the site on how to open the appropriate visits and electronic Case Report Form 
(eCRF) so that the site can then record the interruption and reintroduction accordingly on 
the eCRF.


Atezolizumab—F. Hoffmann-La Roche Ltd
214/Protocol GO29436, Version 8
Appendix 16
Risks Associated with Atezolizumab and Guidelines for
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of 
atezolizumab may not have an immediate therapeutic effect, and in severe cases, 
immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the immune-
mediated event.  Patients can be re-challenged with atezolizumab only after approval 
has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension.  Management guidelines for pulmonary events are provided 
in Table 1.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
215/Protocol GO29436, Version 8
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BAL bronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
216/Protocol GO29436, Version 8
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of 
atezolizumab.Eligible patients must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
LFT liver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
217/Protocol GO29436, Version 8
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
LFT liver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
218/Protocol GO29436, Version 8
Table 3
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate 
treatment with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
219/Protocol GO29436, Version 8
Table 3
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist for evaluation and confirmation 
biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests 
(e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH 
stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 
pituitary sections) may help to differentiate primary pituitary insufficiency from 
primary adrenal insufficiency.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
220/Protocol GO29436, Version 8
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated 
hyperthyroidism. c
MRI magnetic resonance imaging; TSH thyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
221/Protocol GO29436, Version 8
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRI magnetic resonance imaging; TSH thyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
222/Protocol GO29436, Version 8
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.
MRI magnetic resonance imaging; TSH thyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
223/Protocol GO29436, Version 8
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
224/Protocol GO29436, Version 8
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not 
limited to, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging 
abnormalities, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, 
or syncope.  Immune-mediated myocarditis needs to be distinguished from myocarditis 
resulting from infection (commonly viral, e.g., in a patient who reports a recent history 
of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac 
MRI as appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
225/Protocol GO29436, Version 8
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated 
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-mediated 
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated 
myocarditis, Grade 3-4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
ECMO extracorporeal membrane oxygenation; VAD ventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
226/Protocol GO29436, Version 8
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE
SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or 
cytokine-release syndrome (CRS) with atezolizumab may receive premedication with 
antihistamines, anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated 
IRRs because of its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
227/Protocol GO29436, Version 8
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms 

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, 
the infusion rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of 
IV fluids for hydration.

In case of rapid decline or prolonged CRS (2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
228/Protocol GO29436, Version 8
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 2 a
Fever b with 
hypotension not 
requiring 
vasopressors
and/or
Hypoxia requiring 
low-flow oxygen d
by nasal cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated, and 
manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor.

If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
229/Protocol GO29436, Version 8
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids as 
clinically indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e  For patients who are refractory to 
anti-cytokine therapy, experimental treatments g may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
230/Protocol GO29436, Version 8
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive airway 
pressure; CRS cytokine-release syndrome; CTCAE Common Terminology Criteria for 
Adverse Events; eCRF electronic Case Report Form; HLH hemophagocytic 
lymphohistiocytosis; ICU intensive care unit; IRR infusion-related reaction; 
MAS macrophage activation syndrome; NCCN National Cancer Comprehensive Network; 
NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e
There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not 
been established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be considered 
after consulting the Medical Monitor and considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
231/Protocol GO29436, Version 8
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day oral 
prednisone or equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
232/Protocol GO29436, Version 8
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated 
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated 
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GI gastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
233/Protocol GO29436, Version 8
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases 
of rash were mild in severity and self-limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated.  Management guidelines for dermatologic 
events are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids 
if event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or 
equivalent, increasing dose to 12 mg/kg/day if event does not 
improve within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
234/Protocol GO29436, Version 8
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated 
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-mediated 
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
Immune-mediated 
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia gravis 
and Guillain-Barré 
syndrome 
(any grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
235/Protocol GO29436, Version 8
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, 
motor or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, 
or edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated 
Meningoencephalitis
Event
Management
Immune-mediated 
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical 
Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function.  Renal function, 
including serum creatinine, should be monitored throughout study treatment.  Patients 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
236/Protocol GO29436, Version 8
with abnormal renal function should be evaluated and treated for other more common 
etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if 
clinically indicated.  A renal biopsy may be required to enable a definitive diagnosis 
and appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
237/Protocol GO29436, Version 8
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among 
the most common disorders.  Initial diagnosis is based on clinical (muscle weakness, 
muscle pain, skin rash in dermatomyositis), biochemical (serum creatine kinase 
increase), and imaging (electromyography/MRI) features, and is confirmed with a 
muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
238/Protocol GO29436, Version 8
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-mediated
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of
10 mg/day oral prednisone. The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
239/Protocol GO29436, Version 8
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of 
the following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100 109/L (100,000/L)
–
ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should 
be classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181 109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


Appendix 16
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
240/Protocol GO29436, Version 8
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther 
Clin Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.

SAP_000.pdf: 
Offi ci al Titl e:  A P H A S E III, O P E N -L A B E L, R A N D O MI Z E D S T U D Y  
O F A T E Z O LI Z U M A B ( M P D L 3 2 8 0 A, A N TI −P D -L 1  
A N TI B O D Y) I N C O M BI N A TI O N WI T H  
C A R B O P L A TI N +  P A C LI T A X E L WI T H O R WI T H O U T  
B E V A CI Z U M A B C O M P A R E D WI T H  
C A R B O P L A TI N +  P A C LI T A X E L +  B E V A CI Z U M A B  
I N C H E M O T H E R A P Y-N AI V E P A TI E N T S WI T H  
S T A G E I V N O N -S Q U A M O U S N O N −S M A L L C E L L  
L U N G C A N C E R  
N C T N u m b er:  
N C T 0 2 3 6 6 1 4 3  
D o c u m e nt  D at e : 
S A P V er si o n 1 : 2 0 -A pr -1 7  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 6 3
S T A TI S TI C A L A N A L Y SI S P L A N  A P P R O V A L  
C O N FI D E N TI A L  
T hi s i s a n F. H off m a n n -L a R o c h e Lt d d o c u m e nt t h at c o nt ai n s c o nfi d e nti al i nf or m ati o n.  N ot hi n g 
h er ei n i s t o b e di s cl o s e d wit h o ut writt e n c o n s e nt fr o m F. H off m a n n -L a R o c h e Lt d.  
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n G O 2 9 4 3 6  
S T A TI S TI C A L A N A L Y SI S P L A N  
TI T L E:  
A P H A S E III, O P E N -L A B E L, R A N D O MI Z E D S T U D Y  
O F A T E Z O LI Z U M A B ( M P D L 3 2 8 0 A,  A N TI −P D -L 1  
A N TI B O D Y) I N C O M BI N A TI O N W I T H 
C A R B O P L A TI N
 +  P A C LI T A X E L WI T H O R WI T H O U T
B E V A CI Z U M A B C O M P A R E D WI T H  
C A R B O P L A TI N
 +  P A C LI T A X E L  +  B E V A CI Z U M A B
I N C H E M O T H E R A P Y -N AI V E P A TI E N T S WI T H  
S T A G E  I V N O N-S Q U A M O U S N O N −S M A L L C E L L  
L U N G C A N C E R  
P R O T O C O L N U M B E R:  
G O 2 9 4 3 6  
S T U D Y D R U G:  
At e z oli z u m a b ( R O 5 5 4 1 2 6 7)  
V E R SI O N N U M B E R:  
1 
I N D N U M B E R: 
1 1 7 2 9 6  
E U D R A C T N U M B E R:  
2 0 1 4 -0 0 3 2 0 7 -3 0  
S P O N S O R:  
F. H off m a n n -L a R o c h e Lt d
P L A N P R E P A R E D B Y:  
D A T E FI N A L:  
S e e el e ctr o ni c d at e st a m p b el o w .
N a me
Re as o n f or Si g ni n g
D ate a n d Ti me
( U T C)
2 0- A pr- 2 0 1 7 2 1: 3 7: 1 3
C o m pa n y Si g nat or y ( Cli nical)


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 6 4
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
2/ St ati sti c al A n al y si s Pl a n G O 2 9 4 3 6  
T A B L E O F C O N T E N T S  
1.
B A C K G R O U N D  ............................................................................................ 5 
2.
S T U D Y D E SI G N  ........................................................................................... 5  
2. 1  
Pr ot o c ol S y n o p si s  .................................................................... 7 
2. 2  
O ut c o m e M e a s ur e s  ................................................................. 7 
2. 2. 1  
Pri m ar y Effi c a c y O ut c o m e M e a s ur e s  ...................................... 7 
2. 2. 2  
S e c o n d ar y Effi c a c y  O ut c o m e M e a s ur e s .................................. 7 
2. 2. 3  
E x pl or at or y Effi c a c y  O ut c o m e M e a s ur e s  ................................. 8 
2. 2. 4  
P h ar m a c o ki n eti c O ut c o m e M e a s ur e s  ...................................... 9 
2. 2. 5  
S af et y O ut c o m e M e a s ur e s  ...................................................... 9 
2. 3  
D et er mi n ati o n of S a m pl e Si z e  ............................................... 1 0  
2. 4  
A n a l y si s Ti mi n g ..................................................................... 1 2  
2. 4. 1  
Pri m ar y A n al y si s Ti mi n g f or P F S  ........................................... 1 2  
2. 4. 2  
I nt eri m a n d Fi n al A n al y si s Ti mi n g f or O S ............................... 1 3  
3.
S T U D Y C O N D U C T  ..................................................................................... 1 6  
3. 1  
R a n d o mi z at i o n I s su e s  ........................................................... 1 6  
3. 2  
I n d e p e n d e nt R e vi e w F a cilit y .................................................. 1 6  
3. 3  
D at a M o nit ori n g  ..................................................................... 1 6  
4.
S T A TI S TI C A L M E T H O D S  .......................................................................... 1 6  
4. 1  
A n al y si s P o p ul ati o n s  ............................................................. 1 6  
4. 1. 1  
Effi c a c y A n al y si s  P o p ul ati o n s ................................................ 1 6  
4. 1. 2  
P h ar m a c o ki n eti c -E v al u a bl e P o p ul ati o n  ................................. 1 7  
4. 1. 3  
S af et y P o p ul ati o n  .................................................................. 1 7  
4. 2  
A n al y si s of St u d y  C o n d u ct ..................................................... 1 8  
4. 3  
A n al y si s of Tr e at m e nt Gr o u p C o m p ar a bilit y  .......................... 1 8  
4. 4  
Effi c a c y A n al y si s  .................................................................... 1 8  
4. 4. 1  
Pri m ar y Effi c a c y E n d p oi nt  ...................................................... 1 8  
4. 4. 2  
S e c o n d ar y Effi c a c y  E n d p oi nt s ............................................... 2 2  
4. 4. 2. 1  
O S i n t h e t G E −Wil d -T y p e P o p ul ati o n ..................................... 2 2
4. 4. 2. 2  
P F S a n d O S i n P D -L 1 −S el e ct e d Wil d -T y p e
P o p ul ati o n s  ............................................................................ 2 2  
4. 4. 2. 3  
P F S a n d O S i n t h e t G E a n d I T T P o p ul ati o n s ......................... 2 2  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 6 5
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
3/ St ati sti c al A n al y si s Pl a n G O 2 9 4 3 6  
4. 4. 2. 4  
O bj e cti v e R e s p o n s e R at e  ...................................................... 2 2  
4. 4. 2. 5  
D ur ati o n of R e s p o n s e  ............................................................ 2 3  
4. 4. 2. 6  
P F S a s A s s e s s e d b y I n d e p e n d e nt R e vi e w 
F a cilit y  ................................................................................... 2 3  
4 . 4. 2. 7 
O S R at e at t h e 1 - a n d 2 -Y e ar L a n d m ar k Ti m e 
P oi nt s ..................................................................................... 2 3  
4. 4. 2. 8  
I n v e sti g at or-A s s e s s e d P F S a n d O S C o m p ari s o n 
b et w e e n At e z oli z u m a b -C o nt ai ni n g Ar m s  ............................... 2 3  
4. 4. 2. 9  
P ati e nt -R e p ort e d O ut c o m e s  .................................................. 2 3  
4. 4. 3  
E x pl or at or y Eff i c a c y E n d p oi nt s .............................................. 2 5  
4. 4. 3. 1  
Ti m e i n R e s p o n s e  .................................................................. 2 5  
4. 4. 3. 2  
Ti m e t o R e s p o n s e  ................................................................. 2 5  
4. 4. 3. 3  
O R R a n d D O R a s A s s e s s e d b y t h e I R F p er 
R E CI S T v 1. 1  .......................................................................... 2 5  
4. 4. 3. 4  
P F S, O R R, a n d D O R a s A s s e s s e d b y t h e 
I n v e sti g at or U si n g M o difi e d R E CI S T ..................................... 2 5  
4. 4. 3. 5  
Pr o gr e s si o n -Fr e e S ur vi v al R at e s at 6 M o nt h s a n d 
1 Y e ar  .................................................................................... 2 6  
4. 4. 3. 6  
O v er all S ur vi v al R at e at 3 Y e ar s  ............................................ 2 6  
4. 4. 3. 7  
E Q -5 D -3 L H e alt h St at u s D at a  ............................................... 2 6  
4. 4. 3. 1  
A d diti o n al P ati e nt -R e p ort e d O ut c o m e A n al y s e s  .................... 2 7  
4. 4. 4  
S e n siti vit y A n al y s e s  ............................................................... 2 7  
4. 4. 4. 1  
Mi s si n g T u m or A s s e s s m e nt  ................................................... 2 7  
4. 4. 4. 2  
N o n -Pr o p orti o n al H a z ar d  ....................................................... 2 7  
4. 4. 4. 3  
L o s s t o F oll o w - U p .................................................................. 2 9  
4. 4. 4. 4  
I m p a ct of I m b al a n c e b et w e e n  Tr e at m e nt Ar m s  ..................... 2 9  
4. 4. 5  
S u b gr o u p A n al y s e s  ............................................................... 2 9  
4. 5  
P h ar m a c o ki n eti c a n d P h ar m a c o d y n a mi c 
A n al y s e s  ................................................................................ 3 0  
4. 6  
S af et y A n al y s e s  ..................................................................... 3 0  
4. 6. 1  
E x p o s ur e of St u d y M e di c ati o n  ............................................... 3 1  
4. 6. 2  
A d v er s e E v e nt s  ..................................................................... 3 1  
4. 6. 3  
L a b or at or y D at a  ..................................................................... 3 1  
4. 6. 4  
Vit al Si g n s  .............................................................................. 3 2  
4. 6. 5  
A n ti-Dr u g A nti b o d y  ................................................................ 3 2  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 6 6
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4/ St ati sti c al A n al y si s Pl a n G O 2 9 4 3 6  
4. 7  
Mi s si n g D at a  .......................................................................... 3 2  
5.
R E F E R E N C E S  ........................................................................................... 3 3  
LI S T O F T A B L E S  
T a bl e  1 
Fi n al A n al y si s f or  Pr o gr e s si o n-Fr e e S ur vi v al f or Ar m B 
v er s u s Ar m C C o m p ari s o n  .......................................................... 1 3  
T a bl e 2  
A n al y si s f or O v er all S ur vi v al f or t h e C o m p ari s o n of Ar m B 
v er s u s Ar m C  .............................................................................. 1 4  
T a bl e 3  
A n al y si s Ti mi n g a n d St o p pi n g B o u n d ar y f or O v er all S ur vi v al 
i n t h e I nt e nt-t o-Tr e at Wil d -T y p e P o p ul ati o n f or t h e 
C o m p ari s o n of  Ar m B v er s u s Ar m C  ........................................... 1 4  
T a bl e 4  
A n al y si s Ti mi n g a n d St o p pi n g B o u n d ar y f or O v er all S ur vi v al 
i n t h e I nt e nt-t o-Tr e at Wil d -T y p e P o p ul ati o n f or t h e 
C o m p ari s o n of Ar m A v er s u s Ar m C  ........................................... 1 5  
T a bl e  5 
Si g nifi c a n c e L e v el  f or C o m p ari s o n of Ar m A v er s u s Ar m C ........ 2 1  
LI S T O F FI G U R E S  
Fi g ur e 1  
S t u d y S c h e m a ............................................................................... 6 
Fi g ur e 2  
Pr o gr e s si o n -Fr e e S ur vi v al a n d O v er all S ur vi v al A n al y si s 
Hi er ar c h y, α  All o c ati o n, a n d α  R e c y cli n g  .................................... 1 1
LI S T O F A P P E N DI C E S  
A p p e n di x  1 
Pr ot o c ol S y n o p si s  ....................................................................... 3 4  
A p p e n di x  2 
S c h e d ul e of A s s e s s m e nt s  ........................................................... 5 1  
A p p e n di x  3 
S c h e d ul e  of P h ar m a c o ki n eti c, Bi o m ar k er,  a n d 
A nti -T h er a p e uti c A nti b o d y A s s e s s m e nt s  .................................... 5 8  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 6 7
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
1.
B A C K G R O U N D
T hi s St ati sti c al A n al y si s Pl a n ( S A P) pr o vi d e s d et ail s of t h e pl a n n e d a n al y s e s a n d 
st ati sti c al m et h o d s f or S t u d y G O 2 9 4 3 6 (I M p o w er 1 5 0), “ A P h a s e III, O p e n - La b el, 
R a n d o mi z e d St u d y of A t e z oli z u m a b ( M P D L 3 2 8 0 A, A nti−P D- L 1 A nti b o d y) i n C o m bi n ati o n 
wit h C ar b o pl ati n
 +  P a clit a x el wit h or wit h o ut B e v a ci z u m a b  C o m p ar e d w it h 
C ar b o pl ati n
 +  P a clit a x el  +  B e v a ci z u m a b  i n C h e m ot h er a p y-N a iv e P ati e nt s wit h St a g e I V 
N o n -S q u a m o u s N o n −S m all C ell L u n g C a n c er .”  T h e b a c k gr o u n d f or t h e st u d y c a n b e 
f o u n d i n t h e st u d y pr ot o c ol. 
2.
S T U D Y D E SI G N
T hi s r a n d o mi z e d, P h a s e III, m ulti c e nt er, o p e n -l a b el st u d y is d e si g n e d t o  e v al u at e 
t h e s af et y a n d effi c a c y of T E C E N T RI Q  (at e z oli z u m a b ) i n c o m bi n ati o n wit h  
c ar b o pl ati n  +  p a clit a x el wit h or wit h o ut b e v a ci z u m a b c o m p ar e d wit h tr e at m e nt wit h  
c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b i n a p pr o xi m at el y  1 2 0 0 c h e m ot h er a p y -n a i ve 
p ati e nt s wit h St a g e I V n o n -s q u a m o u s n o n −s m all c ell l u n g c a n c er ( N S C L C ). 
Eli gi bl e p ati e nt s w er e  str atifi e d b y s e x ( m al e v s. f e m al e), pr e s e n c e of li v er m et a st a s e s 
at  b a s eli n e ( y e s v s. n o), a n d pr o gr a m m e d d e at h −li g a n d 1 (P D- L 1 ) t u m or e x pr e s si o n b y 
i m m u n o hi st o c h e mi str y (I H C) (t u m or c ell [ T C] 3 a n d a n y t u m or-filtr ati n g i m m u n e c ell [I C] 
v s. T C 0/ 1/ 2 a n d I C 2/ 3 v s. T C 0/ 1/ 2 a n d I C 0/ 1)  t e st e d b y a c e ntr al l a b or at or y.  T C 0/ 1/ 2/ 3 
ar e d efi n e d a s P D- L 1 st ai ni n g i n <  1 %, ≥ 1 % t o <  5 %, ≥ 5 % t o 5 0 % , a n d ≥ 5 0 % of t h e T C s , 
re s p e cti v el y.  I C 0/ 1/ 2/ 3 ar e d efi n e d a s P D-L 1 −st ai n e d I C s c o v eri n g <  1 %, ≥ 1 % t o <  5 %, 
≥ 5 % t o 1 0 % , a n d ≥ 1 0 % of t h e t u m or ar e a , r e s p e cti v el y. 
Eli gi bl e p ati e nt s w e r e r a n d o mi z e d i n a 1: 1: 1 r ati o t o o n e of t h e f oll o wi n g tr e at m e nt 
r e gi m e n s: 
•
Tr e at m e nt Ar m A:  at e z oli z u m a b +  c ar b o pl ati n  +  p a clit a x el ( in d u cti o n:  f o ur or si x
2 1 -d a y c y cl e s); at e z oli z u m a b ( m ai nt e n a n c e: 2 1 -d a y c y cl e s)
•
Tr e at m e nt Ar m B:  at e z oli z u m a b +  c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b ( in d u cti o n:
f o ur or si x 2 1 -d a y c y cl e s); at e z oli z u m a b  +  b e v a ci z u m a b ( m ai nt e n a n c e:  2 1 -d a y
c y cl e s)
•
Tr e at m e nt Ar m C:  car b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b ( in d u cti o n:  f o ur or si x
2 1 -d a y c y cl e s); b e v a ci z u m a b ( m ai nt e n a n c e:  2 1 -d a y c y cl e s)
P ati e nt s w h o w e r e r a n d o mi z e d t o Ar m A or Ar m B m a y c o nti n u e tr e at m e nt wit h 
at e z oli z u m a b b e y o n d r a di o gr a p hi c pr o gr e s si o n b y R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s V er si o n 1. 1 ( R E CI S T v 1. 1 ), pr o vi d e d t h e y w e r e e x p eri e n ci n g cli ni c al b e n efit a s 
a s s e s s e d b y t h e i n v e sti g at or (i. e., i n t h e a b s e n c e of u n a c c e pt a bl e t o xi cit y or 
s y m pt o m ati c d et eri or ati o n attri b ut e d t o di s e a s e pr o gr e s si o n a s d et er mi n e d b y t h e 
i n v e sti g at or aft er a n i nt e gr at e d a s s e s s m e nt of r a di o gr a p hi c d at a, bi o p s y r e s ult s 
[if a v ail a bl e], a n d cli ni c al st at u s).  Fi g ur e 1 ill u str at e s t h e st u d y d e si g n.  T h e d et ail s f or 
t h e st u d y d e si g n c a n b e f o u n d in t h e st u d y pr ot o c ol.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 6 8
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
6/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
Fi g ur e 1 
St u d y S c h e m a  
C h e m ot h er a p y -N ai v e P ati e nt s wit h St a g e I V N o n -S q u a m o u s N S C L C
( n= a p pr o xi m at el y 1 2 0 0)
Ar m A:
At e z oli z u m a b ( 1 2 0 0 m g I V)
+ C ar b o pl ati n ( A U C = 6 I V)
+ P a clit a x el ( 2 0 0 m g/ m2 I V)
Ar m B:
At e z oli z u m a b ( 1 2 0 0 m g I V)
+ C ar b o pl ati n ( A U C = 6 I V)
+ P a clit a x el ( 2 0 0 m g/ m 2 I V)
+ B e v a ci z u m a b ( 1 5 m g/ k g I V)
Ar m C:
C ar b o pl ati n ( A U C = 6 I V)
+ P a clit a x el ( 2 0 0 m g/ m 2 I V)
+ B e v a ci z u m a b ( 1 5 m g/ k g I V)
Tr e at wit h  At e z oli z u m a b u ntil 
L o s s of Cli ni c al B e n efit
Tr e at u ntil 
Di s e a s e Pr o gr e s si o n, p er R E CI S T v 1. 1
S ur vi v al F oll o w -U p
1: 1: 1 R a n d o mi z ati o n
Str atifi c ati o n F a ct or s:
•
S e x
•
Li v er m et a st a s e s
•
P D -L 1 e x pr e s si o n ( b y c e ntr al 
t e sti n g f or P D-L 1 st at u s)
I n d u cti o n Tr e at m e nt:  F o ur or Si x 2 1-D a y C y cl e s
M ai nt e n a n c e Tr e at m e nt:  E v er y 2 1 D a y s
Ar m A:
At e z oli z u m a b ( 1 2 0 0 m g I V)
Ar m B:
At e z oli z u m a b ( 1 2 0 0 m g I V)
+ B e v a ci z u m a b ( 1 5 m g/ k g I V)
Ar m C:
B e v a ci z u m a b ( 1 5 m g /k gI V )
N o Cr o s s o v er P er mitt e d
 
A U C  =  ar e a u n d er t h e c o n c e ntr ati o n – ti m e c ur v e; I V =  i ntr a v e n o u sl y; N S C L C
 =  n o n −s m all c ell l u n g 
c a n c er; P D -L 1  =  pr o gr a m m e d d e at h −li g a n d 1; R E CI S T v. 1. 1  =  R e s p o n s e E v al u ati o n Crit eri a i n 
S oli d T u m or s  V er si o n 1. 1 . 
 
P ati e nt s u n d er g o t u m or a s s e s s m e nt s at b a s eli n e a n d e v er y 6 w e e k s (±  7 d a y s) f or t h e 
fir st 4 8 w e e k s aft er C y cl e 1, D a y 1, r e g ar dl e s s of d o s e d el a y s.  Aft er 4 8 w e e k s, t u m or 
a s s e s s m e nt i s r e q uir e d e v er y 9 w e e k s (±  7 d a y s) .  P ati e nt s u n d er g o t u m or a s s e s s m e nt s 
u ntil r a di o gr a p hi c di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 or l o s s of cli ni c al b e n efit (f or 
at e z oli z u m a b -tr e at e d p ati e nt s w h o c o nti n u e tr e at m e nt aft er r a di o gr a p hi c di s e a s e 
pr o gr e s si o n i n a c c or d a n c e wit h R E CI S T v 1. 1), wit h dr a w al of c o n s e nt, st u d y t er mi n ati o n 
b y S p o n s or, or d e at h, w hi c h e v er o c c ur s fir st.   P ati e nt s w h o di s c o nti n u e tr e at m e nt f or 
r e a s o n s ot h er t h a n r a di o gr a p hi c di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1  (e. g., t o xi cit y) 
c o nti n u e s c h e d ul e d t u m or a s s e s s m e nt s u ntil r a di o gr a p hi c di s e a s e pr o gr e s si o n p e r 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 6 9
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
7/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
R E CI S T v 1. 1 or l o s s of cli ni c al b e n efit (f or at e z oli z u m a b -tr e at e d p ati e nt s w h o c o nti n u e 
tr e at m e nt aft er r a di o gr a p hi c di s e a s e pr o gr e s si o n i n a c c or d a n c e wit h R E CI S T v 1. 1), 
wit h dr a w al of c o n s e nt, st u d y t er mi n ati o n b y S p o n s or, or d e at h, w hi c h e v er o c c ur s fir st, 
r e g ar dl e s s of w h et h er p ati e nt s st art a n e w a nti-c a n c er t h er a p y.  
T h e c o -pri m ar y effi c a c y e n d p oi nt s ar e pr o gr e s si o n -fr e e s ur vi v al (P F S) a s a s s e s s e d b y 
t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1, a n d o v er all s ur vi v al ( O S ).  S e e S e cti o n  2. 2  
f or d et ail s o n c o-pri m ar y effi c a c y e n d p oi nt s, s e c o n d ar y e n d p oi nt s, a n d ot h er e n d p oi nt s 
s u c h a s  s af et y, p h ar m a c o ki n eti c  ( P K), a n d e x pl or at or y o ut c o m e m e a s ur e s. 
T h e pri m ar y a n al y s e s of P F S will b e p erf or m e d o n t h e bi o m ar k er -s el e ct e d p o p ul ati o n 
d efi n e d u si n g e x pr e s si o n of a T- eff e ct or  (T eff ) a n d P D -L 1 g e n e si g n at ur e  i n t u m or ti s s u e 
(t h er e aft er r ef err e d t o a s t G E) a n d e x cl u di n g  pati e nt s wit h a s e n siti zi n g E G F R  m ut ati o n 
or A L K  tr a n sl o c ati o n ( wil d t y p e, t G E−W T ) a n d o n all r a n d o mi z e d p ati e nt s  (t h e i nt e nt-t o-
tr e at [I T T] p o p ul ati o n ) e x cl u d i n g pati e nt s wit h a s e n siti zi n g E G F R  m ut ati o n or A L K  
tr a n sl o c ati o n (I T T−W T) .  S e n siti zi n g E G F R  m ut ati o n s i n cl u d e all E G F R  a cti v ati n g 
m ut ati o n s i n e x o n s 1 8 t hr o u g h 2 1.  T h e pri m ar y a n al y s e s of O S will b e p erf or m e d o n  t h e 
I T T−W T p o p ul ati o n.  S e e S e cti o n  4. 1 f or d et ails o n  a n al y si s p o p ul ati o n s . 
T h er e ar e n o i nt eri m a n al y s e s pl a n n e d f or P F S a n d  t h er e i s o n e  i nt eri m a n al y si s pl a n n e d 
f or O S i n t hi s st u d y.  S e e S e cti o n  2. 4  f or d et ail e d a n al y si s ti mi n g. 
A n e xt er n al i n d e p e n d e nt D at a M o nit ori n g C o m mitt e e (i D M C) will b e s et u p t o e v al u at e 
s a f et y d at a o n a n o n g oi n g b a si s.  
2. 1  
P R O T O C O L S Y N O P SI S  
T h e Pr ot o c ol S y n o p si s i s i n  A p p e n di x  1.  F or a d diti o n al d et ail s, s e e t h e S c h e d ul e s of 
A s s e s s m e nt s i n  A p p e n di x  2  a n d  A p p e n di x 3. 
2. 2  
O U T C O M E M E A S U R E S  
2. 2. 1  
Pri m ar y Effi c a c y O ut c o m e M e a s ur e s  
T h e c o - pri m ar y effi c a c y o ut c o m e m e a s ur e s  f or t hi s st u d y ar e t h e f oll o wi n g: 
•
P F S, d efi n e d a s t h e ti m e fr o m  r a n d o mi z ati o n t o t h e fir st o c c urr e n c e of di s e a s e
pr o gr e s si o n  a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1  or  d e at h,
w hi c h e v er o c c ur s fir st , i n t h e t G E−W T p o p ul ati o n a n d t h e I T T −W T p o p ul ati o n
•
O S , d efi n e d a s t h e ti m e fr o m  r a n d o mi z ati o n t o d e at h fr o m a n y c a u s e  i n t h e I T T−W T
p o p ul ati o n
2. 2. 2  
S e c o n d ar y Effi c a c y O ut c o m e M e a s ur e s  
T h e s e c o n d ar y effi c a c y o ut c o m e m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g : 
•
O S i n t h e t G E −W T p o p ul ati o n
•
P F S, a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1, a n d O S i n t h e
T C 2/ 3 or I C 2/ 3 W T p o p ul ati o n a n d t h e T C 1/ 2/ 3 or I C 1/ 2/ 3 W T p o p ul at i o n


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 0
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
8/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
•  
P F S, a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1, a n d O S i n t h e 
t G E p o p ul ati o n a n d t h e I T T p o p ul ati o n 
•  
O bj e cti v e r e s p o n s e, d efi n e d a s eit h er c o m pl et e r e s p o n s e ( C R) or p arti al r e s p o n s e 
( P R) a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1  i n t h e t G E−W T 
p o p ul ati o n a n d t h e I T T −W T p o p ul ati o n  
•  
D ur ati o n of r e s p o n s e ( D O R ), d efi n e d f or p ati e nt s wit h a n o bj e cti v e r e s p o n s e a s t h e 
ti m e fr o m t h e fir st o c c urr e n c e of a  d o c u m e nt e d o bj e cti v e r e s p o n s e t o t h e ti m e of 
d o c u m e nt e d di s e a s e pr o gr e s si o n a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o  
R E CI S T v 1. 1 or d e at h fr o m a n y c a u s e, w hi c h e v er o c c ur s fir st , i n t h e t G E−W T 
p o p ul ati o n a n d t h e I T T −W T p o p ul ati o n  
•   
P F S a s a s s e s s e d b y t h e i n d e p e n d e nt r e vi e w f a cilit y (I R F), d efi n e d a s t h e ti m e fr o m 
r a n d o mi z ati o n t o t h e fir st o c c urr e n c e of di s e a s e pr o gr e s si o n a s d et er mi n e d b y t h e 
I R F a c c or di n g t o  R E CI S T v 1. 1 or d e at h fr o m a n y c a u s e, w hi c h e v er o c c ur s fir st , i n 
t h e t G E−W T p o p ul ati o n a n d t h e I T T −W T p o p ul ati o n  
•  
O S r at e s at 1 a n d 2 y e ar s , d efi n e d a s t h e pr o p orti o n of p ati e nt s ali v e at 1 a n d 2  
y e ar s aft er r a n d o mi z ati o n e sti m at e d  u si n g K a pl a n -M ei er ( K M) m et h o d ol o g y  f or t h e 
t G E−W T p o p ul ati o n a n d t h e I T T −W T p o p ul ati o n  
•  
P F S a s a s s e s s e d b y t h e i n v e sti g at or a c c or di n g t o  R E CI S T v 1. 1 a n d O S i n t h e t w o 
at e z oli z u m a b -c o nt ai ni n g ar m s i n t h e t G E −W T p o p ul ati o n a n d t h e I T T −W T 
p o p ul ati o n  
•  
Ti m e t o d et eri or ati o n ( T T D ) i n p ati e nt-r e p ort e d l u n g c a n c er s y m pt o m s, d efi n e d a s 
ti m e fr o m r a n d o mi z ati o n t o d et eri or ati o n ( 1 0-p oi nt c h a n g e) o n e a c h of t h e E ur o p e a n 
Or g a ni z ati o n f or t h e R e s e ar c h a n d Tr e at m e nt of C a n c er Q u alit y of Lif e 
Q u e sti o n n air e −C or e  (E O R T C Q L Q -C 3 0 ) a n d t h e s u p pl e m e nt al l u n g c a n c er m o d ul e 
(E O R T C Q L Q -L C 1 3 ) s y m pt o m s u b s c al e s  i n t h e t G E−W T p o p ul ati o n a n d t h e 
I T T−W T p o p ul ati o n  
•  
C h a n g e fr o m b a s eli n e i n p ati e nt -r e p ort e d l u n g c a n c er s y m pt o m s ( c o u g h, d y s p n e a, 
a n d c h e st p ai n) o n t h e s y m pt o m s e v erit y  s c or e of t h e S y m pt o m s i n L u n g C a n c er 
(SI L C ) s c al e  f or t h e t G E−W T p o p ul ati o n a n d t h e I T T −W T p o p ul ati o n  
 
