Conditions: Small Cell Lung Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 503
Healthy volunteers: no

Brief summary:
This randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study was designed to evaluate the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 \[PD-L1\] antibody) in combination with carboplatin plus (+) etoposide compared with treatment with placebo + carboplatin + etoposide in chemotherapy-naive participants with ES-SCLC. Participants will be randomized in a 1:1 ratio to receive either atezolizumab + carboplatin + etoposide or placebo + carboplatin + etoposide on 21-day cycles for four cycles in the induction phase followed by maintenance with atezolizumab or placebo until progressive disease (PD) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Treatment can be continued until persistent radiographic PD or symptomatic deterioration.

Detailed description:

Arms:
arm 1: Participants received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m\^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor. arm 2: Participants received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m\^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m\^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody intervention 2: Carboplatin intervention 3: Etoposide intervention 4: Placebo
Intervention descriptions: intervention 1: Atezolizumab intravenous infusion was administered at a dose of 1200 mg on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward). intervention 2: Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4). intervention 3: Etoposide intravenous infusion was administered at a dose of 100 mg/m\^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4). intervention 4: Placebo intravenous infusion was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase I/III, Randomized, Double-Blind, Placebo-Controlled 
Study of Carboplatin Plus Etoposide With or Without Atezolizumab 
(Anti-PD-L1 Antibody) in Patients With Untreated Extensive-Stage 
Small Cell Lung Cancer 
NCT Number: 
NCT02763579  
Document Dates: 
Protocol Amendment Version 7 : 06 March 2019 
SAP Amendment Version 3: 14 May 2018 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
AtezolizumabF. Hoffmann-La Roche Ltd
Protocol GO30081, Version 7
PROTOCOL
TITLE:
A PHASE I/III, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED STUDY OF 
CARBOPLATIN PLUS ETOPOSIDE WITH OR 
WITHOUT ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN PATIENTS WITH UNTREATED 
EXTENSIVE-STAGE SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO30081/NCT02763579
VERSION NUMBER:
7
EUDRACT NUMBER:
2015-004861-97
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
8 December 2015
DATE(S) AMENDED:
Version 2 (VHP Only):  8 June 2016
Version 3:  25 August 2016
Version 4:  29 August 2017
Version 5 (Spain): 27 February 2018
Version 5 (China): 28 October 2018
Version 6 (Spain): 28 October 2018
Version 7:  See electronic date stamp below.
06-Mar-2019 17:25:16
Title
Approver's Name
Company Signatory
Date and Time (UTC)


AtezolizumabF. Hoffmann-La Roche Ltd
2/Protocol GO30081, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol GO30081 was previously amended locally (Spain and China).  The changes in 
these amendments have been incorporated into this global amendment. In addition, 
there are several changes that are completely new (not previously in local amendments).  
Cumulative changes from the local amendments, as well as the new changes, include 
the following:  

Language has been added to the end of study definition to clarify that if the Sponsor
decides to terminate the study, patients who are still receiving study treatment or are in
survival follow-up may be enrolled into an extension study or a non-interventional
study (Section 3.2).

Language has been added to clarify use of samples after withdrawal of patient consent
(Section 4.5.6).

Language has been added to clarify that, after withdrawal of consent for participation
in the Roche Clinical Repository (RCR), remaining RCR samples will be destroyed or
will no longer linked to the patient. Furthermore, instructions about patient withdrawal
from the RCR after site closure have been modified to indicate that the investigator
must inform the Sponsor of patient withdrawal by emailing the study number and
patient number to 
 (Section 4.5.11.6).

Changes have been added to align the protocol with the statistical analysis plan
(Version 2 and Version 3) for the global cohort:
–
The Study GO30081 Statistical Analysis Plan (SAP) Version 1 was amended to
reflect the final statistical analysis timeline prior to the study database lock and
unblinding.  In SAP Version 1, the interim and final analysis of overall survival
(OS) were planned to be conducted at 220 and 280 death events, i.e., when 55%
and 70% patients have events, respectively.  Recent data from Study GO29436
that are external to Study GO30081 suggest that the treatment effect on OS may
be delayed and an accurate assessment of the magnitude of the treatment effect
will take longer than initially expected.  Thus the interim and final analysis of this
study are planned to be conducted at more mature time points, i.e., when death
event to patient ratio reaches 60% and 77%, respectively, which corresponds to
240 events for the OS interim analysis, and 306 events for the OS final analysis.
Progression-free survival (PFS) analysis timing is adjusted accordingly to be
conducted at the same time as OS interim analysis and 295 PFS events are
expected by that time (Sections 3.2, 6.1, and 6.8.1).
–
The Study GO30081 Statistical Analysis Plan (SAP) Version 2 was amended prior
to the study database lock and unblinding, due to the potential risk of over-
stratification (Akazawa et al. 1997). If at least one stratum (i.e., a combination of
stratification factor levels across sex [male vs female], Eastern Cooperative
Oncology Group [ECOG] performance status [0 vs 1], and brain metastasis
[Yes vs No] per interactive voice/Web response system [IxRS]) has less than
10 events (progression-free survival [PFS] or overall survival [OS] events), the
stratification factor (one of 3 stratification factors: sex, ECOG performance


status, and brain metastasis per IxRS) which contains the level with the 
smallest number of patients will be removed from the stratified analyses. The 
removal of the stratification factor will continue until there is no stratum with less 
than 10 events (PFS or OS events). The final set of stratification factors used in 
stratified analyses will be applied to all endpoints where stratified analyses are 
planned (Section 6.4 and 6.4.1).

The statistical analysis plan and 
 
(Section 6.1.1).  
 

Section 5.1.1 has been amended to align with current atezolizumab risk language and 
information regarding the management of atezolizumab-specific adverse events has 
been included in a new Appendix (Appendix 12).  Included in this appendix are new 
guidelines for the management of myositis and language regarding the fact that 
systemic immune activation is a potential risk with atezolizumab, regardless of 
whether atezolizumab is given alone or in combination with other immunomodulating 
agents. Sections 5.1.1, 5.1.5, 5.1.6.1 and 5.1.8 have been updated (and Section 
5.1.6.1 was moved to Appendix 12) to reflect the addition of Appendix 12.

 

The Appendix 10 (Anaphylaxis Precautions) has been modified to remove the 
requirement for use of a tourniquet.  The application of a tourniquet is no longer 
recommended due to the limited therapeutic benefit and risk of losing time for more 
important measures (Ring J, Beyer K, Biedermann T, et al. Allergo J Int.
2014;23(3):96112).

Language has been added for consistency with Roche's current data retention policy 
and to accommodate more stringent local requirements (if applicable)
(Section 7.6).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.
AtezolizumabF. Hoffmann-La Roche Ltd
3/Protocol GO30081, Version 7


AtezolizumabF. Hoffmann-La Roche Ltd
4/Protocol GO30081, Version 7
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Lung Cancer................................................. 28
1.1.1
Treatment for Extensive-Stage Small Cell Lung 
Cancer................................................................................... 28
1.2
Background on Atezolizumab (MPDL3280A) ........................ 31
1.2.1
Summary of Nonclinical Studies............................................ 32
1.3
Clinical Experience with Atezolizumab .................................. 32
1.3.1
Ongoing Clinical Studies........................................................ 32
1.3.2
Clinical Safety........................................................................ 33
1.3.2.1
Single-Agent Clinical Safety in Patients with Lung 
Cancer................................................................................... 33
1.3.2.2
Clinical Safety in Combination with 
Platinum-Based Doublet Chemotherapy................................ 36
1.3.2.3
Immune-Mediated Adverse Events........................................ 37
1.3.3
Clinical Activity....................................................................... 37
1.3.3.1
Single-Agent Clinical Activity in Patients with 
SCLC in Study PCD4989g..................................................... 38
1.3.3.2
Single-Agent Clinical Activity in Patients with 
NSCLC in Study PCD4989g.................................................. 38
1.3.3.3
Single-Agent Clinical Activity in Patients with 
NSCLC in the POPLAR Study............................................... 39
1.3.3.4
Clinical Efficacy in Combination with 
Carboplatin-Based Doublet Chemotherapy in 
Patients with NSCLC ............................................................. 39
1.3.4
Clinical Pharmacokinetics and Immunogenicity..................... 40
1.3.5
Rationale for Atezolizumab Dosage ...................................... 40
1.4
Study Rationale and Benefit-Risk Assessment...................... 41
1.4.1
Rationale for Testing Atezolizumab in 
Combination with Carboplatin and Etoposide in 
ES-SCLC............................................................................... 41
1.4.2
................................... 44


AtezolizumabF. Hoffmann-La Roche Ltd
5/Protocol GO30081, Version 7
2.
OBJECTIVES.............................................................................................. 44
2.1
Efficacy Objectives ................................................................ 45
2.1.1
Primary Efficacy Objectives................................................... 45
2.1.2
Secondary Efficacy Objectives .............................................. 45
2.2
Safety Objectives................................................................... 45
2.3
Pharmacokinetic Objective .................................................... 45
2.4
Exploratory Objectives........................................................... 46
3.
STUDY DESIGN......................................................................................... 46
3.1
Description of the Study......................................................... 46
3.1.1
Independent Data Monitoring Committee .............................. 49
3.2
End of Study and Length of Study......................................... 50
3.3
Rationale for Study Design.................................................... 50
3.3.1
Rationale for Testing Atezolizumab in 
Combination with Carboplatin and Etoposide in 
Patients with ES-SCLC.......................................................... 50
3.3.2
Rationale for Control Arm ...................................................... 51
3.3.3
Rationale for Progression-Free Survival and 
Overall Survival as Co-Primary Endpoints............................. 51
3.3.4
Rationale for Allowing Selected Patients to 
Continue Treatment Beyond Radiographic 
Disease Progression per RECIST v1.1.................................. 52
3.3.5
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 53
3.3.6
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens ................................................................. 53
3.3.7
Rationale for Blood Biomarker Assessments......................... 54
3.3.8
Rationale for the Collection of Tumor Specimens 
at Radiographic Progression ................................................. 54
3.4
Outcome Measures ............................................................... 54
3.4.1
Efficacy Outcome Measures.................................................. 54
3.4.1.1
Primary Efficacy Outcome Measures .................................... 54
3.4.1.2
Secondary Efficacy Outcome Measures................................ 55
3.4.2
Safety Outcome Measures .................................................... 55
3.4.3
Pharmacokinetic Outcome Measures.................................... 55
3.4.4
Exploratory Outcome Measures ............................................ 55