2. 2. 3  
E x pl or at or y Effi c a c y O ut c o m e M e a s ur e s  
T h e e x pl or at or y effi c a c y  o ut c o m e  m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g : 
•  
Ti m e t o r e s p o n s e ( T T R ), d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st 
o c c urr e n c e of a C R or P R a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o  
R E CI S T  v 1. 1  
•  
Ti m e i n r e s p o n s e ( TI R ), w hi c h s h ar e s  t h e d efi niti o n of  D O R f or p ati e nt s wit h a n 
o bj e cti v e r e s p o n s e a s a s s e s s e d b y i n v e sti g at or a n d w hi c h i s d efi n e d a s 1 d a y f or 
p ati e nt s wit h o ut a n o bj e cti v e r e s p o n s e  
•  
O bj e cti v e r e s p o n s e r at e ( O R R ) a n d D O R  a s a s s e s s e d  b y t h e I R F a c c or di n g t o  
R E CI S T  v 1. 1  
•  
P F S, O R R , a n d D O R  a s a s s e s s e d  b y t h e i n v e sti g at or i n a c c or d a n c e wit h  m o difi e d 
R E CI S T  ( Ar m s A a n d B o nl y ) 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 1
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
9/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
•  
P F S r at e s at 6 m o nt h s a n d 1 y e ar, d efi n e d a s t h e pr o p orti o n of p ati e nt s ali v e a n d 
wit h o ut pr o gr e s si o n a s a s s e s s e d b y t h e i n v e sti g at or  a c c or di n g t o  R E CI S T v 1. 1 at 
6 m o nt h s a n d 1 y e ar aft er r a n d o mi z ati o n , esti m at e d u si n g K M m et h o d ol o g y  
•  
O S r at e at 3 y e ar s, d efi n e d a s t h e pr o p orti o n of p ati e nt s ali v e at 3 y e ar s aft er 
r a n d o mi z ati o n, e sti m at e d u si n g K M m et h o d ol o g y 
•  
C h a n g e fr o m b a s eli n e i n p ati e nt -r e p ort e d o ut c o m e s ( P R O s) of h e alt h -r el at e d q u alit y 
of lif e  ( H R Q o L), l u n g c a n c er−r el at e d s y m pt o m s, a n d h e alt h st at u s a s a s s e s s e d b y 
t h e E O R T C Q L Q-C 3 0 a n d E O R T C Q L Q -L C 1 3  
•  
Utilit y s c or e s of t h e E ur o Q o L 5 Di m e n si o n s 3 -L e v el V er si o n ( E Q- 5 D -3 L ) 
•  
St at u s of P D -L 1 −, i m m u n e-, a n d N S C L C-r el at e d a n d ot h er e x pl or at or y bi o m ar k er s 
i n ar c hi v al a n d/ or fr e s hl y o bt ai n e d t u m or ti s s u e s a n d bl o o d ( or bl o o d d eri v ati v e s) 
c oll e ct e d b ef or e, d uri n g, or aft er tr e at m e nt wit h at e z oli z u m a b or at pr o gr e s si o n a n d 
a s s o ci ati o n wit h di s e a s e st at u s a n d/ or r e s p o n s e t o at e z oli z u m a b i n c o m bi n ati o n 
wit h  c h e m ot h er a p y 
•  
St at u s of I C s a n d ot h er e x pl or at or y bi o m ar k er s i n m a n d at or y bi o p s y s p e ci m e n s a n d 
bl o o d c oll e ct e d at pr o gr e s si o n  
 
2. 2. 4  
P h ar m a c o ki n eti c O ut c o m e M e a s ur e s  
T h e P K o ut c o m e m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g : 
•  
M a xi m u m o b s er v e d s er u m at e z oli z u m a b c o n c e ntr ati o n ( Cm a x ) aft er i nf u si o n ( Ar m s A 
a n d B)  
•  
Mi ni m u m o b s er v e d s er u m at e z oli z u m a b  c o n c e ntr ati o n ( C mi n ) pri or t o i nf u si o n at 
s el e ct e d c y cl e s, at tr e at m e nt di s c o nti n u ati o n, a n d at 1 2 0 d a y s ( ±  3 0 d a y s) aft er t h e 
l a st d o s e of at e z oli z u m a b ( Ar m s A a n d B) 
•  
Pl a s m a c o n c e ntr ati o n s f or c ar b o pl ati n ( Ar m s A , B, a n d C) 
•  
Pl a s m a c o n c e ntr ati o n s f or p a clit a x el ( Ar m s A , B, a n d C) 
•  
B e v a ci z u m a b C m a x  a n d C mi n  ( Ar m s B a n d C ) 
 
2. 2. 5  
S af et y O ut c o m e M e a s ur e s  
T h e s af et y o ut c o m e m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g : 
•  
I n ci d e n c e, n at ur e, a n d s e v eri t y of a d v er s e e v e nt s gr a d e d i n a c c or d a n c e wit h t h e 
N ati o n al C a n c er I n stit ut e C o m m o n T er mi n ol o g y Crit eri a i n A d v er s e E v e nt s 
V er si o n 4. 0 ( N CI  C T C A E v 4. 0)  
•  
C h a n g e s i n vit al si g n s  a n d cli ni c al l a b or at or y t e st r e s ult s d uri n g a n d f oll o wi n g 
at e z oli z u m a b a d mi ni str ati o n  
•  
I n ci d e n c e of a nti -dr u g a nti b o d y ( A D A), al s o k n o w n a s a nt i-t h er a p e uti c a nti b o d y 
( A T A), r e s p o n s e t o at e z oli z um a b a n d b e v a ci z u m a b a n d p ot e nti al c orr el ati o n of 
at e z oli z u m a b A D A wit h P K, p h ar m a c o d y n a mi c s , s af et y, a n d effi c a c y p ar a m et er s  
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 2
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 0 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
2. 3  
D E T E R MI N A TI O N O F S A M P L E S I Z E 
T hi s st u d y will r a n d o mi z e a p pr o xi m at el y 1 2 0 0 p ati e nt s , i n cl u di n g a p pr o xi m at el y 
6 0 0  p ati e nt s i n t h e t G E bi o m ar k e r−s el e ct e d p o p ul ati o n .  P ati e nt s wit h s e n siti zi n g E G F R  
m ut ati o n s or A L K  tr a n sl o c ati o n s will b e  e x cl u d e d fr o m t h e pri m ar y a n al y si s p o p ul ati o n s.  
T h er e ar e  e x p e ct e d t o b e a p pr o xi m at el y 1 0 8 0 p ati e nt s i n t h e I T T −W T  p o p ul ati o n gi v e n 
t h e a p pr o xi m at el y 1 0 % pr e v al e n c e f or t h e s e g e n eti c v ari ati o n s.  T h e bi o m ar k er -s el e ct e d  
t G E−W T p o p ul ati o n will t h er ef or e i n cl u d e a p pr o xi m at ely 5 4 0 p ati e nt s a s s u mi n g 5 0 % 
pr e v al e n c e wit h t h e c h o s e n c ut off v al u e f or e x pr e s si o n.  
T o c o ntr ol t h e o v er all t y p e I err or  r at e f or tr e at m e nt c o m p ari s o n s i n t h e pri m ar y 
e n d p oi nt s at a o n e -si d e d t e st at 0. 0 2 5, a o n e -si d e d α  of  0. 0 0 6 a n d a o n e -si d e d α  of 
0. 0 1 9 will b e fir st  all o c at e d t o P F S a n d O S, r e s p e cti v el y, f or t h e c o m p ari s o n of 
at e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b ( Ar m B) a g ai n st t h e c o ntr ol ar m of 
c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b ( Ar m C).  T h e pri m ar y c o m p ari s o n of P F S will b e 
t e st e d at a o n e-si d e d α  l e v el of 0. 0 0 3 i n t h e t G E−W T a n d I T T −W T p o p ul ati o n s i n p ar all el.  
T h e pri m ar y c o m p ari s o n of O S will b e t e st e d i n t h e I T T −W T p o p ul ati o n at t h e all o c at e d α  
t o g et h er wit h t h e α  r e c y cl e d fr o m t h e P F S a n al y si s if t h e P F S c o m p ari s o n i s st ati sti c all y 
si g nifi c a nt.  
If O S i n t h e I T T−W T  p o p ul ati o n i s st ati sti c all y si g nifi c a nt b et w e e n t h e c o m p ari s o n of 
Ar m B v er s u s Ar m C, P F S i n  t h e t G E−W T  a n d I T T −W T  p o p ul ati o n s a n d O S i n t h e 
I T T−W T  p o p ul ati o n f or t h e pri m ar y c o m p ari s o n of at e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x e l 
( Ar m A) a g ai n st t h e c o ntr ol ar m (Ar m C ) will b e t e st e d wit h t h e s a m e l e v el of  α  s plit wit h 
t h e r ati o of 3: 3: 1 9 b et w e e n t h e s e t hr e e t e st s.  D e p e n di n g o n t h e o ut c o m e s of t h e P F S 
t e sti n g of Ar m A v er s u s Ar m C i n t h e t G E −W T a n d I T T −W T p o p ul ati o n s , t h e α  fr o m 
t h es e t w o P F S c o m p ari s o n s  will b e r e c y cl e d b a c k t o t h e O S c o m p ari s o n i n t h e I T T−W T 
p o p ul ati o n f or  Ar m A v er s u s  Ar m C.  
T h e P F S a n d O S a n al y si s a n d α  all o c ati o n ( B ur m a n et al. 2 0 0 9 ), i n cl u di n g p o s si bl e 
α  re c y cli n g, ar e s h o w n i n  Fi g ur e 2 .  If O S i n t h e I T T−W T p o p ul ati o n i s s t ati sti call y 
si g nifi c a nt b et w e e n t h e c o m p ari s o n of Ar m A v er s u s Ar m C, t h e r e m ai ni n g α  will b e 
f urt h er all o c at e d t o t h e c o m p ari s o n of s e c o n d ar y effi c a c y e n d p oi nt s w h er e P F S a n d O S 
ar e t e st e d i n t h e t G E a n d/ or I T T p o p ul ati o n s.  S e e S e cti o n  4. 4. 2. 3  f or d et ails. 




Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 4
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 2 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
T h e e sti m at e s of t h e n u m b er of e v e nt s r e q uir e d t o d e m o n str at e effi c a c y wit h r e g ar d t o 
P F S i n t h e c o m p ari s o n  f or Ar m B v er s u s  Ar m C  ar e b a s e d  o n t h e f oll o wi n g a s s u m pti o n s:  
•  
O n e -si d e d si g nifi c a n c e l e v el of 0. 0 0 3 f or t h e pri m ar y c o m p ari s o n i n t h e t G E−W T  
p o p ul ati o n  
•  
O n e -si d e d si g nifi c a n c e l e v el of 0. 0 0 3 f or t h e pri m ar y c o m p ari s o n i n t h e I T T−W T  
p o p ul ati o n  
•  
9 8 % p o w er t o d et e ct a h a z ar d r ati o  (H R ) of 0. 5 5, c orr e s p o n di n g t o a n i m pr o v e m e nt 
i n m e di a n P F S fr o m 6 m o nt h s t o 1 0. 9 m o nt h s i n t h e t G E−W T  p o p ul ati o n  
•   
9 8% p o w er t o d et e ct a n H R of 0. 6 5, c orr e s p o n di n g t o a n i m pr o v e m e nt i n m e di a n 
P F S fr o m 6 m o nt h s t o 9. 2 m o nt h s i n t h e I T T −W T  p o p ul ati o n  
•  
N o i nt eri m a n al y si s  f or P F S 
•  
Dr o p o ut r at e of 5 % p er 1 2 m o nt h s  
 
T h e e sti m at e s of t h e n u m b er of e v e nt s r e q uir e d wit h r e g ar d t o O S i n t h e pri m ar y 
c o m p ari s o n f or Ar m B v er s u s  Ar m C ar e b a s e d  o n t h e f oll o wi n g a s s u m pti o n s:  
•  
O n e -si d e d si g nifi c a n c e l e v el of 0. 0 1 9  f or t h e pri m ar y c o m p ari s o n i n t h e I T T −W T  
p o p ul ati o n  
•  
8 7 % p o w er t o d et e ct a n H R of 0. 7 5, c orr e s p o n di n g t o a n i m pr o v e m e nt i n m e di a n 
O S fr o m 1 2 m o nt h s t o 1 6 m o nt h s i n t h e I T T −W T  p o p ul ati o n  
•  
O n e O S i nt eri m a n al y si s p erf or m e d  at t h e ti m e of t h e P F S fi n al a n al y si s ; it i s 
e sti m at e d t h a t a p pr o xi m at el y 7 3% of t h e t ot al O S e v e nt s r e q uir e d f or t h e fi n al 
a n al y si s h a v e o c c urr e d u si n g t h e L a n -D e M et s a p pr o xi m ati o n t o t h e O’ Bri e n -Fl e mi n g 
b o u n d ar y  
•  
Dr o p o ut r at e of 5 % p er 2 4 m o nt h s  
 
T h e e sti m at e of t h e n u m b er of e v e nt s r e q uir e d t o d e m o n str at e effi c a c y wit h r e g ar d t o 
P F S a n d O S i n t h e c o m p ari s o n of Ar m A v er s u s Ar m C i s b a s e d o n a s s u m pti o n s si mil ar 
t o t h o s e o utli n e d a b o v e f or Ar m B v er s u s Ar m C. 
Wit h t h e s e a s s u m pti o n s, a p pr o xi m at el y 1 2 0 0 p ati e nt s i n t ot al will b e r a n d o mi z e d i nt o t hi s 
st u d y .  T h e I T T−W T p o p ul ati o n will i n cl u d e a p pr o xi m at el y 1 0 8 0 p ati e nt s, wit h 
a p pr o xi m at el y 7 2 0 p ati e nt s i n  e a c h pri m ar y c o m p ari s o n (i. e.,  Ar m A v s. Ar m C, Ar m B v s.  
Ar m C).  T h e t G E −W T p o p ul ati o n will i n cl u d e a p pr o xi m at el y 5 4 0 p ati e nt s, wit h 
a p pr o xi m at el y 3 6 0 p ati e nt s i n e a c h pri m ar y c o m p ari s o n (i. e.,  Ar m A v s. Ar m C, Ar m B v s. 
Ar m C).  
2. 4   
AN A L Y SI S TI MI N G  
2. 4. 1  
Pri m ar y A n al y si s Ti mi n g  f or P F S 
N o i nt eri m a n al y s e s ar e pl a n n e d f or t h e c o -pri m ar y e n d p oi nt of P F S i n t hi s st u d y.  T h e 
P F S fi n al a n al y si s f or t h e pri m ar y c o m p ari s o n  of Ar m B v er s u s  Ar m C will b e c o n d u ct e d 
w h e n t h er e ar e a p pr o xi m at el y 5 1 6 P F S e v e nt s i n t h e I T T −W T  p o p ul ati o n  i n t h e 
c o m bi n e d Ar m B a n d Ar m C  or  w h e n t h e l a st p ati e nt i s r a n d o mi z e d, w hi c h e v er o c c ur s 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 5
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 3 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
l a st.  At t h e ti m e of t h e fi n al P F S a n al y si s, it i s e x p e ct e d t h at a p pr o xi m at el y 2 4 9 e v e nt s 
w o ul d  h a v e o c c urr e d i n t h e t G E −W T p o p ul ati o n.  T h e s e n u m b er s of e v e nt s c orr e s p o n d  
t o a mi ni m u m d et e ct a bl e diff er e n c e ( M D D) i n H R of a p pr o xi m at el y 0. 7 0 i n t h e t G E−W T  
p o p ul ati o n a n d of a p pr o xi m at el y 0. 7 8 i n t h e I T T−W T  p o p ul ati o n.  It i s pr oj e ct e d t h at a n 
o b s er v e d H R of 0. 7 0  or l o w er will r e s ult i n a st ati sti c all y si g nifi c a nt diff er e n c e b et w e e n 
tr e at m e nt ar m s i n t h e t G E−W T  p o p ul ati o n at t hi s a n al y si s.  T h e P F S fi n al a n al y si s  i s 
e x p e ct e d t o o c c ur a p pr o xi m at el y 2 9 m o nt h s aft er t h e fir st p ati e nt i s r a n d o mi z e d, b a s e d 
o n t h e st u d y a s s u m pti o n s a n d t h e pr oj e ct e d a c cr u al r at e  ( s e e T a bl e  1). 
T a bl e  1 
Fi n al A n al y si s f or Pr o gr e s si o n-Fr e e S ur vi v al  f or Ar m B v er s u s 
Ar m C C o m p ari s o n  
P o p ul ati o n  
A n al y si s Ti mi n g 
( M o nt h s fr o m F PI) 
N o. of E v e nt s 
( E v e nt R ati o, %) 
M D D i n H a z ar d  R ati o  
P o w er , % 
t G E−W T  
2 9  
2 4 9  ( 6 9) 
0. 7 0  
9 8  
I T T−W T  
2 9  
5 1 6  ( 7 2) 
0. 7 8  
9 8  
F PI  =  fir st p ati e nt i n; I T T =  i nt e nt-t o-tr e at; M D D =  mi ni m u m d et e ct a bl e diff er e n c e; 
P F S  =  pr o gr e s si o n -fr e e s ur vi v al; t G E =  t u m or g e n e e x pr e s si o n; W T =  wil d t y p e.  
 
T h e P F S a n al y si s b et w e e n Ar m  A a n d Ar m C will b e p erf or m e d at t h e s a m e ti m e a s t h e 
Ar m B a n d Ar m C c o m p ari s o n.  H o w e v er, t h e st ati sti c al si g nifi c a n c e will b e cl ai m e d i n 
a c c or d a n c e wit h  t h e t e sti n g str at e g y i n Fi g ur e 2  d e p e n di n g  o n t h e α  r e c y cl e d t o t h e 
c o m p ari s o n of Ar m A v er s u s Ar m C.  
2. 4. 2  
I nt eri m a n d Fi n al A n al y si s Ti mi n g  f or O S 
T h er e i s o n e i nt eri m a n al y si s pl a n n e d f or t h e c o -pri m ar y e n d p oi nt of O S.  
T h e O S i nt eri m a nal y si s f or t h e pri m ar y c o m p ari s o n  of  Ar m B v er s u s  Ar m C will b e 
c o n d u ct e d b y t h e S p o n s or at t h e ti m e of t h e fi n al P F S a n al y si s f or t h e pri m ar y 
c o m p ari s o n s.   It i s e x p e ct e d t h at t h er e will b e a p pr o xi m at el y 3 7 0 O S e v e nt s i n t h e 
I T T-W T  p o p ul ati o n i n  t h e c o m bi n e d Ar m B a n d Ar m C at t hi s ti m e p oi nt, i n w hi c h c a s e  a n 
i nt eri m O S a n al y si s will b e c o n d u ct e d wit h t h e st o p pi n g b o u n d ari e s f or t h e O S 
i nt eri m a n d fi n al a n al y s e s c o m p ut e d u si n g t h e L a n -D e M et s a p pr o xi m ati o n t o t h e 
O’ Bri e n- Fl e mi n g b o u n d ar y.   If t h er e ar e si g nifi c a ntl y f e w er t h a n 3 7 0 O S e v e nt s at t h e 
P F S fi n al a n al y si s, a n o mi n al α  of 0. 0 1 % ( n e gli gi bl e i m p a ct o n o v er all t y p e I err or r at e) 
c o ul d  b e s p e nt o n t h e O S a n al y si s at t h e ti m e of t h e P F S fi n al a n al y si s.  T h e n e xt i nt eri m 
will b e c o n d u ct e d aft er a p pr o xi m at el y 3 7 0 O S e v e nt s ar e o b s er v e d , wit h t h e st o p pi n g 
b o u n d ari e s f or t h e O S i nt eri m a n d fi n al a n al y s e s c al c ul at e d t h e s a m e w a y a s a b o v e.  
T h e fi n al O S a n al y si s f or e a c h of t h e pri m ar y c o m p ari s o n  of  Ar m B v er s u s  Ar m C will b e 
c o n d u ct e d w h e n t h er e ar e a p pr o xi m at el y  5 0 7 O S e v e nt s i n t h e I T T −W T  p o p ul ati o n  i n t h e 
c o m bi n e d Ar m B a n d Ar m C.  T hi s n u m b er of e v e nt s c orr e s p o n d s t o a n M D D i n H R of 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 6
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 4 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
a p pr o xi m at el y 0. 8 3 i n t h e I T T −W T p o p ul ati o n.  T h e O S fi n al a n al y si s i s e x p e ct e d t o 
o c c ur a p pr o xi m at el y 4 0 m o nt h s aft er t h e fir st p ati e nt i s r a n d o mi z e d.  
T h e e x p e ct e d a n al y si s ti mi n g f or O S i nt eri m a n d fi n al a n al y s e s f or t h e c o m p ari s o n of 
Ar m B v er s u s Ar m C i s s h o w n i n T a bl e 2 . 
T a bl e 2 
A n al y si s f or O v er all S ur vi v al  f or t h e C o m p ari s o n of Ar m B v er s u s 
Ar m C  
T y p e of A n al y si s  
A n al y si s Ti mi n g  
I T T−W T P o p ul ati o n  
M o nt h s fr o m 
F PI  
P er c e nt a g e  
I nf or m atio n , % 
N o. of E v e nt s 
( E v e nt R ati o, %) 
P o w er , % a  
O S i nt eri m a n al y si s  
2 9  
7 3  
3 7 0 (5 1 ) 
6 0  
O S fi n al a n al y si s  
4 0  
1 0 0  
5 0 7 (7 0 ) 
8 7  
F PI  =  fir st p ati e nt i n; I T T =  i nt e nt-t o-tr e at; O S
 =  o v er all s ur vi v al; W T  =  wil d t y p e.  
a  P o w er i s c al c ul at e d u si n g o n e -si d e d α  of 0. 0 1 9.  
 
T h e st o p pi n g b o u n d ari e s  f or t h e i nt erim a n d fi n al O S a n al y s e s will b e c al c ul at e d u si n g 
t h e L a n-D e M et s a p pr o xi m ati o n t o t h e O’ Bri e n -Fl e mi n g b o u n d ar y.  T h e st o p pi n g 
b o u n d ari e s f or t h e c o m p ari s o n of Ar m B v er s u s  Ar m C i n t h e I T T −W T p o p ul ati o n, 
a s s u mi n g t h e s p e cifi e d o b s er v e d n u m b er of e v e nt s ( 3 7 0 a n d 5 0 7 , r e s p e cti v el y), ar e 
s h o w n i n  T a bl e 3 .  T h e p-v al u e will b e u s e d t o cl ai m cr o s si n g of t h e b o u n d ari e s.  F or 
e x a m pl e, if 3 7 0 e v e nt s h a v e o c c ur r e d at t h e ti m e of t h e O S i nt eri m a n al y si s i n t h e 
I T T−W T p o p ul ati o n f or Ar m B a n d Ar m C c o m bi n e d, st ati sti c al si g nifi c a n c e of t h e O S 
e n d p oi nt i n t h e I T T−W T p o p ul ati o n will b e d e cl ar e d f or Ar m B if p ≤ 0. 0 0 7 3 w h e n P F S 
h a s cl ai m e d si g nifi c a n c e i n eit h er  t h e t G E−W T or  t h e I T T−W T p o p ul ati o n.  
T a bl e 3 
A n al y si s Ti mi n g a n d St o p pi n g B o u n d ar y f or O v er all S ur vi v al  
i n t h e I nt ent -t o-Tr e at Wil d -T y p e  P o p ul ati o n  f or t h e C o m p ari s o n 
of  Ar m B v er s u s  Ar m C  
A n al y si s  
St o p pi n g B o u n d ar y i n H R ( p -v al u e)  
If α  =  0. 0 1 9  
If α  =  0. 0 2 2  
If α  =  0. 0 2 5 
O S i nt eri m a n al y si s  
H R
 ≤ 0. 7 7 0  
( p-v al u e  ≤ 0. 0 0 6 4) 
H R
 ≤ 0. 7 7 6  
( p-v al u e  ≤ 0. 0 0 7 3)  
H R
 ≤ 0. 7 8 1  
p- v al u e  ≤ 0. 0 0 8 7)  
O S fi n al a n al y si s  
H R
 ≤ 0. 8 2 9  
( p-v al u e  ≤ 0. 0 1 7 2)  
H R
 ≤ 0. 8 3 3  
( p-v al u e  ≤ 0. 0 1 9 8)  
H R
 ≤ 0. 8 3 7  
( p-v al u e  ≤ 0. 0 2 2 4)  
H R
 =  h a z ar d r ati o;  O S
 =  o v er all s ur vi v a l. 
N ot e:  α  a n d p -v al u e ar e o n e -si d e d.  
 
T h e O S a n al y si s b et w e e n Ar m  A a n d Ar m C will b e p erf or m e d at t h e s a m e ti m e a s t h e 
Ar m B v er s u s Ar m C c o m p ari s o n.  H o w e v er, t h e st ati sti c al si g nifi c a n c e will b e cl ai m e d i n 
a c c or d a n c e wit h t h e t e sti n g str at e g y i n Fi g ur e 2  d e p e n di n g o n t h e α  r ec y cl e d t o t h e 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 7
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 5 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
c o m p ari s o n of Ar m  A v er s u s Ar m C.  If t h e diff er e n c e i n O S b et w e e n Ar m B a n d Ar m C 
i n t h e I T T−W T p o p ul ati o n i s st ati sti c all y si g nifi c a nt at a n α  of 0. 0 1 9, 0. 0 2 2, or 0. 0 2 5, t h at 
s a m e α  will b e c o m e t h e o v er all o n e -si d e d t y p e I err or r at e f or t h e c o m p ari s o n of Ar m A 
v er s u s Ar m C, a s d e s cri b e d i n  S e cti o n  2. 3 .  T h e st o p pi n g b o u n d ari e s f or t h e i nt eri m a n d 
fi n al O S a n al y s e s f or t h e co m p ari s o n of Ar m A v er s u s Ar m C i n t h e I T T −W T p o p ul ati o n, 
a s s u mi n g t h e s p e cifi e d o b s er v e d n u m b er of e v e nt s ( 3 7 0 a n d 5 0 7, r e s p e cti v el y), ar e 
pr o vi d e d f or t h e t hr e e s c e n ari o s (α  =   0. 0 1 9, 0. 0 2 2, or 0. 0 2 5) i n  T a bl e 4 . 
T a bl e 4 
A n al y si s  Ti mi n g a n d St o p pi n g B o u n d ar y f or O v er all S ur vi v al  i n 
t h e I nt e nt-t o-Tr e at Wil d -T y p e  P o p ul ati o n  f or t h e C o m p ari s o n of 
Ar m A  v er s u s  Ar m C  
A.  O S  Is T e st e d St ati sti c all y Si g nifi c a nt at α  =  0. 0 1 9 i n t h e I T T−W T P o p ul ati o n f or t h e  
Ar m B v er s u s  Ar m C C o m p ari s o n  
A n al y si s  Ti mi n g  
St o p pi n g B o u n d ar y i n H R ( p -v al u e)  
If α  =  0. 0 1 4 4 4  
If α  =  0. 0 1 6 7 2  
If α  =  0. 0 1 9  
O S i nt eri m a n al y si s  
H R
 ≤ 0. 7 6 0  
( p-v al u e  ≤ 0. 0 0 4 2)  
H R
 ≤ 0. 7 6 6  
( p-v al u e  ≤ 0. 0 0 5 1)  
H R
 ≤ 0. 7 7 0  
( p-v al u e  ≤ 0. 0 0 6 4) 
O S fi n al a n al y si s  
H R
 ≤ 0. 8 2 1  
( p-v al u e  ≤ 0. 0 1 3 2)  
H R
 ≤ 0. 8 2 5  
( p-v al u e  ≤ 0 . 0 1 5 2) 
H R
 ≤ 0. 8 2 9  
( p-v al u e  ≤ 0. 0 1 7 2)  
 
B.  O S  Is T e st e d St ati sti c all y Si g nifi c a nt at  α  =  0. 0 2 2  i n t h e I T T−W T P o p ul ati o n f or  t h e 
Ar m B v er s u s  Ar m C C o m p ari s o n  
A n al y si s  Ti mi n g  
St o p pi n g B o u n d ar y i n H R ( p -v al u e)  
If α  =  0. 0 1 6 7 2  
If α  =  0. 0 1 9 3 6  
If α  =  0. 0 2 2  
O S  i nt eri m a n al y si s 
H R
 ≤ 0. 7 6 6  
( p-v al u e  ≤ 0. 0 0 5 1)  
H R
 ≤ 0. 7 7 1  
( p-v al u e  ≤ 0. 0 0 6 2)  
H R
 ≤ 0. 7 7 6  
( p-v al u e  ≤ 0. 0 0 7 3)  
O S fi n al a n al y si s  
H R
 ≤ 0. 8 2 5  
( p-v al u e  ≤ 0. 0 1 5 2)  
H R
 ≤ 0. 8 2 9  
( p-v al u e  ≤ 0 . 01 7 5)  
H R
 ≤ 0. 8 3 3  
( p-v al u e  ≤ 0. 0 1 9 8)  
 
C.  O S  Is T e st e d St ati sti c al l y Si g nifi c a nt at α  =  0. 0 2 5 i n t h e I T T−W T P o p ul ati o n f or th e 
Ar m B v er s u s Ar m C C o m p ari s o n  
A n al y si s  Ti mi n g  
St o p pi n g B o u n d ar y i n H R ( p -v al u e)  
If α  =  0. 0 1 9  
If α  =  0. 0 2 2  
If α  =  0. 0 2 5  
O S i nt eri m a n al y si s  
H R
 ≤ 0. 7 7 0  
( p-v al u e  ≤ 0. 0 0 6 4) 
H R
 ≤ 0. 7 7 6  
( p-v al u e  ≤ 0. 0 0 7 3)  
H R
 ≤ 0. 7 8 1  
( p-v al u e  ≤ 0. 0 0 8 7)  
O S fi n al a n al y si s  
H R
 ≤ 0. 8 2 9  
( p-v al u e  ≤ 0. 0 1 7 2)  
H R
 ≤ 0. 8 3 3  
( p-v al u e  ≤ 0. 0 1 9 8)  
H R
 ≤ 0. 8 3 7  
( p-v al u e  ≤ 0. 0 2 2 4)  
I T T =  i nt e nt t o tr e at; H R
 =  h a z ar d r at i o; O S
 =  o v er all s ur vi v al ; W T =  wil d t y p e . 
N ot e:  α  a n d p -v al u e ar e o n e -si d e d.  
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 8
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 6 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
3.  
S T U D Y C O N D U C T  
3. 1  
R A N D O MI Z A TI O N I S S U E S  
R a n d o mi z ati o n t o t h e tr e at m e nt a n d c o ntr ol ar m s will o c c ur i n a 1: 1: 1 r ati o u si n g a 
p er m ut e d -bl o c k r a n d o mi z ati o n m et h o d.  R a n d o mi z ati o n will b e str atifi e d b y t h e f oll o wi n g 
f a ct or s: 
•  
S e x ( m al e v s. f e m al e)  
•  
Pr e s e n c e of li v er m et a st a s e s at b a s eli n e ( y e s v s. n o)  
•  
P D-L 1 e x pr e s si o n b y I H C ( T C 3 a n d a n y I C v s. T C 0/ 1/ 2 a n d I C 2/ 3 v s. T C 0/ 1/ 2 
a n d I C 0/ 1)  
 