AtezolizumabF. Hoffmann-La Roche Ltd
6/Protocol GO30081, Version 7
4.
MATERIALS AND METHODS .................................................................... 56
4.1
Patients.................................................................................. 56
4.1.1
Inclusion Criteria.................................................................... 56
4.1.2
Exclusion Criteria................................................................... 58
4.2
Method of Treatment Assignment and Blinding..................... 61
4.2.1
Unblinding at the Patient Level.............................................. 62
4.2.1.1
Emergency Unblinding........................................................... 62
4.2.2
Unblinding at the Study Level................................................ 62
4.3
Study Treatment.................................................................... 62
4.3.1
Formulation, Packaging, and Handling.................................. 62
4.3.1.1
Atezolizumab and Placebo .................................................... 62
4.3.1.2
Carboplatin and Etoposide .................................................... 62
4.3.2
Dosage, Administration, and Compliance.............................. 63
4.3.2.1
Atezolizumab/Placebo ........................................................... 64
4.3.2.2
Carboplatin + Etoposide ........................................................ 66
4.3.3
Investigational Medicinal Product Accountability ................... 67
4.3.4
Post-Study Access to Atezolizumab ...................................... 67
4.4
Concomitant Therapy ............................................................ 68
4.4.1
Permitted Therapy................................................................. 68
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 69
4.4.3
Prohibited Therapy ................................................................ 69
4.5
Study Assessments ............................................................... 70
4.5.1
Informed Consent Forms and Screening Log........................ 70
4.5.2
Medical History and Demographic Data ................................ 70
4.5.3
Physical Examinations........................................................... 70
4.5.4
Vital Signs.............................................................................. 71
4.5.5
Tumor and Response Evaluations......................................... 71
4.5.6
Laboratory Assessments and Biomarker 
Samples................................................................................. 73
4.5.7
Tumor Tissue Samples.......................................................... 74
4.5.7.1
Archival and Freshly Collected Tumor Tissue 
Samples................................................................................. 74


AtezolizumabF. Hoffmann-La Roche Ltd
7/Protocol GO30081, Version 7
4.5.7.2
Optional Tumor Samples after Completion of 
Induction Treatment............................................................... 75
4.5.7.3
Optional Tumor Samples at the Time of 
Radiographic Progression ..................................................... 76
4.5.7.4
Tumor Samples at Other Timepoints..................................... 76
4.5.7.5
Use and Storage of Remaining Samples from 
Study-Related Procedures..................................................... 77
4.5.8
Anti-Therapeutic Antibody Testing......................................... 77
4.5.9
Electrocardiograms................................................................ 77
4.5.10
Patient-Reported Outcomes .................................................. 77
4.5.11
Samples for Roche Clinical Repository.................................. 79
4.5.11.1
Overview of the Roche Clinical Repository............................ 79
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 79
4.5.11.3
Sample Collection.................................................................. 79
4.5.11.4
Confidentiality........................................................................ 80
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 81
4.5.11.6
Withdrawal from the Roche Clinical Repository..................... 81
4.5.11.7
Monitoring and Oversight....................................................... 82
4.5.12
Timing of Assessments.......................................................... 82
4.5.12.1
Screening and Baseline Assessments .................................. 82
4.5.12.2
Assessments during Treatment............................................. 82
4.5.12.3
Assessments at Study Drug Discontinuation Visit ................. 83
4.5.12.4
Follow-Up Assessments ........................................................ 83
4.5.12.5
Assessments at Unplanned Visits ......................................... 84
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 84
4.6.1
Patient Discontinuation.......................................................... 84
4.6.2
Study Treatment Discontinuation........................................... 85
4.6.3
Study and Site Discontinuation.............................................. 86
5.
ASSESSMENT OF SAFETY....................................................................... 87
5.1
Safety Plan ............................................................................ 87
5.1.1
Risks Associated with Atezolizumab ..................................... 88


AtezolizumabF. Hoffmann-La Roche Ltd
8/Protocol GO30081, Version 7
5.1.2
Risks Associated with Etoposide........................................... 88
5.1.3
Risks Associated with Carboplatin......................................... 88
5.1.4
Management of Patients Who Experience 
Specific Adverse Events........................................................ 88
5.1.4.1
Monitoring.............................................................................. 88
5.1.5
Dose Modification.................................................................. 89
5.1.5.1
General Notes Regarding Dose Modification......................... 89
5.1.5.2
Atezolizumab Dose Modification, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events .............................. 90
5.1.6
Management of Atezolizumab-Specific Adverse 
Events.................................................................................... 90
5.1.7
Chemotherapy Dose Modifications, Treatment 
Delays, or Treatment Discontinuation and 
Management of Specific Adverse Events .............................. 90
5.1.8
Potential Overlapping Toxicities ............................................ 92
5.2
Safety Parameters and Definitions ........................................ 93
5.2.1
Adverse Events ..................................................................... 93
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 94
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 94
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 95
5.3.1
Adverse Event Reporting Period ........................................... 95
5.3.2
Eliciting Adverse Event Information....................................... 96
5.3.3
Assessment of Severity of Adverse Events ........................... 96
5.3.4
Assessment of Causality of Adverse Events ......................... 97
5.3.5
Procedures for Recording Adverse Events............................ 98
5.3.5.1
Infusion-Related Reactions.................................................... 98
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 98
5.3.5.3
Adverse Events That are Secondary to Other 
Events.................................................................................... 98
5.3.5.4
Persistent or Recurrent Adverse Events................................ 99
5.3.5.5
Abnormal Laboratory Values ................................................. 99
5.3.5.6
Abnormal Vital Sign Values ................................................. 100


AtezolizumabF. Hoffmann-La Roche Ltd
9/Protocol GO30081, Version 7
5.3.5.7
Abnormal Liver Function Tests............................................ 100
5.3.5.8
Deaths ................................................................................. 101
5.3.5.9
Preexisting Medical Conditions............................................ 101
5.3.5.10
Lack of Efficacy or Worsening of SCLC............................... 101
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 102
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 102
5.3.5.13
Patient-Reported Outcome Data ......................................... 103
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 103
5.4.1
Emergency Medical Contacts.............................................. 103
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 104
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 104
5.4.2.2
Events That Occur after Study Drug Initiation...................... 104
5.4.3
Reporting Requirements for Pregnancies............................ 104
5.4.3.1
Pregnancies in Female Patients.......................................... 104
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 105
5.4.3.3
Abortions ............................................................................. 105
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 106
5.5
Follow-Up of Patients after Adverse Events ........................ 106
5.5.1
Investigator Follow-Up......................................................... 106
5.5.2
Sponsor Follow-Up .............................................................. 106
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 106
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 107
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 107
6.1
Determination of Sample Size ............................................. 108
6.1.1
....................................................... 109
6.2
Summaries of Conduct of Study.......................................... 110
6.3
Summaries of Treatment Group Comparability ................... 110
6.4
Efficacy Analyses ................................................................ 110


AtezolizumabF. Hoffmann-La Roche Ltd
10/Protocol GO30081, Version 7
6.4.1
Primary Efficacy Endpoints.................................................. 110
6.4.2
Secondary Efficacy Endpoints............................................. 112
6.4.2.1
Objective Response Rate.................................................... 112
6.4.2.2
Duration of Response.......................................................... 112
6.4.2.3
Landmark Analysis on Progression-Free Survival 
and Overall Survival ............................................................ 112
6.4.2.4
Patient-Reported Outcomes ................................................ 112
6.4.3
Handling of Missing Data..................................................... 113
6.5
Safety Analyses................................................................... 114
6.6
Pharmacokinetic Analyses................................................... 114
6.7
Exploratory Analyses........................................................... 114
6.7.1
Objective Response Rate, Duration of Response, 
and Progression-Free Survival per Modified 
RECIST ............................................................................... 114
6.7.2
Exploratory Analyses of Progression-Free 
Survival................................................................................ 115
6.7.2.1
Non-Protocol-Specified Anti-Cancer Therapy...................... 115
6.7.2.2
Subgroup Analysis............................................................... 115
6.7.2.3
Sensitivity Analyses............................................................. 115
6.7.3
Exploratory Analyses of Overall Survival............................. 116
6.7.3.1
Subgroup Analysis............................................................... 116
6.7.4
Exploratory Biomarker Analysis........................................... 116
6.8
Interim Analyses .................................................................. 116
6.8.1
Planned Interim Analyses.................................................... 116
6.8.2
Optional Interim Analysis..................................................... 117
6.9
................................................... 117
7.
DATA COLLECTION AND MANAGEMENT ............................................. 118
7.1
Data Quality Assurance....................................................... 118
7.2
Electronic Case Report Forms............................................. 118
7.3
Electronic Patient-Reported Outcome Data......................... 118
7.4
Source Data Documentation................................................ 119
7.5
Use of Computerized Systems ............................................ 119
7.6
Retention of Records........................................................... 120
8.
ETHICAL CONSIDERATIONS.................................................................. 120


AtezolizumabF. Hoffmann-La Roche Ltd
11/Protocol GO30081, Version 7
8.1
Compliance with Laws and Regulations .............................. 120
8.2
Informed Consent................................................................ 120
8.3
Institutional Review Board or Ethics Committee.................. 122
8.4
Confidentiality...................................................................... 122
8.5
Financial Disclosure ............................................................ 122
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION ................................................................................... 123
9.1
Study Documentation .......................................................... 123
9.2
Protocol Deviations.............................................................. 123
9.3
Site Inspections ................................................................... 123
9.4
Administrative Structure....................................................... 123
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 123
9.6
Protocol Amendments ......................................................... 124
10. REFERENCES ......................................................................................... 125
LIST OF TABLES
Table 1
Results from Randomized Studies Using Platinum-Based 
Chemotherapy for ES-SCLC....................................................... 30
Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades................................................................ 34
Table 3
Adverse Events Reported in at Least 10% of Patients in the 
POPLAR Study GO28753........................................................... 36
Table 4
Study GP28328:  All Reported Adverse Events.......................... 37
Table 5
Study GO30081 Treatment Arms................................................ 46
Table 6
Administration of First and Subsequent Infusions of 
Atezolizumab/Placebo ................................................................ 65
Table 7
Vital Sign Measurements at Cycle 1 and All Subsequent 
Cycles ......................................................................................... 71
Table 8
Chemotherapy Dose Modification for Hematologic Toxicities ..... 91
Table 9
Dose Modifications or Treatment Discontinuation for 
Non-Hematologic Toxicities ........................................................ 92
Table 10
Etoposide Dose Modification for Renal Impairment .................... 92
Table 11
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 97
Table 12
Analysis Timing and Stopping Boundary of Overall Survival..... 117


AtezolizumabF. Hoffmann-La Roche Ltd
12/Protocol GO30081, Version 7
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 49
Figure 2
Criteria for Continuing Treatment in the Presence of 
Increased Radiographic Tumor Size........................................... 86
Figure 3
Group Sequential Holm Procedure ........................................... 109
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 132
Appendix 2
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Therapeutic Antibody Assessments............................ 138
Appendix 3
Veterans Administration Lung Study Group (VALG) Staging 
System for SCLC ...................................................................... 140
Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication ............................... 141
Appendix 5
Modified Response Evaluation Criteria in Solid Tumors ........... 153
Appendix 6
EORTC QLQ-C30..................................................................... 160
Appendix 7
EORTC QLQ-LC13................................................................... 162
Appendix 8
EQ-5D-5L.................................................................................. 163
Appendix 9
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 166
Appendix 10
Anaphylaxis Precautions........................................................... 167
Appendix 11
Preexisting Autoimmune Diseases ........................................... 168
Appendix 12
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 169


AtezolizumabF. Hoffmann-La Roche Ltd
13/Protocol GO30081, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE I/III, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED STUDY OF 
CARBOPLATIN PLUS ETOPOSIDE WITH OR 
WITHOUT ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN PATIENTS WITH UNTREATED 
EXTENSIVE-STAGE SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO30081
VERSION NUMBER:
7
EUDRACT NUMBER:
2015-004861-97
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy to 
the Sponsor or their designee.  Contact details will be provided to the investigator prior 
to study start.


AtezolizumabF. Hoffmann-La Roche Ltd
14/Protocol GO30081, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE I/III, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED STUDY OF CARBOPLATIN PLUS 
ETOPOSIDE WITH OR WITHOUT ATEZOLIZUMAB (ANTIPD-L1 
ANTIBODY) IN PATIENTS WITH UNTREATED 
EXTENSIVE-STAGE SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
GO30081
VERSION NUMBER:
7
EUDRACT NUMBER:
2015-004861-97
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (MPDL3280A, RO5541267)
PHASE:
I/III
INDICATION:
Small cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
The following objective statements apply to the global enrollment phase, 
 
Efficacy Objectives
Primary Efficacy Objectives
The co-primary objectives of this study are the following:

To evaluate the efficacy of atezolizumab carboplatin etoposide compared with
placebo carboplatin etoposide in the intent-to-treat (ITT) population as measured by
investigator-assessed progression-free survival (PFS) according to Response Evaluation
Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

To evaluate the efficacy of atezolizumab carboplatin etoposide compared with
placebo carboplatin etoposide in the ITT population as measured by overall survival (OS)
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are:

To evaluate the efficacy of atezolizumab carboplatin etoposide compared with
placebo carboplatin etoposide in the ITT population as measured by
investigator-assessed objective response rate (ORR) according to RECIST v1.1

To evaluate the efficacy of atezolizumab carboplatin etoposide compared with
placebo carboplatin etoposide in the ITT population as measured by
investigator-assessed duration of response (DOR) according to RECIST v1.1

To evaluate the PFS rate at 6 months and at 1 year in each treatment arm for the ITT
population

To evaluate the OS rate at 1 and 2 years in each treatment arm for the ITT population


AtezolizumabF. Hoffmann-La Roche Ltd
15/Protocol GO30081, Version 7

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, arm/shoulder pain, or fatigue using the European Organization for
the Research and Treatment of Cancer (EORTC) Quality of Life QuestionnaireCore
30 (QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) in patients treated
with atezolizumab carboplatin etoposide compared with placebo carboplatin etoposide
in the ITT population
Safety Objectives
The safety objectives for this study are:

To evaluate the safety and tolerability of atezolizumab in combination with
carboplatin etoposide compared with carboplatin etoposide

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 Objective
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of 
atezolizumab, carboplatin, and etoposide in chemotherapy-naive patients with extensive-stage 
small cell lung cancer (ES-SCLC).
Exploratory Objectives
The exploratory objectives for this study are:

To evaluate investigator-assessed PFS, ORR, DCR, DOR, TIR, and TTR according to
modified RECIST for the atezolizumab-containing treatment arm in the ITT population

To evaluate the relationship between tumor biomarkers (including but not limited to PD-L1,
programmed death-1 (PD-1), somatic mutations, and others), as defined by
immunohistochemistry (IHC) or quantitative reverse transcriptasepolymerase chain
reaction (qRT-PCR), next generation sequencing (NGS), and/or other methods and
measures of efficacy

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival
and/or fresh tumor tissue, blood, plasma and serum and their association with disease
status, mechanisms of resistance, and/or response to study treatment

To evaluate and compare patient’s health status as assessed by the EuroQoL
5 Dimensions 5-Level (EQ-5D-5L) questionnaire to generate utility scores for use in
economic models for reimbursement

To determine the impact of atezolizumab carboplatin etoposide compared with
placebo carboplatin etoposide as measured by change from baseline in patient-reported
outcomes (PRO) of health-related quality of life, lung cancerrelated symptoms, physical
functioning, and health status as assessed by the EORTC QLQ-C30 and LC13

To evaluate the impact of chemotherapy (both carboplatin and etoposide) on peripheral and
tumor-specific T-cell populations during and after induction therapy and its relationship to
efficacy and safety outcomes
Study Design
Description of Study
This is a randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study 
designed to evaluate the safety and efficacy of atezolizumab in combination with 
carboplatin etoposide compared with treatment with placebo carboplatin etoposide in 
patients who have ES-SCLC and are chemotherapy-naive for their extensive-stage disease.  
Eligible patients will be stratified by sex (male vs. female), Eastern Cooperative Oncology Group 
(ECOG) performance status (0 vs. 1), and presence of brain metastases (yes vs. no) and 
randomized 1:1 to receive one of the following treatment regimens:  A) 
atezolizumabcarboplatinetoposide or B) placebocarboplatinetoposide.


AtezolizumabF. Hoffmann-La Roche Ltd
16/Protocol GO30081, Version 7
Induction treatment will be administered on a 21-day cycle for four cycles.
Following the induction phase, patients will continue maintenance therapy with either 
atezolizumab or placebo.  During the maintenance phase, prophylactic cranial irradiation is 
permitted as per local standard-of-care and will be reported on the Prophylactic Cranial 
Irradiation electronic Case Report Form (eCRF).  Thoracic radiation with curative intent or the 
intent to eliminate residual disease is not permitted.  Palliative thoracic radiation is allowed.   
Treatment should be discontinued in all patients (in both treatment arms) who exhibit evidence 
of disease progression per RECIST v1.1.  However, to better accommodate standard clinical 
practice which is guided by the fact that patients with ES-SCLC whose disease progresses after 
first-line treatment have limited treatment options and such options have limited efficacy and 
significant toxicity, patients may be considered for treatment beyond radiographic disease 
progression per RECIST v1.1, at the discretion of the investigator and after appropriate 
discussion with the patient and obtaining informed consent, only if all of the following criteria are 
met:

Evidence of clinical benefit as assessed by the investigator 

No decline in ECOG performance status that can be attributed to disease progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions

Patients must provide written consent to acknowledge deferring other treatment options in 
favor of continuing study treatment at the time of initial progression
Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 
should be closely monitored clinically and with a follow-up scan in 6 weeks or sooner if 
symptomatic deterioration occurs.  Treatment should be discontinued if clinical deterioration due 
to disease progression occurs at any time, or if persistent disease growth is confirmed in a 
follow-up scan.  In addition, patients should be discontinued for unacceptable toxicity or for any 
other signs or symptoms of deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic data and clinical status.
If clinically feasible, it is recommended that the patient undergo a tumor biopsy sample 
collection at the time of radiographic disease progression.  These data will be used to explore 
whether radiographic findings are consistent with the presence of a tumor.  Additionally, these 
data will be analyzed to evaluate the association between changes in tumor tissue and clinical 
outcome and to further understand 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 will undergo tumor assessments at baseline and every 6 weeks (7 days) for 48 
weeks following Cycle 1, Day 1, regardless of treatment dose delays.  After completion of the 
Week 48 tumor assessment, tumor assessments will be required every 9 weeks (7 days)
thereafter, regardless of treatment dose delays.  Patients will undergo tumor assessments until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, study termination by 
the Sponsor, or death, whichever occurs first. 
Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 will 
continue to undergo tumor assessments every 6 weeks (7 days), or sooner if symptomatic 
deterioration occurs.  For these patients, tumor assessments will continue every 6 weeks 
(7 days), regardless of time in the study, until study treatment is discontinued.
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 at the same frequency as would have been followed if the patient had remained 
on study treatment (i.e., every 6 weeks [7 days] for 48 weeks following Cycle 1, Day 1 and 
then every 9 weeks [7 days] thereafter, regardless of treatment dose delays) until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, study termination by the Sponsor, 
or death, whichever occurs first, regardless of whether patients start a new anti-cancer therapy.
In case of an early termination of the study, patients who are deriving clinical benefit from 
treatment with atezolizumab will be permitted to continue treatment with atezolizumab at the 
discretion of the investigator.


AtezolizumabF. Hoffmann-La Roche Ltd
17/Protocol GO30081, Version 7
Number of Patients
Approximately 400 patients will be randomized into the global enrollment phase of this study.  
Target Population
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Male or female, 18 years of age or older

ECOG performance status of 0 or 1

Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration Lung
Study Group (VALG) staging system

No prior systemic treatment for ES-SCLC

Patients who have received prior chemoradiotherapy for limited-stage SCLC must have
been treated with curative intent and experienced a treatment-free interval of at least
6 months since last chemotherapy, radiotherapy, or chemoradiotherapy cycle from
diagnosis of extensive-stage SCLC

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 evidence of interim progression between the completion of CNS-directed therapy 
and randomization
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.

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)


AtezolizumabF. Hoffmann-La Roche Ltd
18/Protocol GO30081, Version 7
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

Patients must submit a pre-treatment tumor tissue sample.  Any available tumor tissue
sample can be submitted.  The tissue sample should be submitted before or within 4 weeks
after randomization; however, patients may be enrolled into the study before the
pre-treatment tumor tissue sample is submitted.

For women of childbearing potential:  agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1%
per year during the treatment period and for at least 5 months after the last dose of study
treatment.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during treatment with chemotherapy 
(i.e., carboplatin and etoposide) and for at least 6 months after the last dose of 
chemotherapy to avoid exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical study and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods)
and withdrawal are not acceptable methods of contraception.

Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Active or untreated CNS metastases as determined by computed tomography (CT) or
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic
assessments

Spinal cord compression not definitively treated with surgery and/or radiation or previously
diagnosed and treated spinal cord compression without evidence that disease has been
clinically stable for 1 week prior to randomization

Leptomeningeal disease


AtezolizumabF. Hoffmann-La Roche Ltd
19/Protocol GO30081, Version 7

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 regardless of drainage 
frequency.

Uncontrolled or symptomatic hypercalcemia
Patients who are receiving denosumab prior to randomization must be willing and 
eligible to discontinue its use and replace it with a bisphosphonate while in the study.