3. 2  
I N D E P E N D E N T R E VI E W F A CI LI T Y 
A n I R F will b e u s e d t o c o n d u ct  a bli n d e d r a di ol o g y r e vi e w of t h e i m a gi n g d at a a n d will 
pr o vi d e a n i n d e p e n d e nt a s s e s s m e nt of  t u m or r e s p o n s e a n d pr o gr e s si o n f or all p ati e nt s  
a c c or di n g t o  a s e p ar at e I R F c h art er .  I R F-a s s e s s e d e n d p oi nt s will b e u s e d f or s e c o n d ar y 
a n d e x pl or at or y a n al y s e s . 
3. 3  
D A T A M O NI T O RI N G  
A n e xt er n al i D M C will b e u s e d t o e v al u at e s af et y d uri n g t h e st u d y o n a p eri o di c b a si s, 
a p pr o xi m at el y e v er y 6 m o nt h s fr o m t h e p oi nt of fir st p ati e nt i n  until t h e ti m e t h e d at a b a s e 
i s l o c k e d a n d t h e st u d y i s u n bli n d e d f or t h e pri m ar y P F S a n al y si s a n d i nt eri m O S 
a n al y si s.  I n a d diti o n, t h e i D M C will r e vi e w s af et y d at a o n c e 1 2 p ati e nt s  h a v e b e e n 
e nr oll e d i nt o e a c h tr e at m e nt ar m a n d h a v e r e c ei v e d tr e at m e nt f or t w o c y cl e s.  All 
s u m m ari e s a n d a n al y s e s b y tr e at m e nt ar m f or t h e i D M C r e vi e w will b e pr e p ar e d b y a n 
i n d e p e n d e nt d at a c o or di n ati n g c e nt er.  F oll o wi n g t h e d at a r e vi e w, t h e i D M C will pr o vi d e 
a r e c o m m e n d ati o n a s t o w h et h er t h e st u d y m a y c o nti n u e, w h et h er a m e n d m e nt s  t o t h e 
pr ot o c ol s h o ul d b e i m pl e m e nt e d, or w h et h er t h e st u d y s h o ul d b e st o p p e d.  T h e fi n al 
d e ci si o n will r e st wit h t h e S p o n s or.  
M e m b er s of t h e i D M C will b e e xt er n al t o t h e S p o n s or a n d will f oll o w a s e p ar at e i D M C 
c h art er t h at o utli n e s t h eir r ol e s a n d r e s p o n si biliti e s, a s w ell  a s a d et ail e d m o nit ori n g pl a n.  
4.  
S T A TI S TI C A L M E T H O D S  
T h e a n al y s e s d e s cri b e d i n t hi s S A P will s u p er s e d e t h o s e s p e cifi e d i n Pr ot o c ol  G O 2 9 4 3 6  
f or t h e p ur p o s e s of a r e g ul at ory fili n g.  
4. 1  
A N A L Y SI S P O P U L A TI O N S  
4. 1. 1  
Effi c a c y A n al y s i s P o p ul ati o n s 
T h e r a n d o mi z e d p o p ul ati o n or I T T p o p ul ati o n i s d efi n e d a s all r a n d o mi z e d p ati e nt s, 
r e g ar dl e s s of r e c ei pt of t h e a s si g n e d tr e at m e nt. 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 7 9
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 7 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
T h e I T T -W T  p o p ul ati o n i s d efi n e d a s t h e I T T p o p ul ati o n e x cl u di n g p ati e nt s wit h a 
s e n siti zi n g E G F R  m ut ati o n or A L K  tr a n sl o c ati o n. 
T h e t G E bi o m ar k er -s el e ct e d  p o p ul ati o n i s d efi n e d a s I T T p ati e nt s wit h a si g n at ur e s c or e 
gr e at er  t h a n or e q u al t o −1. 9 1 i n b a s eli n e t u m or ti s s u e s.  T h e si g n at ur e s c or e c a pt ur e s 
th e g e n e e x pr e s si o n of P D- L 1( C D 2 7 4) , C X C L 9 , a n d I F N-γ, r el ati v e t o a h o u s e k e e pi n g 
g e n e, u si n g R N A i s ol at e d fr o m p ati e nt s’ f or m ali n -fi x e d p ar affi n -e m b e d d e d  t u m or ti s s u e 
a n d i s m e a s ur e d o n a R o c h e M ol e c ul ar S y st e m c o b a s 4 8 0 0 pl atf or m.  
T h e t G E−W T  p o p ul ati o n i s  d efi n e d a s t h e t G E p o p ul ati o n e x cl u di n g p ati e nt s  wit h a 
s e n siti zi n g E G F R  m ut ati o n or A L K  tr a n sl o c ati o n. 
T h e P D -L 1 −s el e ct e d  T C 2/ 3 or I C 2/ 3 p o p ul ati o n i s d efi n e d a s I T T p ati e nt s wit h  P D-L 1 
T C 2/ 3 or I C 2/ 3  e x pr e s si o n i n b a s eli n e t u m or ti s s u e .  Si mil arl y t h e P D- L 1 −s el e ct e d  
T C 1/ 2/ 3 or I C 1/ 2/ 3 p o p ul ati o n i s  d efi n e d a s I T T p ati e nt s wit h P D- L 1 T C 1/ 2/ 3 or I C 1/ 2/ 3 
e x pr e s si o n i n b a s eli n e t u m or ti s s u e . 
T h e P D -L 1 −s el e ct e d  W T  p o p ul ati o n s ar e d efi n e d a s t h e P D -L 1 −s el e ct e d  p o p ul ati o n s  
( T C 2/3 or I C 2 / 3 p o p ul ati o n or T C 1 / 2/3 or I C 1 / 2/ 3 p o p ul ati o n ) e x cl u di n g p ati e nt s wit h a 
s e n siti zi n g E G F R  m ut ati o n or A L K  tr a n sl o c ati o n. 
T h e pri m ar y a n al y s e s of P F S will b e p erf or m e d o n t h e I T T −W T  po p ul ati o n a n d t h e 
t G E-W T  p o p ul ati o n s , a n d t h e pri m ar y a n al y s e s of O S will b e p erf or m e d o n t h e I T T −W T  
p o p ul ati o n.  P ati e nt s ar e gr o u p e d a c c or di n g t o t h e tr e at m e nt a s si g n e d at r a n d o mi z ati o n, 
r e g ar dl e s s of w h et h er t h e y r e c ei v e d a n y a s si g n e d st u d y dr u g. 
O R R  will b e a n al y z e d f or p ati e nt s  i n t h e t G E−W T a n d I T T −W T p o p ul ati o n s w h o h a v e 
m e a s ur a bl e di s e a s e a s a s s e s s e d b y i n v e sti g at or at b a s eli n e.  D O R will b e a s s e s s e d i n 
p ati e nt s i n t h e t G E−W T a n d I T T −W T p o p ul ati o n s w h o h a v e a n o bj e cti v e r e s p o n s e  a n d 
m e a s ur a bl e di s e a s e a s a s s e s s e d b y i n v e sti g at or at b a s eli n e .  T T D a n al y s e s will b e 
c o n d u ct e d o n t h e t G E−W T a n d I T T -W T p o p ul ati o n s .  C h a n g e fr o m b a s eli n e a n al y si s in 
P R O s will b e p erf or m e d f or  p ati e nt s i n t h e t G E-W T a n d I T T −W T p o p ul ati o n s w h o h a v e 
b ot h a n o n -mi s si n g b a s eli n e a s s e s s m e nt a n d at l e a st o n e n o n -mi s si n g p o st -b a s eli n e 
a s s e s s m e nt.  
4. 1. 2  
P h ar m a c o ki n eti c -E v al u a bl e P o p u l ati o n 
T h e p h ar m a c o ki n eti c -e v al u a bl e p o p ul ati o n i s d efi n e d a s  all p ati e nt s w h o r e c ei v e d a n y 
d o s e of at e z oli z u m a b, b e v a ci z u m a b, c ar b o pl ati n, or p a clit a x el  a n d w h o h a v e e v al u a bl e 
P K s a m pl e s p o st -d o s e . 
4. 1. 3  
S af et y P o p ul ati o n  
T h e s af et y p o p ul ati o n i n cl u d e s tr e at e d p ati e nt s, d efi n e d a s r a n d o mi z e d p ati e nt s w h o 
r e c ei v e d a n y pr ot o c ol tr e at m e nt.  F or t h e s af et y a n al y s e s, p ati e nt s will b e gr o u p e d 
a c c or di n g t o  w h et h er a n y a m o u nt  of at e z oli z u m a b  w a s r e c ei v e d, i n cl u di n g w h e n 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 0
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 8 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
at e z oli z u m a b w a s r e c ei v e d i n err or.  S p e cifi c all y f or p ati e nt s r a n d o mi z e d t o Ar m C, if 
at e z oli z u m a b  w a s r e c ei v e d i n err or i n a d diti o n t o Ar m C tr e at m e nt, t h e p ati e nt s will b e 
gr o u p e d wit h  Ar m B f or t h e s af et y a n al y s e s. 
4. 2  
A N A L Y SI S O F S T U D Y C O N D U C T  
St u d y e nr oll m e nt, m aj or pr ot o c ol d e vi ati o n s i n cl u di n g m aj or d e vi ati o n s of i n cl u si o n  or 
e x cl u si o n crit eri a, a n d r e a s o n s f or st u d y t er mi n ati o n will b e s u m m ari z e d o v er all a n d b y 
tr e at m e nt ar m f or t h e bi o m ar k er-s el e ct e d  t G E, t h e t G E−W T, t h e I T T, a n d t h e I T T −W T 
p o p ul ati o n s .   St u d y tr e at m e nt a d mi ni str ati o n a n d r e a s o n s f or di s c o nti n u ati o n fr o m st u d y 
tr e at m e nt will b e s u m m ari z e d f or t h e s af et y p o p ul ati o n.  
4. 3  
A N A L Y SI S O F T R E A T M E N T G R O U P C O M P A R A BI LI T Y  
D e m o gr a p hi c c h ar a ct eri sti c s, s u c h a s a g e, r a c e/ et h ni cit y, b a s eli n e di s e a s e 
c h ar a ct eri sti c s ( e. g., E a st er n C o o p er ati v e O n c ol o g y Gr o u p [ E C O G] p erf or m a n c e st at u s), 
a n d str atifi c ati o n f a ct or s ( s e x, pr e s e n c e of li v e r m et a st a si s at b a s eli n e, P D- L 1 t u m or 
e x pr e s si o n b y I H C ) will b e s u m m ari z e d b y tr e at m e nt ar m s f or t h e bi o m ar k er−s el e ct e d  
t G E−W T a n d t h e I T T −W T  p o p ul ati o n s.  D e s cri pti v e st ati s ti c s ( m e a n, m e di a n, S D , a n d 
r a n g e) will b e pr e s e nt e d f or c o nti n u o u s d at a, a n d fr e q u e n ci e s a n d p er c e nt a g e s will b e 
pr e s e nt e d f or c at e g ori c al d at a.  
U nl e s s ot h er wi s e st at e d, b a s eli n e v al u e s ar e t h e l a st a v ail a bl e d at a o bt ai n e d pri or t o t h e 
p ati e nt r e c ei vi n g t h e fir st d o s e of a n y c o m p o n e nt of st u d y tr e at m e nt o n C y cl e 1, D a y 1.  
F or E C O G  p erf or m a n c e st at u s, t h e b a s eli n e i s d efi n e d a s t h e v al u e at s cr e e ni n g.  
4. 4  
E F FI C A C Y A N A L Y SI S  
P ati e nt s will b e gr o u p e d f or effi c a c y a n al y s e s i n a c c or d a n c e wit h t h e tr e at m e nt a s si g n e d 
at r a n d o mi z ati o n, w h et h er or n ot t h e a s si g n e d tr e at m e nt w a s r e c ei v e d.  
4. 4. 1  
Pri m ar y Effi c a c y E n d p oi nt  
T h e c o -pri m ar y effi c a c y e n d p oi nt s ar e  P F S a n d O S . 
P F S i s  d efi n e d a s  t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st d o c u m e nt e d di s e a s e 
pr o gr e s si o n a s d et er mi n e d b y t h e i n v e sti g at or wit h t h e u s e of R E CI S T v 1. 1 or d e at h 
fr o m a n y c a u s e, w hi c h e v er o c c ur s fir st.  D at a f or p ati e nt s w h o ar e ali v e a n d w h o h a v e 
n ot e x p eri e n c e d di s e a s e pr o gr e s si o n at t h e ti m e of a n al y si s will b e c e n s or e d at t h e d at e 
of t h e l a st t u m or a s s e s s m e nt.   D at a f or p ati e nt s wit h n o p o st -b a s eli n e t u m or a s s e s s m e nt 
will b e c e n s or e d at t h e d at e of r a n d o mi z ati o n  pl u s 1 d a y . 
O S i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o d e at h fr o m a n y c a u s e.  D at a f or p ati e nt s 
w h o ar e n ot r e p ort e d a s h a vi n g di e d at t h e ti m e of  a n al y si s will b e c e n s or e d at t h e d at e 
l a st k n o w n t o b e ali v e.  D at a f or p ati e nt s w h o d o n ot h a v e p o st-b a s eli n e i nf or m ati o n will 
b e c e n s or e d at t h e d at e of r a n d o mi z ati o n  pl u s 1 d a y . 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 1
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
1 9 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
T h e n ull a n d alt er n ati v e h y p ot h e s e s r e g ar di n g P F S  a n d O S  i n e a c h p o p ul ati o n (t G E−W T , 
I T T−W T ) c an b e p hr a s e d i n t er m s of t h e  s ur vi v al f u n cti o n s S A (t) or  S B (t) f or t h e 
at e z oli z u m a b  ar m s ( Ar m  A or Ar m B, r e s p e cti v el y) a n d S C (t) f or t h e c o ntr ol ar m ( Ar m C) : 
H 0 :  SA (t) =  S C (t) v er s u s H1 : SA (t) >  S C (t) 
or H 0 :  SB (t) =  S C (t) v er s u s H1 : SB (t) >  S C (t) 
 
T h e H R s, λ A /λ C  a n d  λ B /λ C  (w h er e λ A , λ B , a n d λ C  r e pr e s e nt t h e h a z ar d of h a vi n g a P F S or 
d e at h i n Ar m A, Ar m B , a n d Ar m C, r e s p e cti v el y ), c o m p ari n g t h e tr e at m e nt eff e ct 
b et w e e n t h e t w o tr e at m e nt ar m s , will b e e sti m at e d u si n g a str atifi e d C o x  r e gr e s si o n 
m o d el wit h t h e s a m e str atifi c ati o n v ari a bl e s u s e d f or t h e str atifi e d l o g -r a n k t e st, a n d t h e 
9 5 % CI will b e pr o vi d e d.  
F or P F S a n al y si s i n t h e t G E −W T p o p ul ati o n, t h e  str atifi c ati o n f a ct or s will b e s e x ( m al e v s. 
f e m al e) a n d  pr e s e n c e of li v er m et a st a s e s at b a s eli n e ( y e s v s. n o) .  F or P F S a n d O S 
a n al y s e s i n t h e I T T −W T p o p ul ati o n, t h e str atifi c ati o n f a ct or s will b e s e x ( m al e v s. f e m al e) , 
pr e s e n c e of li v er m et a st a s e s at b a s eli n e ( y e s v s. n o), a n d P D -L 1 t u m or e x pr e s si o n b y 
I H C ([T C 3 a n d a n y I C, T C 0/ 1/ 2 a n d I C 2/ 3 c o m bi n e d] v s. T C 0/ 1/ 2 a n d I C 0/ 1 ).  Th e 
str atifi c ati o n f a ct or s  will b e t h o s e u s e d d uri n g r a n d o mi z ati o n  a s r e c or d e d i n t h e 
i nt er a cti v e v oi c e a n d W e b r e s p o n s e s y s t e m p er t h e r e q u e st of t h e U. S. F o o d a n d Dr u g 
A d mi ni str ati o n.  T h e a n al y s e s b a s e d o n str atifi c ati o n f a ct or s a s r e c or d e d o n t h e  
el e ctr o ni c C a s e R e p ort F or m  m a y  al s o b e pr o vi d e d.   R e s ult s fr o m a n u n str atifi e d 
a n al y si s will al s o b e pr o vi d e d.  
Tr e at m e nt c o m p ari s o n s will b e c o n d u ct e d b y fir st c o m p ari n g Ar m B v er s u s  Ar m C a n d 
t h e n c o m p ari n g Ar m A v er s u s Ar m C b a s e d o n a str atifi e d l o g -r a n k t e st i n t h e 
bi o m ar k er -s el e ct e d t G E −W T a n d I T T −W T p o p ul ati o n s f or t h e P F S e n d p oi nt a n d i n t h e 
I T T−W T p o p ul ati o n f or t h e O S e n d p oi nt.  F or e a c h c o m p ari s o n, a n al y s e s will b e 
c o n d u ct e d a c c or di n g t o a n a n al y si s hi er ar c h y a n d a n α -s p e n di n g al g orit h m t o c o ntr ol f or 
t h e t y p e I err or r at e ( s e e Fi g ur e 2  i n S e cti o n 2. 3) a n d t o a c c o u nt f or a n i nt eri m a n al y si s 
( s e e S e cti o n 2. 4. 2). 
T o c o ntr ol  t he o v er all t y p e I err or r at e f or t h e o n e -si d e d t e st at 0. 0 2 5, t h e h y p ot h e si s 
t e sti n g f or t h e c o m p ari s o n of Ar m B v er s u s Ar m C will b e d o n e at t h e s p e cifi e d 
si g nifi c a n c e l e v el s i n t h e or d er d e s cri b e d b el o w: 
1.  
P F S i n t h e t G E−W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 3 ( o n e si d e d).  If t h e 
e sti m at e of t h e H R i s <  1 a n d t h e o n e -si d e d p -v al u e c orr e s p o n di n g t o t h e str atifi e d 
l o g-r a n k t e st i s <  0. 0 0 3, t h e n ull h y p ot h e si s will b e r ej e ct e d, a n d it will b e c o n cl u d e d 
t h at at e z oli z u m a b +  c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b pr ol o n g s t h e d ur ati o n of 
P F S r el ati v e t o t h e c o ntr ol ar m i n t h e t G E −W T p o p ul ati o n.  
2.  
P F S i n t h e I T T −W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 3 ( o n e si d e d).  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 2
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
2 0 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
3.  
α  r e c y cli n g fr o m P F S t o O S will b e c o n d u ct e d a s f ollo w s:  
If t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er t h e t G E−W T p o p ul ati o n or 
t h e I T T−W T p o p ul ati o n, O S i n t h e I T T −W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 9 
( o n e si d e d). 
If t h e P F S r e s ult i s o nl y st ati sti c all y si g nifi c a nt i n t h e t G E−W T p o p ul ati o n or t h e 
I T T−W T p o p ul ati o n, O S i n t h e I T T −W T p o p ul ati o n will b e t e st e d at α  =  0. 0 2 2 
( o n e si d e d).  
If t h e P F S r e s ult i s st ati sti c all y si g nifi c a nt i n b ot h t h e t G E−W T p o p ul ati o n a n d t h e 
I T T−W T p o p ul ati o n, O S i n t h e I T T −W T p o p ul ati o n will b e t e st e d at α  =  0. 0 2 5 
( o n e si d e d).  
 
If t h e diff er e n c e i n O S b et w e e n Ar m B a n d Ar m C i n t h e I T T−W T  p o p ul ati o n i s 
st ati sti c all y si g nifi c a nt, t h e c o m p ari s o n of Ar m  A v er s u s Ar m C will b e st ati sti c all y t e st e d 
at t h e s a m e si g nifi c a n c e l e v el, wit h α  all o c at e d t o P F S i n t h e t G E −W T  p o p ul ati o n, t o P F S 
i n t h e I T T−W T  p o p ul ati o n, a n d t o O S i n t h e I T T -W T  p o p ul ati o n at t h e s a m e 3: 3: 1 9 r ati o 
( s e e Fi g ur e 2  i n S e cti o n 2. 3 ).  D e p e n di n g o n t h e o ut c o m e of t h e P F S t e sti n g of Ar m A 
v er s u s Ar m C i n t h e t G E −W T a n d I T T −W T p o p ul ati o n s, t h e α  fr o m t h e s e t w o P F S 
c o m p ari s o n s will b e r e c y cl e d b a c k t o t h e O S c o m p ari s o n i n t h e I T T −W T p o p ul ati o n f or 
Ar m A v er s u s Ar m C.  T h e si g nifi c a n c e l e v el s at w hi c h t h e P F S a n d O S will b e t e st e d f or 
t h e c o m p ari s o n of Ar m A v er s u s Ar m C ar e s h o w n i n T a bl e  5 f or all s c e n ari o s 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 3
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d 
2 1/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6 
 
 
T a bl e 5 
Si g nifi c a n c e L e v el f or C o m p ari s o n of Ar m A v er s u s Ar m C 
Ar m B v er s u s Ar m C 
Ar m A v er s u s Ar m C 
α  l e v el at w hi c h t h e O S i s t e st e d 
st ati sti c all y si g nifi c a nt i n t h e 
I T T−W T p o p ul ati o n 
α  l e v el at w hi c h t h e P F S will b e 
t e st e d i n t h e t G E- W T a n d 
I T T- W T p o p ul ati o n s 
α  l e v el at w hi c h t h e O S will b e t e st e d i n t h e I T T- W T p o p ul ati o n 
0. 0 1 9 
0. 0 0 2 2 8 
0. 0 1 4 4 4, if t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er 
P F S p o p ul ati o n 
0. 0 1 6 7 2, if t h e P F S r e s ult i s st ati sti c all y si g nifi c a nt i n o nl y o n e of 
t h e P F S p o p ul ati o n s 
0. 0 1 9, if t h e P F S r e s ult s ar e st ati sti c all y si g nifi c a nt i n b ot h P F S 
p o p ul ati o n s 
0. 0 2 2 
0. 0 0 2 6 4 
0. 0 1 6 7 2, if t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er 
P F S p o p ul ati o n 
0. 0 1 9 3 6, if t h e P F S r e s ult i s st at i sti c all y si g nifi c a nt i n o n e of t h e 
P F S p o p ul ati o n s 
0. 0 2 2, if t h e P F S r e s ult s ar e st ati sti c all y si g nifi c a nt i n b ot h P F S 
p o p ul ati o n s 
0. 0 2 5 
0. 0 0 3 
0. 0 1 9, if t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er P F S 
p o p ul ati o n 
0. 0 2 2, if t h e P F S r e s ult i s st ati sti c all y si g nifi c a nt i n o n e of t h e P F S 
p o p ul ati o n s 
0. 0 2 5, if t h e P F S r e s ult s ar e st ati sti c all y si g nifi c a nt i n b ot h P F S 
p o p ul ati o n s 
I T T =  i nt e nt t o tr e at; O S =  o v er all s ur vi v al; P F S  =  pr o gr e s si o n-fr e e s ur vi v al; W T  =  wil d t y p e. 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 4
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d 
2 2/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6 
K M m et h o d ol o g y will b e u s e d t o e sti m at e m e di a n P F S a n d O S a n d t o c o n str u ct s ur vi v al 
c ur v e s f or e a c h tr e at m e nt ar m f or a vi s u al d e s cri pti o n of t h e diff er e n c e a m o n g ar m s.  
T h e Br o o k m e y er- Cr o wl e y m et h o d ol o g y will b e u s e d t o c o n str u ct t h e 9 5 % CI f or t h e 
m e di a n P F S a n d O S ( Br o o k m e y er a n d Cr o wl e y 1 9 8 2 ). 
F oll o w- u p f or O S, d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o  d e at h or l a st k n o w n d at e 
ali v e, will b e s u m m ari z e d f or all p ati e nt s i n cl u d e d i n t h e a n al y si s ( w h et h er p ati e nt i s ali v e 
or h a s di e d).  F oll o w- u p will b e s u m m ari z e d u si n g t h e K M m et h o d wit h d at a f or p ati e nt s 
w h o di e d c e n s or e d at t h e d at e of d e at h. 
4. 4. 2  
S e c o n d ar y Effi c a c y E n d p oi nt s 
4. 4. 2. 1  
O S i n t h e t G E −Wil d- T y p e P o p ul ati o n 
O S i n t G E −W T p o p ul ati o n will b e a n al y z e d u si n g si mil ar m et h o d s a s d e s cri b e d 
i n S e cti o n 4. 4. 1. 
4. 4. 2. 2  
P F S a n d O S i n P D- L 1 −S el e ct e d Wil d- T y p e P o p ul ati o n s 
P F S a n d O S i n P D- L 1- s el e ct e d T C 2/ 3 or I C 2/ 3 W T a n d T C 1/ 2/ 3 or I C 1/ 2/ 3 W T 
p o p ul ati o n s will b e a n al y z e d u si n g si mil ar m et h o d s a s d e s cri b e d i n S e cti o n 4. 4. 1 . 
4. 4. 2. 3  
P F S a n d O S i n t h e t G E a n d I T T P o p ul ati o n s 
P F S a n d O S i n t h e t G E a n d I T T p o p ul ati o n s will b e a n al y z e d u si n g t h e s a m e m et h o d s 
a s d e s cri b e d i n S e cti o n  4. 4. 1. 
If t h e diff er en c e i n O S b et w e e n Ar m A a n d Ar m C i n t h e I T T −W T p o p ul ati o n i s 
st ati sti c all y si g nifi c a nt, a c o m p ari s o n of Ar m B v er s u s Ar m C a n d a c o m p ari s o n of Ar m A 
v er s u s Ar m C will b e c o n d u ct e d i n t h e t G E p o p ul ati o n a n d t h e I T T p o p ul ati o n, wit h a 
c o m p ari s o n of Ar m B v er s u s Ar m C pri oriti z e d si mil arl y a s s h o w n i n  Fi g ur e 2.  T h e 
α  all o c ati o n will f oll o w t h e s a m e α - s p e n di n g al g orit h m a n d all o c ati o n r ati o ( 3: 3: 1 9) 
d e s cri b e d f or a n al y si s of t h e c o- pri m ar y effi c a c y e n d p oi nt s a s d e s cri b e d i n S e cti o n  2. 3. 
4. 4. 2. 4  
O bj e cti v e R e s p o n s e R at e 
O R R ( c o nfir m ati o n n ot r e q uir e d) i s d efi n e d a s t h e pr o p orti o n of p ati e nt s wit h a n o bj e cti v e 
r e s p o n s e, eit h er C R or P R, wit h t h e u s e of R E CI S T v 1. 1, a s d et er mi n e d b y t h e 
i n v e sti g at or.  P ati e nt s n ot m e eti n g t hi s crit eri a, i n cl u di n g t h o s e wit h o ut a n y p o st- b a s eli n e 
a s s e s s m e nt, will b e c o n si d er e d n o n-r e s p o n d er s.  C o nfir m ati o n of r e s p o n s e a c c or di n g t o 
R E CI S T v 1. 1 i s n ot r e q uir e d, b ut f or t h e e x pl or at or y p ur p o s e s, O R R wit h c o nfir m ati o n 
m a y b e r e p ort e d.  T h e a n al y si s p o p ul ati o n f or O R R will b e t h e t G E −W T a n d I T T −W T 
p o p ul ati o n s wit h m e a s ur a bl e di s e a s e at b a s eli n e, i. e., p ati e nt s wit h at l e a st o n e 
m e a s ur e a bl e l e si o n i n a c c or d a n c e wit h R E CI S T v 1. 1 b a s e d o n i n v e sti g at or a s s e s s m e nt.  
O R R will b e c o m p ar e d b et w e e n tr e at m e nt ar m s u si n g t h e str atifi e d C o c hr a n- M a nt el-
H a e n s z el t e st.  T h e 9 5 % CI f or t h e diff er e n c e i n O R R s b et w e e n t h e t w o tr e at m e nt ar m s 
will b e c o m p ut e d u si n g t h e n or m al a p pr o xi m ati o n t o t h e bi n o mi al di stri b uti o n.  A n 
e sti m at e of O R R a n d it s 9 5 % CI will b e c al c ul at e d f or e a c h tr e at m e nt ar m u si n g t h e 
Cl o p p er- P e ar s o n m et h o d. 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 5
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
2 3 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
4. 4. 2. 5  
D ur ati o n of R e s p o n s e  
D O R  i s d efi n e d f or p ati e nt s wit h a n o bj e cti v e r e s p o n s e a s t h e ti m e fr o m t h e fir st 
d o c u m e nt e d o bj e cti v e r e s p o n s e t o d o c u m e nt e d d i s e a s e pr o gr e s si o n a s d et er mi n e d b y 
t h e i n v e sti g at or a c c or di n g t o  R E CI S T v 1. 1  or d e at h fr o m a n y c a u s e, w hi c h e v er o c c ur s 
fir st.  D at a f or p ati e nt s w h o ar e ali v e a n d w h o h a v e n ot e x p eri e n c e d di s e a s e pr o gr e s si o n 
at t h e ti m e of a n al y si s will b e c e n s or e d at t h e d at e of t h e l a st t u m or a s s e s s m e nt.  If n o 
t u m or a s s e s s m e nt s w er e p erf or m e d aft er t h e d at e of t h e fir st o c c urr e n c e of t h e o bj e cti v e 
r e s p o n s e ( C R or P R), D O R will b e c e n s or e d at t h e d at e of t h e fir st o c c urr e n c e of t h e 
o bj e cti v e r e s p o n s e.  B e c a u s e t h e d et er mi n ati o n of D O R i s b a s e d o n a n o n -r a n d o mi z e d 
s u b s et of p ati e nt s, f or m al h y p ot h e si s t e sti n g will n ot b e p erf or m e d.  D O R will b e 
e sti m at e d u si n g K M m et h o d ol o g y.  C o m p ari s o n s b et w e e n tr e at m e nt ar m s will b e m a d e 
u si n g t h e str atifi e d a n d u n str at ifi e d l o g-r a n k t e st f or d e s cri pti v e p ur p o s e s o nl y. 
C o nfir m ati o n of r e s p o n s e a c c or di n g t o R E CI S T v 1. 1 will n ot b e r e q uir e d, b ut f or 
e x pl or at or y p ur p o s e s, D O R f or p ati e nt s wit h c o nfir m e d r e s p o n s e m a y b e r e p ort e d.  
4. 4. 2. 6  
P F S a s A s s e s s e d b y I n d e p e n d e nt R e vi e w F a cility 
P F S a s a s s e s s e d b y t h e I R F i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st 
d o c u m e nt e d di s e a s e pr o gr e s si o n a s d et er mi n e d b y t h e I R F u si n g t h e R E CI S T v 1. 1 or 
d e at h fr o m a n y c a u s e, w hi c h e v er o c c ur s fir st.  
P F S a s a s s e s s e d b y  t h e I R F will b e a n al y z e d u si n g t h e s a m e m et h o d s t h at will b e u s e d 
f or P F S a s a s s e s s e d b y t h e i n v e sti g at or. 
4. 4. 2. 7  
O S R at e at t h e 1- a n d 2 -Y e ar  L a n d m ar k Ti m e P oi nt s  
T h e  O S r at e at t h e 1- a n d 2 -y e ar  l a n d m ar k ti m e p oi nt s aft er r a n d o mi z ati o n wit hi n t h e 
t G E−W T  a n d I T T −W T  p o p ul ati o n s will b e e sti m at e d f or e a c h tr e at m e nt ar m u si n g K M 
m et h o d ol o g y, al o n g wit h 9 5 % CI c al c ul at e d wit h t h e st a n d ar d err or d eri v e d fr o m  t h e 
Gr e e n w o o d  f or m ul a.  T h e 9 5 % CI f or t h e diff er e n c e i n O S r at e s b et w e e n t h e t w o 
tr e at m e nt ar m s will b e e sti m at e d u si n g t h e n or m al a p pr o xi m ati o n m et h o d, wit h st a n d ar d 
err or s c o m p ut e d u si n g t h e Gr e e n w o o d m et h o d.  
4. 4. 2. 8  
I n v e sti g at or- As s e s s e d P F S a n d O S C o m p ari s o n b et w e e n 
At e z o li z u m a b- Co nt ai ni n g A r m s 
T h e c o m p ari s o n b et w e e n t h e at e z oli z u m a b-c o nt ai ni n g ar m s, i. e., Ar m A a n d Ar m B, will 
al s o b e m a d e u si n g i n v e sti g at or -a s s e s s e d P F S p er R E CI S T v 1. 1 a n d O S e n d p oi nt s.  
4. 4. 2. 9  
P ati e nt -R e p ort e d O ut c o m e s  
T hr o u g h t h e u s e of t h e SI L C a n d t h e E O R T C Q L Q -C 3 0 a n d E O R T C  Q L Q -L C 1 3, l u n g 
c a n c er s y m pt o m  d at a will b e c oll e ct e d a b o ut s y m pt o m s c o m m o nl y a s s o ci at e d wit h 
c a n c er tr e at m e nt s, a n d di s e a s e a n d tr e at m e nt  i m p a ct o n p ati e nt s’ f u n cti o ni n g. 
T h e E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q -L C 1 3 will b e s c or e d a c c or di n g t o t h e E O R T C 
s c ori n g m a n u al ( F a y er s et al. 2 0 0 1 ).  T h e Q L Q-C 3 0 a n d Q L Q -L C 1 3  c o n si st  of b ot h 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 6
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
2 4 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
m ulti -it e m s c al e s a n d si n gl e-it e m m e a s ur e s s u c h a s f u n cti o n al s c al e s, s y m pt o m s c al e s, 
a n d a gl o b al h e alt h st at u s/ q u alit y -of -lif e s c al e. 
F or m ulti -it e m s u b s c al e s, if ≤ 5 0 % of it e m s wit hi n t h e m ulti -it e m s u b s c al e ar e mi s si n g at 
a gi v e n ti m e p oi nt, t h e m ulti -it e m s c or e will b e c al c ul at e d o n t h e b a si s of t h e n o n-mi s si n g 
it e m s.  If >  5 0 % of it e m s ar e mi s si n g or if a si n gl e -it e m m e a s ur e i s mi s si n g, t h e s u b s c al e 
i s mi s si n g. 
All of t h e E O R T C s c al e s a n d si n gl e -it e m m e a s ur e s will b e li n e arl y tr a n sf or m e d s o t h at 
e a c h s c or e h a s  a r a n g e of  0−1 0 0.  A hi g h s c or e f or a f u n cti o n al s c al e r e pr e s e nt s a hi g h  
or h e alt h y l e v el of f u n cti o ni n g, a n d a hi g h s c or e f or t h e gl o b al h e alt h st at u s  a n d H R Q o L 
r e pr e s e nt s a hi g h H R Q o L; h o w e v er, a hi g h s c or e f or a s y m pt o m s c al e or it e m r e pr e s e nt s 
a hi g h l e v el of s y m pt o m at ol o g y or pr o bl e m s.  
Ti m e t o D et eri or ati o n  i n P ati e nt-R e p ort e d O ut c o m e s  
T T D wit h u s e of t h e E O R T C i s d efi n e d a s t h e ti m e fr o m b a s eli n e t o t h e fir st c o nfir m e d 
cli ni c all y m e a ni n gf ul d et eri or ati o n i n t h e E O R T C s y m pt o m s c or e.  C o nfir m e d cli ni c all y 
m e a ni n gf ul d et eri or ati o n i n l u n g c a n c er s y m pt o m s i s d efi n e d a s a ≥ 1 0 -p oi nt i n cr e a s e 
a b o v e b a s eli n e i n a s y m pt o m s c or e t h at m u st b e h el d f or at l e a st t w o c o n s e c uti v e 
a s s e s s m e nt s or a n i niti al ≥ 1 0 -p oi nt i n cr e a s e a b o v e b a s eli n e f oll o w e d b y d e at h wit hi n 
3 w e e k s fr o m t h e l a st a s s e s s m e nt.  A ≥ 1 0 -p oi nt c h a n g e i n t h e E O R T C s c al e s c or e i s 
p er c ei v e d b y p ati e nt s a s cli ni c all y si g nifi c a nt ( O s o b a et al. 1 9 9 8 ). 
T T D  will b e d o c u m e nt e d f or e a c h of th e f ol l o wi n g E O R T C-b a s e d s y m pt o m s c or e s:  
•  
C o u g h ( Q u e sti o n 3 1 o n t h e E O R T C Q L Q -L C 1 3)  
•  
D y s p n e a si n gl e it e m ( Q u e sti o n 8 o n t h e Q L Q -C 3 0)  
•  
D y s p n e a m ulti -it e m s u b s c al e ( Q ue st i o n s 3 3 -3 5 o n t h e Q L Q -L C 1 3)  
•  
C h e st p ai n  ( Q u e sti o n 4 0 o n t h e Q L Q-L C 1 3)  
•   
Ar m a n d/ or s h o ul d er p ai n ( Q u e sti o n 4 1 o n t h e Q L Q -L C 1 3)  
 