Malignancies other than SCLC 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)

Women who are pregnant, lactating, or intending to become pregnant during the study

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on thyroid replacement 
hormone therapy are eligible.
Patients with controlled Type I diabetes mellitus on an insulin regimen are eligible.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are eligible 
for the study provided that they meet the following conditions:
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and only requires low potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months (not 
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency, or oral steroids)

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test result for HIV
All patients must be tested for HIV; patients who test positive for HIV will be excluded. 

Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test result at screening) or hepatitis C virus (HCV)
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.  HBV DNA should be obtained in these patients prior to randomization.
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

Active tuberculosis

Severe infections at the time of randomization, including but not limited to hospitalization for 
complications of infection, bacteremia, or severe pneumonia

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months 
prior to randomization, unstable arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or left ventricular ejection fraction 50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate.


AtezolizumabF. Hoffmann-La Roche Ltd
20/Protocol GO30081, Version 7

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

Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates
the use of an investigational drug or that may affect the interpretation of the results or
render the patient at high risk for treatment complications

Patients with illnesses or conditions that interfere with their capacity to understand, follow,
and/or comply with study procedures

Treatment with any other investigational agent with therapeutic intent within 28 days prior to
randomization

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
Patients must not receive live, attenuated influenza vaccines (e.g., FluMist) within 
4 weeks prior to randomization, during treatment, and for 5 months following the last 
dose of atezolizumab/placebo.

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, antiPD-1,
and antiPD-L1 therapeutic antibodies

Treatment with systemic immunosuppressive medications (including, but not limited to
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 1 week prior to randomization
Patients who have received acute systemic immunosuppressant medications (e.g., use
of corticosteroids for nausea, vomiting, or management of or premedication for allergic 
reactions) may be enrolled in the study after discussion with and approval by the 
Medical Monitor.  In those patients, the need and length of the washout period prior to 
randomization will also be established in conjunction with the Medical Monitor.
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.

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 allergic reactions to carboplatin or etoposide
End of Study
The end of study is will occur when all of the following criteria have been met:

The last patient last visit (LPLV) has occurred (i.e., last patient in the global 
).

Approximately 306 deaths have been observed among the randomized patients in the
global enrollment phase.

Additionally, the Sponsor may decide to terminate the study at any time. If the Sponsor decides 
to terminate the study, patients who are still receiving study treatment or undergoing 
survival follow-up may be enrolled in an extension study or a non-interventional study.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 31 months.


AtezolizumabF. Hoffmann-La Roche Ltd
21/Protocol GO30081, Version 7
Outcome Measures
Efficacy Outcome Measures
Primary Efficacy Outcome Measures
The primary efficacy outcome measures for this study are:

PFS, defined as the time from randomization to the first occurrence of disease progression 
as determined by the investigator using RECIST v1.1 or death from any cause, whichever 
occurs first. 

OS, defined as the time from randomization to death from any cause.
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are:

Objective response, defined as PR or CR as determined by the investigator according to 
RECIST v1.1 

DOR, defined as the time interval from first occurrence of a documented objective response 
to the time of disease progression as determined by the investigator using RECIST v1.1 or 
death from any cause, whichever comes first

PFS rates at 6 months and at 1 year

OS rates at 1 and 2 years

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 maintained for two assessments or one assessment followed by death 
from any cause within 3 weeks
Safety Outcome Measures
The safety outcome measures for this study are:

Incidence, nature, and severity of adverse events graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

Changes in vital signs, physical findings, and clinical laboratory results during and following 
study treatment administration

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are:

Maximum observed serum atezolizumab concentration (Cmax) after infusion 

Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at selected 
cycles, at treatment discontinuation, and at 120 days (30 days) after the last dose of 
atezolizumab

Plasma concentrations for carboplatin 

Plasma concentrations for etoposide 
Exploratory Outcome Measures
The exploratory outcome measures for this study are:

Objective response, PFS and DOR as determined by the investigator according to modified 
RECIST

Status of PD-L1, immune-, and SCLC-related and other exploratory biomarkers in archival 
and/or freshly obtained tumor tissues, and blood (or blood derivatives) collected before, 
during, or after treatment with atezolizumab or at progression and association with disease 
status and/or response to atezolizumab

Utility scores of the EQ-5D-5L


AtezolizumabF. Hoffmann-La Roche Ltd
22/Protocol GO30081, Version 7

Change from baseline in PROs of health-related quality of life, lung cancerrelated
symptoms, physical functioning, and health status as assessed by the EORTC QLQ-C30
and QLQ-LC13

Changes in levels and type of peripheral and tumor-specific T-cell populations during and
after induction therapy and its relationship to efficacy and safety outcomes
Investigational Medicinal Products
The induction phase of the study will consist of four cycles of atezolizumab/placebo plus 
chemotherapy, with each cycle being 21 days in duration.  On Day 1 of each cycle, all eligible 
patients will receive drug infusions in the following order:
Arm A:  atezolizumab carboplatin etoposide 
Arm B:  placebo carboplatin etoposide
On Days 2 and 3, patients will receive etoposide alone. 
After the induction phase, patients will begin maintenance therapy with atezolizumab/placebo 
every 3 weeks. 
Test Product (Investigational Drug)
The test products in this study are atezolizumab and atezolizumab placebo.  Patients will 
receive atezolizumab/placebo 1200 mg (equivalent to an average body weight-based dose of 
15 mg/kg) administered by IV infusion every 21 [2] days in a monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.  For information on the formulation, packaging, and handling of 
atezolizumab and atezolizumab placebo refer to the atezolizumab Pharmacy Manual and 
Investigator’s Brochure.  Atezolizumab and atezolizumab placebo will be supplied by the 
Sponsor.
Non-Investigational Medicinal Products
Carboplatin and etoposide are background treatment and are considered non-investigational 
medicinal products (NIMPs).  For information on the formulation, packaging, and handling of 
carboplatin and etoposide see the prescribing information for each drug.
Carboplatin should be administered after completion of atezolizumab/placebo by IV infusion 
over 3060 minutes to achieve an initial target area under the concentration-time curve (AUC) 
of 5 mg/mL/min (Calvert formula dosing) with standard anti-emetics per local practice guidelines.
During the induction phase (Cycles 14), on Day 1 of each cycle, etoposide (100 mg/m2) should 
be administered intravenously over 60 minutes following carboplatin administration.  On 
Days 2 and 3 of each cycle, etoposide (100 mg/m2) should be administered intravenously over 
60 minutes.  Premedication should be administered according to local standard-of-care.  
Because the effects of corticosteroids on T-cell proliferation have the potential to attenuate 
atezolizumab-mediated anti-tumor immune activity, premedication with corticosteroids should 
be minimized to the extent that is clinically feasible.
Statistical Methods
All analyses will be restricted to the patients enrolled in the global enrollment phase only (
 
), unless otherwise noted. The analysis populations used 
in this section, such as the ITT (i.e., all randomized patients) and the PD-L1selected
populations will not 
, unless otherwise noted.
The analyses of PFS and OS will be performed on all randomized patients (ITT), with patients 
grouped according to the treatment assigned at randomization, regardless of whether they 
receive any assigned study drug.  ORR will be analyzed using all randomized patients who 
have measurable disease at baseline.  DOR will be assessed in patients who have an objective 
response.  TTD analyses will be conducted on all patients with a non-missing baseline PRO 
assessment.  Change from baseline analysis on PROs will be performed using patients who 
have both a non-missing baseline assessment and at least one post-baseline assessment with 
patients grouped according to the treatment assigned at randomization.


AtezolizumabF. Hoffmann-La Roche Ltd
23/Protocol GO30081, Version 7
Primary Analysis
To adjust for multiplicity due to having two co-primary endpoints, a group sequential Holm’s 
procedure will be implemented: initially the hypothesis test for PFS will be conducted at a 
two-sided alpha of 0.005 and OS will be tested at a two-sided alpha of 0.045.  Once a null 
hypothesis is rejected, the test mass predefined for that endpoint becomes available and can be 
recycled to the other unrejected test.
The null and alternative hypotheses regarding PFS or OS in the ITT population can be phrased 
in terms of the PFS or OS survival functions SA(t) and SB(t) for Arm A 
(atezolizumabcarboplatin etoposide) and Arm B (placebocarboplatinetoposide), 
respectively:
H0: SA(t) SB(t) versus H1: SA(t) ≠SB(t)
One of the co-primary efficacy endpoints is PFS as assessed by the investigator using 
RECIST v1.1.  PFS is defined as the time between the date of randomization and the date of 
first documented disease progression or death, whichever occurs first.  Patients who have not 
experienced disease progression or death at the time of analysis will be censored at the time of 
the last tumor assessment.  Patients with no post-baseline tumor assessment will be censored 
at the date of randomization plus 1 day.
The stratified log-rank test, will be used as the primary analysis to compare PFS between the 
two treatment arms.  The results from the unstratified log-rank will also be provided. 
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm.  The 
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median PFS for 
each treatment arm.  Cox proportional-hazards models will be used to estimate the stratified 
HR and its 95% CI.  The unstratified HR will also be presented.
OS, the other co-primary efficacy endpoint, is defined as the time from the date of 
randomization to the date of death from any cause.  Patients who are alive at the time of the 
analysis data cutoff will be censored at the last date they were known to be alive.  Patients with 
no post-baseline information will be censored at the date of randomization plus 1 day. Methods 
for OS analyses are similar to those described for the PFS endpoint.
Determination of Sample Size  
Approximately 400 patients will be randomized into the global enrollment phase of this study to 
the atezolizumab carboplatin etoposide arm and the placebo carboplatin etoposide arm in 
a 1:1 ratio.
There are two co-primary efficacy endpoints: PFS and OS. To control the overall two-sided 
Type I error rate at 0.05, the two-sided significance levels of 0.005 and 0.045 are allocated to 
the primary comparisons for PFS and OS, respectively.
The following sample size calculation applies to the global enrollment phase, 
 
unless otherwise noted.
The sample size of the study is determined by the analysis of OS. To detect an improvement of 
HR 0.68 in OS using a log-rank test, approximately 306 deaths in the ITT population will be 
required to achieve 91% power at a two-sided significance level of 0.045. One OS interim 
analysis will be performed when approximately 240 OS events in the ITT population are 
observed, which by estimation will occur at approximately 25 months after the first patient is 
randomized. 
The primary analysis of PFS is planned to be conducted at the time of the OS interim analysis, 
and is estimated to be when approximately 295 PFS events in the ITT population have occurred, 
which is expected at approximately 25 months after the first patient is randomized. This 
provides 99% power to detect an improvement of HR 0.55 in PFS at a two-sided significance 
level of 0.005. There will be no interim analysis for PFS.
By a group sequential Holm procedure, if the primary analysis of PFS is significant, then the 
two-sided 0.005 alpha will be recycled to OS. Otherwise, iIf the OS analysis at either interim or 
final is significant, the allocated test mass of two-sided 0.045 alpha can be returned to PFS so 
PFS primary analysis can be tested at a two-sided 0.05 level. Additional details will be provided
in the SAP.


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The final analysis of OS will be performed when approximately 306 OS events in the ITT 
population have been observed, which is expected at approximately 36 months after the first 
patient is randomized.
The calculation of sample size and estimates of the analysis timelines are based on the 
following assumptions:

PFS and OS are exponentially distributed.

The median duration of PFS in the control arm is 6 months.

The median duration of OS in the control arm is 10 months.

The two interim and final analyses of OS use the Lan-DeMets alpha spending function to
approximate the O’Brien-Fleming boundary.

The dropout rate is 5% over 12 months for PFS and OS.
The sample size of the
 
 
 
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 IRBs/ECs.  A detailed plan will be included in the iDMC 
Charter. 
One interim efficacy analysis of OS is planned when approximately 240 OS events have been 
observed.  The primary analysis of PFS will be conducted at the same time of the interim OS 
analysis and is estimated to occur when approximately 295 PFS events in the ITT population 
have occurred, which is expected at approximately 25 months after the first patient is 
randomized.
The final OS analysis will be conducted when approximately 306 OS events in the ITT 
population have been observed.  This is expected to occur approximately 36 months after the 
first patient is randomized, but the exact timing of this analysis will depend on the actual number 
of OS events.  
To control the type I error for OS, the stopping boundaries for OS interim and final analyses are 
to be computed with use of the Lan-DeMets approximation to the O’Brien-Fleming boundary.


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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
Cmax
maximum observed serum concentration
Cmin
minimum observed serum concentration
CAV
cyclophosphamide, doxorubicin, and vincristine
CR
complete response
CRCL
creatinine clearance
CT
computed tomography
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 Organization for Research and Treatment of Cancer
ePRO
electronic PRO
EQ-5D-5L
EuroQoL 5 Dimensions 5-Level Version
ES-SCLC
extensive-stage small cell lung cancer
ESMO
European Society for Medical Oncology
FDA
U.S. Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
GFR
glomerular filtration rate
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life
IC
tumor-infiltrating immune cell
ICH
International Conference on Harmonisation
iDCC
independent Data Coordinating Center


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Abbreviation
Definition
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
imAE
immune-modulated adverse event
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
intent-to-treat
IxRS
interactive voice/Web response system
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NGS
next-generation sequencing
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD-1
programmed death1
PD-L1
programmed deathligand 1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
PUVA
psoralen plus ultraviolet A radiation
q3w
every 3 weeks
QLQ-C30
Quality-of-Life Questionnaire Core 30
QLQ-LC13
Quality-of-Life Questionnaire Lung Cancer Module
qRT-PCR
quantitative reverse transcriptasepolymerase chain reaction
RCC
renal cell carcinoma
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
Statistical Analysis Plan
SCLC
small cell lung cancer
SIRS
systemic inflammatory response syndrome
TC
tumor cell


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Abbreviation
Definition
TIR
time in response
TNF
tumor necrosis factor
TSH
thyroid-stimulating hormone
TTD
time to deterioration
TTR
time to response
UBC
urothelial bladder cancer
ULN
upper limit of normal
VALG
Veterans Administration Lung Study Group


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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 men and accounted for approximately 13% of all new cancers in 
2008 (Jemal et al. 2011).  In 2012, it was estimated that there were 313,000 new cases 
of lung cancer and 268,000 lung cancer deaths in Europe (GLOBOCAN 2012).  Similar 
data from the United States estimated that there would be 221,200 new cases of lung 
cancer and 158,040 lung cancer deaths in 2015 (Siegel et al. 2015).
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung 
cancer (Molina et al. 2008; Howlader et al. 2014).  Small cell lung cancer (SCLC) 
accounts for approximately 13% of all cases, and is distinguished from NSCLC by its 
rapid growth time and early development of metastatic disease (Govindan et al. 2006).  
Nearly all cases of SCLC are attributable to cigarette smoking (Pesch et al. 2012).  Poor 
prognostic factors for survival in patients with SCLC include extensive-stage disease, 
poor performance status, weight loss, and markers associated with excessive bulk of 
disease (e.g., lactate dehydrogenase) (Yip et al. 2000; Foster et al. 2009). 
Patients with limited-stage SCLC can be treated with chemotherapy and radiation with 
the potential for long-term survival (Stinchcombe et al. 2010).  However, the majority 
(approximately 70%) of patients with SCLC are diagnosed with extensive-stage disease 
(ES-SCLC), which has poor survival prospects (median overall survival [OS] 
approximately 10 months) (Socinsk et al. 2009).  Chest pain, dyspnea, and cough are 
among the most frequent disease-related symptoms experienced by patients with lung 
cancer.  Chemotherapy alone can palliate symptoms and prolong survival for patients 
with ES-SCLC, however long-term survival is rare (Johnson et al. 2004; 
Demedts et al. 2010). 
1.1.1
Treatment for Extensive-Stage Small Cell Lung Cancer
The current standard first-line treatment for patients with ES-SCLC is platinum-based 
chemotherapy with etoposide, a topoisomerase II inhibitor (NCCN 2015, 
Fruh et al. 2013).  In the mid-1980s, clinical studies with the combination of cisplatin and 
etoposide as first-line treatment in patients with ES-SCLC showed complete response 
(CR) rates 40% and median survival time of approximately 9 months 
(Evans et al. 1985).  Subsequently, small randomized studies have suggested similar 
efficacy of cisplatin and carboplatin in patients with SCLC (Skarlos et al. 1994; 
Okamoto et al. 2007).  A meta-analysis of four randomized studies compared 
cisplatin-based versus carboplatin-based regimens in patients with SCLC 
(Rossi et al. 2012).  Of the 663 patients included in this meta-analysis, 68% had 
extensive-stage disease.  In patients receiving cisplatin- versus carboplatin-containing 
regimens, there was no significant difference observed in response rate (67% vs. 66%), 
progression-free survival (PFS) (5.5 vs. 5.3 months; hazard ratio [HR]: 1.10; 95% CI: 
0.94, 1.29) or OS (9.6 vs. 9.4 months; HR: 1.08; 95% CI: 0.92, 1.27), suggesting 


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equivalent efficacy in patients with SCLC.  Several studies using cisplatin or carboplatin 
with etoposide (at various doses) have shown consistent outcomes (see Table 1).


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Table 1
Results from Randomized Studies using Platinum-Based Chemotherapy for ES-SCLC
Platinum Dosing
Etoposide Dosing
ORR
(%)
Median 
PFS
(months)
Median 
OS
(months)
Roth et al. 1992 
Cisplatin 20 mg/m2 Days 15
80 mg/m2 Days 15
61%
4.3
8.6
Pujol et al. 2001
Cisplatin 100 mg/m2 Day 2
100 mg/m2 Days 13
61%
6.3
9.3
Noda et al. 2002
Cisplatin 80 mg/m2 Day 1
100 mg/m2 Days 13
68%
4.8
9.4
Eckardt et al. 2006
Cisplatin 80 mg/m2 Day 1
100 mg/m2 Days 13
69%
6.3
10.1
Hanna et al. 2006
Cisplatin 60 mg/m2 Day 1
120 mg/m2 Days 13
44%
4.6
10.2
Okamoto et al. 2007
Cisplatin 25 mg/m2 Days 13
80 mg/m2 Days 13
73%
4.7
9.9
Okamoto et al. 2007
Carboplatin AUC 5 Day 1
80 mg/m2 Days 13
73%
5.2
10.6
Rudin et al. 2008
Carboplatin AUC 5 Day 1
100 mg/m2 Days 13
52%
5.4
10.6
Socinski et al. 2009
Carboplatin AUC 5 Day 1
80 mg/m2 Days 13
60%
7.6
10.6
Nagel et al. 2011
Carboplatin AUC 6 Day 1
120 mg/m2 Days 13
67%
7.0
11.0
Schmittel et al. 2011
Carboplatin AUC 5 Day 1
140 mg/m2 Days 13
52%
6.0
9.0
AUCarea under the concentration-time curve; ES-SCLCextensive-stage small cell lung cancer; 
ORRobjective response rate; OSoverall survival; PFSprogression-free survival.


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In the second-line setting, single-agent topotecan is approved by the U.S. Food and 
Drug Administration (FDA) as subsequent therapy for patients with SCLC who initially 
respond to chemotherapy but then progress after 23 months.  This is based on a 
Phase III study in which intravenous topotecan was compared with the combination 
regimen CAV (cyclophosphamide, doxorubicin, and vincristine).  Both arms had similar 
response rates and survival; however, the proportion of patients who experienced 
symptom improvement was greater in the topotecan group than in the CAV group for 
4 of 8 symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as 
well as interference with daily activity (von Pawel et al. 1999).  Subsequently, a Phase III 
study also showed the superiority of oral topotecan versus best supportive care for 
patients with relapsed SCLC not considered candidates for standard intravenous therapy 
(O’Brien et al. 2006).
Despite the impressive initial response rates observed with first-line chemotherapy 
regimens, most patients with ES-SCLC develop chemotherapy resistant disease and 
their prognosis is poor.  PFS is approximately 6 months and median survival remains 
under a year.  Therefore, there is a significant need for improved novel treatment options 
for patients with ES-SCLC.  Against this background, immunotherapeutic agents, 
including 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)
Programmed deathligand 1 (PD-L1) is an extracellular protein that downregulates 
immune responses primarily in peripheral tissues through binding to its two receptors 
programmed death1 (PD-1) and B7.1. PD-1 is an inhibitory receptor expressed on 
T cells following T-cell activation, which is sustained in states of chronic stimulation such 
as in chronic infection or cancer (Blank et al. 2005; Keir et al. 2008). Ligation of PD-L1 
with PD-1 inhibits T-cell proliferation, cytokine production, and cytolytic activity, leading 
to the functional inactivation or exhaustion of T cells.  B7.1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  PD-L1 binding to B7.1 on T cells and 
antigen-presenting cells can mediate downregulation of immune responses, 
including inhibition of T-cell activation and cytokine production (Butte et al. 2007; 
Yang et al. 2011).
Overexpression of PD-L1 on tumor cells (TCs) has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumor-specific T-cell immunity.
Atezolizumab (MPDL3280A; antiPD-L1 antibody) is a humanized IgG1 monoclonal 
antibody consisting of two heavy chains (448 amino acids) and two light chains 
(214 amino acids), and is produced in Chinese hamster ovary cells.  Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid substitution at 
position 298 on the heavy chain, which results in a non-glycosylated antibody that has 


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minimal binding to Fc receptors and prevents Fc-effector function at expected 
concentrations in humans.  Atezolizumab targets human PD-L1 and inhibits its 
interaction with its receptors, PD-1 and B7.1 (CD80, B7-1).  Both of these interactions 
are reported to provide inhibitory signals to T cells.
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.  Atezolizumab is approved for the treatment of 
patients with metastatic NSCLC after prior chemotherapy and for the treatment of 
patients with locally advanced or metastatic urothelial cancer after prior chemotherapy.
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 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 (refer to the 
Atezolizumab Investigator’s Brochure for study descriptions).  
Single-agent safety and efficacy data in patients with lung cancer are presented below 
from the following two 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 given 


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every 3 weeks (Q3W) to patients with locally advanced or metastatic solid 
malignancies or hematologic malignancies.