T T D a n al y s e s will b e p erf or m e d f or t h e I T T −W T p o p ul ati o n a n d will i n cl u d e all d at a 
c oll e ct e d t hr o u g h di s e a s e pr o gr e s si o n a n d s ur vi v al f oll o w -u p.  T T D a n al y s e s m a y b e 
p erf or m e d f or t h e t G E −W T p o p ul ati o n w h e n a P F S b e n efit h a s b e e n d e m o n str at e d f or 
t hi s bi o m ar k er-s el e ct e d p o p ul ati o n.  T h e m et h o d ol o gi e s t h at ar e o utli n e d f or t h e a n al y si s 
of O S will b e u s e d f or t h e a n al y s e s of T T D f or pr e s p e cifi e d s y m pt o m s of t h e E O R T C 
Q L Q -C 3 0 a n d E O R T C Q L Q -L C 1 3 m e a s ur e s.  T T D of t h e pr e s p e cifi e d s y m pt o m s will b e 
s u m m ari z e d u si n g t h e K M m et h o d.   C o m p ari s o n of T T D u si n g t h e E O R T C Q L Q -C 3 0 
a n d E O R T C Q L Q -L C 1 3 m e a s ur e s b et w e e n tr e at m e nt ar m s will b e p erf or m e d u si n g t h e 
str atifi e d l o g -r a n k t e st; t h e str atifi e d H R s a n d 9 5 % CI s will al s o b e r e p ort e d.  If n o 
b a s eli n e or p o st -b a s eli n e a s s e s s m e nt i s p erf or m e d, p ati e nt s will b e c e n s or e d at t h e 
r a n d o mi z ati o n d at e pl u s 1 d a y.  P ati e nt s wit h o ut d et eri or ati o n at t h e ti m e of a n al y si s will 
b e c e n s or e d at t h e l a st ti m e t h e y w er e k n o w n t o h a v e n ot d et eri or at e d.  T h er e will b e n o 
i m p ut ati o n f or mi s si n g b a s eli n e or p o st-b a s eli n e d at a f or t h e T T D a n al y si s.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 7
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
2 5 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
C h a n g e fr o m B a s eli n e p er SI L C S c al e  
S u m m ar y st ati sti c s ( m e a n, S D, m e di a n, 2 5t h a n d 7 5t h p er c e ntil e s, a n d r a n g e) of t h e 
c h a n g e fr o m b a s eli n e p er SI L C s c al e will b e pr o vi d e d.  T h e a n al y si s will b e p erf or m e d 
f or p ati e nt s i n t h e I T T−W T p o p ul ati o n wit h a b a s eli n e a n d a p o st -b a s eli n e P R O 
a s s e s s m e nt  a n d m a y b e p erf or m e d f or t h e t G E −W T p o p ul ati o n w h e n a P F S b e n efit h a s 
b e e n d e m o n str at e d f or t hi s bi o m ar k er -s el e ct e d p o p ul ati o n .  Gr a p h s of t h e m e a n 
c h a n g e s a n d st a n d ar d err or s o v er ti m e fr o m t h e b a s eli n e a s s e s s m e nt f or t h e t ot al s c or e 
a n d s u b s c al e s will b e pr o vi d e d f or e a c h tr e at m e nt ar m.  
T h e  a n al y si s of SI L C c h a n g e fr o m b a s eli n e will b e p erf or m e d at all o n -tr e at m e nt 
ti m e p oi nt s, a s w ell a s at t h e ti m e of di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 ( P R O 
a s s e s s m e nt c o m pl et e d wit hi n ±  7 d a y s of d at e of r a di o gr a p hi c di s e a s e pr o gr e s si o n), at 
t h e l a st d o s e of tr e at m e nt r e c ei v e d b ef or e tr e at m e nt di s c o nti n u ati o n f or a n y c a u s e, a n d 
at t h e s ur vi v al f oll o w -u p vi sit s t hr o u g h 6  m o nt h s.  
4. 4. 3  
E x pl or at or y Effi c a c y E n d p oi nt s  
4. 4. 3. 1  
Ti m e i n R e s p o n s e  
TI R i s d efi n e d a s  f or D O R f or p ati e nt s wit h a n o bj e cti v e r e s p o n s e a s d et er mi n e d b y t h e 
i n v e sti g at or u si n g R E CI S T v 1. 1 or a s 1 d a y f or  p ati e nt s wit h o ut a n o bj e cti v e r e s p o n s e.  
F or p ati e nt s wit h a n o bj e cti v e r e s p o n s e, TI R will b e a n al y z e d a s c e n s or e d or a n e v e nt 
a c c or di n g t o w h et h er t h eir D O R w a s a n al y z e d a s c e n s or e d or h a vi n g a P F S  e v e nt.   
P ati e nt s wit h o ut a n o bj e cti v e r e s p o n s e will b e a n al y z e d a s h a vi n g a n e v e nt o n t h e d a y of 
r a n d o mi z ati o n pl u s 1 d a y .  TI R will b e e sti m at e d u si n g K M m et h o d ol o g y.  TI R will b e 
c o m p ar e d b et w e e n tr e at m e nt ar m s f or  p ati e nt s  wit h m e a s ur a bl e di s e a s e at b a s eli n e 
u si n g t h e s a m e a n al y si s m et h o d s t h at will b e u s e d f or O S.  
4. 4. 3. 2  
Ti m e t o R e s p o n s e  
T T R i s d efi n e d f or p ati e nt s wit h a n o bj e cti v e r e s p o n s e a s t h e ti m e fr o m r a n d o mi z ati o n 
t o t h e fir st o c c urr e n c e of a C R or P R a s d et er mi n e d b y t h e i n v e sti g at or u si n g 
R E CI S T  v 1. 1.  T T R  will b e s u m m ari z e d f or d e s cri pti v e p ur p o s e s.  T h e m e a n, st a n d ar d 
err or, m e di a n , a n d r a n g e of T T R will b e pr o vi d e d.  N o f or m al tr e at m e nt c o m p ari s o n s will 
b e p erf or m e d.  
4. 4. 3. 3  
O R R a n d D O R a s A s s e s s e d b y t h e I R F p er R E CI S T v 1. 1  
T h e m et h o d ol o gi e s o utli n e d f or t h e s e c o n d ar y effi c a c y e n d p oi nt a n al y s e s will b e u s e d f or 
t h e a n al y s e s of O R R a n d  D O R a s a s s e s s e d b y t h e I R F  p er R E CI S T v 1. 1 . 
4. 4. 3. 4  
P F S, O R R, a n d D O R a s A s s e s s e d b y t h e I n v e sti g at or U si n g 
M o difi e d R E CI S T  
T h e e n d p oi nt s a s s e s s e d wit h  m o difi e d R E CI S T will b e li mit e d t o t h e at e z oli z u m a b -
c o nt ai ni n g  ar m s, i. e., Ar m A a n d Ar m B  o nl y, wit h n o c o m p ari s o n wit h  t h e c o ntr ol Ar m C .  
C o m p ari s o n s will b e m a d e  b et w e e n Ar m A a n d Ar m B.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 8
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d 
2 6/ St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6 
P F S b y m o difi e d R E CI S T i s d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o di s e a s e 
pr o gr e s si o n a s d et er mi n e d b y t h e i n v e sti g at or p er m o difi e d R E CI S T or d e at h fr o m a n y 
c a u s e, w hi c h e v er o c c ur s fir st.  A p ati e nt i s c o n si d er e d t o h a v e di s e a s e pr o gr e s si o n b y 
m o difi e d R E CI S T if eit h er of t h e f oll o wi n g c o n diti o n s ar e m et: 
a) 
M o difi e d R E CI S T f or pr o gr e s si o n ar e m et at a t u m or a s s e s s m e nt a n d n o 
s u b s e q u e nt t u m or a s s e s s m e nt i s p erf or m e d. 
b) 
M o difi e d R E CI S T f or pr o gr e s si o n ar e m et at a t u m or a s s e s s m e nt, a n d at t h e 
s u b s e q u e nt t u m or a s s e s s m e nt, t h e crit eri a f or c o nfir m e d pr o gr e s si o n b y m o difi e d 
R E CI S T ar e al s o m et. 
 
F or p ati e nt s w h o m e et crit eri o n a), t h e d at e of pr o gr e s si o n i s t h e d at e of t h e t u m or 
a s s e s s m e nt t h at m et t h e crit eri a f or pr o gr e s si o n p er m o difi e d R E CI S T.  F or p ati e nt s w h o 
m e et crit eri o n b), t h e d at e of pr o gr e s si o n i s t h e d at e of t h e t u m or a s s e s s m e nt at w hi c h 
t h e m o difi e d R E CI S T f or pr o gr e s si o n ar e fir st m et.  P ati e nt s w h o d o n ot m e et eit h er of 
t h e a b o v e c o n diti o n s ar e n ot c o n si d er e d t o h a v e di s e a s e pr o gr e s si o n b y m o difi e d 
R E CI S T. 
O R R b y m o difi e d R E CI S T i s d efi n e d a s t h e pr o p orti o n of p ati e nt s w h o s e b e st o v er all 
r e s p o n s e i s eit h er a P R or C R p er m o difi e d R E CI S T. 
D O R b y m o difi e d R E CI S T i s d efi n e d f or p ati e nt s w h o e x p eri e n c e d a n o bj e cti v e r e s p o n s e 
( C R or P R p er m o difi e d R E CI S T) a s a s s e s s e d b y t h e i n v e sti g at or a s t h e ti m e fr o m t h e 
fir st t u m or a s s e s s m e nt t h at s u p p ort s t h e p ati e nt’ s o bj e cti v e r e s p o n s e ( C R or P R, 
w hi c h e v er i s r e c or d e d fir st) t o di s e a s e s pr o gr e s si o n or d e at h fr o m a n y c a u s e, w hi c h e v er 
o c c ur s fir st.  D at a f or p ati e nt s w h o ar e ali v e a n d w h o h a v e n ot e x p eri e n c e d di s e a s e 
pr o gr e s si o n at t h e ti m e of a n al y si s will b e c e n s or e d at t h e l a st t u m or a s s e s s m e nt d at e. 
T h e m et h o d ol o gi e s o utli n e d f or t h e pri m ar y a n d s e c o n d ar y effi c a c y e n d p oi nt a n al y s e s 
will b e u s e d f or t h e a n al y s e s of P F S, O R R, a n d D O R a s a s s e s s e d b y t h e i n v e sti g at or 
u si n g m o difi e d R E CI S T. 
4. 4. 3. 5  
Pr o gr e s si o n- Fr e e S ur vi v al R a t e s at 6 M o nt h s a n d 1 Y e ar 
P F S r at e s at 6 m o nt h s a n d 1 y e ar will b e e sti m at e d a n d a n al y z e d u si n g t h e s a m e 
m et h o d a s d e s cri b e d i n S e cti o n 4. 4. 2. 7 . 
4. 4. 3. 6 
O v er all S ur vi v al R at e at 3 Y e ar s 
O S r at e at 3 y e ar s will b e e sti m at e d a n d a n al y z e d u si n g t h e s a m e m et h o d a s d e s cri b e d 
i n S e cti o n 4. 4. 2. 7 . 
4. 4. 3. 7  
E Q- 5 D- 3 L H e alt h St at u s D at a 
T h e E Q- 5 D- 3 L q u e sti o n n air e will al s o b e c oll e ct e d t o g e n er at e H R Q o L a n d utilit y s c or e s 
f or u s e i n e c o n o mi c m o d el s f or r ei m b ur s e m e nt. 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 8 9
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
2 7 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
H e alt h st at u s i s a s s e s s e d b y t h e E Q -5 D -3 L.  F or t h e E Q -5 D -3 L h e alt h -st at e pr ofil e s, 
d e s cri pti v e st ati sti c s t h at s u m m ari z e t h e pr o p orti o n s of p ati e nt s w h o r e p ort e d h a vi n g 
“ n o,” “ s o m e,” or “ e xtr e m e” pr o bl e m s at e a c h ti m e p oi nt will b e r e p ort e d.  Fr e q u e n ci e s a n d 
p er c e nt a g e s of mi s si n g d at a will al s o b e r e p ort e d at e a c h ti m e p oi nt.  P ati e nt s wit h o ut 
p o st -b a s eli n e a s s e s s m e nt s will b e e x cl u d e d fr o m t hi s a n al y si s.  A si n gl e s u m m ar y i n d e x 
fr o m t h e E Q-5 D -3 L h e alt h st at u s will b e u s e d  i n t hi s st u d y f or e c o n o mi c m o d eli n g.  T hi s 
a n al y si s will n ot b e i n cl u d e d i n t h e Cli ni c al St u d y R e p ort ( C S R ) f or t hi s st u d y. 
4. 4. 3. 1  
A d diti o n al P ati e nt -R e p ort e d O ut c o m e  A n al y s e s  
E O R T C s c or e  c h a n g e s fr o m b a s eli n e will b e d e s cri pti v el y a n al y z e d u si n g m e a n s, S D s, 
m e di a n s, a n d r a n g e b y tr e at m e nt ar m  f or p ati e nt s wit h a b a s eli n e a s s e s s m e nt a n d at 
l e a st o n e po st -b a s eli n e a s s e s s m e nt .  T h e a n al y s e s will b e p erf or m e d at ti m e p oi nt s 
si mil ar t o t h o s e u s e d f or t h e a n al y s e s of c h a n g e fr o m b a s eli n e p er SI L C s c al e.  
T T D m a y al s o b e d o c u m e nt e d f or a c o m p o sit e s y m pt o m e n d p oi nt ( c o u g h, d y s p n e a, 
c h e st p ai n)  wit h u s e of t h e E O R T C . 
C o m pli a n c e r at e s will b e s u m m ari z e d b y li sti n g t h e n u m b er a n d pr o p orti o n of p ati e nt s i n 
t h e P R O-e v al u a bl e s u b s et w h o c o m pl et e d t h e P R O a s s e s s m e nt s at e a c h ti m e p oi nt b y 
tr e at m e nt ar m.  R e a s o n s f or n o n-c o m pl eti o n will b e s u m m ari z e d if a v ail a bl e i n t h e C a s e 
R e p ort F or m.  
4. 4. 4  
S e n siti vit y A n al y s e s  
4. 4. 4. 1  
Mi s si n g T u m or A s s e s s m e nt  
T h e i m p a ct of mi s si n g s c h e d ul e d t u m or a s s e s s m e nt s o n P F S will b e a s s e s s e d 
d e p e n di n g o n t h e n u m b er of p ati e nt s w h o mi s s e d a s s e s s m e nt s s c h e d ul e d i m m e di at el y 
pri or t o t h e d at e of di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 or t h e d at a c ut off.  If  >  5 % of 
p ati e nt s mi s s e d t w o or m or e a s s e s s m e nt s s c h e d ul e d i m m e di at el y pri or t o t h e d at e of 
di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 or t h e d at a c ut off i n a n y tr e at m e nt ar m, t h e 
f oll o wi n g t w o s e n siti vit y a n al y s e s will b e p erf or m e d: 
•  
P ati e nt s w h o mi s s e d t w o or m or e s c h e d ul e d a s s e s s m e nt s i m m e di at el y pri or t o t h e 
d at e of di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 or t h e d at a c ut off will b e c e n s or e d at 
t h e l a st t u m or a s s e s s m e nt pri or t o t h e mi s s e d vi sit s. 
•  
P ati e nt s w h o mi s s e d t w o or m or e s c h e d ul e d a s s e s s m e nt s i m m e di at el y pri or t o t h e 
d at e of di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 or t h e d at a c ut off will b e c o u nt e d a s 
h a vi n g pr o gr e s s e d o n t h e d at e of t h e fir st of t h e s e mi s si n g a s s e s s m e nt s.  
 
St ati sti c al m et h o d ol o gi e s a n al o g o u s t o t h o s e u s e d i n t h e pri m ar y a n al y si s of P F S a s 
s p e cifi e d i n S e cti o n  4. 4. 1  will b e u s e d f or t hi s s e n siti vit y a n al y si s . 
4. 4. 4. 2  
N o n -Pr o p ort i o n al H a z ar d 
N o n −Pr ot o c ol -S p e cifi e d A nti -C a n c er T h er a p y  
T h e i m p a ct of n o n −pr ot o c ol -s p e cifi e d a nti -c a n c er t h er a p y ( N P T) o n P F S a s d et er mi n e d 
b y t h e i n v e sti g at or will b e a s s e s s e d, d e p e n di n g o n t h e n u m b er of p ati e nt s w h o r e c ei v e d 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 0
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
2 8 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
N P T  b ef or e a P F S e v e nt.  If >  5 % of p ati e nt s r e c ei v e d N P T  b ef or e a P F S e v e nt i n t h e 
c o ntr ol ar m, a s e n siti vit y a n al y si s will b e p erf or m e d f or t h e c o m p ari s o n s b et w e e n t w o 
tr e at m e nt ar m s (i. e., Ar m A v s. Ar m C, Ar m B v s. Ar m C) i n w hi c h d at a fr o m p ati e nt s 
w h o r e c ei v e N P T  b ef or e a P F S  e v e nt will b e c e n s or e d at t h e l a st t u m or a s s e s s m e nt d at e 
b ef or e r e c ei pt of N P T . 
T h e i m p a ct of s u b s e q u e nt N P T  o n O S will b e a s s e s s e d d e p e n di n g o n t h e n u m b er of 
p ati e nt s w h o r e c ei v e d N P T .  If >  1 0 % of p ati e nt s r e c ei v e d a n N P T  i n t h e c o ntr ol ar m, t h e 
f oll o wi n g a n al y s e s m a y b e p erf or m e d t o c o m p ar e tr e at m e nt ar m s: 
•  
T h e di s c o u nt m et h o d u s e s a “di s c o u nt e d ” s ur vi v al ti m e aft er s wit c hi n g f or p ati e nt s 
w h o s wit c h tr e at m e nt s b a s e d o n a u s er -s p e cifi e d a s s u m pti o n f or t h e eff e ct o n O S.  
O S will b e di s c o u nt e d i n a c c or d a n c e wit h a r a n g e of p o s si bl e eff e ct s o n O S of t h e 
s u b s e q u e nt N P T aft er tr e at m e nt s wit c hi n g o c c urr e d ( e. g. , 1 0 %, 2 0 %, 3 0 %).  
•  
R a n k -pr e s er vi n g str u ct ur al f ail ur e ti m e  pr o vi d e s a n e sti m at e of t h e O S ti m e f or t h e 
c o ntr ol gr o u p h a d N P T n ot o c c urr e d  (R o bi n s a n d T si ati s  1 9 9 1 ).  It e sti m at e s O S  
m e a s ur e d fr o m t h e ti m e of N P T b y a p pl yi n g a n e sti m at e of t h e b e n efit of t h e N P T .  
T h e t ot al o v er all s ur vi v al ti m e ( s u m of ti m e t o N P T a n d t h e e sti m at e d s ur vi v al ti m e 
aft er N P T st art e d) will t h e n b e a n al y z e d u si n g t h e s a m e m et h o d ol o g y a s f or t h e 
pri m ar y a n al y si s of O S. 
•  
T h e i n v er s e pr o b a bilit y of c e n s ori n g w ei g hti n g  m et h o d c e n s or s p ati e nt s at st art of 
N P T a n d u s e s t h e c o ntr ol ar m p ati e nt s t o cr e at e w ei g ht s t h at r e pr e s e nt h o w 
N P T -tr e at e d−li k e a n o n−N P T -tr e at e d p ati e nt i s ( R o bi n s a n d Fi n k el st ei n  2 0 0 0 ).  
T h e s e ti m e - var yi n g w ei g ht s  ar e i n cl u d e d i n t h e O S a n al y si s t o c orr e ct t h e eff e ct of 
N P T b y gi vi n g i n cr e a s e d w ei g ht t o n o n -c e n s or e d p ati e nt s wit h si mil ar c h ar a c t eri sti c s 
t o c e n s or e d p ati e nt s. 
 
D el a y e d Cli ni c al Eff e ct  
If a d el a y e d s e p ar ati o n of t h e K M c ur v e s i s o b s er v e d at t h e b e gi n ni n g of t h e c ur v e s a n d 
t h e d el a y i s ≥ 3 m o nt h s, t h e f oll o wi n g a n al y s e s c o ul d b e c o n d u ct e d t o a s s e s s a p ot e nti al 
d el a y e d cli ni c al eff e ct f or t h e tr e at m e nt gr o u p.  
Mil e st o n e O S A n al y si s  
T o a s s e s s t h e  p ot e nti al  eff e ct of l o n g -t er m s urvi v al a n d d el a y e d cli ni c al eff e ct s, a 
mil e st o n e O S a n al y si s will b e c o n d u ct e d ( C h e n 2 0 1 5 ).  T h e mil e st o n e  ti m e p oi nt s will b e 
c h o s e n s u c h t h at t h e p ati e nt s i n cl u d e d  i n t h e a n al y si s will a c hi e v e a c ert ai n p ati e nt-e v e nt 
r ati o. 
T h e mil e st o n e O S a n al y si s will b e c o n d u ct e d o nl y w h e n t h e mil e st o n e d ur ati o n h a s 
el a p s e d fr o m t h e ti m e t h e l a st p ati e nt e nt er e d t h e st u d y, u si n g t h e s a m e m et h o d s a s 
t h o s e s p e cifi e d f or t h e pri m ar y O S a n al y si s. 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 1
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
2 9 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
R e stri ct e d M e a n S ur vi v al Ti m e  
T h e r e stri ct e d m e a n s ur vi v al ti m e ( R M S T) will b e c o m p ut e d f or O S u si n g t h e a r e a u n d er 
t h e c ur v e fr o m b a s eli n e to s e v er al ti m e p oi nt s.  R M S T will b e c o m p ut e d f or e a c h 
tr e at m e nt ar m a n d t h e diff er e n c e wit h it s 9 5 % CI  will b e di s pl a y e d.  
W ei g ht e d L o g -R a n k A n al y si s  
W h er e t h e d el a y e d cli ni c al eff e ct i s >  1 0 % of t h e m e di a n s ur vi v al ti m e of t h e c o ntr ol 
gr o u p, a n a n al y si s of O S m a y  b e p erf or m e d u si n g t h e w ei g ht e d l o g -r a n k t e st 
(Fl e mi n g  a n d H arri n gt o n 1 9 9 1 ) t h at w ei g hts  m or e  h e a vil y  o n l at e e v e nt s t o a c c o u nt f or 
t h e d el a y e d cli ni c al eff e ct (Fi n e 2 0 0 7 ). 
4. 4. 4. 3  
L o s s t o F oll o w -u p  
T h e i m p a ct of l o s s t o f oll o w -u p o n O S will b e a s s e s s e d d e p e n di n g o n t h e n u m b er of 
p ati e nt s w h o ar e l o st t o f oll o w -u p.  If  >  5 % of p ati e nt s ar e l o st t o f oll o w -u p f or O S i n eit h er 
tr e at m e nt ar m, a s e n siti vit y a n al y si s will b e p erf or m e d f or t h e c o m p ari s o n s b et w e e n t w o 
tr e at m e nt ar m s (i. e., Ar m A v s. Ar m C, Ar m B v s. Ar m C) i n w hi c h p ati e nt s w h o ar e l o st 
t o f oll o w-u p will b e c o n si d er e d a s h a vi n g di e d at t h e l a st d at e t h e y w er e k n o w n t o b e 
ali v e.  
4. 4. 4. 4  
I m p a ct of I m b al a n c e b et w e e n Tr e at m e nt Ar m s  
R a n d o mi z ati o n i s n ot str atifi e d b y f a ct or s d efi ni n g t h e I T T −W T or t G E −W T  a n al y si s 
p o p ul ati o n s .  T hi s c o ul d c a u s e a p ot e nti al i m b al a n c e b et w e e n tr e at m e nt ar m s wit h 
r e s p e ct t o b a s eli n e c h ar a ct eri sti c s, i n cl u di n g pr o g n o sti c f a ct or s, a n d t h e n u m b er of 
p ati e nt s.  M ai n b a s eli n e c o v ari at e s ( e. g. , str atifi c ati o n f a ct or s) will b e s u m m ari z e d b y 
tr e at m e nt ar m i n t h e I T T−W T p o p ul ati o n a n d/ or t h e t G E−W T  p o p ul ati o n ( d e p e n di n g o n 
t h e r e s ult s of t h e pri m ar y e n d p oi nt a n al y s e s).  W h e n str o n g b a s eli n e i m b al a n c e s ar e 
o b s er v e d, t h e str atifi e d C o x r e gr e s si o n a n al y si s f or P F S a n d/ or O S e n d p oi nt s i n cl u di n g 
s u c h pr o g n o sti c f a ct or s a s c o v ari at e s i n t h e m o d el will b e p erf or m e d  t o i n v e sti g at e t h e 
p ot e nti al i m p a ct of s u c h i m b al a n c e s o n t h e tr e at m e nt eff e c t. 
4. 4. 5  
S u b gr o u p A n al y s e s  
T h e c o n si st e n c y of P F S a n d O S  r e s ult s i n s u b gr o u p s wi ll b e e x a mi n e d i n t h e p o p ul ati o n s 
w h er e P F S a n d/ or O S b e n efit h a s b e e n d e m o n str at e d.  T h e s u b gr o u p s ar e d efi n e d b y 
t h e f oll o wi n g: 
•   
De m o gr a p hi c s ( a g e, s e x, r a c e/ et h ni cit y)  
•   
Ba s eli n e di s e a s e c h ar a ct eri sti c s ( e. g., E C O G p erf or m a n c e st at u s ; pr e s e n c e of li v er 
m et a st a s e s at b a s eli n e ; s m o ki n g st at u s ; m et a st ati c sit e s s u c h a s br ai n, b o n e, et c. ; 
E G F R  m ut ati o n st at u s ; K R A S  m ut ati o n st at u s ) 
•   
P D-L 1  I H C st at u s ( e. g., T C 3 or I C 3, T C 2/ 3 or I C 2/ 3, T C 1/ 2/ 3 or I C 1/ 2/ 3, a n d t h eir 
c orr e s p o n di n g c o m pl e m e nt ar y gr o u p s ) 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 2
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
3 0 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
•  
C o m pl e m e nt ar y bi o m ar k er p o p ul ati o n d efi n e d b y  a t G E c ut off v al u e l e s s t h a n −1. 9 1  
a n d  a d diti o n al bi o m ar k er p o p ul ati o n s  a n d  c orr e s p o n di n g c o m pl e m e nt ar y bi o m ar k er 
p o p ul ati o n s  d efi n e d b y t h e  t G E c ut off v al u es of −2. 3 8 a n d −2. 9 3 
 
S u m m ari e s of P F S a n d O S, i n cl u di n g t h e u n str atifi e d H R e sti m at e d fr o m a C o x 
pr o p orti o n al h a z ar d s m o d el a n d K M e sti m at e s of m e di a n P F S a n d O S , will b e pr o d u c e d 
s e p ar at el y f or e a c h l e v el of t h e s u b gr o u p f or t h e c o m p ari s o n s b et w e e n t w o tr e at m e nt 
ar m s (i. e., Ar m A v s . Ar m C, Ar m B v s . Ar m C) a n d di s pl a y e d i n a for e st pl ot 
(L e wi s  a n d  Cl ar k e 2 0 0 1 ).  K M  pl ot s of P F S a n d/ or O S  will al s o b e pr o d u c e d f or 
s el e ct e d  s u b gr o u p s.  
S u m m ari e s of O R R b y s u b gr o u p will al s o b e pr o vi d e d.  
4. 5  
P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C A N A L Y S E S  
P K s a m pl e s will b e c oll e ct e d i n t hi s st u d y.  At e z oli z u m a b a n d b e v a ci z u m a b s er u m 
c o n c e ntr ati o n d at a ( C mi n  a n d C m a x ) will b e t a b ul at e d a n d s u m m ari z e d.  D e s cri pti v e 
st ati sti c s will i n cl u d e m e a n s, m e di a n s, r a n g e s, a n d S D s , a s a p pr o pri at e. 
Pl a s m a c o n c e ntr ati o n s of c ar b o pl ati n a n d p a clit a x el will b e c oll e ct e d i n t hi s st u d y a s 
o utli n e d i n  A p p e n di x  3 .  T h e c o n c e ntr ati o n s of c ar b o plati n a n d p a clit a x el will b e 
s u m m ari z e d u si n g d e s cr i pti v e st ati sti c s a s d e s cri b e d a b o v e. 
A d diti o n al P K a n al y s e s will b e c o n d u ct e d, a s a p pr o pri at e, b a s e d o n t h e a v ail a bilit y of 
d at a.   T h e s e a d diti o n al a n al y s e s will n ot b e i n cl u d e d i n t h e C S R f or t hi s st u d y.  
E x pl or at or y bi o m ar k er a n al y s e s will b e p erf or m e d i n a n eff ort t o u n d er st a n d t h e 
a s s o ci ati o n of t h e s e m ar k er s wit h  r e s p o n s e t o st u d y dr u g, i n cl u di n g effi c a c y a n d/ or 
s af et y .  T h e t u m or bi o m ar k er s i n cl u d e b ut ar e n ot li mit e d t o P D-L 1 a n d C D 8, a s d efi n e d 
b y I H C, q u a ntit ati v e r e v er s e tr a n s cri pt a s e −p ol y m er a s e c h ai n r e a cti o n, or ot h er m et h o d s.  
I n ad diti o n, pr e di cti v e, pr o g n o sti c , a n d p h ar m a c o d y n a mi c e x pl or at or y bi o m ar k er s i n 
ar c hi v al a n d/ or fr e s h t u m or ti s s u e a n d/ or bl o o d will b e e x a mi n e d f or t h eir a s s o ci ati o n 
wit h di s e a s e st at u s a n d/ or cli ni c al o ut c o m e s.  T h e s e e x pl or at or y a n al y s e s will n ot b e 
i n cl u d e d i n t h e C S R f or t hi s st u d y. 
4. 6  
S A F E T Y A N A L Y S E S  
T h e s af et y p o p ul ati o n i n cl u d e s tr e at e d p ati e nt s, d efi n e d a s r a n d o mi z e d p ati e nt s w h o 
r e c ei v e d a n y pr ot o c ol tr e at m e nt.  F or t h e s af et y a n al y s e s, p ati e nt s will b e gr o u p e d 
a c c or di n g t o  w h et h er a n y a m o u nt of at e z oli z u m a b w a s r e c ei v e d, i n cl u di n g w h e n 
at e z oli z u m a b w a s r e c ei v e d i n err or.  S p e cifi c all y f or p ati e nt s r a n d o mi z e d t o Ar m C, if 
at e z oli z u m a b w a s r e c ei v e d i n err or  i n a d diti o n t o Ar m C tr e at m e nt, t h e p ati e nt s will b e 
gr o u p e d wit h  Ar m B f or t h e s af et y a n al y s e s.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 3
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
3 1 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
4. 6. 1  
E x p o s ur e of St u d y M e di c ati o n  
St u d y dr u g e x p o s ur e, i n cl u di n g tr e at m e nt d ur ati o n, n u m b er of c y cl e s, a n d d o s e i nt e n sit y, 
will b e s u m m ari z e d f or  e a c h tr e at m e nt ar m wit h d e s cri pti v e st ati sti c s. 
4. 6. 2  
A d v er s e E v e nt s  
V er b ati m d e s cri pti o n of a d v er s e e v e nt s will b e m a p p e d t o M e d D R A t h e s a ur u s t er m s.  
A d v er s e e v e nt s will  b e gr a d e d b y t h e i n v esti g at or i n a c c or d a n c e wit h t h e 
N CI  C T C A E  v 4. 0.  Tr e at m e nt -e m er g e nt a d v er s e e v e nt s will b e s u m m ari z e d b y 
m a p p e d  t er m, a p pr o pri at e t h e s a ur u s l e v el, N CI C T C A E gr a d e , a n d tr e at m e nt ar m.  
M ulti pl e o c c urr e n c e s of t h e s a m e e v e nt will b e c o u nt e d o n c e at t h e m a xi m u m gr a d e.  
A d v er s e e v e nt s , c o m m o n a d v er s e e v e nt s ( d efi n e d a s a d v er s e e v e nt s t h at o c c ur i n 
≥ 1 0 % of p ati e nt s), s eri o u s a d v er s e e v e nt s, tr e at m e nt -r el at e d s eri o u s a d v er s e e v e nt s , 
s e v er e a d v er s e e v e nt s ( Gr a d e ≥ 3), a d v er s e e v e nt s of s p e ci al i nt er e st , i m m u n e-m e di at e d 
a d v er s e e v e nt s  ( d efi n e d a s a d v er s e e v e nt s  t h at r e q uire t h e u s e of s y st e mi c 
c orti c o st er oi d s wit h n o cl e ar alt er n at e eti ol o g y), a n d a d v er s e e v e nt s  t h at l e a d t o st u d y 
dr u g di s c o nti n u ati o n or i nt err u pti o n will b e s u m m ari z e d.  
“Tr e at m e nt  e m er g e nt ” i s d efi n e d f or all e v e nt s wit h o n s et o n or aft er t h e fir st st u d y dr u g 
tr e at m e nt u p t o t h e d at a c ut off d at e. 
I n a d diti o n, a d v er s e e v e nt s wit h a n o n s et o n or aft er t h e fir st st u d y dr u g tr e at m e nt a n d 
u p t o 1  d a y b ef or e t h e d at e of t h e fir st d o s e of t h e m ai nt e n a n c e t h er a p y will b e d efi n e d 
a s a d v er s e e v e nt s t h at o c c urr e d d uri n g t h e  i n d u cti o n t h er a p y p h a s e.  A d v er s e e v e nt s 
wit h a n o n s et o n or aft er t h e fir st d o s e of t h e m ai nt e n a n c e t h er a p y a n d u p t o t h e d at a 
c ut off d at e ar e d efi n e d a s a d v er s e e v e nt s t h at o c c urr e d d uri n g  t h e m ai nt e n a n c e t h er a p y  
p h a s e.  K e y a d v er s e e v e nt s t h at o c c urr e d d uri n g t h e  i n d u cti o n a n d m ai nt e n a n c e t h er a p y 
p h a s e s m a y  al s o b e s u m m ari z e d s e p ar at el y.  
L i sti n g s of a d v er s e e v e nt s  will i n cl u d e all a d v er s e e v e nt s  wit h o n s et o n or aft er t h e fir st 
st u d y dr u g tr e at m e nt u p t o t h e d at a c ut off d at e.  
D e at h s d uri n g t h e st u d y tr e at m e nt p eri o d a n d t h o s e r e p ort e d d uri n g t h e f oll o w -u p p eri o d 
aft er tr e at m e nt c o m pl eti o n  or di s c o nti n u ati o n a n d c a u s e s of d e at h will b e s u m m ari z e d b y 
tr e at m e nt ar m. 
4. 6. 3  
L a b or at or y D at a  
L a b or at or y d at a will b e s u m m ari z e d o v er ti m e i n cl u di n g c h a n g e fr o m b a s eli n e b y 
tr e at m e nt ar m.  V al u e s o ut si d e t h e n or m al r a n g e s will b e s u m m ari z e d.  I n a d diti o n, 
s el e ct e d l a b or at or y d at a will b e cl a s sifi e d i n a c c or d a n c e wit h N CI C T C A E a n d will b e 
s u m m ari z e d b y gr a d e .  Hi g h e st N CI C T C A E gr a d e p o st -b a s eli n e will al s o b e r e p ort e d , 
a n d s hift t a bl e s fr o m b a s eli n e  v al u e  t o w or st v al u e d uri n g t h e st u d y p o st-b a s eli n e will b e 
pr e s e nt e d.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 4
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
3 2 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
4. 6. 4  
Vit al Si g n s  
C h a n g e s i n s el e ct e d vit al si g n s will b e s u m m ari z e d b y tr e at m e nt ar m a n d b y c h a n g e 
o v er ti m e i n cl u di n g c h a n g e fr o m b a s eli n e . 
E C O G p erf or m a n c e st at u s will al s o b e s u m m ari z e d o v er ti m e.  
4. 6. 5  
A nt i-Dr u g  Anti b o d y  
S er u m l e v el s a n d i n ci d e n c e of A D A s a g ai n st at e z oli z u m a b a n d b e v a ci z u m a b will b e 
s u m m ari z e d.  T h e a n al y s e s of p h ar m a c o ki n eti c s, k e y effi c a c y, a n d s af et y b y 
at e z oli z u m a b A D A st at u s m a y  b e c o n d u ct e d t o e x pl or e t h e p ot e nti al i m p a ct of 
i m m u n o g e ni cit y a s a p pr o pri at e . 
4. 7  
MI S SI N G D A T A  
S e e S e cti o n  4. 4. 1  a n d S e cti o n  4. 4. 2  f or m et h o d s of h a n dli n g mi ssi n g d at a f or t h e 
pri m ar y a n d s e c o n d ar y  effi c a c y e n d p oi nt s. 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 5
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
3 3 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
5.  
R E F E R E N C E S  
Br o o k m e y er R, Cr o wl e y J. A c o nfi d e n c e i nt er v al f or t h e m e di a n s ur vi v al ti m e. Bi o m etri c s 
1 9 8 2; 3 8: 2 9 −4 1.  
B ur m a n C F, S o n e s s o n C, G uil b a u d O, et al. A r e c y cli n g fr a m e w or k f or t h e c o n str u cti o n 
of B o nf err o ni -b a s e d m ulti pl e t e st s. St at M e d 2 0 0 9; 2 8: 7 3 9 −6 1.  
C h e n T T. Mil e st o n e s ur vi v al: a p ot e nti al i nt er m e di at e e n d p oi nt f or i m m u n e c h e c k p oi nt 
i n hi bit or s. J N atl C a n c er I n st 2 0 1 5; 1 0 7: dj v 1 5 6. 
F a y er s P M, A ar o n s o n N K, Bj or d al K, et al. T h e E O R T C Q L Q -C 3 0 s c ori n g m a n u al. 3r d 
e d. Br u s s el s: E ur o p e a n Or g a ni s ati o n f or R e s e ar c h a n d Tr e at m e nt of C a n c er, 2 0 0 1.  
Fi n e G D. C o n s e q u e n c e s of d el a y e d tr e at m e nt eff e ct s o n a n al y si s of ti m e -t o-e v e nt 
e n d p oi nt s. T h er I n n o v R e g ul S ci  2 0 0 7; 4 1: 5 3 5 −9.  
Fl e mi n g T R, H arri n gt o n D P. C o u nti n g pr o c e s s e s a n d s ur vi v al a n al y si s. N e w Y or k: J o h n 
Wil e y & S o n s, 1 9 9 1.  
L e wi s S, Cl ar k e M. F or e st pl ot s: tr yi n g t o s e e t h e w o o d a n d t h e tr e e s. B M J 
2 0 0 1; 3 2 2: 1 4 7 9 −8 0.  
O s o b a D, R o dri g u e s G, M yl e s J, et al. I nt er pr eti n g t h e si g nifi c a n c e of c h a n g e s i n 
h e alt h -r el at e d q u alit y-of -lif e s c or e s. J Cli n O n c ol 1 9 9 8; 1 6: 1 3 9−4 4.  
R o bi n s J M, T si ati s A A. C orr e cti n g f or n o n -c o m pli a n c e i n r a n d o mi z e d tri al s u si n g r a n k 
pr e s er vi n g str u ct ur al f ail ur e ti m e m o d el s. C o m m u n St at  T h e or y M et h o d s 
1 9 9 1; 2 0: 2 6 0 9 −3 1.  
R o bi n s J M, Fi n k el st ei n D M. C orr e cti n g f or n o n c o m pli a n c e a n d d e p e n d e nt c e n s ori n g i n 
a n AI D S cli ni c al tri al wit h i n v er s e pr o b a bilit y of c e n s ori n g w ei g ht e d (I P C W) 
l o g-r a n k t e st s. Bi o m etri c s 2 0 0 0 ;5 6: 7 7 9 −8 8.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 6
At e z oli z u m a b — F. H off m a n n- L a  R o c h e Lt d  
3 4 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  
P R O T O C O L S Y N O P SI S  
TI T L E: 
A P H A S E III, O P E N -L A B E L, R A N D O MI Z E D S T U D Y O F 
A T E Z O LI Z U M A B ( M P D L 3 2 8 0 A,  A N TI −P D -L 1 A N TI B O D Y) I N 
C O M BI N A TI O N WI T H C A R B O P L A TI N  +  P A C LI T A X E L  WI T H O R 
WI T H O U T B E V A CI Z U M A B C O M P A R E D WI T H 
C A R B O P L A TI N  +  P A C LI T A X E L  +  B E V A CI Z U M A B I N 
C H E M O T H E R A P Y -N A I V E P A TI E N T S WI T H S T A G E  I V 
N O N -S Q U A M O U S N O N −S M A L L C E L L L U N G C A N C E R  
P R O T O C O L N U M B E R:  
G O 2 9 4 3 6  
V E R SI O N N U M B E R:  
6 
E U D R A C T N U M B E R:  
2 0 1 4 -0 0 3 2 0 7 -3 0  
I N D N U M B E R: 
1 1 7 2 9 6  
T E S T P R O D U C T:  
At e z oli z u m a b ( M P D L 3 2 8 0 A, R O 5 5 4 1 2 6 7)  
P H A S E:  
III 
I N DI C A TI O N: 
N o n -s q u a m o u s n o n −s m all c ell l u n g c a n c er  
S P O N S O R:  
F. H off m a n n -L a R o c h e Lt d  
 
O bj e cti v e s  
Effi c a c y O bj e cti v e s  
U nl e s s ot h er wi s e s p e cifi e d, effi c a c y o bj e cti v e s will b e a n al y z e d f or t h e f oll o wi n g t w o tr e at m e nt 
c o m p ari s o n s:  
•  
At e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el   +  b e v a ci z u m a b ( Ar m  B) v er s u s 
c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b ( Ar m  C)  
•  
At e z oli z u m a b  +  c ar b o pl ati n  +  p a c lit a x el ( Ar m A) v er s u s c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b 
( Ar m C)  
T h e t er m “ wil d t y p e” ( W T) r ef er s t o r a n d o mi z e d p ati e nt s w h o d o n ot h a v e a s e n siti zi n g E G F R  
m ut ati o n or A L K  tr a n sl o c ati o n. 
T h e t er m “t u m or g e n e e x pr e s si o n” (t G E) r ef er s t o r a n d o mi z e d p ati e nt s wit h a d efi n e d l e v el of 
e x pr e s si o n of a P D -L 1 a n d T -eff e ct or g e n e si g n at ur e i n t u m or ti s s u e, a s a n al y z e d t hr o u g h u s e 
of a c e ntr all y p erf or m e d R N A -b a s e d a s s a y.  
S o m e effi c a c y e n d p oi nt s will b e a n al y z e d i n a p o p ul ati o n of r a n d o mi z e d p ati e nt s wit h a d efi n e d 
l e v el of P D-L 1 e x pr e s si o n o n t u m or c ell s ( T C s) a n d i m m u n e c ell s (I C s), a s a n al y z e d t hr o u g h 
u s e of a c e ntr all y p erf or m e d I H C t e st.  
T h e c o -pri m ar y o bj e cti v e s of t hi s st u d y ar e t h e f oll o wi n g:  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y i n v e sti g at or -a s s e s s e d 
pr o gr e s si o n -fr e e s ur vi v al ( P F S) a c c or di n g t o R E CI S T v 1. 1 i n t h e t G E -W T p o p ul ati o n a n d 
t h e I T T-W T p o p ul ati o n  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y o v er all s ur vi v al ( O S) i n t h e 
I T T-W T p o p ul ati o n  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 7
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
3 5 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( co nt .) 
T h e s e c o n d ar y effi c a c y o bj e cti v e s f or t hi s st u d y ar e t h e f oll o wi n g:  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y O S i n t h e t G E -W T p o p ul ati o n  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y i n v e sti g at or -a s s e s s e d P F S 
a c c or di n g t o R E C I S T v 1. 1 a n d O S i n t h e T C 2/ 3 or I C 2/ 3 W T p o p ul ati o n a n d t h e T C 1/ 2/ 3 or 
I C 1/ 2/ 3 W T p o p ul ati o n 
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y i n v e sti g at or -a s s e s s e d P F S 
a c c or di n g t o R E CI S T v 1. 1 a n d O S i n t h e t G E p o p ul ati o n a n d t h e I T T p o p ul ati o n  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y i n v e sti g at or -a s s e s s e d o bj e cti v e 
r e s p o n s e r at e ( O R R) a c c or di n g t o R E CI S T v 1. 1 i n t h e t G E-W T p o p ul ati o n a n d t h e I T T - W T 
p o p ul ati o n  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y i n v e sti g at or -a s s e s s e d d ur ati o n of 
r e s p o n s e ( D O R) a c c or di n g t o R E CI S T v 1. 1 i n t h e t G E-W T p o p ul ati o n a n d t h e I T T -W T 
p o p ul ati o n  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y a n I n d e p e n d e nt R e vi e w F a cilit y 
(I R F)-a s s e s s e d P F S a c c or di n g t o R E CI S T v 1. 1 i n  t h e t G E-W T p o p ul a ti o n a n d t h e I T T- W T 
p o p ul ati o n  
•  
T o e v al u at e t h e O S r at e at 1 a n d 2 y e ar s i n e a c h tr e at m e nt ar m f or t h e t G E -W T p o p ul ati o n 
a n d t h e I T T -W T p o p ul ati o n  
•  
T o c o m p ar e t h e effi c a c y of t h e t w o at e z oli z u m a b -c o nt ai ni n g ar m s, Ar m A v er s u s Ar m B,   a s 
m e a s ur e d b y i n v e sti g a t or-a s s e s s e d P F S a c c or di n g t o R E CI S T v 1. 1 a n d b y O S i n t h e 
t G E-W T p o p ul ati o n a n d t h e I T T -W T p o p ul ati o n  
•  
T o d et er mi n e t h e i m p a ct of at e z oli z u m a b a s m e a s ur e d b y ti m e t o d et eri or ati o n ( T T D) i n 
p ati e nt -r e p ort e d l u n g c a n c er s y m pt o m s of c o u g h, d y s p n e a ( si n gl e-it em a n d m ulti -it e m 
s u b s c al e s), c h e st p ai n, or ar m/ s h o ul d er p ai n, u si n g t h e E ur o p e a n Or g a ni s ati o n f or t h e 
R e s e ar c h a n d Tr e at m e nt of C a n c er ( E O R T C) Q u alit y -of -Lif e Q u e sti o n n air e −C or e 
( Q L Q-C 3 0) a n d t h e s u p pl e m e nt al l u n g c a n c er m o d ul e ( Q L Q -L C 1 3) i n t h e t G E -W T 
p o p ul ati o n a n d t h e I T T -W T p o p ul ati o n  
•  
T o d et er mi n e t h e i m p a ct of at e z oli z u m a b a s m e a s ur e d b y c h a n g e i n b a s eli n e  (i.e., 
i m pr o v e m e nt or d et eri or ati o n b a s e d u p o n pr e s e nti n g s y m pt o m at ol o g y) i n p ati e nt-r e p ort e d 
l u n g c a n c er s ym pt o m ( c h e st p ai n, d y s p n e a, a n d c o u g h) s c or e u si n g t h e S y m pt o m s i n L u n g 
C a n c er ( SI L C) s c al e s y m pt o m s e v erit y s c or e f or t h e t G E -W T p o p ul ati o n a n d t h e I T T -W T  
 
S af et y O bj e cti v e s  
T h e s af et y o bj e cti v e s f or t hi s st u d y ar e t h e f oll o wi n g:  
•  
T o e v al u at e t h e s af et y a n d t ol er a bilit y of at e z oli z u m a b i n e a c h of t h e t w o 
tr e at m e nt c o m p ari s o n s  
•  
T o e v al u at e t h e i n ci d e n c e a n d tit er s of a nti -t h er a p e uti c a nti b o di e s ( A T A s) a g ai n st 
at e z oli z u m a b a n d t o e x pl or e t h e p ot e nti al r el ati o n s hi p of  t h e i m m u n o g e ni cit y r e s p o n s e wit h 
p h ar m a c o ki n eti c s, s af et y, a n d effi c a c y  
 
P h ar m a c o ki n eti c O bj e cti v e s  
T h e p h ar m a c o ki n eti c ( P K) o bj e cti v e s f or t hi s st u d y ar e t h e f oll o wi n g:  
•  
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of at e z oli z u m a b w h e n gi v e n i n c o m bi n ati o n wit h 
c ar b o pl ati n  a n d  p a clit a x el  wit h a n d wit h o ut b e v a ci z u m a b ( Ar m s A a n d B)  
•  
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of c ar b o pl ati n w h e n gi v e n i n c o m bi n ati o n wit h 
p a clit a x el wit h a n d wit h o ut at e z oli z u m a b a n d/ or b e v a ci z u m a b ( Ar m s A, B, a n d C)  
•  
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of p a clit a x el w h e n gi v e n i n c o m bi n ati o n wit h 
c ar b o pl ati n wit h a n d wit h o ut at e z oli z u m a b  a n d/ or b e v a ci z u m a b ( Ar m s A, B, a n d C)  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 8
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
3 6 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
•  
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of b e v a ci z u m a b w h e n gi v e n i n c o m bi n ati o n wit h 
c ar b o pl ati n a n d p a clit a x el wit h a n d wit h o ut at e z oli z u m a b ( Ar m s B a n d C)  
 
E x pl or at or y O bj e cti v e s  
T h e e x pl or at or y o bj e cti v e s f or t hi s st u d y ar e t h e f oll o wi n g:  
•  
T o e v al u at e t h e effi c a c y of at e z oli z u m a b a s m e a s ur e d b y i n v e sti g at or -a s s e s s e d ti m e t o 
r e s p o n s e ( TT R) a n d ti m e -i n-r e s p o n s e ( TI R) a c c or di n g t o R E CI S T v 1. 1 
•  
T o e v al u at e O R R a n d D O R a c c or di n g t o R E CI S T v 1. 1 a s a s s e s s e d b y t h e I R F  
•  
T o e v al u at e i n v e sti g at or -a s s e s s e d O R R, P F S, a n d D O R a c c or di n g t o m o difi e d R E CI S T f or 
t h e at e z oli z u m a b-c o nt ai ni n g tr e at m e nt ar m s  
•  
T o e v al u at e P F S at 6 m o nt h s a n d at 1 y e ar i n e a c h tr e at m e nt ar m  
•  
T o e v al u at e t h e O S r at e at 3 y e ar s i n e a c h tr e at m e nt ar m  
•  
T o a s s e s s pr e di cti v e, pr o g n o sti c, a n d p h ar m a c o d y n a mi c e x pl or at or y bi o m ar k er s i n ar c hi v al 
a n d/ or fr e s h t u m or ti s s u e a n d bl o o d a n d t h eir a s s o ci ati o n wit h di s e a s e st at u s, m e c h a ni s m s 
of r e si st a n c e, a n d/ or r e s p o n s e t o st u d y tr e at m e nt  
•  
T o e v al u at e t h e utilit y of bi o p s y at t h e ti m e of a p p ar e nt di s e a s e pr o gr e s si o n t o di sti n g ui s h 
a p p ar e nt i n cr e a s e s i n t u m or v ol u m e r el at e d t o t h e i m m u n o m o d ul at or y a c ti vit y of 
at e z oli z u m a b (i. e., p s e u d o pr o gr e s si o n/t u m or -i m m u n e i nfiltr ati o n) fr o m tr u e di s e a s e 
pr o gr e s si o n  
•  
T o e v al u at e a n d c o m p ar e p ati e nt’ s h e alt h st at u s a s a s s e s s e d b y t h e E ur o Q o L 
5 Di m e n si o n s 3 -L e v el ( E Q -5 D -3 L) q u e sti o n n air e t o g e n er at e utilit y s c or e s f or  u s e i n 
e c o n o mi c m o d el s f or r ei m b ur s e m e nt  
•  
T o d et er mi n e t h e i m p a ct of at e z oli z u m a b a s m e a s ur e d b y c h a n g e fr o m b a s eli n e i n p ati e nt -
r e p ort e d o ut c o m e s of h e alt h-r el at e d q u alit y of lif e, l u n g c a n c er−r el at e d s y m pt o m s, a n d 
f u n cti o ni n g a s a s s e s s e d b y t h e E O R T C Q L Q-C 3 0 a n d L C 1 3  
 
St u d y D e si g n  
D e s cri pti o n of St u d y  
T hi s i s a r a n d o mi z e d, P h a s e III, m ulti c e nt er, o p e n -l a b el st u d y (I M p o w er 1 5 0) d e si g n e d t o 
e v al u at e t h e s af et y a n d effi c a c y of at e z oli z u m a b i n c o m bi n ati o n wit h c ar b o pl ati n  +  p a clit a x el wit h 
or wit h o ut b e v a ci z u m a b c o m p ar e d wit h tr e at m e nt wit h c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b i n 
a p pr o xi m at el y 1 2 0 0 c h e m ot h er a p y -n ai v e p ati e nt s wit h St a g e I V n o n -s q u a m o u s  n o n −s m all c ell 
l u n g c a n c er ( N S C L C). 
T u m or s p e ci m e n s will b e pr o s p e cti v el y t e st e d f or P D -L 1 e x pr e s si o n b y a c e ntr al l a b or at or y.  
Eli gi bl e p ati e nt s will b e str atifi e d b y s e x ( m al e v s. f e m al e), pr e s e n c e of li v er m et a st a s e s at 
b a s eli n e ( y e s v s. n o), a n d b y P D -L 1 t u m or e x pr e s si o n b y I H C ( T C 3 a n d a n y I C v s. T C 0/ 1/ 2 a n d 
I C 2/ 3 v s. TC 0/ 1/ 2 a n d I C 0/ 1).  P ati e nt s will b e r a n d o mi z e d i n a 1: 1: 1 r ati o t o r e c ei v e o n e of t h e 
f oll o wi n g tr e at m e nt r e gi m e n s: 
Tr e at m e nt Ar m A:  At e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el (I n d u cti o n: f o ur or si x 2 1 -d a y 
c y cl e s); at e z oli z u m a b ( M ai nt e n a n c e: 2 1 -d a y c y cl e s)  
Tr e at m e nt Ar m B:  At e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b (I n d u cti o n: f o ur or 
si x 2 1 -d a y c y cl e s); at e z oli z u m a b  +  b e v a ci z u m a b  ( M ai nt e n a n c e: 2 1-d a y c y cl e s)  
Tr e at m e nt Ar m C:  C ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b (I n d u cti o n: f o ur or si x 2 1 -d a y  
c y cl e s); b e v a ci z u m a b ( M ai nt e n a n c e: 2 1 -d a y c y cl e s)  
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 6 9 9
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
3 7 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
T h e n u m b er of c y cl e s of i n d u cti o n tr e at m e nt (f o ur or si x) will b e at t h e di s cr eti o n of t h e 
i n v e sti g at or a n d will b e d et er mi n e d a n d d o c u m e nt e d pri or t o r a n d o mi z ati o n.  I n d u cti o n tr e at m e nt 
will b e a d mi ni st er e d o n a 2 1 -d a y c y cl e u ntil t h e f oll o wi n g o c c ur ( w hi c h e v er o c c ur s fir st):  
1)  a d mi ni str ati o n of f o ur or si x c y cl e s or 2) di s e a s e pr o gr e s si o n ( Ar m C) or l o s s of c li ni c al b e n efit 
( Ar m s A a n d B) i s d o c u m e nt e d.  
F oll o wi n g t h e i n d u c ti o n p h a s e, p ati e nt s will c o nti n u e tr e at m e nt wit h m ai nt e n a n c e t h er a p y.  
P ati e nt s w h o ar e r a n d o mi z e d t o Ar m s B a n d C will c o nti n u e tr e at m e nt wit h b e v a ci z u m a b u ntil 
pr o gr e s si v e di s e a s e, u n a c c e pt a bl e t o xi cit y, or d e at h.  P ati e nt s w h o ar e r a n d o mi z e d t o  Ar m s A 
or B m a y c o nti n u e tr e at m e nt wit h at e z oli z u m a b b e y o n d r a di o gr a p hi c pr o gr e s si o n a c c or di n g t o 
R E CI S T v 1. 1, pr o vi d e d t h e y ar e e x p eri e n ci n g cli ni c al b e n efit a s a s s e s s e d b y t h e i n v e sti g at or 
(i. e., i n t h e a b s e n c e of u n a c c e pt a bl e t o xi cit y or s y m pt o m ati c d et eri or ati o n attri b ut e d t o di s e a s e 
pr o gr e s si o n a s d et er mi n e d b y t h e i n v e sti g at or aft er a n i nt e gr at e d a s s e s s m e nt of r a di o gr a p hi c 
d at a, bi o p s y r e s ult s [if a v ail a bl e], a n d cli ni c al st at u s).   
Tr e at m e nt wit h c h e m ot h er a p y ( Ar m s A, B, a n d C) a n d b e v a ci z u m a b ( Ar m s  B a n d C) m u st b e 
di s c o nti n u e d i n all p ati e nt s w h o e x hi bit e vi d e n c e of pr o gr e s si v e di s e a s e.  
P ati e nt s will u n d er g o t u m or a s s e s s m e nt s at b a s eli n e a n d e v er y 6 w e e k s f or t h e fir st 4 8  w e e k s  
f oll o wi n g C y cl e 1, D a y 1, r e g ar dl e s s of d o s e d el a y s.  Aft er 4 8 w e e k s , tu m or a s s e s s m e nt will b e 
r e q uir e d e v er y 9 w e e k s.  P ati e nt s will u n d er g o t u m or a s s e s s m e nt s u ntil r a di o gr a p hi c di s e a s e 
pr o gr e s si o n p er R E CI S T v 1. 1 ( or l o s s of cli ni c al b e n efit f or at e z oli z u m a b -tr e at e d p ati e nt s w h o 
h a d c o nti n u e d tr e at m e nt wit h at e z oli z u m a b aft er r a di o gr a p hi c di s e a s e pr o gr e s si o n a c c or di n g t o 
R E CI S T v 1. 1), wit h dr a w al of c o n s e nt, st u d y t er mi n ati o n b y S p o n s or, or d e at h, w hi c h e v er o c c ur s 
fir st.  P ati e nt s w h o di s c o nti n u e tr e at m e nt f or r e a s o n s ot h er t h a n r a di o gr a p hi c di s e a s e 
pr o gr e s si o n ( e. g., t o xi cit y) will c o nti n u e s c h e d ul e d t u m or a s s e s s m e nt s u ntil r a di o gr a p hi c 
di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 ( or l o s s of cli ni c al b e n efit f or at e z oli z u m a b -tr e at e d 
p ati e nt s w h o h a d c o nti n u e d tr e at m e nt aft er r a di o gr a p hi c di s e a s e pr o gr e s si o n a c c or di n g t o 
R E CI S T v 1. 1),  wit h dr a w al of c o n s e nt, st u d y t er mi n ati o n b y S p o n s or, or d e at h, w hi c h e v er o c c ur s 
fir st, r e g ar dl e s s of w h et h er p ati e nt s st art a n e w a nti-c a n c er t h er a p y . 
A s e c o n d ar y e n d p oi nt of t hi s st u d y i s I R F -a s s e s s e d P F S a c c or di n g t o R E CI S T  v 1. 1.  A n I R F will 
t h er ef or e c o n d u ct a n i n d e p e n d e nt r e vi e w of t h e r e s p o n s e s of all p ati e nt s, i n cl u di n g a bli n d e d 
r e vi e w of c o m p ut e d t o m o gr a p h y ( C T) s c a n s.  All pri m ar y i m a gi n g d at a u s e d f or t u m or 
a s s e s s m e nt will b e c oll e ct e d b y t h e S p o n s or t o e n a bl e c e ntr ali z e d, i n d e p e n d e nt r e vi e w of 
r e s p o n s e e n d p oi nt s.  T h e s e r e vi e w s will b e p erf or m e d pri or t o t h e fi n al effi c a c y a n al y s e s. 
F or Tr e at m e nt Ar m s A a n d B O nl y  
At a n y p oi nt d uri n g tr e at m e nt, p ati e nt s r e c ei vi n g at e z oli z u m a b w h o s h o w e vi d e n c e of cli ni c al 
b e n efit will b e p er mitt e d t o c o nti n u e at e z oli z u m a b aft er R E CI S T v 1. 1 f or pr o gr e s si v e di s e a s e 
ar e m et if t h e y m e et all of t h e f oll o wi n g crit eri a:  
•  
E vi d e n c e of cli ni c al b e n efit a s a s s e s s e d b y t h e i n v e sti g at or  
•  
A b s e n c e of s y m pt o m s a n d si g n s (i n cl u di n g w or s e ni n g of l a b or at or y v al u e s, e. g., n e w or 
w or s e ni n g h y p er c al c e mi a) i n di c ati n g u n e q ui v o c al pr o gr e s si o n of di s e a s e  
•  
N o d e cli n e i n E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) p erf or m a n c e st at u s t h at c a n 
b e attri b ut e d t o di s e a s e pr o gr e s si o n  
•  
A b s e n c e of t u m or pr o gr e s si o n at criti c al a n at o mi c al sit e s ( e. g., l e pt o m e ni n g e al di s e a s e) t h at 
c a n n ot b e m a n a g e d b y pr ot o c ol -all o w e d m e di c al i nt er v e nti o n s  
•  
P ati e nt s m u st pr o vi d e writt e n c o n s e nt t o a c k n o wl e d g e d ef erri n g ot h er tr e at m e nt o pti o n s i n 
f a v or of c o nti n ui n g at e z oli z u m a b at t h e ti m e of i niti al pr o gr e s si o n 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 0
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
3 8 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
P ati e nt s i n all tr e at m e nt ar m s will u n d er g o a m a n d at or y t u m or bi o p s y s a m pl e c oll e cti o n, u nl e s s 
n ot cli ni c all y f e a si bl e a s a s s e s s e d a n d d o c u m e nt e d b y i n v e sti g at or s, at t h e ti m e of r a di o gr a p hi c 
di s e a s e pr o gr e s si o n.  T h e s e d at a will b e u s e d t o e x pl or e w h et h er r a di o gr a p hi c fi n di n g s ar e 
c o n si st e nt wit h t h e pr e s e n c e of t u m or.  A d diti o n all y, t h e s e d at a will b e a n al y z e d t o e v al u at e t h e 
a s s o ci ati o n b et w e e n c h a n g e s i n t u m or ti s s u e a n d cli ni c al o ut c o m e a n d t o u n d er st a n d f urt h er t h e 
p ot e nti al m e c h a ni s m s of pr o gr e s si o n a n d r e si st a n c e t o at e z oli z u m a b a s c o m p ar e d wit h s u c h 
m e c h a ni s m s aft er tr e at m e nt wit h c h e m ot h er a p y al o n e.  T hi s e x pl or at or y bi o m ar k er e v al u ati o n 
will n ot b e u s e d f or a n y tr e at m e nt -r el at e d d e ci si o n s.  P ati e nt s i n Ar m s A a n d B w h o ar e u n a bl e 
t o u n d er g o bi o p s y s a m pl e c oll e cti o n b ut w h o ot h er wi s e m e et t h e crit eri a li st e d a b o v e m a y 
c o nti n u e t o r e c ei v e at e z oli z u m a b.  
N u m b er of P ati e nt s  
A p pr o xi m at el y 2 7 0 sit e s gl o b all y will p arti ci p at e i n t h e st u d y, a n d a p pr o xi m at el y 1 2 0 0  p ati e nt s 
will b e r a n d o mi z e d.  
T ar g et P o p ul ati o n  
I n cl u si o n Crit eri a 
P ati e nt s m a y b e eli gi bl e if t h e y h a v e c h e m ot h er a p y -n ai v e , St a g e IV, n o n -s q u a m o u s N S C L C.  
P ati e nt s m u st m e et all of t h e f oll o wi n g crit eri a t o b e eli gi bl e f or st u d y e ntr y:  
•  
Si g n e d I nf or m e d C o n s e nt F or m  
•  
M al e or f e m al e, 1 8 y e ar s  of a g e or ol d er  
•  
E C O G p erf or m a n c e st at u s of 0 or 1  
•  
Hi st ol o gi c all y or c yt ol o gi c all y c o nfir m e d, St a g e I V n o n -s q u a m o u s N S C L C ( p er t h e U ni o n 
I nt er n ati o n al e c o ntr e l e C a n c er/ A m eri c a n J oi nt C o m mitt e e o n C a n c er st a gi n g s y st e m, 7t h 
e diti o n).  
P ati e nt s  wit h t u m or s of mi x e d hi st ol o g y (i. e., s q u a m o u s a n d n o n -s q u a m o u s) ar e eli gi bl e 
if t h e m aj or hi st ol o gi c al c o m p o n e nt a p p e ar s t o b e n o n-s q u a m o u s.  
•  
N o pri or tr e at m e nt f or St a g e I V n o n -s q u a m o u s N S C L C  
P ati e nt s wit h a s e n siti zi n g m ut ati o n i n t h e e pi d er m al gr o wt h f a ct or r e c e pt or ( E G F R ) 
g e n e m u st h a v e e x p eri e n c e d di s e a s e pr o gr e s si o n ( d uri n g or aft er tr e at m e nt) or 
i nt ol er a n c e t o tr e at m e nt wit h o n e or m or e E G F R  T KI s, s u c h a s  erl oti ni b, g efiti ni b, or 
a n ot h er E G F R  t yr o si n e ki n a s e i n hi bit or ( T KI) a p pr o pri at e f or t h e tr e at m e nt of 
E G F R -m ut a nt N S C L C.  
P ati e nt s wit h a n a n a pl a sti c l y m p h o m a ki n a s e ( A L K ) f u si o n o n c o g e n e m u st h a v e 
e x p eri e n c e d di s e a s e pr o gr e s si o n ( d uri n g or aft er tr e at m e nt) or i nt ol er a n c e t o tr e at m e nt 
wit h o n e or m or e A L K  i n hi bit or s (i. e., cri z oti ni b) a p pr o pri at e f or t h e tr e at m e nt of N S C L C 
i n p ati e nt s h a vi n g a n A L K  f u si o n o n c o g e n e.   
P ati e nt s wit h u n k n o w n E G F R  a n d/ or A L K  st at u s r e q uir e t e st r e s ult s at s cr e e ni n g.  A L K  
a n d/ or E G F R  m a y b e a s s e s s e d l o c all y or at a c e ntr al l a b or at or y.  
•  
P ati e nt s w h o h a v e r e c ei v e d pri or n e o -a dj u v a nt, a dj u v a nt c h e m ot h er a p y, r a di ot h er a p y, or 
c h e m or a di ot h er a p y wit h c ur ati v e i nt e nt f or n o n -m et a st ati c di s e a s e m u st h a v e e x p eri e n c e d a 
tr e at m e nt-fr e e i nt er v al of at l e a st 6 m o nt h s fr o m r a n d o mi z ati o n si n c e t h e l a st c h e m ot h er a p y, 
r a di ot h er a p y, or c h e m or a di ot h er a p y. 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 1
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
3 9 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
•  
P ati e nt s wit h a hi st or y of tr e at e d a s y m pt o m ati c C N S m et a st a s e s ar e eli gi bl e, pr o vi d e d t h e y 
m e et all of t h e f oll o wi n g crit eri a:  
O nl y s u pr at e nt ori al a n d c er e b ell ar m et a st a s e s all o w e d (i. e., n o m et a st a s e s t o mi d br ai n, 
p o n s, m e d ull a or s pi n al c or d ) 
N o o n g oi n g r e q uir e m e nt f or c orti c o st er oi d s a s t h er a p y f or C N S di s e a s e  
N o st er e ot a cti c r a di ati o n wit hi n 7 d a y s or w h ol e -br ai n r a di ati o n wit hi n 1 4 d a y s pri or t o 
r a n d o mi z ati o n 
N o e vi d e n c e of i nt eri m pr o gr e s si o n b et w e e n t h e c o m pl eti o n of C N S -dir e ct e d t h er a p y 
a n d t h e s cr e e ni n g r a di o gr a p hi c st u d y  
P ati e nt s wit h n e w a s y m pt o m ati c C N S m et a st a s e s d et e ct e d at t h e s cr e e ni n g s c a n m u st 
r e c ei v e r a di ati o n t h er a p y a n d/ or s ur g er y f or C N S m et a st a s e s.  F oll o wi n g tr e at m e nt, t h e s e 
p ati e nt s m a y t h e n b e eli gi bl e wit h o ut t h e n e e d f or a n a d diti o n al br ai n s c a n pri or t o 
r a n d o mi z ati o n, if all ot h er crit eri a ar e m et. 
•  
K n o w n P D -L 1 t u m or st at u s a s d et er mi n e d b y a n I H C a s s a y p erf or m e d b y a c e ntr al 
l a b or at or y o n pr e vi o u sl y o bt ai n e d ar c hi v al t u m or ti s s u e or ti s s u e o bt ai n e d fr o m a bi o p s y at 
s cr e e ni n g  
A r e pr e s e nt ati v e f or m ali n-fi x e d p ar affi n-e m b e d d e d ( F F P E) t u m or s p e ci m e n i n p ar affi n 
bl o c k ( pr ef err e d) or 1 5  or m or e  u n st ai n e d, fr e s hl y c ut, s eri al s e cti o n s o n sli d e s  fr o m a n 
F F P E t u m or s p e ci m e n i s r e q uir e d f or p arti ci p ati o n i n t hi s st u d y.  If f e w er t h a n 1 5  sli d e s 
ar e a v ail a bl e at b a s eli n e ( b ut n o f e w er t h a n 1 0), t h e p ati e nt m a y still b e eli gi bl e, u p o n 
di s c u s si o n wit h t h e M e di c al M o nit or.   T hi s s p e ci m e n m u st b e a c c o m p a ni e d b y t h e 
a s s o ci at e d p at h ol o g y r e p ort.  
Fi n e -n e e dl e a s pir ati o n (d efi n e d a s s a m pl e s t h at d o n ot pr e s er v e ti s s u e ar c hit e ct ur e a n d 
yi el d c ell s u s p e n si o n a n d/ or c ell s m e ar s), br u s hi n g, c ell p ell et s p e ci m e n s ( e. g., fr o m 
pl e ur al eff u si o n, a n d l a v a g e s a m pl e s) ar e n ot a c c e pt a bl e.  
T u m or ti s s u e fr o m b o n e m et a st a s e s  t h at i s s u bj e ct t o d e c al cifi c ati o n i s n ot a c c e pt a bl e. 
F or c or e n e e dl e bi o p s y s p e ci m e n s, pr ef er a bl y at l e a st t hr e e c or e s  e m b e d d e d i n a si n gl e 
p ar affi n bl o c k, s h o ul d b e s u b mitt e d f or e v al u ati o n.  
•  
M e a s ur a bl e di s e a s e, a s d efi n e d b y R E CI S T v 1. 1  
Pr e vi o u sl y  irr a di at e d l e si o n s c a n o nl y b e c o n si d er e d a s m e a s ur a bl e di s e a s e if di s e a s e 
pr o gr e s si o n h a s b e e n u n e q ui v o c all y d o c u m e nt e d at t h at sit e si n c e r a di ati o n a n d t h e 
pr e vi o u sl y irr a di at e d l e si o n i s n ot t h e o nl y sit e of di s e a s e.  
•  
A d e q u at e h e m at ol o gi c a n d e n d or g a n  f u n cti o n, d efi n e d b y t h e f oll o wi n g l a b or at or y r e s ult s 
o bt ai n e d wit hi n 1 4 d a y s pri or t o r a n d o mi z ati o n:  
A N C ≥ 1 5 0 0 c ell s/ µ L wit h o ut gr a n ul o c yt e c ol o n y -sti m ul ati n g f a ct or s u p p ort  
L y m p h o c yt e c o u nt ≥ 5 0 0/ µ L 
Pl at el et c o u nt ≥ 1 0 0, 0 0 0/ µ L wit h o ut tr a n sf u si o n  
H e m o gl o bi n ≥ 9. 0 g/ d L  
P ati e nt s m a y b e tr a n sf u s e d t o m e et t hi s crit eri o n.  
I N R or a P T T  ≤ 1. 5  ×  u p p er li mit of n or m al ( U L N ) 
T hi s a p pli e s o nl y t o p ati e nt s w h o ar e n ot r e c ei vi n g t h er a p e uti c a nti c o a g ul ati o n; 
p ati e nt s r e c ei vi n g t h er a p e uti c a nti c o a g ul ati o n s h o ul d b e o n a st a bl e d o s e.  
A S T, A L T, a n d al k ali n e p h o s p h at a s e ≤ 2. 5  ×  U L N, wit h t h e f oll o wi n g e x c e pti o n s:  
P ati e nt s wit h d o c u m e nt e d li v er m et a st a s e s:  A S T a n d/ or A L T ≤ 5  ×  U L N  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 2
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 0 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
P ati e nt s wit h d o c u m e nt e d li v er or b o n e m et a st a s e s:  al k ali n e p h o s p h at a s e ≤ 5  ×  U L N.  
S er u m bilir u bi n  ≤ 1. 2 5  ×  U L N  
P ati e nt s wit h k n o w n Gil b ert di s e a s e w h o h a v e s er u m bilir u bi n l e v el ≤ 3  ×  U L N m a y b e 
e nr oll e d . 
S er u m cr e ati ni n e  ≤ 1. 5  ×  U L N  
•  
F or f e m al e p ati e nt s of c hil d b e ari n g p ot e nti al, a gr e e m e nt ( b y p ati e nt a n d/ or p art n er) t o u s e a 
hi g hl y eff e cti v e f or m( s) of c o ntr a c e pti o n t h at r e s ult s i n a l o w f ail ur e r at e ( <  1 % p er y e ar) 
w h e n u s e d c o n si st e ntl y a n d c orr e ctl y, a n d t o c o nti n u e it s u s e f or 5 m o nt h s aft er t h e l a st 
d o s e of at e z oli z u m a b a n d/ or 6  m o nt h s aft er t h e l a st d o s e of b e v a ci z u m a b or p a clit a x el, 
w hi c h e v er i s l at er).  S u c h m et h o d s i n cl u d e:  c o m bi n e d ( e str o g e n a n d pr o g e st o g e n 
c o nt ai ni n g) h or m o n al c o ntr a c e pti o n, pr o g e st o g e n -o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d 
wit h i n hi biti o n of o v ul ati o n t o g et h er wit h a n ot h er a d diti o n al b arri er m et h o d al w a y s c o nt ai ni n g 
a s p er mi ci d e, i ntr a ut eri n e d e vi c e (I U D): i ntr a ut eri n e h or m o n e -r el e a si n g s y st e m (I U S), 
bil at er al t u b al o c cl u si o n, v a s e ct o mi z e d p art n er ( o n t h e u n d er st a n di n g t h at t hi s i s t h e o nl y 
o n e p art n er d uri n g t h e w h ol e st u d y d ur ati o n), a n d s e x u al a b sti n e n c e.  
•  
F or m al e p ati e nt s wit h f e m al e p art n er s of c hil d b e ari n g p ot e nti al, a gr e e m e nt ( b y p ati e nt 
a n d/ or p art n er) t o u s e a hi g hl y eff e cti v e f or m( s) of c o ntr a c e pti o n t h at r e s ult s i n a l o w f ail ur e 
r at e [<  1 % p er y e ar] w h e n u s e d c o n si st e ntl y a n d c orr e ctl y, a n d t o c o nti n u e it s u s e f or 
6 m o nt h s aft er t h e l a st d o s e of b e v a ci z u m a b, c ar b o pl ati n, or p a clit a x el.  M al e  p ati e nt s 
s h o ul d n ot d o n at e s p er m d uri n g t hi s st u d y a n d f or at l e a st 6 m o nt h s aft er t h e l a st d o s e of 
b e v a ci z u m a b, c ar b o pl ati n, or p a clit a x el.  
•  
Or al c o ntr a c e pti o n s h o ul d al w a y s b e c o m bi n e d wit h a n a d diti o n al c o ntr a c e pti v e m et h o d 
b e c a u s e of a p ot e nti al i nt er a cti o n wit h t h e st u d y dr u g.  T h e s a m e r ul e s ar e v ali d f or m al e 
p ati e nt s i n v ol v e d i n t hi s cli ni c al st u d y if t h e y h a v e a p art n er of c hil d birt h p ot e nti al.  M al e 
p ati e nt s m u st al w a y s u s e a c o n d o m.  
•  
W o m e n w h o ar e n ot p o st m e n o p a u s al ( ≥ 1 2 m o nt h s of n o n −t h er a p y-i n d u c e d a m e n orr h e a) or 
s ur gi c all y st eril e m u st h a v e a n e g ati v e s er u m pr e g n a n c y t e st r e s ult wit hi n 1 4 d a y s pri or t o 
i niti ati o n of st u d y dr u g 
 