Study GO28753 (POPLAR):  a randomized, Phase II, open-label study assessing
the clinical benefit of atezolizumab as a single agent versus docetaxel in patients
with locally advanced or metastatic NSCLC that has progressed during or following
treatment with a platinum-containing regimen.
In addition, the safety and efficacy data of atezolizumab in combination with 
platinum-based chemotherapy are also summarized below from the Phase Ib 
Study GP28328 that is investigating the safety and efficacy of atezolizumab in 
combination with chemotherapy in patients with advanced solid tumors.
1.3.2
Clinical Safety
1.3.2.1
Single-Agent Clinical Safety in Patients with Lung Cancer 
Study PCD4989g is a Phase Ia dose escalation and expansion study in which 
atezolizumab is being used as a single agent in patients with locally advanced or 
metastatic solid tumors or hematologic malignancies, and provides the majority of data 
(with 558 safety-evaluable patients as of the data cutoff date of 11 May 2015) for the 
safety profile of atezolizumab as monotherapy.
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined.
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications, including SCLC, NSCLC, urothelial bladder cancer (UBC), renal cell 
carcinoma (RCC), melanoma, gastric cancer, colorectal cancer, head and neck cancer, 
breast cancer, and sarcoma.  
Single-Agent Clinical Safety in Patients in Study PCD4989g
Of the 558 patients in Study PCD4989g, 520 patients (93.2%) experienced at least one 
adverse event, including 376 patients (67.4%) who experienced one treatment-related 
adverse event.  Commonly reported events (reported in 10% of all patients) included 
fatigue, decreased appetite, nausea, pyrexia, constipation, and cough (see Table 2).


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Table 2
Study PCD4989g:  Adverse Events with Frequency 10% of 
Patients for All Grades
Preferred Term
All Grades
n (%)
All Grades 
Related
n (%)
Grade 34
n (%)
Grades 34 
Related
n (%)
Any adverse event
520 (93.2)
376 (67.4)
239 (42.8)
66 (11.8)
Fatigue
192 (34.4)
115 (20.6)
13 (2.3)
6 (1.1)
Decreased Appetite
142 (25.4)
62 (11.1)
4 (0.7)
0 (0.0)
Nausea
136 (24.4)
65 (11.6)
5 (0.9)
2 (0.4)
Pyrexia
117 (21.0)
63 (11.3)
2 (0.4)
0 (0.0)
Constipation
116 (20.8)
8 (1.4)
2 (0.4)
0 (0.0)
Cough
113 (20.3)
11 (2.0)
1 (0.2)
1 (0.2)
Dyspnea
112 (20.1)
18 (3.2)
18 (3.2)
4 (0.7)
Diarrhea
110 (19.7)
53 (9.5)
2 (0.4)
1 (0.2)
Anemia
104 (18.6)
26 (4.7)
23 (4.1)
5 (0.9)
Vomiting
96 (17.2)
28 (5.0)
3 (0.5)
2 (0.4)
Asthenia
88 (15.8)
53 (9.5)
8 (1.4)
4 (0.7)
Back Pain
85 (15.2)
9 (1.6)
8 (1.4)
1 (0.2)
Headache
83 (14.9)
32 (5.7)
2 (0.4)
1 (0.2)
Arthralgia
79 (14.2)
35 (6.3)
2 (0.4)
0 (0.0)
Pruritus
75 (13.4)
55 (9.9)
0 (0.0)
0 (0.0)
Rash
73 (13.1)
53 (9.5)
0 (0.0)
0 (0.0)
Abdominal Pain
63 (11.3)
12 (2.2)
8 (1.4)
0 (0.0)
Insomnia
62 (11.1)
7 (1.3)
1 (0.2)
0 (0.0)
Peripheral edema
59 (10.6)
7 (1.3)


Chills
57 (10.2)
31 (5.6)
0 (0.0)
0 (0.0)
Note:  “” refers to missing Common Terminology Criteria grade.
‘Related’ refers to investigator designation of causality to atezolizumab.
Single-Agent Clinical Safety in Patients with SCLC in Study PCD4989g 
Seventeen patients with SCLC in Study PCD4989g had received at least one dose of 
atezolizumab as of 15 December 2015.  Of these 17 patients, 16 patients experienced at 
least one adverse event.  Sixty-five percent of patients experienced treatment-related 
adverse events, with the most frequently reported adverse event being fatigue (24%).  
There were eight treatment-related, Grade 3-5, adverse events reported in 3 patients, 
including one Grade 3 pneumonitis leading to treatment discontinuation and one Grade 
5 hepatic failure.  Although the patient numbers are limited, the adverse events reported 
in the SCLC cohort in Study PCD4989g are consistent with the safety profile of 
atezolizumab observed in the entire study.


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Refer to the Atezolizumab Investigator’s Brochure for details on adverse events 
observed in patients treated with atezolizumab.
Single-Agent Clinical Safety in Patients with NSCLC in POPLAR 
Study GO28753
As of the 8 May 2015 data cutoff date, the Phase II POPLAR study (GO28753) included 
data from 142 patients with NSCLC treated with atezolizumab as a fixed dose of 
1200 mg IV every 3 weeks and 135 patients treated with 75 mg/m2 IV docetaxel every 
3 weeks.  The frequency of patients who reported any adverse event regardless of 
attribution was 96.3% for the atezolizumab arm and 95.8% for the docetaxel arm.  A 
higher number of Grade 3 adverse events were observed in the docetaxel arm (56.3% 
vs. 44.4%), explained primarily by the difference in adverse events due to bone marrow 
suppression.  Adverse events reported in at least 10% of patients in either treatment arm 
are listed in Table 3.


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Table 3
Adverse Events Reported in at Least 10% of Patients in the 
POPLAR Study GO28753
No. of Patients (%)
MedDRA Preferred Term
Atezolizumab
(n142)
Docetaxel
(n135)
Fatigue
55 (38.7)
54 (40.0)
Decreased appetite
49 (34.5)
28 (20.7)
Dyspnoea
38 (26.8)
27 (20.0)
Cough
38 (26.8)
33 (24.4)
Nausea
31 (21.8)
45 (33.3)
Constipation
29 (20.4)
32 (23.7)
Pyrexia
24 (16.9)
16 (11.9)
Diarrhoea
24 (16.9)
38 (28.1)
Arthralgia
22 (15.5)
12 (8.9)
Anaemia
23 (16.2)
26 (19.3)
Insomnia
19 (13.4)
11 (8.1)
Musculoskeletal pain
19 (13.4)
7 (5.2)
Vomiting
18 (12.7)
18 (13.3)
Back Pain
16 (11.3)
11 (8.1)
Asthenia
14 (9.9)
22 (16.3)
Pneumonia
15 (10.6)
4 (3.0)
Rash
15 (10.6)
16 (11.9)
Myalgia
8 (5.6)
18 (13.3)
Alopecia
3 (2.1)
52 (38.5)
Neuropathy peripheral
2 (1.4)
16 (11.9)
Neutropenia
2 (1.4)
17 (12.6)
MedDRAMedical Dictionary for Regulatory Activities.
For additional information, refer to the Atezolizumab Investigator’s Brochure.
1.3.2.2
Clinical Safety in Combination with Platinum-Based Doublet 
Chemotherapy
Study GP28328 is a Phase 1b study investigating atezolizumab in combination with 
chemotherapy in patients with multiple tumor types including NSCLC, triple-negative 
breast cancer, RCC, and colorectal cancer.  Patients with NSCLC were enrolled in 
Arms C, D, and E of the study and received atezolizumab in combination with 
carboplatin-based doublet chemotherapy.  As of 1 September 2015, 25 patients were 
enrolled in Arm C (atezolizumabcarboplatin and paclitaxel), 25 patients in Arm D 
(atezolizumabcarboplatin and pemetrexed), and 26 patients in Arm E 
(atezolizumabcarboplatin and nab-paclitaxel).  The treatment combinations have been 


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generally well tolerated.  No DLTs have been reported during the dose-escalation stage 
in any study arm. 
All patients enrolled in Arms C and D experienced an adverse event and 95% of patients 
enrolled in Arm E experienced an adverse event (see Table 4).  The adverse events 
commonly reported in 2 or more patients across these study arms included anemia, 
decreased appetite, hypomagnesemia, nausea, neutropenia, constipation, vomiting, 
fatigue, rash, cough, and diarrhea.  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 4
Study GP28328:  All Reported Adverse Events
Parameter
Arm C
Atezolizumab
carboplatin
paclitaxel
(n25)
No. (%)
Arm D
Atezolizumab
carboplatin
pemetrexed
(n25)
No. (%)
Arm E
Atezolizumab
carboplatin
nab-paclitaxel
(n26)
No. (%)
Any AEs
25 (100)
25 (100)
25 (96.2)
Related AEs
24 (96)
25 (100)
25 (96.2)
Grade 35 AEs
19 (76.0)
19 (76.0
24 (92.3)
Related Grade 35 AEs
18 (72.0)
13 (52.0)
23 (88.5)
Serious AEs
11 (44.0
11 (44.0)
11 (42.3
AEs leading to discontinuation of 
atezolizumab
1 (4.0)
1 (4.0)
1 (3.8)
AEs leading to death (Grade 5)
1 (4.0)
1 (4.0)
1 (3.8)
Related AEs leading to death (Grade 5)
1 (4.0)
1 (4.0)
0 (0)
Immune-mediated AEs
17 (68.0
13 (52.0)
14 (53.8)
AEadverse event.
1.3.2.3
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 observed in patients treated with atezolizumab. 
1.3.3
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1-based responses (RECIST v1.1 responses), have been observed in patients 
with different tumor types treated with atezolizumab monotherapy in Study PCD4989g.