E x cl u si o n Crit eri a  
P ati e nt s w h o m e et a n y of t h e crit eri a b el o w will b e e x cl u d e d fr o m st u d y e ntr y.  
C a n c er -S p e cifi c E x cl u si o n s  
•  
A cti v e or u ntr e at e d C N S m et a st a s e s a s d et er mi n e d b y C T or m a g n eti c r e s o n a n c e i m a gi n g 
( M RI) e v al u ati o n d uri n g s cr e e ni n g a n d pri or r a di o gr a p hi c a s s e s s m e nt s 
•  
S pi n al c or d c o m pr e s si o n n ot d efi niti v el y tr e at e d wit h s ur g er y a n d/ or  r a di ati o n or pr e vi o u sl y 
di a g n o s e d a n d tr e at e d s pi n al c or d c o m pr e s si o n wit h o ut e vi d e n c e t h at di s e a s e h a s b e e n 
cli ni c all y st a bl e f or >  2 w e e k s pri or t o r a n d o mi z ati o n  
•  
L e pt o m e ni n g e al di s e a s e  
•  
U n c o ntr oll e d t u m or -r el at e d p ai n 
P ati e nt s r e q uiri n g p ai n m e di c ati o n m u st b e o n a st a bl e r e gi m e n at st u d y e ntr y.  
S y m pt o m ati c l e si o n s a m e n a bl e t o p alli ati v e r a di ot h er a p y ( e. g., b o n e m et a st a s e s or 
m et a st a s e s c a u si n g n er v e i m pi n g e m e nt) s h o ul d b e tr e at e d pri or t o r a n d o mi z ati o n.  
P ati e nt s s h o ul d b e r e c o v er e d fr o m t h e eff e ct s of r a di ati o n.  T h er e i s n o r e q uir e d 
mi ni m u m r e c o v er y p eri o d.  
A s y m pt o m ati c m et a st ati c l e si o n s w h o s e f urt h er gr o wt h w o ul d li k el y c a u s e f u n cti o n al 
d efi cit s or i ntr a ct a bl e p ai n ( e. g., e pi d ur al m et a st a si s t h at i s n ot c urr e ntl y a s s o ci at e d wit h 
s pi n al c or d c o m pr e s si o n) s h o ul d b e c o n si d er e d f or  l o c or e gi o n al t h er a p y, if a p pr o pri at e, 
pri or t o r a n d o mi z ati o n.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 3
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 1 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
•  
U n c o ntr oll e d pl e ur al eff u si o n, p eri c ar di al  eff u si o n, or a s cit e s r e q uiri n g r e c urr e nt dr ai n a g e 
pr o c e d ur e s ( o n c e m o nt hl y or m or e fr e q u e ntl y)  
P ati e nt s wit h i n d w elli n g c at h et er s ( e. g., Pl e ur X ® ) ar e all o w e d. 
•  
U n c o ntr oll e d or s y m pt o m ati c h y p er c al c e mi a ( >  1. 5 m m ol/ L i o ni z e d c al ci u m or C a >  1 2 m g/ d L 
or c orr e ct e d s er u m c al ci u m >  U L N)  
P ati e nt s w h o ar e r e c ei vi n g d e n o s u m a b pri or t o r a n d o mi z ati o n m u st b e willi n g a n d 
eli gi bl e t o r e c ei v e a bi s p h o s p h o n at e i n st e a d w hil e i n t h e st u d y.  
•  
M ali g n a n ci e s ot h er t h a n N S C L C wit hi n 5 y e ar s pri or t o r a n d o mi z ati o n, wit h t h e e x c e pti o n of 
t h o s e wit h a n e gli gi bl e ri s k of m et a st a si s or d e at h ( e. g., e x p e ct e d 5-y e ar O S >  9 0 %) tr e at e d 
wit h e x p e ct e d c ur ati v e o ut c o m e ( s u c h a s a d e q u at el y tr e at e d c ar ci n o m a i n sit u of t h e c er vi x, 
b a s al or s q u a m o u s -c ell s k i n c a n c er, l o c ali z e d pr o st at e c a n c er tr e at e d s ur gi c all y wit h 
c ur ati v e i nt e nt, d u ct al c ar ci n o m a i n sit u tr e at e d s ur gi c all y wit h c ur ati v e i nt e nt)  
•  
K n o w n t u m or P D -L 1 e x pr e s si o n st at u s a s d et er mi n e d b y a n I H C a s s a y fr o m ot h er cli ni c al 
st u di e s ( e. g., p ati e nt s w h o s e P D -L 1 e x pr e s si o n st at u s w a s d et er mi n e d d uri n g s cr e e ni n g f or 
e ntr y i nt o a st u d y wit h P D -1 or a nti -P D -L 1 a nti b o di e s b ut w er e n ot eli gi bl e ar e e x cl u d e d)  
 
G e n er al M e di c al E x cl u si o n s  
•  
W o m e n w h o ar e pr e g n a nt, l a ct ati n g, or i nt e n di n g t o b e c o m e pr e g n a nt d uri n g t h e st u d y  
•  
Hi st or y of s e v er e all er gi c, a n a p h yl a cti c, or ot h er h y p er s e n siti vit y r e a cti o n s t o  c hi m eri c or 
h u m a ni z e d a nti b o di e s or f u si o n pr ot ei n s  
•  
K n o w n  h y p er s e n siti vit y or all er g y t o bi o p h ar m a c e uti c al s pr o d u c e d i n C hi n e s e h a m st er o v ar y 
c ell s or a n y c o m p o n e nt of t h e at e z oli z u m a b f or m ul ati o n   
•  
Hi st or y of a ut oi m m u n e di s e a s e, i n cl u di n g b ut n ot li mit e d t o m y a st h e ni a gr a vi s, m y o siti s, 
a ut oi m m u n e h e p atiti s, s y st e mi c l u p u s er yt h e m at o s u s, r h e u m at oi d art hriti s, i nfl a m m at or y 
b o w el di s e a s e, v a s c ul ar t hr o m b o si s a s s o ci at e d wit h a nti p h o s p h oli pi d s y n dr o m e, W e g e n er’ s 
gr a n ul o m at o si s, Sj ö gr e n’ s s y n dr o m e, G uill ai n -B arr é s y n dr o m e, m ulti pl e s cl er o si s, v a s c uliti s, 
or gl o m er ul o n e p hriti s  
P ati e nt s wit h a hi st or y of a ut oi m m u n e -r el at e d h y p ot h yr oi di s m o n a st a bl e d o s e of 
t h yr oi d r e pl a c e m e nt h or m o n e ar e eli gi bl e f or t hi s st u d y.  
P ati e nt s wit h c o ntr oll e d T y p e 1 di a b et e s m ellit u s o n a st a bl e d o s e of i n s uli n r e gi m e n ar e 
eli gi bl e f or t hi s st u d y  
P ati e nt s wit h e c z e m a, p s ori a si s, li c h e n si m pl e x c hr o ni c u s, or vitili g o wit h d er m at ol o gi c 
m a nif e st ati o n s o nl y ( e. g., p ati e nt s wit h p s ori ati c art hriti s w o ul d b e e x cl u d e d) ar e 
p er mitt e d pr o vi d e d t h at t h e y  m e et t h e f oll o wi n g c o n diti o n s:  
R a s h m u st c o v er l e s s t h a n 1 0 % of b o d y s urf a c e ar e a ( B S A).  
Di s e a s e i s w ell c o ntr oll e d at b a s eli n e a n d o nl y r e q uiri n g l o w -p ot e n c y  t o pi c al 
st er oi d s.  
N o a c ut e e x a c er b ati o n s of u n d erl yi n g c o n diti o n wit hi n t h e pr e vi o u s 1 2  m o nt h s ( n ot 
r e q uiri n g P U V A [ p s or al e n pl u s ultr a vi ol et A r a di ati o n], m et h otr e x at e, r eti n oi d s, 
bi ol o gi c a g e nt s, or al c al ci n e uri n i n hi bit or s, hi g h -p ot e n c y or or al st er oi d s)  
•  
Hi st or y of i di o p at hi c p ul m o n ar y fi br o si s, or g a ni zi n g p n e u m o ni a ( e. g., br o n c hi oliti s o blit er a n s), 
dr u g -i n d u c e d p n e u m o niti s, i di o p at hi c p n e u m o niti s, or e vi d e n c e of a cti v e p n e u m o niti s o n 
s cr e e ni n g c h e st C T s c a n  
Hi st or y of r a di ati o n p n e u m o niti s i n t h e r a di ati o n fi el d (fi br o si s) i s p er mitt e d.  
•  
P o siti v e t e st f or HI V  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 4
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 2 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
All p ati e nt s will b e t e st e d f or HI V pri or t o i n cl u si o n i nt o t h e st u d y; p ati e nt s w h o t e st 
p o siti v e f or HI V will b e e x cl u d e d fr o m t h e cli ni c al st u d y.  
•  
P ati e nt s wit h a cti v e h e p atiti s B ( c hr o ni c or a c ut e; d efi n e d a s h a vi n g a p o siti v e h e p atiti s B 
s urf a c e a nti g e n  [ H B s A g] t e st at s cr e e ni n g) or h e p atiti s C  
P ati e nt s wit h p a st h e p atiti s B vir u s ( H B V) i nf e cti o n or r e s ol v e d H B V i nf e cti o n ( d efi n e d 
a s t h e pr e s e n c e of h e p atiti s B c or e a nti b o d y [ H B c A b] a n d a b s e n c e o f H B s A g) ar e 
eli gi bl e o nl y if t h e y ar e n e g ati v e f or H B V D N A.  
P ati e nt s p o siti v e f or h e p atiti s C vir u s ( H C V) a nti b o d y ar e eli gi bl e o nl y if P C R i s n e g ati v e 
f or H C V R N A. 
•  
A cti v e t u b er c ul o si s  
•  
S e v er e i nf e cti o n s wit hi n 4 w e e k s pri or t o r a n d o mi z ati o n, i n cl u di n g b ut n ot li mit e d t o 
h o s pit ali z ati o n f or c o m pli c ati o n s of i nf e cti o n, b a ct er e mi a, or s e v er e p n e u m o ni a  
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R e c ei v e d t h er a p e uti c or al or I V a nti bi oti c s wit hi n 2 w e e k s pri or t o r a n d o mi z ati o n  
P ati e nt s r e c ei vi n g pr o p h yl a cti c a nti bi oti c s ( e. g., f or pr e v e nti o n of a uri n ar y tr a ct i nf e cti o n 
or t o pr e v e nt c hr o ni c o b str u cti v e p ul m o n ar y di s e a s e e x a c er b ati o n) ar e eli gi bl e.  
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Si g nifi c a nt c ar di o v a s c ul ar di s e a s e, s u c h a s N e w Y or k H e art A s s o ci ati o n c ar di a c di s e a s e 
( Cl a s s II or gr e at er), m y o c ar di al i nf ar cti o n, or c er e br o v a s c ul ar a c ci d e nt wit hi n 3 m o nt h s 
pri or t o r a n d o mi z ati o n, u n st a bl e arr h yt h mi a s, or u n st a bl e a n gi n a  
P ati e nt s wit h k n o w n c or o n ar y art er y di s e a s e, c o n g e sti v e h e art f ail ur e n ot m e eti n g t h e 
a b o v e crit eri a, or l eft v e ntri c ul ar ej e cti o n fr a cti o n <  5 0 % m u st b e o n a st a bl e m e di c al 
r e gi m e n t h at i s o pti mi z e d i n t h e o pi ni o n of t h e tr e ati n g p h y si ci a n, i n c o n s ult ati o n wit h a 
c ar di ol o gi st if a p pr o pri at e.  
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M aj or s ur gi c al pr o c e d ur e ot h er t h a n f or di a g n o si s wit hi n 2 8 d a y s pri or t o r a n d o mi z ati o n or 
a nti ci p ati o n of n e e d f or a m aj or s ur gi c al pr o c e d ur e d uri n g t h e c o ur s e of t h e st u d y  
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Pri or all o g e n ei c b o n e m arr o w tr a n s pl a nt ati o n or s oli d or g a n tr a n s pl a nt  
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A d mi ni str ati o n of a li v e, att e n u at e d v a c ci n e wit hi n 4 w e e k s b ef or e r a n d o mi z ati o n or 
a nti ci p ati o n t h at s u c h a li v e att e n u at e d v a c ci n e will b e r e q uir e d d uri n g t h e st u d y  
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A n y ot h er di s e a s e s, m et a b oli c d y sf u n cti o n, p h y si c al e x a mi n ati o n fi n di n g, or cli ni c al 
l a b or at or y fi n di n g gi vi n g r e a s o n a bl e s u s pi ci o n of a di s e a s e or c o n diti o n t h at c o ntr ai n di c at e s 
t h e u s e of a n i n v e sti g ati o n al dr u g or t h at m a y aff e ct t h e i nt er pr et ati o n of t h e r e s ult s or 
r e n d er s t h e p ati e nt at hi g h ri s k fr o m tr e at m e nt c o m pli c ati o n s 
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P ati e nt s wit h ill n e s s e s or c o n diti o n s t h at i nt erf er e wit h t h eir c a p a cit y t o u n d er st a n d, f oll o w 
a n d/ or c o m pl y wit h st u d y pr o c e d ur e s  
 
E x cl u si o n Crit eri a R el at e d t o M e di c ati o n s  
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A n y a p pr o v e d a nti -c a n c er t h er a p y, i n cl u di n g h or m o n al t h er a p y, wit hi n 3  w e e k s pri or t o 
i niti ati o n of st u d y tr e at m e nt; t h e f oll o wi n g e x c e pti o n s ar e all o w e d: 
T KI s a p pr o v e d f or tr e at m e nt of N S C L C di s c o nti n u e d  >  7 d a y s pri or t o r a n d o mi z ati o n; 
t h e b a s eli n e s c a n m u st b e o bt ai n e d aft er di s c o nti n u ati o n of pri or T KI s. 
•  
Tr e at m e nt wit h a n y ot h er i n v e sti g ati o n al a g e nt wit h t h er a p e uti c i nt e nt wit hi n 2 8 d a y s pri or t o 
r a n d o mi z ati o n 
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Pri or tr e at m e nt wit h C D 1 3 7 a g o ni st s or i m m u n e c h e c k p oi nt bl o c k a d e t h er a pi e s, a nti −P D -1, 
a n d a nti −P D -L 1 t h er a p e uti c a nti b o di e s  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 5
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 3 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
P ati e nt s w h o h a v e h a d pri or a nti −C T L A- 4 tr e at m e nt m a y b e e nr oll e d, pr o vi d e d t h e 
f oll o wi n g r e q uir e m e nt s ar e m et: 
L a st d o s e of a nti −C T L A- 4 at l e a st 6 w e e k s  pri or t o r a n d o mi z ati o n  
N o hi st or y of s e v er e i m m u n e -m e di at e d a d v er s e eff e ct s fr o m a nti −C T L A- 4 
( N ati o n al C a n c er I n stit ut e C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s 
[ N CI C T C A E] Gr a d e 3 a n d 4)  
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Tr e at m e nt wit h s y st e mi c i m m u n o sti m ul at or y a g e nt s (i n cl u di n g, b ut n ot li mit e d t o, I F N s, I L -2) 
wit hi n 4 w e e k s or fi v e h al f-li v e s of t h e dr u g, w hi c h e v er i s l o n g er, pri or t o r a n d o mi z ati o n  
Pri or tr e at m e nt wit h c a n c er v a c ci n e s i s all o w e d.  
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Tr e at m e nt wit h s y st e mi c i m m u n o s u p pr e s si v e m e di c ati o n s (i n cl u di n g b ut n ot li mit e d t o 
c orti c o st er oi d s, c y cl o p h o s p h a mi d e, a z at hi o pri n e, m et h otr e x at e, t h ali d o mi d e, a n d a nti −t u m or 
n e cr o si s f a ct or [ a nti -T N F] a g e nt s) wit hi n 2 w e e k s pri or t o r a n d o mi z ati o n  
P ati e nt s w h o h a v e r e c ei v e d a c ut e, l o w -d o s e ( ≤ 1 0  m g or al pr e d ni s o n e or e q ui v al e nt) , 
s y st e mi c i m m u n o s u p pr e s s a nt m e di c ati o n s m a y b e e nr oll e d i n t h e st u d y.  
T h e u s e of c orti c o st er oi d s ( ≤ 1 0  m g or al pr e d ni s o n e or e q ui v al e nt) f or c hr o ni c 
o b str u cti v e p ul m o n ar y di s e a s e,  mi n er al o c orti c oi d s ( e. g., fl u dr o c orti s o n e) f or p ati e nt s 
wit h ort h o st ati c h y p ot e n si o n, a n d l o w -d o s e s u p pl e m e nt al c orti c o st er oi d s f or 
a dr e n o c orti c al i n s uffi ci e n c y i s all o w e d  
 
E x cl u si o n s R el at e d t o B e v a ci z u m a b  
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I n a d e q u at el y c o ntr oll e d h y p ert e n si o n ( d efi n e d a s s y st oli c bl o o d pr e s s ur e  > 1 5 0  m m H g 
a n d/ or di a st oli c bl o o d pr e s s ur e   > 1 0 0 m m H g)  
A nti -h y p ert e n si v e t h er a p y  t o a c hi e v e t h e s e p ar a m et er s i s all o w a bl e. 
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Pri or hi st or y of h y p ert e n si v e cri si s or h y p ert e n si v e e n c e p h al o p at h y  
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Si g nifi c a nt v a s c ul ar di s e a s e ( e. g., a orti c a n e ur y s m r e q uiri n g s ur gi c al r e p air or r e c e nt 
p eri p h er al art eri al t hr o m b o si s) wit hi n 6 m o nt h s pri or t o r a n d o mi z ati o n  
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Hi st or y of h e m o pt y si s ( ≥ o n e -h alf t e a s p o o n of bri g ht r e d bl o o d p er e pi s o d e) wit hi n 1  m o nt h 
pri or t o r a n d o mi z ati o n  
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E vi d e n c e of bl e e di n g di at h e si s or c o a g ul o p at h y (i n t h e a b s e n c e of t h er a p e uti c 
a nti c o a g ul ati o n)  
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C urr e nt or r e c e nt ( wit hi n 1 0 d a y s of r a n d o mi z ati o n) u s e of a s piri n ( >  3 2 5 m g/ d a y) or 
tr e at m e nt wit h di p yr a mi d ol e, ti cl o pi di n e, cl o pi d o gr el, a n d cl o st a z ol 
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C urr e nt u s e of f ull -d o s e or al or p ar e nt er al a nti c o a g ul a nt s or t hr o m b ol yti c a g e nt s f or 
t h er a p e uti c p ur p o s e s t h at h a s n ot b e e n st a bl e f or >  2 w e e k s pri or t o r a n d o mi z ati o n  
T h e u s e of f ull -d o s e or al or p ar e nt er al a nti c o a g ul a nt s i s p er mitt e d a s l o n g a s t h e I N R or 
a P T T i s wit hi n t h er a p e uti c li mit s ( a c c or di n g t o t h e m e di c al st a n d ar d of t h e e nr olli n g 
i n stit uti o n) a n d t h e p ati e nt h a s b e e n o n a st a bl e d o s e of a nti c o a g ul a nt s f or at l e ast 
2 w e e k s pri or t o r a n d o mi z ati o n.  
Pr o p h yl a cti c a nti c o a g ul ati o n f or t h e p at e n c y of v e n o u s a c c e s s d e vi c e s i s all o w e d, 
pr o vi d e d t h e a cti vit y of t h e a g e nt r e s ult s i n a n I N R <  1. 5  ×  U L N  a n d a P T T i s wit hi n 
n or m al li mit s wit hi n 1 4 d a y s pri or t o r a n d o mi z ati o n.  
Pr o p h yl a cti c u s e of l o w -m ol e c ul ar -w ei g ht h e p ari n (i. e., e n o x a p ari n 4 0 m g/ d a y) i s 
p er mitt e d.  
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C or e bi o p s y or ot h er mi n or s ur gi c al pr o c e d ur e, e x cl u di n g pl a c e m e nt of a v a s c ul ar a c c e s s 
d e vi c e, wit hi n 7 d a y s pri or t o t h e fir st d o s e of b e v a ci z u m a b  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 6
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 4 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
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Hi st or y of a b d o mi n al or tr a c h e o s p h a g e al fi st ul a or g a str oi nt e sti n al p erf or ati o n wit hi n 
6 m o nt h s pri or t o r a n d o mi z ati o n  
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Cli ni c al si g n s of g a str oi nt e sti n al o b str u cti o n or r e q uir e m e nt f or r o uti n e p ar e nt er al h y dr ati o n, 
p ar e nt er al n utriti o n, or t u b e f e e di n g  
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E vi d e n c e of a b d o mi n al fr e e air n ot e x pl ai n e d b y p ar a c e nt e si s or r e c e nt s ur gi c al pr o c e d ur e  
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S eri o u s, n o n -h e ali n g w o u n d, a cti v e ul c er, or u ntr e at e d b o n e fr a ct ur e  
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Pr ot ei n uri a, a s d e m o n str at e d b y uri n e di p sti c k or >  1. 0 g of pr ot ei n i n a 2 4 -h o ur uri n e 
c oll e cti o n  
All p ati e nt s wit h ≥ 2 +  pr ot ei n o n di p sti c k uri n al y si s at b a s eli n e m u st u n d er g o a 2 4 -h o ur 
uri n e c oll e cti o n a n d m u st d e m o n str at e  ≤ 1 g of pr ot ei n i n 2 4  h o ur s.  
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K n o w n s e n siti vit y t o a n y c o m p o n e nt of b e v a ci z u m a b  
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Cl e ar t u m or i nfiltr ati o n i nt o t h e t h or a ci c gr e at v e s s el s i s s e e n o n i m a gi n g  
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Cl e ar c a vit ati o n of p ul m o n ar y l e si o n s i s s e e n o n i m a gi n g  
 
E x cl u si o n s R el at e d t o C h e m ot h er a p y  
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K n o w n hi st or y of s e v er e all er gi c r e a cti o n s t o pl ati n u m -c o nt ai ni n g c o m p o u n d s or m a n nit ol  
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K n o w n s e n siti vit y t o a n y c o m p o n e nt of p a clit a x el  
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Gr a d e  ≥ 2 p eri p h er al n e ur o p at h y a s d efi n e d b y N CI C T C A E v 4. 0 ( p a clit a x el)  
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K n o w n hi st or y of s e v er e h y p er s e n siti vit y r e a cti o n s t o pr o d u ct s c o nt ai ni n g Cr e m o p h or ®  E L 
( e. g., c y cl o s p ori n f or i nj e cti o n c o n c e ntr at e a n d t e ni p o si d e f or i nj e cti o n c o n c e ntr at e) 
 
L e n gt h of St u d y 
T h e fi n al P F S a n al y si s will b e c o n d u ct e d w h e n b ot h of t h e f oll o wi n g crit eri a h a v e b e e n m et:  
a p pr o xi m at el y 5 1 6 P F S e v e nt s h a v e o c c urr e d i n Ar m s  B a n d C c o m bi n e d i n t h e I T T - W T 
p o p ul ati o n a n d t h e l a st p ati e nt h a s b e e n e nr oll e d i n t h e st u d y.  T h e fi n al P F S a n al y si s i s 
e x p e ct e d t o o c c ur a p pr o xi m at el y 2 9  m o nt h s aft er t h e fir st p ati e nt i s e nr oll e d.  At t h e ti m e of t h e 
fi n al P F S a n al y si s, it i s e x p e ct e d t h at a p pr o xi m at el y 2 4 9 e v e nt s will h a v e o c c urr e d i n t h e 
t G E-W T p o p ul ati o n.  
Wit h a s a m pl e si z e of 7 2 0 p ati e nt s, a p pr o xi m at el y 5 0 7 O S e v e nt s ar e e x p e ct e d t o o c c ur i n 
Ar m s  B a n d C c o m bi n e d i n t h e I T T -W T p o p ul ati o n f or t h e fi n al O S a n al y si s.  T h e fi n al O S 
a n al y si s i s e x p e ct e d t o o c c ur a p pr o xi m at el y 4 0 m o nt h s aft er t h e fir st p ati e nt i s e nr oll e d.  T hi s 
n u m b er of e v e nt s c orr e s p o n d s t o a mi ni m u m d et e ct a bl e diff er e n c e i n H R of a p pr o xi m at el y 0. 8 3 
i n t h e I T T-W T p o p ul ati o n  
E n d of St u d y  
T h e e n d of st u d y i s d efi n e d a s w h e n t h e r e q uir e d n u m b er of d e at h s f or t h e fi n al a n al y si s of O S 
h a s b e e n o b s er v e d, w hi c h i s e x p e ct e d t o b e a p pr o xi m at el y 4 4  m o nt h s aft er t h e fir st p ati e nt i s 
r a n d o mi z e d.  A d diti o n all y, t h e S p o n s or m a y d e ci d e t o t er mi n at e t h e st u d y at a n y ti m e.  If t h e 
S p o n s or d e ci d e s t o t er mi n at e t h e st u d y, p ati e nt s w h o ar e still r e c ei vi n g st u d y tr e at m e nt or 
u n d er g oi n g s ur vi v al f o ll o w-u p m a y b e e nr oll e d i nt o a n e xt e n si o n st u d y or a n o n -i nt er v e nti o n al 
st u d y.  
O ut c o m e M e a s ur e s  
Effi c a c y O ut c o m e M e a s ur e s  
T h e c o -pri m ar y effi c a c y o ut c o m e m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g:  
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P F S, d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st o c c urr e n c e of di s e a s e pr o gr e s si o n 
a s d et er mi n e d b y t h e i n v e sti g at or u si n g R E CI S T v 1. 1 or d e at h fr o m a n y c a u s e, w hi c h e v er 
o c c ur s fir s t i n t h e t G E-W T p o p ul ati o n a n d t h e I T T -W T p o p ul ati o n  
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 7
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 5 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
•  
O S, d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o d e at h fr o m a n y c a u s e i n t h e  I T T- W T 
p o p ul ati o n  
 
T h e s e c o n d ar y effi c a c y o ut c o m e m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g:  
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O S i n t h e t G E -W T p o p ul ati o n  
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P F S, a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1, a n d O S i n t h e T C 2/ 3 or 
I C 2/ 3 W T p o p ul ati o n a n d t h e T C 1/ 2/ 3 or I C 1/ 2/ 3 W T p o p ul ati o n  
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P F S, a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1, a n d O S i n t h e t G E 
p o p ul ati o n a n d t h e I T T p o p ul ati o n  
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O bj e cti v e r e s p o n s e, d efi n e d a s p arti al r e s p o n s e ( P R) or c o m pl et e r e s p o n s e ( C R) a s 
d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1 i n t h e t G E-W T p o p ul ati o n a n d t h e 
I T T-W T p o p ul ati o n  
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D O R, d efi n e d a s t h e ti m e i nt er v al fr o m fir st o c c urr e n c e of a d o c u m e nt e d o bj e cti v e r e s p o n s e 
t o t h e ti m e of di s e a s e pr o gr e s si o n a s d et er mi n e d b y t h e i n v e sti g at or u si n g R E CI S T v 1. 1 or 
d e at h fr o m  a n y c a u s e, w hi c h e v er o c c ur s fir st  i n t h e t G E-W T p o p ul ati o n a n d t h e I T T - W T 
p o p ul ati o n  
•  
P F S, d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o t h e fir st o c c urr e n c e of di s e a s e pr o gr e s si o n 
a s d et er mi n e d b y t h e I R F u si n g R E CI S T v 1. 1 or d e at h fr o m a n y c a u s e, w hi c h e v er o c c ur s 
fir st i n t h e t G E-W T p o p ul ati o n a n d t h e I T T -W T p o p ul ati o n  
•  
O S r at e s at 1 a n d 2 y e ar s  i n t h e t G E-W T p o p ul ati o n a n d t h e I T T -W T p o p ul ati o n  
•  
P F S, a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1, a n d O S i n t h e  t w o 
at e z oli z u m a b -c o nt ai ni n g ar m s i n t h e t G E -W T p o p ul ati o n a n d t h e I T T -W T p o p ul ati o n  
•  
T TD i n p ati e nt -r e p ort e d l u n g c a n c er s y m pt o m s, d efi n e d a s ti m e fr o m r a n d o mi z ati o n t o 
d et eri or ati o n ( 1 0 -p oi nt c h a n g e) o n e a c h of t h e E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q -L C 1 3 
s y m pt o m  su b s c al e s i n t h e t G E -W T p o p ul ati o n a n d t h e I T T -W T p o p ul ati o n  
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C h a n g e fr o m b a s eli n e i n p ati e nt -r e p ort e d l u n g c a n c er s y m pt o m s ( c h e st p ai n, d y s p n e a, a n d 
c o u g h) o n t h e s y m pt o m s e v erit y s c or e of t h e S y m pt o m s i n  L u n g C a n c er s c al e i n t h e 
t G E-W T p o p ul ati o n a n d t h e  I T T-W T p o p ul ati o n  
 