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Refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in all 
patients treated to date, regardless of tumor type.
Single-agent data are summarized below from Study PCD4989g for the SCLC and 
NSCLC cohorts.  In addition, data from the randomized Study GO28753 (POPLAR) in 
patients with advanced NSCLC and from the Phase Ib Study GP28328 evaluating 
atezolizumab plus carboplatin-based chemotherapy in patients with NSCLC, are also 
provided.
1.3.3.1
Single-Agent Clinical Activity in Patients with SCLC in 
Study PCD4989g
As of the clinical data cutoff date of 15 December 2015, 17 patients in the SCLC cohort 
of Study PCD4989g with a minimum follow-up of 6.7 months were evaluable for efficacy.  
Sixty-five percent of patients were male and 88% of the patients had an Eastern 
Cooperative Oncology Group (ECOG) performance status of 1. The median age was 63 
years (range 4480 years) and patients were heavily pre-treated (65% of patients had 
received 3 prior therapies).
The confirmed objective response rate (ORR) by RECIST v1.1 was 6% (1 partial 
response [PR], with a duration of response [DOR] of 7 months).  The ORR by 
immune-related response criteria (irRC) was 24%.  Four of 17 patients received 
atezolizumab for 6 months (2 of these patients for 12 months). One patient with irPR 
stopped atezolizumab treatment per protocol after 1 year and remained in PR by 
immune-related response criteria for an additional 1 year until progression of disease.  
After retreatment, the patient again derived benefit and was still receiving atezolizumab 
treatment as of the data cutoff (i.e., 2.6 years after receiving the first treatment dose).  
Median PFS by RECIST v1.1 was 1.5 months (95% CI: 1.2, 2.7), and median OS was 
5.9 months (95% CI: 4.3, 20.1).  PD-L1 expression was low overall, consistent with 
published data.  
Although the patient numbers are limited, the preliminary safety and efficacy results 
provide evidence of an acceptable safety profile and encouraging single-agent activity of 
atezolizumab in patients with SCLC based on the irRC response rate and the prolonged 
duration of treatment and clinical benefit experienced by a subset of patients.  
Furthermore, a Phase I study investigating atezolizumab in combination with carboplatin 
and etoposide in patients with ES-SCLC is ongoing and will also provide additional 
efficacy and safety data. 
1.3.3.2
Single-Agent Clinical Activity in Patients with NSCLC in 
Study PCD4989g
As of the 2 December 2014 cutoff date, 88 patients with NSCLC in Study PCD4989g 
who received their first dose of atezolizumab by 21 October 2013 were evaluable for 
efficacy.  The median age was 60.5 years; the group represented a heavily pre-treated 
patient population.  RECIST v1.1 responses (confirmed) were observed in a total of 


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20 patients (20 of 88 patients; 22.7%), inclusive of squamous and non-squamous 
histologies and across all treatment cohorts (treatment dose levels: 120 mg/kg).  A total 
of 8 of 20 responding patients have continued to respond at the time of the clinical data 
cutoff.
1.3.3.3
Single-Agent Clinical Activity in Patients with NSCLC in the 
POPLAR Study
The primary OS analysis in Study GO28753 (POPLAR) was conducted when 
173 deaths had occurred (clinical cutoff: 8 May 2015).  Demographic characteristics 
were comparable between the atezolizumab and docetaxel treatment arms in the 
intent-to-treat (ITT) population.  The median age was 62 years in both treatment arms, 
and the majority of patients had one prior therapy (64.6% for atezolizumab and 67.1% 
for docetaxel), non-squamous histology (66.0% for atezolizumab and 66.4% for 
docetaxel), and ECOG performance status of 1 (67.6% for atezolizumab and 68.3% for 
docetaxel).  More females were enrolled in the docetaxel arm (46.9% vs. 35.4%).
Atezolizumab showed significant improvement in OS compared with docetaxel in 
patients with advanced, previously treated NSCLC unselected for PD-L1 expression.  
OS in the ITT population was 12.6 months (95% CI: 9.7, 16.4) for atezolizumab versus 
9.7 months (95% CI: 8.6, 12.0) for docetaxel (HR 0.73; 95% CI: 0.53, 0.99; p = 0.04).  
PFS was similar between groups (2.7 months with atezolizumab vs. 3.0 months with 
docetaxel).  Objective responses with atezolizumab were durable, with a median 
duration of 14.3 months (95% CI: 11.6, not estimable) compared with 7.2 months 
(95% CI: 5.6, 12.5) for docetaxel (Fehrenbacher et al. 2016).
1.3.3.4
Clinical Efficacy in Combination with Carboplatin-Based 
Doublet Chemotherapy in Patients with NSCLC
As of the 10 February 2015 data cutoff, 58 patients with NSCLC were enrolled into 
Arm C (atezolizumabcarboplatin and paclitaxel), Arm D (atezolizumabcarboplatin
and pemetrexed), and Arm E (atezolizumabcarboplatin and nab-paclitaxel) of 
Study GP28328.  Patients who had received their first dose of atezolizumab by 
10 November 2014 were evaluable for efficacy (n 41).  All patients had histologically or 
cytologically documented Stage IIIB, Stage IV, or recurrent NSCLC and had not received 
prior chemotherapy for advanced disease.  For safety evaluable patients who received 
any amount of atezolizumab by the cutoff date, the median age was 65 years and 79% 
(46 of 58) of patients had non-squamous histology.  The overall confirmed objective 
response rate per RECIST v1.1 in all three arms combined was 63% (26 of 41 patients).
Within each cohort, the ORR was 50% (95% CI: 16%, 84%) in Arm C (four 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 (five PRs and four 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).


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1.3.4
Clinical Pharmacokinetics and Immunogenicity
On the basis of available preliminary PK data (0.0320 mg/kg) in Study PCD4989g, 
atezolizumab appeared to show linear pharmacokinetics at doses 1 mg/kg.  For the 
1-mg/kg and 20-mg/kg dose groups, the mean apparent clearance and the mean volume 
of distribution under steady-state conditions had a range of 3.114.14 mL/kg and 
48.167.0 mL/kg, respectively, which is consistent with the expected profile of an 
IgG1 antibody in humans.
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses from 1020 mg/kg.  
Patients dosed at the 10-, 15-, and 20-mg/kg dose levels have maintained the expected 
target trough levels of drug despite the detection of ATAs.  To date, no clear relationship 
between the detection of ATAs and adverse events, infusion reactions, or efficacy has 
been observed.
1.3.5
Rationale for Atezolizumab Dosage
The fixed dose of 1200 mg (equivalent to an average body weight-based dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below.
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors. The 
target trough concentration (Ctrough) was projected to be 6 g/mL on the basis of several 
assumptions, including the following:  1) 95% tumor-receptor saturation is needed for 
efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue 
distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, 
pharmacokinetics, and immunogenicity data. Anti-tumor activity has been observed 
across doses from 1 mg/kg to 20 mg/kg. The MTD of atezolizumab was not 
reached, and no DLTs have been observed at any dose in Study PCD4989g. Currently 
available PK and ATA data suggest that the 15-mg/kg atezolizumab q3w regimen (or 
fixed-dose equivalent) for Phase II and Phase III studies would be sufficient to both 
maintain Ctrough 6 g/mL and further safeguard against both interpatient variability and 
the potential effect of ATAs that could lead to subtherapeutic levels of atezolizumab 
relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose equivalent).  From 
inspection of available observed Ctrough data, moving further to the 20-mg/kg 
atezolizumab q3w regimen does not appear to be warranted to maintain targeted Ctrough 
levels relative to the proposed 15-mg/kg atezolizumab q3w level. 


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Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose or a dose adjusted for weight.  Therefore, a fixed dose 
of 1200 mg has been selected (equivalent to an average body weightbased dose of 
15 mg/kg).  Selection of an every-21-day dosing interval is supported by this preliminary 
pharmacokinetics evaluation.
Refer to the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012).
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1. PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is sustained in 
states of chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008). Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of 
T cells.  B7.1 is a molecule expressed on antigen-presenting cells and activated T cells.  
PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate 
downregulation of immune responses, including inhibition of T-cell activation and 
cytokine production (Butte et al. 2007; Yang et al. 2011).
Overexpression of PD-L1 on TCs has been reported to impede anti-tumor immunity, 
resulting in immune evasion (Blank and Mackensen 2007).  Therefore, interruption of the 
PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific 
T-cell immunity.
1.4.1
Rationale for Testing Atezolizumab in Combination with 
Carboplatin and Etoposide in ES-SCLC
Platinum-based regimens remain the standard first-line option for patients with ES-SCLC.  
The combination of cisplatin or carboplatin with etoposide has shown response rates 
ranging from 50%70% in patients with ES-SCLC.  Studies using cisplatin or carboplatin 
with etoposide (at various doses) have shown consistent outcomes, suggesting their 
efficacy is equivalent in patients with ES-SCLC, and in clinical practice, carboplatin is 
frequently substituted for cisplatin to reduce the risk of emesis, neuropathy, and 
nephropathy.  The combination of carboplatin and etoposide is included in the National 
Cancer Comprehensive Network (NCCN) and the European Society of Medical 
Oncology (ESMO) guidelines (NCCN 2015; Fruh et al. 2013). 


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Despite the initial response rates observed with first-line chemotherapy regimens, 
median survival remains under a year, leaving considerable room for improvement in 
outcomes.  TC killing by cytotoxic chemotherapy can reasonably be expected to expose 
the immune system to high levels of tumor antigens.  Therefore, invigorating 
tumor-specific T-cell immunity 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 SCLC will enable future tests of this hypothesis.
Whole exome sequencing studies have shown that SCLC exhibits a high mutation rate 
(7.4 mut/Mb) compared with other tumor types, and therefore may be a highly 
immunogenic tumor that may potentially benefit from treatment with immune checkpoint 
inhibitors (Rudin et al. 2012).  In addition, nearly all cases of SCLC are attributable to 
cigarette smoking, which has been shown to be associated with benefit from 
antiPD-L1/antiPD-1 antibodies (Borghaei et al. 2015; Garon et al. 2015). 
The preliminary safety and efficacy results for atezolizumab given as monotherapy in 
patients with SCLC in the Phase Ia Study PCD4989g provide evidence of an acceptable 
safety profile and clinical activity of atezolizumab, although the patient numbers are 
limited.  Furthermore, a Phase I/II study investigating atezolizumab in combination with 
carboplatin and etoposide in patients with ES-SCLC is ongoing and will provide efficacy 
and safety data for the combination treatment in this patient population.
Efficacy results from the POPLAR (GO28753) study demonstrated an OS benefit of 
single-agent atezolizumab compared to docetaxel in patients with advanced NSCLC, 
which is a disease that is similar to SCLC in its high mutational load, anatomical location, 
and association with smoking.  In addition, the preliminary efficacy and safety results 
from the Phase Ib Study GP28328 evaluating atezolizumab in combination with 
platinum-based chemotherapy demonstrate an acceptable safety profile when combining 
atezolizumab with platinum-based doublet chemotherapy in a nonPD-L1selected
population.  In this study, ORRs ranging from 50%75% were observed in patients with 
NSCLC (see Section 1.3.3.4).  Objective responses were seen at all levels of PD-L1 
expression.  No additive adverse effects were observed when atezolizumab was 
administered with carboplatin-based chemotherapy.
Other checkpoint inhibitors targeting the PD-L1/PD-1 pathway have shown clinical 
activity in patients with recurrent SCLC.  In the Phase I/II CheckMate 032 study, the 
PD-1 inhibitor nivolumab given as monotherapy in unselected patients with SCLC whose 
disease progressed after at least one line of therapy, including a first-line platinum-based 
regimen, demonstrated an ORR (by blinded independent central review) of 10% and a 
median OS of 4.4 months (95% CI: 3.0, 9.3) (Antonia et al. 2016).  In the Phase Ib 
KEYNOTE-028 study, the PD-1 inhibitor pembrolizumab showed an ORR of 35% (95% 
CI: 15%, 59%) in heavily pre-treated patients with ES-SCLC whose disease was PD-L1 
positive (Ott et al. 2015). 