S af et y O ut c o m e M e a s ur e s  
T h e s af et y o ut c o m e m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g:  
•  
I n ci d e n c e, n at ur e, a n d s e v erit y of a d v er s e e v e nt s gr a d e d a c c or di n g t o t h e N CI C T C A E v 4. 0  
•  
C h a n g e s i n vit al si g n s, p h y si c al fi n di n g s, a n d cli ni c al l a b or at or y r e s ult s d uri n g a n d f oll o wi n g 
at e z oli z u m a b a d mi ni str ati o n  
•  
I n ci d e n c e of A T A r e s p o n s e t o at e z oli z u m a b a n d p ot e nti al c orr el ati o n wit h P K, 
p h ar m a c o d y n a mi c, s af et y, a n d effi c a c y p ar a m et er s  
 
P h ar m a c o ki n eti c O ut c o m e M e a s ur e s  
T h e P K o ut c o m e m e a s ur e s f or t hi s st u d y ar e t h e f oll o wi n g:  
•  
M a xi m u m o b s er v e d s er u m at e z oli z u m a b c o n c e ntr ati o n ( C
m a x ) aft er i nf u si o n ( Ar m s A a n d B) 
•  
Mi ni m u m o b s er v e d s er u m at e z oli z u m a b c o n c e ntr ati o n ( C
mi n ) pri or t o i nf u si o n at s el e ct e d 
c y cl e s, at tr e at m e nt di s c o nti n u ati o n, a n d at 1 2 0  d a y s ( ±  3 0  d a y s) aft er t h e l a st d o s e of 
at e z oli z u m a b ( Ar m s A a n d B) 
•  
Pl a s m a c o n c e ntr ati o n s f or c ar b o pl ati n ( Ar m s A, B, a n d C)  
•  
Pl a s m a c o n c e ntr ati o n s f or p a clit a x el ( Ar m s A, B, a n d C)  
•  
B e v a ci z u m a b C m a x  a n d C mi n  ( Ar m s B a n d C) 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 8
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 6 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
E x pl or at or y O ut c o m e M e a s ur e s  
T h e e x pl or at or y o ut c o m e m e a s ur e s f or t hi s st u d y ar e:  
•  
T T R, d efi n e d a s t h e ti m e fr o m r a n d o mi z ati o n t o fir st o c c urr e n c e of a d o c u m e nt e d o bj e cti v e 
r e s p o n s e a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1 
•  
Ti m e i n r e s p o n s e ( TI R), d efi n e d a s 1 d a y f or n o n -r e s p o n der s a n d d efi n e d t h e s a m e a s D O R 
f or r e s p o n d er s, a s d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o R E CI S T v 1. 1  
•  
O bj e cti v e r e s p o n s e a n d D O R, a s d et er mi n e d b y t h e I R F a c c or di n g t o R E CI S T  v 1. 1  
•  
O bj e cti v e r e s p o n s e, P F S, a n d D O R, i n t h e t w o at e z oli z u m a b -c o nt ai ni n g ar m s, a s 
d et er mi n e d b y t h e i n v e sti g at or a c c or di n g t o m o difi e d R E CI S T ( Ar m s A a n d B)  
•  
P F S at 6 m o nt h s a n d at 1 y e ar  
•  
O S r at e at 3 y e ar s  
•  
St at u s of P D -L 1 − , i m m u n e- a n d N S C L C -r el at e d a n d ot h er e x pl or at or y bi o m ar k er s i n 
ar c hi v al a n d/ or fr e s hl y o bt ai n e d t u m or ti s s u e s, a n d bl o o d ( or bl o o d d eri v ati v e s) c oll e ct e d 
b ef or e, d uri n g, or aft er tr e at m e nt wit h at e z oli z u m a b or at pr o gr e s si o n a n d a s s o ci ati o n wit h 
di s e a s e st at u s a n d/ or r e s p o n s e t o at e z oli z u m a b  i n c o m bi n ati o n wit h c h e m ot h er a p y 
•  
St at u s of t u m or -i nfiltr ati n g i m m u n e cell s a n d ot h er e x pl or at or y bi o m ar k er s i n m a n d at or y 
bi o p s y s p e ci m e n s a n d bl o o d c oll e ct e d at pr o gr e s si o n  
•  
Utilit y s c or e s of t h e E Q -5 D -3 L  
•  
C h a n g e fr o m b a s eli n e i n p ati e nt -r e p ort e d o ut c o m e s of h e alt h-r el at e d q u alit y of lif e, 
l u n g c a n c er −r el at e d s y m pt o m s, a n d f u n cti o ni n g a s a s s e s s e d b y t h e E O R T C Q L Q-C 3 0 a n d 
L C 1 3  
 
I n v e sti g ati o n al M e di ci n al Pr o d u ct s 
T e st Pr o d u ct (I n v e sti g ati o n al Dr u g)  
At e z oli z u m a b ( 1 2 0 0 m g I V) will b e a d mi ni st er e d o n D a y 1 of e a c h 2 1 – d a y c y cl e.  At e z oli z u m a b 
will b e a d mi ni st er e d t o p ati e nt s w h o ar e r a n d o mi z e d t o Ar m s A a n d B.  
C o m p ar at or  
B e v a ci z u m a b ( 1 5 m g/ k g I V)  will b e a d mi ni st er e d o n D a y  1 of e a c h 2 1 -d a y c y cl e f or f o ur or 
si x  c y cl e s d uri n g t h e i n d u cti o n p h a s e a n d d uri n g t h e m ai nt e n a n c e p h a s e.  
B e v a ci z u m a b will b e a d mi ni st er e d t o p ati e nt s r a n d o mi z e d t o Ar m s B a n d C.  
N o n- I n v e sti g ati o n al M e di ci n al Pr o d u ct s 
•  
C ar b o pl ati n will b e a d mi ni st er e d b y I V i nf u si o n t o a c hi e v e a n i niti al t ar g et ar e a u n d er t h e 
c o n c e ntr ati o n −ti m e c ur v e ( A U C) of 6 m g/ m L/ mi n o n D a y 1 of e a c h 2 1-d a y c y cl e f or f o ur or 
si x c y cl e s d uri n g t h e i n d u cti o n p h a s e.  
•  
P a clit a x el ( 2 0 0 m g/ m 2  I V) will b e a d mi ni st er e d o n D a y 1 of e a c h 2 1-d a y c y cl e f or f o ur or 
si x  c y cl e s d uri n g t h e i n d u cti o n p h a s e.  
 
C ar b o pl ati n a n d p a clit a x el will b e a d mi ni st er e d t o p ati e nt s i n i n all tr e at m e nt ar m s.   
St ati sti c al M et h o d s  
Pri m ar y A n al y si s  
T h e c o -pri m ar y effi c a c y e n d p oi nt s ar e P F S a s a s s e s s e d b y t h e i n v e sti g at or u si n g R E CI S T v 1. 1, 
a n d O S.  T h e pri m ar y e n d p oi nt of P F S will b e a n al y z e d i n t h e t G E -W T p o p ul ati o n a n d i n t h e 
I T T-W T p o p ul ati o n, a n d t h e pri m ar y e n d p oi nt of O S will b e a n al y z e d i n t h e I T T -W T p o p ul ati o n.  
P F S i s  d efi n e d a s t h e ti m e b et w e e n t h e d at e of r a n d o mi z ati o n a n d t h e d at e of fir st d o c u m e nt e d 
di s e a s e pr o gr e s si o n or d e at h,  w hi c h e v er o c c ur s fir st.  P ati e nt s w h o h a v e n ot e x p eri e n c e d 
di s e a s e pr o gr e s si o n or di e d at t h e ti m e of a n al y si s will b e c e n s or e d at  t h e ti m e of t h e l a st t u m or  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 0 9
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 7 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x 1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
a s s e s s m e nt.  P ati e nt s wit h n o p o st -b a s eli n e t u m or a s s e s s m e nt will b e c e n s or e d at t h e d at e of 
r a n d o mi z ati o n pl u s 1 d a y. 
O S i s d efi n e d a s t h e ti m e b et w e e n t h e d at e of r a n d o mi z ati o n a n d d e at h fr o m a n y c a u s e.  D at a 
f or p ati e nt s w h o ar e n ot r e p ort e d a s h a vi n g di e d at t h e d at e of a n al y si s will b e c e n s or e d at t h e 
d at e w h e n t h e y w er e l a st k n o w n t o b e ali v e.  D at a f or p ati e nt s w h o d o n ot h a v e p o st -b a s eli n e 
i nf or m ati o n will b e c e n s or e d at t h e d at e of r a n d o mi z ati o n pl u s 1 d a y.  
T h e f oll o wi n g a n al y s e s will b e p erf or m e d f or b ot h P F S e n d p oi nt s d e s cri b e d a b o v e a n d f or O S.  
P F S a n d O S will b e c o m p ar e d b et w e e n tr e at m e nt  ar m s wit h t h e u s e of t h e str atifi e d l o g -r a n k 
t e st.  T h e H R f or P F S a n d O S f or e a c h c o m p ari s o n (i. e., Ar m A v s. Ar m C, Ar m B v s. Ar m C) 
will b e e sti m at e d u si n g a str atifi e d C o x r e gr e s si o n m o d el, r e s p e cti v el y.  T h e 9 5 % CI f or t h e H R 
will b e pr o vi d e d.  
T h e h y p ot h e si s t e sti n g will b e d o n e i n t h e or d er d e s cri b e d b el o w:  
C o m p ari s o n of Ar m  B v er s u s Ar m  C 
T o c o ntr ol t h e o v er all t y p e I err or r at e f or t h e o n e -si d e d t e st at 0. 0 2 5, a o n e -si d e d t y p e I err or ( α ) 
will b e all o c at e d t o P F S i n t h e t G E -W T  p o p ul ati o n, P F S i n t h e I T T-W T  p o p ul ati o n, a n d O S i n t h e 
I T T-W T  p o p ul ati o n i n a 3: 3: 1 9 r ati o f or c o m p ari s o n of Ar m B v er s u s Ar m  C 
1.  P F S i n t h e t G E -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 3 ( o n e si d e d).  If t h e e sti m at e of t h e 
H R i s <  1 a n d t h e o n e -si d e d p -v al u e c orr e s p o n di n g t o t h e str atifi e d l o g-r a n k t e st i s <  0. 0 0 3, 
t h e n ull h y p ot h e si s will b e r ej e ct e d, a n d it will b e c o n cl u d e d t h at at e z oli z u m a b +  
c ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b pr ol o n g s t h e d ur ati o n of P F S r el ati v e t o t h e c o ntr ol 
ar m i n t h e t G E -W T p o p ul ati o n.  
2.  P F S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 3 ( o n e si d e d).  
3.  α  r e c y cli n g fr o m P F S t o O S will b e c o n d u ct e d a s f oll o w s: 
a.  If t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er t h e t G E-W T p o p ul ati o n or t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 9 ( o n e si d e d).  
b.  If t h e P F S r e s ult i s o nl y st ati sti c all y si g nifi c a nt i n t h e t G E-W T p o p ul ati o n or t h e I T T - W T 
p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 2 2 ( o n e si d e d).  
c.  
If t h e P F S r e s ult i s st ati sti c all y si g nifi c a nt i n b ot h t h e t G E-W T p o p ul ati o n a n d t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 2 5 ( o n e si d e d).  
 
C o m p ari s o n of Ar m  A v er s u s Ar m  C 
If t h e diff er e n c e i n O S b et w e e n Ar m B a n d Ar m C i n t h e I T T-W T  p o p ul ati o n i s st ati sti c all y 
si g nifi c a nt at a n α  of 0. 0 1 9, 0. 0 2 2, or 0. 0 2 5 ( St e p 3 a b o v e), t h at s a m e α  will b e c o m e t h e o v er all 
o n e -si d e d t y p e I err or r at e f or t h e c o m p ari s o n of Ar m  A v er s u s Ar m C, wit h α  all o c at e d t o P F S 
i n t h e t G E-W T  p o p ul ati o n, P F S i n t h e I T T -W T  p o p ul ati o n, a n d O S i n t h e I T T -W T  p o p ul ati o n at 
t h e s a m e 3: 3: 1 9 r ati o.  If t h e diff er e n c e i n O S b et w e e n Ar m B a n d Ar m C i n t h e I T T- W T 
p o p ul ati o n i s n ot st ati sti c all y si g nifi c a nt, t h er e will b e n o f or m al c o m p ari s o n of Ar m  A v er s u s 
Ar m  C f or t h e c o -pri m ar y e n d p oi nt s of P F S a n d O S.  
D e p e n di n g o n t h e o ut c o m e of t h e P F S t e sti n g of Ar m A v s. Ar m C i n t h e t G E -W T a n d I T T - W T 
p o p ul ati o n s, t h e α  fr o m t h e s e t w o P F S c o m p ari s o n s will b e r e c y cl e d b a c k t o t h e O S c o m p ari s o n 
i n t h e I T T-W T p o p ul at i o n f or Ar m A v s. Ar m C. 
1.  If t h e diff er e n c e i n O S b et w e e n Ar m B a n d Ar m C i s st ati sti c all y si g nifi c a nt at α  =  0. 0 1 9 
( o n e si d e d):  
a.  P F S i n t h e t G E -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 2 2 8 ( o n e si d e d).  If t h e e sti m at e 
of t h e H R i s <  1 a n d t h e o n e -si d e d p -v al u e c orr e s p o n di n g t o t h e str atifi e d l o g -r a n k t e st 
i s <  0. 0 0 2 2 8, t h e n ull h y p ot h e si s will b e r ej e ct e d, a n d it will b e c o n cl u d e d t h at 
at e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el pr ol o n g s t h e d ur ati o n of P F S r el ati v e t o t h e 
c o ntr ol ar m i n t h e t G E -W T p o p ul ati o n.  
b.  P F S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 2 2 8 ( o n e si d e d ) 
c.  
α  r e c y cli n g fr o m P F S t o O S will b e c o n d u ct e d a s f oll o w s: 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 0
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 8 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
•  
If t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er t h e t G E-W T p o p ul ati o n or 
t h e I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 4 4 4 
( o n e si d e d). 
•  
If t h e P F S r e s ult i s o nl y st ati sti c all y si g nifi c a nt i n t h e t G E-W T p o p ul ati o n or t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 6 7 2 
( o n e si d e d) . 
•  
If t h e P F S r e s ult is st ati sti c all y si g nifi c a nt i n b ot h t h e t G E -W T p o p ul ati o n a n d t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 9 
( o n e si d e d).  
2.  If t h e diff er e n c e i n O S b et w e e n Ar m B a n d Ar m C i s st ati sti c all y si g nifi c a nt at α  =  0. 0 2 2 
( o n e si d e d):  
a.  P F S i n t h e t G E -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 2 6 4 ( o n e si d e d).  If t h e e sti m at e 
of t h e H R i s <  1 a n d t h e o n e -si d e d p -v al u e c orr e s p o n di n g t o t h e str atifi e d l o g -r a n k t e st 
i s <  0. 0 0 2 6 4, t h e n ull h y p ot h e si s will b e r ej e ct e d, a n d it will b e c o n cl u d e d t h at 
at e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el pr ol o n g s t h e d ur ati o n of P F S r el ati v e t o t h e 
c o ntr ol ar m i n t h e t G E -W T p o p ul ati o n.  
b.  P F S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 2 6 4 ( o n e si d e d ) 
c.  
α  r e c y cli n g fr o m P F S t o O S will b e c o n d u ct e d a s f oll o w s: 
•  
If t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er t h e t G E-W T p o p ul ati o n or 
t h e I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 6 7 2 
( o n e si d e d). 
•  
If t h e P F S r e s ult i s o nl y st ati sti c all y si g nifi c a nt i n t h e t G E -W T p o p ul ati o n or t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 9 3 6 
( o n e si d e d) . 
•  
If t h e P F S r e s ult i s st ati sti c all y si g nifi c a nt i n b ot h t h e t G E-W T p o p ul ati o n a n d t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 2 2 
( o n e si d e d).  
3.  If t h e diff er e n c e i n O S b et w e e n Ar m B a n d Ar m C i s st ati sti c all y si g nifi c a nt at α  =  0. 0 2 5 
( o n e si d e d):  
a.  P F S i n t h e t G E -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 3 ( o n e si d e d).  If t h e e sti m at e of 
t h e H R i s <  1 a n d t h e o n e -si d e d p -v al u e c orr e s p o n di n g t o t h e str atifi e d l o g -r a n k t e st 
i s <  0. 0 0 3, t h e n ull h y p ot h e si s will b e r ej e ct e d, a n d it will b e c o n cl u d e d t h at 
at e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el pr ol o n g s t h e d ur ati o n of P F S r el ati v e t o t h e 
c o ntr ol ar m i n t h e t G E -W T p o p ul ati o n.  
b.  P F S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 0 3( o n e si d e d ) 
c.  
α  r e c y cli n g fr o m P F S t o O S will b e c o n d u ct e d a s f oll o w s: 
•  
If t h e P F S r e s ult i s n ot st ati sti c all y si g nifi c a nt i n eit h er t h e t G E-W T p o p ul ati o n o r 
t h e I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 1 9 
( o n e si d e d). 
•  
If t h e P F S r e s ult i s o nl y st ati sti c all y si g nifi c a nt i n t h e t G E-W T p o p ul ati o n or t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 2 2  
( o ne si d e d) . 
•  
If t h e P F S r e s ult i s st ati sti c all y si g nifi c a nt i n b ot h t h e t G E-W T p o p ul ati o n a n d t h e 
I T T-W T p o p ul ati o n, O S i n t h e I T T -W T p o p ul ati o n will b e t e st e d at α  =  0. 0 2 5 
( o n e si d e d).  
 
T h e str atifi c ati o n f a ct or s will b e t h o s e u s e d d uri n g r a n d o mi z ati o n (i. e. , s e x [ m al e v s. f e m al e], 
pr e s e n c e of li v er m et a st a s e s at b a s eli n e [ y e s v s. n o], a n d P D -L 1 t u m or e x pr e s si o n b y I H C [ T C 3 
a n d a n y I C v s. T C 0/ 1/ 2 a n d I C 2/ 3 v s. T C 0/ 1/ 2 a n d I C 0/ 1]), a s r e c or d e d i n t h e i nt er a cti v e v oi c e  
a n d W e b r e s p o n s e s y st e m . 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 1
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
4 9 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
R e s ult s fr o m a n u n str atifi e d a n al y si s will al s o b e pr e s e nt e d.  K a pl a n -M ei er m et h o d ol o g y will b e 
u s e d t o e sti m at e t h e m e di a n P F S a n d t h e m e di a n O S f or e a c h tr e at m e nt ar m, a n d a 
K a pl a n -M ei er c ur v e will b e c o n str u ct e d t o pr o vi d e a vi s u al d e s cri pti o n of t h e diff er e n c e b et w e e n 
tr e at m e nt ar m s.  T h e Br o o k m e y er-Cr o wl e y m et h o d ol o g y will b e u s e d t o c o n str u ct t h e 9 5 % CI 
f or t h e m e di a n P F S a n d t h e m e di a n O S f or e a c h tr e at m e nt ar m. 
D et er mi n ati o n of S a m pl e Si z e  
T hi s st u d y will e nr oll a p pr o xi m at el y 1 2 0 0 p ati e nt s.  T h e I T T -W T p o p ul ati o n wi ll i n cl u d e 
a p pr o xi m at el y 1 0 8 0 p ati e nt s, a s s u mi n g a 1 0 % pr e v al e n c e f or s e n siti zi n g E G F R  m ut ati o n s or 
A L K  tr a n sl o c ati o n s.  T h e t G E-W T p o p ul ati o n will i n cl u d e a p pr o xi m at el y 5 4 0  p ati e nt s, a s s u mi n g 
a 5 0 % pr e v al e n c e wit h t h e c h o s e n t G E c ut off.  
T h e s a m pl e si z e of  t hi s st u d y i s b a s e d o n t h e n u m b er of e v e nt s r e q uir e d t o d e m o n str at e 
effi c a c y wit h r e g ar d t o b ot h P F S a n d O S ( c o -pri m ar y e n d p oi nt s).  
T h e e sti m at e of t h e n u m b er of e v e nt s r e q uir e d t o d e m o n str at e effi c a c y wit h r e g ar d t o P F S i n  t h e 
c o m p ari s o n of Ar m A v er s u s Ar m B i s b a s e d o n t h e f oll o wi n g a s s u m pti o n s:  
•  
O n e -si d e d si g nifi c a n c e l e v el of 0. 0 0 3 f or t h e c o m p ari s o n of Ar m B v er s u s Ar m C i n t h e 
t G E-W T p o p ul ati o n  
•  
O n e -si d e d si g nifi c a n c e l e v el of 0. 0 0 3 f or t h e c o m p ari s o n of Ar m B v er s u s Ar m C i n t h e 
I T T-W T p o p ul ati o n  
•  
9 8 %  po w er t o d et e ct a n H R of 0. 5 5, c orr e s p o n di n g t o a n i m pr o v e m e nt i n m e di a n P F S fr o m 
6 m o nt h s t o 1 0. 9  m o nt h s i n t h e t G E -W T p o p ul ati o n  
•  
9 8 % p o w er t o d et e ct a n H R of 0. 6 5, c orr e s p o n di n g t o a n i m pr o v e m e nt i n m e di a n P F S fr o m 
6 m o nt h s t o 9. 2 m o nt h s i n t h e I T T -W T p o p ul ati o n  
•  
N o i nt eri m a n al y si s f or P F S  
•  
Dr o p o ut r at e of 5 % p er 1 2 m o nt h s  
  
T h e e sti m at e of t h e n u m b er of e v e nt s r e q uir e d t o d e m o n str at e effi c a c y wit h r e g ar d t o O S i n t h e 
c o m p ari s o n of Ar m A v er s u s Ar m B i s b a s e d o n t h e f o ll o wi ng a s s u m pti o n s:  
•  
O n e -si d e d si g nifi c a n c e l e v el  of 0. 0 1 9 f or t h e c o m p ari s o n of Ar m B v er s u s Ar m C i n t h e 
I T T-W T p o p ul a ti o n 
•  
8 7 % p o w er t o d et e ct a n H R of 0. 7 5, c orr e s p o n di n g t o a n i m pr o v e m e nt i n m e di a n O S fr o m 
1 2 m o nt h s t o 1 6 m o nt h s i n t h e  I T T-W T p o p ul ati o n 
•  
O n e i nt eri m O S a n al y si s p erf or m e d at t h e ti m e of t h e fi n al P F S a n al y si s, at w hi c h ti m e 
a p pr o xi m at el y 7 3 % of t h e t ot al n u m b er of O S e v e nt s r e q uir e d f or t h e fi n al a n al y si s ar e 
e x p e ct e d t o h a v e o c c urr e d a s d et er mi n e d t hr o u g h u s e of t h e L a n -D e M et s a p pr o xi m ati o n t o 
t h e O’ Bri e n-Fl e mi n g b o u n d ar y  
•  
Dr o p o ut r at e of 5 % p er 1 2 m o nt h s  
 
T h e e sti m at e of t h e n u m b er of e v e nt s r e q uir e d t o d e m o n str at e effi c a c y wit h r e g ar d t o P F S a n d 
O S i n t h e c o m p ari s o n of Ar m A v er s u s Ar m C i s b a s e d o n a s s u m pti o n s si mil ar t o t h o s e o utli n e d 
a b o v e f or Ar m B v er s u s Ar m C.  
Wit h t h e s e a s s u m pti o n s, a p pr o xi m at el y 1 2 0 0 p ati e nt s i n t ot al will b e e nr oll e d i nt o t hi s st u d y, 
wit h a p pr o xi m at el y 7 2 0 p ati e nt s i n e a c h c o m p ari s o n (i. e., Ar m B v s. Ar m C a n d Ar m A v s. 
Ar m  C) i n t h e I T T -W T p o p ul ati o n.  T h e fi n al  P F S a n al y si s will b e c o n d u ct e d w h e n b ot h of t h e 
f oll o wi n g crit eri a h a v e b e e n m et:  a p pr o xi m at el y 5 1 6 P F S e v e nt s h a v e o c c urr e d i n Ar m s B a n d 
C c o m bi n e d i n t h e I T T -W T p o p ul ati o n a n d t h e l a st p ati e nt h a s b e e n e nr oll e d i n t h e st u d y.  T h e 
fi n al P F S a n al y si s i s e x p e ct e d t o o c c ur a p pr o xi m at el y 2 9  m o nt h s aft er t h e fir st p ati e nt i s 
e nr oll e d.  At t h e ti m e of t h e fi n al P F S a n al y si s, it i s e x p e ct e d t h at a p pr o xi m at el y 2 4 9 e v e nt s will 
h a v e o c c urr e d i n t h e t G E -W T p o p ul ati o n.  T h e s e n u m b er s of e v e nt s w o ul d all o w f or a mi n i m u m 
d et e ct a bl e diff er e n c e c orr e s p o n di n g t o a n H R of a p pr o xi m at el y 0. 7 0 i n t h e t G E -W T p o p ul ati o n 
a n d 0. 7 8 i n t h e I T T -W T p o p ul ati o n.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 2
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 0 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  1  
Pr ot o c ol S y n o p si s  ( c o nt.) 
Wit h a s a m pl e si z e of 7 2 0 p ati e nt s, a p pr o xi m at el y 5 0 7 O S e v e nt s ar e e x p e ct e d t o o c c ur i n 
Ar m s  B a n d C c o m bi n e d i n t h e I T T -W T  p o p ul ati o n f or t h e fi n al O S a n al y si s.  T h e fi n al O S 
a n al y si s i s e x p e ct e d t o o c c ur a p pr o xi m at el y 4 0 m o nt h s aft er t h e fir st p ati e nt i s e nr oll e d.  T hi s 
n u m b er of e v e nt s c orr e s p o n d s t o a mi ni m u m d et e ct a bl e diff er e n c e i n H R of a p pr o xi m at el y 0. 8 3 
i n t h e I T T-W T p o p ul ati o n  
I nt eri m A n al y s e s 
T h er e will b e n o i nt eri m a n al y s e s pl a n n e d f or P F S i n t hi s st u d y.  A n e xt er n al i n d e p e n d e nt D at a 
M o nit ori n g C o m mitt e e (i D M C) will b e s et u p t o e v al u at e s af et y d at a o n a n o n g oi n g b a si s.  All 
s u m m ari e s/ a n al y s e s b y tr e at m e nt ar m f or t h e i D M C’ s r e vi e w will b e pr e p ar e d b y a n 
i n d e p e n d e nt D at a C o or di n ati n g C e nt er (i D C C).  M e m b er s of t h e i D M C will b e e xt er n al t o t h e 
S p o n s or a n d will f oll o w a c h art er t h at o utli n e s t h eir r ol e s a n d r e s p o n si biliti e s.  A n y o ut c o m e s of 
t h e s e s af et y r e vi e w s t h at aff e ct st u d y c o n d u ct will b e c o m m u ni c at e d i n a ti m el y m a n n er t o t h e 
i n v e sti g at or s f or n otifi c ati o n of t h e I n stit uti o n al R e vi e w B o ar d s (I R B s)/ Et hi c s C o m mitt e e s ( E C s).  
A d et ail e d pl a n will b e i n cl u d e d i n t h e i D M C C h art er.  
If a p pr o xi m at el y 3 7 0 O S e v e nt s h a v e o c c urr e d i n Ar m s B a n d C c o m bi n e d i n t h e I T T- W T 
p o p ul ati o n at t h e ti m e of t h e fi n al P F S a n al y si s ( s e e crit eri a f or fi n al P F S a n al y si s), a n i nt eri m 
O S a n al y si s will b e c o n d u ct e d f or Ar m B v er s u s Ar m C i n t h e I T T -W T p o p ul ati o n.  If t h er e ar e 
si g nifi c a ntl y f e w er t h a n t h e e x p e ct e d 3 7 0 O S e v e nt s at t h e ti m e of t h e fi n al P F S a n al y si s, a 
n o mi n al α  of 0. 0 1 % ( n e gli gi bl e i m p a ct o n o v er all t y p e I err or r at e) will b e s p e nt o n t h e O S 
a n al y si s at t h e ti m e of t h e fi n al P F S a n al y si s a n d a s e c o n d i nt eri m O S a n al y si s will t h e n b e 
c o n d u ct e d aft er a p pr o xi m at el y 3 7 0 O S e v e nt s h a v e o c c urr e d.  
T h e fi n al O S a n al y si s f or t h e c o m p ari s o n of Ar m B v er s u s Ar m C will b e c o n d u ct e d w h e n 
a p pr o xi m at el y 5 0 7 O S e v e nt s h a v e o c c urr e d i n Ar m s B a n d C c o m bi n e d i n t h e I T T - W T 
p o p ul ati o n.  T hi s i s e x p e ct e d t o o c c ur a p pr o xi m at el y 4 0 m o nt h s aft er t h e fir st p ati e nt i s e nr oll e d.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 3
 
 
 
 
 
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 1 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  2  
S c h e d ul e of A s s e s s m e nt s  
Pr o c e d ur e  
S cr e e ni n g  
All Tr e at m e nt C y cl e s a  
Tr e at m e nt 
Di s c o nti n u ati o n  Vi sit  
S ur vi v al F oll o w -U p  
D a y s – 2 8  
t o – 1  
I nd u cti o n P h a s e  
(C y cl e s 1 t o 4 or 6)  
M ai nt e n a n c e  
P h a s e  
≤ 3 0 D a y s aft er L a st 
D o s e  
E v er y 3 M o nt h s 
aft er Di s e a s e 
Pr o gr e s si o n or 
L o s s of Cli ni c al 
B e n efit  
E v er y 2 1 d a y s  
(±  3 D a y s) b  
E v er y 2 1 d a y s  
(±  3 D a y s)  
I nf or m e d c o n s e nt  
x 
 
 
 
 
T u m or ti s s u e s p e ci m e n f or P D-L 1 t e sti n g 
( 1 5 F F P E sli d e s r e q uir e d; bl o c k s pr ef err e d) c 
Fr e s h or ar c hi v al ti s s u e c a n b e u s e d.  
x 
 
 
 
 
A L K  a n d/ or E G F R  a s s e s s m e nt if  st at u s i s 
u n k n o w n ( m a y b e d o n e l o c all y or c e ntr all y)  
x  
 
 
 
 
D e m o gr a p hi c d at a  
x 
 
 
 
 
M e di c al hi st or y a n d b a s eli n e c o n diti o n s  
x 
 
 
 
 
N S C L C c a n c er hi st or y  
x 
 
 
 
 
Vit al si g n s  d 
x 
x  d 
x  d 
x  d 
 
W ei g ht  
x 
x 
x 
x 
 
H ei g ht  
x 
 
 
 
 
C o m pl et e p h y si c al e x a mi n ati o n  
x 
 
 
 
 
Li mit e d p h y si c al e x a mi n ati o n e  
 
x 
x 
x 
 
E C O G p erf or m a n c e  st at u s  
x 
x 
x 
x 
 
1 2 -L e a d E C G  
x 
x f 
x f 
x f 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 4
 
 
 
 
 
 
A p p e n di x  2  
S c h e d ul e of A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 2 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
Pr o c e d ur e  
S cr e e ni n g  
All Tr e at m e nt C y cl e s a  
Tr e at m e nt 
Di s c o nti n u ati o n  Vi sit  
S ur vi v al F oll o w -U p  
D a y s – 2 8  
t o – 1  
I nd u cti o n P h a s e  
(C y cl e s 1 t o 4 or 6)  
M ai nt e n a n c e  
P h a s e  
≤ 3 0 D a y s aft er L a st 
D o s e  
E v er y 3 M o nt h s 
aft er Di s e a s e 
Pr o gr e s si o n or 
L o s s of Cli ni c al 
B e n efit  
E v er y 2 1 d a y s  
(±  3 D a y s) b  
E v er y 2 1 d a y s  
(±  3 D a y s)  
H e m at ol o g y  g 
x 
x 
x 
x 
 
S er u m c h e mi str y  h 
x 
x 
x 
x 
 
C o a g ul ati o n  t e st ( a P T T or IN R)  
x 
 
 
x 
 
P r e g n a n c y t e st  ( w o m e n of chil d b e ari n g -p ot e nti al 
O N L Y)  
x  i 
x  j 
x  j 
x  j 
x  x 
T S H, fr e e T 3, fr e e T 4  k 
x 
x  k 
x  k 
x 
 
HI V, H B V, H C V s er ol o g y  l 
x 
 
 
 
 
Uri n al y si s  m 
x 
x 
x 
x 
 
D et er mi n at i o n of d ur ati o n of in d u cti o n tr e at m e nt   
x 
 
 
 
 
I n d u cti o n tr e at m e nt a d mi ni str ati o n 
Ar m A: At e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el  
Ar m B: At e z oli z u m a b  +  c ar b o pl ati n  +  p a clit a x el  +   
b e v a ci z u m a b  
Ar m C: C ar b o pl ati n  +  p a clit a x el  +  b e v a ci z u m a b  
 
x  n 
 
 
 
M ai nt e n a n c e tr e at m e nt a d mi ni str ati o n  
Ar m A:  At e z oli z u m a b  
Ar m B:   At e z oli z u m a b +  b e v a ci z u m a b  
Ar m C:  B e v a ci z u m a b  
 
 
x  n 
 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 5
 
 
 
 
 
 
A p p e n di x  2  
S c h e d ul e of A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 3 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
Pr o c e d ur e  
S cr e e ni n g  
All Tr e at m e nt C y cl e s a  
Tr e at m e nt 
Di s c o nti n u ati o n  Vi sit  
S ur vi v al F oll o w -U p  
D a y s – 2 8  
t o – 1  
I nd u cti o n P h a s e  
(C y cl e s 1 t o 4 or 6)  
M ai nt e n a n c e  
P h a s e  
≤ 3 0 D a y s aft er L a st 
D o s e  
E v er y 3 M o nt h s 
aft er Di s e a s e 
Pr o gr e s si o n or 
L o s s of Cli ni c al 
B e n efit  
E v er y 2 1 d a y s  
(±  3 D a y s) b  
E v er y 2 1 d a y s  
(±  3 D a y s)  
T u m or r e s p o n s e a s s e s s m e nt   
x  o 
x  p 
x  p 
 
x  q 
S er u m s a m pl e f or at e z oli z u m a b AT A a s s e s s m e nt 
(at e z oli z u m a b p ati e nt s o nl y)  r 
 
x 
x 
x 
1 2 0 ( ±  3 0)  d a y s 
aft er l a st d o s e of 
at e z oli z u m a b  
S er u m s a m pl e f or P K s a m pli n g ( at e z oli z u m a b-
tr e at e d p ati e nt s o nl y) r 
 
x 
x 
x 
1 2 0 ( ±  3 0)  d a y s 
aft er l a st d o s e of 
at e z oli z u m a b  
C ar b o pl ati n, p a clit a x el, a n d b e v a ci z u m a b 
( Ar m s B a n d C) P K s a m pli n g ( 2 0 p ati e nt s p er 
ar m)  r 
 
x 
 
x 
 
B e v a ci z u m a b A T A a n d P K s a m pli n g  
( Ar m s B a n d C p ati e nt s)  r 
 
x 
 
x 
 
Bl o o d  s a m pl e s f or  P D bi o m ar k er s 
r 
x 
x 
x 
x 
1 2 0 ( ±  3 0)  d ay s 
aft er l a st d o s e of 
at e z oli z u m a b  
O pti o n al bl o o d f or D N A e xtr a cti o n ( R C R o nl y) r, s  
 
x 
I nf or m e d c o n s e nt t o c o nti n u e tr e at m e nt b e y o n d 
r a di o gr a p hi c pr o gr e s si o n ( at e z oli z u m a b-tr e at e d 
p ati e nt s)  
 
At ti m e of r a di o gr a p hi c pr o gr e s si o n  
 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 6
 
 
 
 
 
 
A p p e n di x  2  
S c h e d ul e of A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 4 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
Pr o c e d ur e  
S cr e e ni n g  
All Tr e at m e nt C y cl e s a  
Tr e at m e nt 
Di s c o nti n u ati o n  Vi sit  
S ur vi v al F oll o w -U p  
D a y s – 2 8  
t o – 1  
I nd u cti o n P h a s e  
(C y cl e s 1 t o 4 or 6)  
M ai nt e n a n c e  
P h a s e  
≤ 3 0 D a y s aft er L a st 
D o s e  
E v er y 3 M o nt h s 
aft er Di s e a s e 
Pr o gr e s si o n or 
L o s s of Cli ni c al 
B e n efit  
E v er y 2 1 d a y s  
(±  3 D a y s) b  
E v er y 2 1 d a y s  
(±  3 D a y s)  
T u m or bi o p s y  
 
At ti m e of r a di o gr a p hi c pr o gr e s si o n y 
 
 
O pti o n al t u m or bi o p s y at ot h er ti m e p oi nt s ( R C R 
o nl y)  
 
A n y ti m e d ur i n g st u d y tr e at m e nt or d uri n g s ur vi v al f oll o w-u p  
A d v er s e e v e nt s  
x   
x 
x 
x  t 
x  t 
C o n c o mit a nt m e di c ati o n s  
x u 
x 
x 
x 
 
P ati e nt -r e p ort e d o utc o m e s ( E O R T C Q L Q -C 3 0, 
E O R T C Q L Q -L C 1 3, SI L C, P GI S, a n d  
E Q- 5 D -3 L) v 
 
x v 
x  v 
 
x v 
S ur vi v al a n d a nti -c a n c er t h er a p y f oll o w -u p  
 
 
 
 
x  w 
 
A T A  =  a nti -t h er a p e uti c a nti b o d y; C T  =  c o m p ut e d t o m o gr a p h y; E C O G  =  E a st er n C o o p er ati v e O n c ol o g y Gr o u p; E O R T C  =  E ur o p e a n 
Or g a ni z ati o n f or R e s e ar c h a n d Tr e at m e nt of C a n c er; e P R O  =  el e ctr o ni c P ati e nt -R e p ort e d O ut c o m e; E Q -5 D -3 L  =  E ur o Q o L 5 Di m e n si o n s 3 -
L e v el V er si o n; F F P E  =  f or m ali n fi x e d p ar affi n e m b e d d e d; H B c A b  =  h e p atiti s B c or e a nti b o d y; H B V  =  h e p atiti s B vir u s; H C V  =  h e p atiti s C vir u s; 
I V =  i ntr a v e n o u s; L C 1 3 =  L u n g C a n c er m o d ul e; M RI  =  m a g n eti c r e s o n a n c e i m a gi n g; N S C L C  =  n o n −s m all c ell l u n g c a n c er; 
P D  =  p h ar m a c o d y n a mi c; P GI S  =  P ati e nt Gl o b al I m pr e s si o n of S e v erit y; P K  =  p h ar m a c o ki n eti c; Q L Q -C 3 0  =  Q u alit y -of -Lif e Q u e sti o n n air e C or e 
3 0; R C R  =  R o c h e Cli ni c al R e p o sit or y; SI L C  =  S y m pt o m s i n L u n g C a n c er; T S H  =  t h yr oi d-sti m ul ati n g h or m o n e.  
  
a A s s e s s m e nt s s h o ul d b e p erf or m e d b ef or e st u d y dr u g i nf u si o n u nl e s s ot h er wi s e  n ot e d.  
  
b C y cl e 1, D a y 1 m u st b e p erf or m e d wit hi n 5 d a y s aft er t h e p ati e nt i s r a n d o mi z e d.  S cr e e ni n g a s s e s s m e nt s p erf or m e d ≤ 9 6 h o ur s b ef or e C y cl e 1 
 D a y 1 ar e n ot r e q uir e d t o b e r e p e at e d f or C y cl e 1 D a y 1.  I n a d diti o n, E C O G p erf or m a n c e st at u s, li mit e d p h y si c al e x a mi n ati o n, a n d l o c al 
 l a b or at or y t e st s m a y b e p erf or m e d ≤ 9 6 h o ur s b ef or e D a y 1 of e a c h c y cl e.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 7
 
 
 
 
 
 
A p p e n di x  2  
S c h e d ul e of A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 5 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
c If a r e pr e s e nt ati v e F F P E t u m or s p e ci m e n i n p ar affi n bl o c k ( pr ef err e d) or 1 5 or m or e u n st ai n e d, fr e s hl y c ut, s eri al s e cti o n s o n sli d e s fr o m a n 
F F P E t u m or s p e ci m e n i s n ot a v ail a bl e f or P D -L 1 t e sti n g, c o nt a ct t h e M e di c al M o nit or t o di s c u s s t o d et er mi n e if t h e p ati e nt m a y p arti ci p at e i n t h e 
st u d y.  Fi n e -n e e dl e a s pir ati o n  (d efi n e d a s s a m pl e s t h at d o n ot pr e s er v e ti s s u e ar c hit e ct ur e a n d yi el d a c ell s u s p e n si o n a n d/ or c ell s m e ar s), 
br u s hi n g, c ell p ell et s fr o m pl e ur al eff u si o n, a n d l a v a g e s a m pl e s ar e N O T a c c e pt a bl e.  F or c or e n e e dl e bi o p s y s p e ci m e n s, at l e a st t hr e e c or e s 
s h o ul d b e s u b mitt e d f or e v al u ati o n.  R etri e v al of ar c hi v al t u m or s a m pl e c a n o c c ur o ut si d e t h e 2 8 -d a y s cr e e ni n g p eri o d pri or t o e nr oll m e nt.  
d Vit al si g n s i n cl u d e  p ul s e  r at e, r e s pir at or y r at e, bl o o d pr e s s ur e s, a n d t e m p er at ur e.  Vit al si g n s s h o ul d b e r e c or d e d a s d e s cri b e d.  F or all sit e s i n 
Ar g e nti n a, p ul s e o xi m etr y will b e p erf or m e d at e v er y vi sit a n d t h e s e d at a will n ot b e r e c or d e d.  
e S y m pt o m -dir e ct e d p h y si c al e x a mi n ati o n s . 
f E C G r e c or di n g s will b e o bt ai n e d w h e n cli ni c all y i n di c at e d.  
g  H e m at ol o g y c o n si st s of C B C, i n cl u di n g R B C c o u nt, h e m o gl o bi n, h e m at o crit, W B C c o u nt wit h diff er e nti al  (n e utr o p hil s, l y m p h o c yt e s, e o si n o p hil s, 
m o n o c yt e s, b a s o p hil s, a n d ot h er c ell s), a n d pl at el et c o u nt.  
h  S er u m c h e mi str y i n cl u d e s B U N or ur e a, cr e ati ni n e, s o di u m, p ot a s si u m, m a g n e si u m, c hl ori d e, bi c ar b o n at e or t ot al C O 2 , c al ci u m, p h o s p h or u s, 
gl u c o s e, t ot al  bilir u bi n, A L T, A S T, al k ali n e p h o s p h at a s e, L D H, t ot al pr ot ei n, a n d al b u mi n . 
i S er u m pr e g n a n c y t e st wit hi n 1 4 d a y s b ef or e C y cl e 1, D a y 1.  
j Uri n e pr e g n a n c y t e st s; if  a uri n e pr e g n a n c y t e st i s p o siti v e, it m u st b e c o nfir m e d b y a s er u m pr e g n a n c y t e st.  
k T h yr oi d f u n cti o n t e sti n g (t h yr oi d -sti m ul ati n g h or m o n e, fr e e T 3, fr e e T 4) c oll e ct e d at C y cl e 1, D a y 1 a n d e v er y f o urt h c y cl e t h er e aft er.  T ot al T 3 will 
b e t e st e d o nl y at sit e s w h er e fr e e T 3 i s n ot p erf or m e d.  
l All p ati e nt s wi ll b e t e st e d f or HI V pri or t o t h e i n cl u si o n i nt o t h e st u d y a n d HI V-p o siti v e p ati e nt s will b e e x cl u d e d fr o m t h e cli ni c al st u d y.  P ati e nt s 
wit h a cti v e h e p atiti s B ( c hr o ni c or a c ut e; d efi n e d a s h a vi n g a p o siti v e H B s A g t e st r e s ult at s cr e e ni n g) will b e e x cl u d e d fr o m t h e st u d y.  P ati e nt s 
wit h p a st or r e s ol v e d H B V i nf e cti o n ( d efi n e d a s t h e pr e s e n c e of H B c A b a n d a b s e n c e of H B s A g) ar e eli gi bl e o nl y if t h eir H B V D N A t e st i s n e g ati v e.  
P ati e nt s wit h H C V will b e e x cl u d e d fr o m t h e st u d y; p ati e nt s w h o t e st p o siti v e f or H C V a nti b o d y ar e eli gi bl e o nl y if p ol y m er a s e c h ai n r e a cti o n i s 
n e g ati v e f or H C V R N A . 
m  Uri n al y si s b y di p sti c k ( s p e cifi c gr a vit y, p H, gl u c o s e, pr ot ei n, k et o n e s, a n d bl o o d).  
n  F or at e z oli z u m a b, t h e i niti al d o s e will b e d eli v er e d o v er 6 0 ( ±  1 5) mi n ut e s.  If t h e fir st i nf u si o n i s w ell t ol er at e d, all  s u b s e q u e nt i nf u si o n s m a y b e 
d eli v er e d o v er 3 0 ( ±  1 0)  mi n ut e s u ntil di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 or l o s s of cli ni c al b e n efit.  F or b e v a ci z u m a b, c ar b o pl ati n, a n d 
p a clit a x el, st u d y dr u g will b e a d mi ni st er e d a c c or di n g t o t h e l o c al pr e s cri bi n g i nf or m ati o n, i n cl u di n g pr e m e di c ati o n wit h st er oi d s.  
o  C T s c a n s ( wit h  or al/I V c o ntr a st u nl e s s c o ntr ai n di c at e d) or M RI of t h e c h e st a n d a b d o m e n.  A C T or M RI s c a n of t h e p el vi s i s r e q uir e d at 
s cr e e ni n g a n d a s cli ni c all y i n di c at e d or a s p er l o c al st a n d ar d of c ar e at s u b s e q u e nt r e s p o n s e e v al u ati o n s.  A C T ( wit h c o ntr a st) or M RI s c a n  of 
t h e h e a d m u st b e d o n e at s cr e e ni n g t o e v al u at e C N S m et a st a si s i n all p ati e nt s.  


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 8
 
 
 
 
 
 
A p p e n di x  2  
S c h e d ul e of A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 6 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
p  P erf or m e v er y 6 w e e k s (  ±  7 d a y s) ( a p pr o xi m at el y e v er y t w o c y cl e s) f or 4 8 w e e k s  f oll o wi n g C y cl e 1, D a y 1 a n d t h e n e v er y 9 w e e k s (±  7 d a y s) 
t h er e aft er aft er c o m pl eti o n of t h e W e e k 4 8 t u m or a s s e s s m e nt, r e g ar dl e s s of tr e at m e nt d el a y s, u ntil r a di o gr a p hi c di s e a s e pr o gr e s si o n ( or l o s s of 
cli ni c al b e n efit  f or p ati e nt s a s si g n e d t o at e z oli z u m a b w h o h a d c o nti n u e d tr e at m ent wit h at e z oli z u m a b aft er r a di o gr a p hi c di s e a s e pr o gr e s si o n 
a c c or di n g t o R E CI S T v 1. 1), wit h dr a w al of c o n s e nt, d e at h, or st u d y t er mi n ati o n b y t h e S p o n s or, w hi c h e v er o c c ur s f ir st. 
q  If a p ati e nt  di s c o nti n u e s st u d y tr e at m e nt f or a n y r e a s o n ot h er t h a n r a di o gr a p hi c di s e a s e pr o gr e s si o n  p er R E CI S T v 1. 1 ( e. g., t o xi cit y, 
s y m pt o m ati c d et eri or ati o n), t u m or a s s e s s m e nt s will c o nti n u e at t h e s a m e fr e q u e n c y a s w o ul d h a v e b e e n f oll o w e d if t h e p ati e nt h a d r e m ai n e d o n 
st u d y tr e at m e nt u ntil r a di o gr a p hi c di s e a s e  pr o gr e s si o n  ( or l o s s of cli ni c al b e n efit f or p ati e nt s tr e at e d wit h at e z oli z u m a b w h o h a d c o nti n u e d 
tr e at m e nt wit h at e z oli z u m a b after r a di o gr a p hi c di s e a s e pr o gr e s si o n a c c or di n g t o R E CI S T v 1. 1 ), wit h dr a w al of c o n s e nt, d e at h, or st u d y 
t er mi n ati o n b y t h e S p o n s or, w hi c h e v er o c c ur s fir st, e v e n if p ati e nt st art s a n ot h er a nti -c a n c er t h er a p y aft er st u d y tr e at m e nt di s c o nti n u ati o n . 
r S e e A p p e n di x  3  f or t h e d et ail e d s c h e d ul e. 
s T h e o pti o n al R C R  w h ol e bl o o d s a m pl e r e q uir e s a n a d diti o n al i nf or m e d c o n s e nt  a n d t h e s a m pl e c a n b e c oll e ct e d at a n y ti m e d uri n g t h e c o ur s e of 
t h e st u d y. 
t  All  s eri o u s a d v er s e e v e nt s a n d a d v er s e e v e nt s of s p e ci al i nt er e st, r e g ar dl e s s of r el ati o n s hi p t o st u d y tr e at m e nt , will b e re p ort e d u ntil 9 0  d a y s 
aft er t h e l a st d o s e of st u d y tr e at m e nt  or i niti ati o n of n e w n o n -pr ot o c ol s y st e mi c  a nti -c a n c er t h er a p y  aft er t h e l a st d o s e of st u d y tr e at m e nt , 
w hi c h e v er o c c ur s fir st.  All ot h er a d v er s e e v e nt s, r e g ar dl e s s of r el ati o n s hi p t o st u d y tr e at m e nt, will b e r e p ort e d u ntil 3 0 d a y s aft er t h e l a st d o s e of 
st u d y tr e at m e nt  or i niti ati o n of n e w n o n -pr ot o c ol s y st e mi c  a nti -c a n c er t h er a p y  aft er t h e l a st d o s e of st u d y tr e at m e nt , w hi c h e v er o c c ur s fir st.  Aft er 
t hi s p eri o d, all d e at h s will b e r e p ort e d.  I n a d diti o n, t h e S p o n s or s h o ul d b e n otifi e d if t h e i n v e sti g at or b e c o m e s a w ar e of a n y s eri o u s a d v er s e 
e v e nt or a d v er s e e v e nt of s p e ci al i nt er e st t h at i s b eli e v e d t o b e r el at e d t o pri or e x p o s ur e t o st u d y tr e at m e nt  
u  Fr o m 7  d a y s b ef or e s cr e e ni n g.  
v E O R T C Q L Q -C 3 0, E O R T C Q L Q -L C 1 3, P GI S, a n d E Q -5 D -3 L q u e sti o n n air e s will b e c o m pl et e d b y t h e p ati e nt s o n t h e e P R O t a bl et at e a c h 
s c h e d ul e d st u d y vi sit pri or t o a d mi ni str ati o n of st u d y dr u g a n d pri or t o a n y ot h er st u d y a s s e s s m e nt( s).  SI L C will b e c o m pl et e d u si n g a n el e ct r o ni c 
d e vi c e at t h e p ati e nt’ s h o m e o n a w e e kl y b a si s.  D uri n g s ur vi v al f oll o w -u p, t h e E O R T C Q L Q -C 3 0, E O R T C Q L Q -L C 1 3, a n d E Q -5 D -3 L will b e 
c o m pl et e d at 3 a n d 6 m o nt h s f oll o wi n g di s e a s e pr o gr e s si o n ( or l o s s of cli ni c al b e n efit f or at e z oli z u m a b -tr e at e d p ati e nt s).  T h e SI L C will b e 
c o m pl et e d m o nt hl y d uri n g s ur vi v al f oll o w -u p f or 6 m o nt h s f oll o wi n g di s e a s e pr o gr e s si o n ( or l o s s of cli ni c al b e n efit f or at e z oli z u m a b -tr e at e d 
p ati e nt s w h o h a d c o nti n u e d tr e at m e nt wit h at e z oli z u m a b aft er r a di o gr a p hi c di s e a s e pr o gr e s si o n a c c or di n g t o R E CI S T v 1. 1).  T h e P GI S i s n ot 
r e q uir e d d uri n g s ur vi v al f oll o w-u p.  P ati e nt s w h o di s c o nti n u e st u d y tr e at m e nt f or a n y r e a s o n ot h er t h a n pr o gr e s si v e di s e a s e  or l o s s of cli ni c al 
b e n efit will c o m pl et e t h e E O R T C Q L Q -C 3 0, E O R T C Q L Q -L C 1 3, P GI S, a n d  E Q-5 D -3 L at e a c h t u m or a s s e s s m e nt vi sit a n d will c o m pl et e t h e 
SI L C at h o m e o n a w e e kl y b a si s, u ntil r a di o gr a p hi c di s e a s e pr o gr e s si o n p er R E CI S T v 1. 1 ( or l o s s of cli ni c al b e n efit f or at e z o li z u m a b-tr e at e d 
p ati e nt s w h o h a d c o nti n u e d tr e at m ent wit h at e z oli z u m a b aft er r a di o gr a p hi c di s e a s e pr o gr e s si o n) a s d et er mi n e d b y t h e i n v e sti g at or ( u nl e s s t h e 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 1 9
 
 
 
 
 
 
A p p e n di x  2  
S c h e d ul e of A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 7 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
p ati e nt wit h dr a w s c o n s e nt or t h e S p o n s or t er mi n at e s t h e st u d y) .  St u d y p er s o n n el s h o ul d r e vi e w all q u e sti o n n air e s f or c o m pl et e n e s s b ef or e t h e 
p ati e nt l e a v e s t h e i n v e sti g ati o n al sit e.  P ati e nt s w h o s e n ati v e l a n g u a g e i s n ot a v ail a bl e o n t h e e P R O d e vi c e or w h o ar e d e e m e d b y t h e 
i n v e sti g at or i n c a p a bl e of i n p utti n g t h eir e P R O a s s e s s m e nt aft er u n d er g oi n g a p pr o pri at e tr ai ni n g ar e e x e m pt fr o m all e P R O a s s es s m e nt s.  
w  S ur vi v al f o ll o w-u p i nf or m ati o n will b e c oll e ct e d vi a t el e p h o n e c all s, p ati e nt m e di c al r e c or d s, a n d/ or cli ni c vi sit s e v er y 3  m o nt h s or m or e fr e q u e ntl y 
u ntil d e at h, l o s s t o f oll o w -u p, or st u d y t er mi n ati o n b y t h e S p o n s or, w hi c h e v er o c c ur s fir st.  All p ati e nt s will b e p eri o di c all y c o nt a ct e d f or s ur vi v al 
a n d n e w a nti -c a n c er t h er a p y i nf or m ati o n u nl e s s t h e p ati e nt r e q u e st s t o b e wit h dr a w n fr o m f oll o w -u p (t hi s r e q u e st m u st b e d o c u m e nt e d i n t h e 
s o ur c e d o c u m e nt s a n d si g n e d b y t h e i n v e sti g at or).  If t h e p ati e nt wit h dr a w s fr o m t h e st u d y, st u d y st aff m a y u s e a p u bli c i nf or m ati o n s o ur c e 
( e. g., c o u nt y r e c or d s) w h e n p er mi s si bl e, t o o bt ai n i nf or m ati o n a b o ut s ur vi v al st at u s o nl y.  
x F or Ar g e nti n a sit e s o nl y:  A uri n e pr e g n a n c y t e st i s r e q uir e d m o nt hl y u ntil 6 m o nt h s aft er t h e l a st d o s e of st u d y tr e at m e nt . 
y M a n d at or y bi o p s y, if cli ni c all y f e a si bl e, wit hi n 4 0 d a y s of r a di o gr a p hi c pr o gr e s si o n or pri or t o t h e st art of t h e n e xt a nti -c a n c er t h er a p y, w hi c h e v er 
i s s o o n er. 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 2 0
 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 8 / St ati sti c al A n al y si s Pl a n  G O 2 9 4 3 6  
A p p e n di x  3  
S c h e d ul e of P h ar m a c o ki n eti c, Bi o m ar k er,  
a n d A nti -T h er a p e uti c A nti b o d y A s s e s s m e nt s  
St u d y Vi sit  
Ti m e  
Ar m A  
(At e z oli z u m a b  +   
C ar b o pl ati n
 +   
P a clit a x el)  
Ar m B  
(At e z oli z u m a b  +   
C ar b o pl ati n
 +   
P a clit a x el  +   
B e v a ci z u m a b ) 
Ar m C  
(C ar b o pl ati n
 +   
P a clit a x el  +   
B e v a ci z u m a b ) 
S cr e e ni n g  
N/ A  
•  Bi o m ar k er s  b 
•  Bi o m ar k er s  b 
•  Bi o m ar k er s  b 
C y cl e 1,  
D a y 1 f 
Pr e -d o s e 
( s a m e d a y a s 
tr e at m e nt 
a d mi ni str ati o n)  
•  At e z oli z u m a b A T A  
•  At e z oli z u m a b 
p h ar m a c o ki n eti c s  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s  a 
•  P a clit a x el 
p h ar m a c o ki n eti c s  a  
•  Bi o m ar k er s  d 
•  At e z oli z u m a b A T A  
•  At e z oli z u m a b 
p h ar m a c o k i n eti c s 
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s  a  
•  P a clit a x el 
p h ar m a c o ki n eti c s  a 
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s  
•  B e v a ci z u m a b A T A  
•  Bi o m ar k er s  d 
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s  
•  B e v a ci z u m a b A T A  
•  Bi o m ar k er s  d 
3 0 mi n  
(±  1 0 mi n) 
aft er e n d of 
at e z oli z u m a b  
i nf u si o n 
•  At e z oli z u m a b 
p h ar m a c o ki n eti c  
•  At e z oli z u m a b 
p h ar m a c o ki n eti c s  
 
 
3 0 mi n (±  1 0 
mi n) aft er e n d 
of 
b e v a ci z u m a b 
i nf u si o n a  
 
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s a  
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s a  
 
5 −1 0  mi n 
b ef or e t h e e n d 
of  c ar b o pl ati n 
i nf u si o n a  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
 
1 hr aft er e n d 
of c ar b o pl ati n 
i nf u si o n a  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a   
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
 
5 −1 0 mi n 
b ef or e t h e e n d 
of  p a clit a x el 
i nf u si o n a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
 
1 hr aft er e n d 
of p a clit a x el 
i nf u si o n a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 2 1
A p p e n di x  3  
S c h e d ul e of P h ar m a c o ki n eti c , Bi o m ar k er,  
a n d A nti - Th er a p e uti c A nti b o d y  A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
5 9 / St a ti sti c al A n al y si s Pl a n G O 2 9 4 3 6  
St u d y Vi sit  
Ti m e  
Ar m A  
( At e z oli z u m a b +   
C ar b o pl ati n
 +   
P a clit a x el)  
Ar m B  
(At e z oli z u m a b  +   
C ar b o pl ati n
 +   
P a clit a x el  +   
B e v a ci z u m a b ) 
Ar m C  
(C ar b o pl ati n
 +   
P a clit a x el  +   
B e v a ci z u m a b ) 
C y cl e 2,  
D a y 1 
(±  3 d a y s)   
Pr e -d o s e 
( s a m e d a y a s 
tr e at m e nt 
a d mi ni str ati o n)  
•  At e z oli z u m a b 
A T A  
•  At e z oli z u m a b 
p h ar m a c o ki n eti c s  
•  Bi o m ar k er s d  
•  At e z oli z u m a b 
A T A  
•  At e z oli z u m a b 
p h ar m a c o ki n eti c s  
•  Bi o m ar k er s d  
•  Bi o m ar k er s d  
C y cl e 3, 
D a y 1 
(±  3 d a y s)   
Pr e -d o s e 
( s a m e d a y a s 
tr e at m e nt 
a d mi ni str ati o n)  
•  At e z oli z u m a b 
A T A  
•  At e z oli z u m a b 
p h ar m a c o ki n e ti c s 
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s
a  
•  P a clit a x el 
p h ar m a c o ki n eti c s
a  
•  Bi o m ar k er s d  
•  At e z oli z u m a b A T A  
•  At e z oli z u m a b 
p h ar m a c o ki n eti c s  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
•  P a clit a x el 
p h ar m a c o ki n eti c s a  
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s  
•  B e v a ci z u m a b A T A  
•  Bi o m ar k er s d  
•  C ar b o pl ati n 
p h a r m a c o ki n eti c sa  
•  P a clit a x el 
p h ar m a c o ki n eti c s a   
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s  
•  B e v a ci z u m a b A T A  
•  Bi o m ar k er s d  
 
3 0 mi n  
(±  1 0 mi n)  
af t er e n d of 
at e z oli z u m a b  
i nf u si o n 
•  At e z oli z u m a b 
p h ar m a c o ki n eti c  
•  At e z oli z u m a b 
p h ar m a c o ki n eti c s  
 
 
3 0 mi n 
(±  1 0  mi n)  aft er  
e n d of 
b e v a ci z u m a b 
i nf u si o n a 
 
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s  a 
•  B e v a ci z u m a b 
p h ar m a c o ki n eti c s a  
 
5 −1 0  mi n 
b ef or e t h e e n d 
of  c ar b o pl ati n 
i nf u si o n a 
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
•  C ar b o pl ati n 
p h ar m a c o ki n eti c s a  
 
 
 


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 2 2
A p p e n di x  3 
S c h e d ul e of P h ar m a c o ki n eti c , Bi o m ar k er,  
a n d A nti - Th er a p e uti c A nti b o d y  A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
6 0 / St a ti sti c al A n al y si s Pl a n G O 2 9 4 3 6  
St u d y Vi sit  
Ti m e  
Ar m A  
( At e zoli z u m a b  +
C ar b o pl ati n
 +
P a clit a x el)  
Ar m B  
(At e z oli z u m a b  +
C ar b o pl ati n
 +
P a clit a x el  +
B e v a ci z u m a b ) 
Ar m C  
(C ar b o pl ati n
 +  
P a clit a x el  +
B e v a ci z u m a b ) 
C y cl e 3, 
D a y 1 
(±  3 d a y s)  
( c ont.)  
1 hr aft er e n d 
of c ar b o pl ati n 
i nf u si o n a 
•
C ar b o pl ati n
p h ar m a c o ki n eti c s a  
•
C ar b o pl ati n
p h ar m a c o ki n eti c s a
• C ar b o pl ati n
p h ar m a c o ki n eti c s a
5 −1 0 mi n 
b ef or e t h e e n d 
of p a clit a x el 
i nf u si o n a 
•
P a clit a x el
p h ar m a c o ki n eti c s a  
•
P a clit a x el
p h ar m a c o ki n eti c s a
• P a clit a x el
p h ar m a c o ki n eti c s a
1 hr aft er e n d 
of p a c lit a x el 
i nf u si o n a  
•
P a clit a x el
p h ar m a c o ki n eti c  a
•
P a clit a x el
p h ar m a c o ki n eti c s a
• P a clit a x el
p h ar m a c o ki n eti c s a
C y cl e s 4, 8, 
a n d 1 6,  
D a y  1 
(±  3 d a y s)  
Pr e -d o s e 
(s a m e d a y a s 
tr e at m e nt 
a d mi ni str ati o n)  
•
At e z oli z u m a b
A T A
•
At e z oli z u m a b
p h ar m a c o ki n eti c s
•
Bi o m ar k er s d
•
At e z oli z u m a b
A T A
•
At e z oli z u m a b
p h a r m a c o ki n eti c
•
Bi o m ar k er s d
• Bi o m ar k er s d
Aft er 
C y cl e  1 6 
a n d e v er y 
ei g ht h c y cl e, 
D a y  1 
(±  3 d a y s)  
Pr e -d o s e 
( s a m e d a y a s 
tr e at m e nt 
a d mi ni str ati o n)  
•
At e z oli z u m a b
A T A
•
At e z oli z u m a b
p h ar m a c o ki n eti c s
•
Bi o m ar k er s d
•
At e z oli z u m a b
A T A
•
At e z oli z u m a b
p h ar m a c o ki n eti c s
•
Bi o m ar k er s d
• Bi o m ar k er s  d
At ti m e of 
fr e s h bi o p s y 
( o n- 
tre at m e nt or 
at 
pr o gr e s si o n, 
i n cl u di n g 
d uri n g 
f oll o w-u p)  
At vi sit  
•
Bi o m ar k er s  d
•
Bi o m ar k er s d
• Bi o m ar k er s d


Cli ni c al St u d y R e p ort: R O 5 5 4 1 2 6 7 - F. H off m a n n- L a R o c h e Lt d
Pr ot o c ol G O 2 9 4 3 6     R e p ort N u m b er 1 0 7 7 7 2 6
1 7 7 2 3
A p p e n di x  3 
S c h e d ul e of P h ar m a c o ki n eti c , Bi o m ar k er,  
a n d A nti - Th er a p e uti c A nti b o d y  A s s e s s m e nt s  ( c o nt.) 
At e z oli z u m a b — F. H off m a n n- L a R o c h e Lt d  
6 1 / St a ti sti c al A n al y si s Pl a n G O 2 9 4 3 6  
St u d y Vi sit  
Ti m e  
Ar m A  
( At e z oli z u m a b +
C ar b o pl ati n
 +
P a clit a x el)  
Ar m B  
(At e z oli z u m a b  +
C ar b o pl ati n
 +
P a clit a x el  +
B e v a ci z u m a b ) 
Ar m C  
(C ar b o pl ati n
 +  
P a clit a x el  +
B e v a ci z u m a b ) 
Tr e at m e nt 
di s c o nti n u ati o n 
vi s it 
At vi sit  
• At e z oli z u m a b
A T A
• At e z oli z u m a b
p h ar m a c o ki n eti c s
• Bi o m ar k er s  d
•
At e z oli z u m a b
A T A
•
At e z oli z u m a b
p h ar m a c o ki n eti c s
•
B e v a ci z u m a b
p h ar m a c o ki n eti c s e
•
B e v a ci z u m a b
A T A e
•
Bi o m ar k er s  d
• B e v a ci z u m a b
p h ar m a c o ki n eti c s e
• B e v a ci z u m a b
A T A e
• Bi o m ar k er s  d
1 2 0   
(±  3 0 d a y s) 
aft er l a st d o s e 
of at e z oli z u m a b  
At vi sit  
• At e z oli z u m a b
A T A
• At e z oli z u m a b
p h ar m a c o ki n eti c s
• Bi o m ar k er s  d
•
At e z oli z u m a b
A T A
•
At e z oli z u m a b
p h ar m a c o ki n eti c s
•
Bi o m ar k er s  d
A n y ti m e p oi nt 
d uri n g st u d y 
( R C R c o n s e nt 
r e q uir e d) 
• O pti o n al R C R
bl o o d ( D N A
e xtr a cti o n)  c
•
O pti o n al R C R
bl o o d ( D N A
e xtr a cti o n)  c
O pti o n al R C R bl o o d 
( D N A e xtr a cti o n) c 
A T A  =  a nti -t h er a p e uti c a nti b o d y; P K  =  p h ar m a c o ki n eti c; R C R  =  R o c h e Cli ni c al R e p o sit or y . 
N ot e s:  S er u m P K s a m pl e s f or at e z oli z u m a b a n d b e v a ci z u m a b; pl a s m a P K s a m pl e s f or 
c ar b o pl ati n, a n d p a clit a x el.  
All p ati e nt s  i n Ar m B a n d C will u n d er g o t h e a d diti o n al A T A a n d P K a s s e s s m e nt s f or 
b e v a ci z u m a b at C y cl e 1 pr e -d o s e, C y cl e  3 pr e -d o s e, a n d at t h e ti m e of b e v a ci z u m a b 
di s c o nti n u ati o n.  
a At s el e ct e d c e nt er s, 2 0 p ati e nt s i n e a c h tr e at m e nt ar m will u n d er g o a d diti o n al P K a s s e s s m e nt s 
f or c ar b o pl ati n, p a clit a x el, a n d b e v a ci z u m a b w h er e a p pli c a bl e. 
b W h ol e bl o o d f or bi o m ar k er s.  
c T h e o pti o n al R C R bl o o d s a m pl e (f or D N A e xtr a cti o n) r e q uir e s a n a d diti o n al i nf or m e d c o n s e nt 
a n d t h e s a m pl e c a n b e c oll e ct e d at a n y ti m e d uri n g t h e c o ur s e of t h e st u d y.  
d  Pl a s m a a n d s er u m f or bi o m ar k er s.  
e B e v a ci z u m a b P K a n d A T A ar e r e q uir e d at ti m e of b e v a ci z u m a b di s c o nti n u ati o n.  
f Bi o m ar k er s a m pli n g b ef or e C y cl e 1, D a y 1 s h o ul d b e p erf or m e d b ef or e p ati e nt s ar e tr e at e d 
wit h t h e fir st d o s e of st er oi d s.