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In light of these observations, this study (Study GO30081; IMpower133) 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 andetoposide compared with placebo, 
carboplatin, and etoposide in patients with chemotherapy-naive ES-SCLC.  This study 
will allow for the evaluation of efficacy of atezolizumab in the ITT population and for the 
evaluation of exploratory immune endpoints such as, but not limited to a retrospective 
evaluation by PD-L1 expression and their association with patient outcomes. 
Patients with SCLC frequently present with symptoms of widespread metastatic disease 
and may experience fast clinical deterioration; therefore, there is a need for rapid 
treatment initiation for these patients.  In addition, tissue sample collection for 
investigational biomarker testing may be difficult in this patient population because the 
amount of tissue available in many cases is limited.  As demonstrated in Study GP28328, 
objective responses were observed at all levels of PD-L1 expression when atezolizumab 
was added to cytotoxic chemotherapy.  This study will therefore enroll patients with 
ES-SCLC whose disease is unselected for PD-L1 expression.  Pre-treatment tumor 
tissue samples will be collected to allow for the analysis of immune endpoints such as, 
but not limited to PD-L1 expression, and patient outcomes. 
This study will enroll patients with ES-SCLC who are chemotherapy-naive for their 
extensive-stage disease, and for whom the experimental arm can represent a valuable 
treatment option and a reasonable benefit-risk balance. 
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 to receive treatment beyond the initial apparent radiographic progression per 
RECIST v1.1 (see Section 3.3.4 and Section 4.6) and will use modified RECIST criteria 
(in addition to RECIST v1.1) to evaluate clinical benefit (Appendix 5).  
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.  Patients who continue 
treatment beyond radiographic disease progression per RECIST v1.1 should be closely 
monitored clinically and with a follow-up scan in 6 weeks, or sooner if symptomatic 
deterioration occurs.  Treatment should be discontinued if clinical deterioration as a 
result of disease progression occurs at any time or if persistent disease growth is 
confirmed in a follow-up scan.  In addition, patients should be discontinued for 
unacceptable toxicity, or for any other signs or symptoms of 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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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 continue to receive treatment may experience further 
progression of SCLC and delay treatment with subsequent therapies for which they are 
eligible.  Patients will be fully informed of the risk of continuing study treatment in spite 
of apparent radiographic progression, and consent must be documented appropriately 
before treatment may continue.  Investigators should make a careful assessment of the 
potential benefit of continuing study treatment beyond radiographic disease progression, 
considering radiographic data and the clinical status of the patient.
Atezolizumab has been generally well tolerated as a single agent and in combination 
with cytotoxic chemotherapy (see Section 1.3.2).  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Type 1 diabetes mellitus, 
pancreatitis, hepatitis, pneumonitis, colitis, meningoencephalitis, myasthenia 
gravis/myasthenic syndrome, and Guillain-Barré syndrome have been observed in 
clinical studies with atezolizumab.  To date, these events have been manageable with 
treatment.
In summary, treatment with atezolizumab in combination with carboplatinetoposide 
offers the potential for clinical benefit in patients with ES-SCLC.  
1.4.2
2.
OBJECTIVES
The following objective statements apply to the global enrollment phase, 
 
 


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2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objectives
The co-primary objectives of this study are the following:

To evaluate the efficacy of atezolizumabcarboplatinetoposide compared with 
placebocarboplatinetoposide in the ITT population as measured by 
investigator-assessed PFS according to RECIST v1.1

To evaluate the efficacy of atezolizumabcarboplatinetoposide compared with 
placebocarboplatinetoposide in the ITT population as measured by OS
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are:

To evaluate the efficacy of atezolizumabcarboplatinetoposide compared with 
placebocarboplatinetoposide in the ITT population as measured by 
investigator-assessed ORR according to RECIST v1.1

To evaluate the efficacy of atezolizumabcarboplatinetoposide compared with 
placebocarboplatinetoposide in the ITT population as measured by 
investigator-assessed duration of response (DOR) according to RECIST v1.1 

To evaluate the PFS rate at 6 months and at 1 year in each treatment arm for the 
ITT population

To evaluate the OS rate at 1 and 2 years in each treatment arm for the ITT 
population

To determine the impact of atezolizumabas measured by time to deterioration (TTD) 
in patient-reported lung cancer symptoms of cough, dyspnea (single-item and 
multi-item subscales), chest pain, arm/shoulder pain, or fatigue using the European 
Organization for the Research and Treatment of Cancer (EORTC) Quality of Life 
QuestionnaireCore 30 (QLQ-C30) and the supplemental lung cancer module 
(QLQ-LC13) in patients treated with atezolizumabcarboplatinetoposide 
compared with placebocarboplatinetoposide in the ITT population
2.2
SAFETY OBJECTIVES
The safety objectives for this study are:

To evaluate the safety and tolerability of atezolizumab in combination with 
carboplatinetoposide compared with carboplatinetoposide 

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 OBJECTIVE
The PK objective for this study is to characterize the pharmacokinetics of atezolizumab, 
carboplatin, and etoposide in chemotherapy-naive patients with ES-SCLC.


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2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are:

To evaluate investigator-assessed PFS, ORR, and DOR modified RECIST for the 
atezolizumab-containing treatment arm in the ITT population

To evaluate the relationship between tumor biomarkers (including but not limited to 
PD-L1, PD-1, somatic mutations, and others), as defined by immunohistochemistry 
(IHC) or quantitative reverse transcriptasepolymerase chain reaction (qRT-PCR), 
next generation sequencing (NGS), and/or other methods and measures of efficacy

To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in 
archival and/or fresh tumor tissue, blood, plasma and serum and their association 
with disease status, mechanisms of resistance, and/or response to study treatment

To evaluate and compare patient’s health status as assessed by the EuroQoL 
5 Dimensions 5-Level (EQ-5D-5L) questionnaire to generate utility scores for use in 
economic models for reimbursement

To determine the impact of atezolizumabcarboplatinetoposide compared with 
placebocarboplatinetoposide as measured by change from baseline in 
patient-reported outcomes (PRO) of health-related quality of life, lung 
cancerrelated symptoms, physical functioning, and health status as assessed by 
the EORTC QLQ-C30 and LC13 

To evaluate the impact of chemotherapy (both carboplatin and etoposide) on 
peripheral and tumor-specific T-cell populations during and after induction therapy 
and its relationship to efficacy and safety outcomes
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study 
designed to evaluate the safety and efficacy of atezolizumab in combination with 
carboplatinetoposide compared with treatment with placebocarboplatinetoposide in 
patients who have ES-SCLC and are chemotherapy-naive for their extensive-stage 
disease.  Figure 1 illustrates the study design.  Schedules of assessments are provided 
in Appendix 1 and Appendix 2.
Eligible patients will be stratified by sex (male vs. female), ECOG performance status 
(0 vs. 1), and presence of brain metastases (yes vs. no) and randomized 1:1 to receive 
one of the following treatment regimens as shown in Table 5.
Table 5
Study GO30081 Treatment Arms
Treatment Arm
Induction
(Four 21-Day Cycles)
Maintenance
(21-Day Cycles)
A
atezolizumabcarboplatinetoposide
atezolizumab
B
placebocarboplatinetoposide
placebo


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Induction treatment will be administered on a 21-day cycle for four cycles. 
Following the induction phase, patients will continue maintenance therapy with either 
atezolizumab or placebo.  During the maintenance phase, prophylactic cranial irradiation 
is permitted as per local standard-of-care and will be reported on the Prophylactic 
Cranial Irradiation electronic Case Report Form (eCRF).  Thoracic radiation with curative 
intent or the intent to eliminate residual disease is not permitted.  Palliative thoracic 
radiation is allowed.  
Treatment should be discontinued in all patients (in both treatment arms) who exhibit 
evidence of disease progression per RECIST v1.1.  However, to better accommodate 
standard clinical practice which is guided by the fact that patients with ES-SCLC whose 
disease progresses after first-line treatment have limited treatment options and such 
options have limited efficacy and significant toxicity, patients may be considered for 
treatment beyond radiographic disease progression per RECIST v1.1, at the discretion 
of the investigator and after appropriate discussion with the patient and obtaining 
informed consent, only if all of the following criteria are met:

Evidence of clinical benefit as assessed by the investigator

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Patients must provide written consent to acknowledge deferring other treatment 
options in favor of continuing study treatment at the time of initial progression
Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 should be closely monitored clinically and with a follow-up scan in 6 weeks 
or sooner if symptomatic deterioration occurs.  Treatment should be discontinued if 
clinical deterioration due to disease progression occurs at any time, or if persistent 
disease growth is confirmed in a follow-up scan.  In addition, patients should be 
discontinued for unacceptable toxicity or for any other signs or symptoms of deterioration 
attributed to disease progression as determined by the investigator after an integrated 
assessment of radiographic data and clinical status.
If clinically feasible, it is recommended that the patient undergo a tumor biopsy sample 
collection at the time of radiographic disease progression.  These data will be used to 
explore whether radiographic findings are consistent with the presence of a tumor.  
Additionally, these data will be analyzed to evaluate the association between changes in 
tumor tissue and clinical outcome and to further understand 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.  


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Patients will undergo tumor assessments at baseline and every 6 weeks (7 days) for 
48 weeks following Cycle 1, Day 1, regardless of treatment dose delays.  After 
completion of the Week 48 tumor assessment, tumor assessments will be required every 
9 weeks (7 days) thereafter, regardless of treatment dose delays.  Patients will 
undergo tumor assessments until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs first.  
Patients who continue treatment beyond radiographic disease progression per RECIST 
v1.1 will continue to undergo tumor assessments every 6 weeks (7 days), or sooner if 
symptomatic deterioration occurs.  For these patients, tumor assessments will continue 
every 6 weeks (7 days), regardless of time in the study, until study treatment is 
discontinued. 
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 at the same frequency as would have been followed if the 
patient had remained on study treatment (i.e., every 6 weeks [7 days] for 48 weeks 
following Cycle 1, Day 1 and then every 9 weeks [7 days] thereafter, regardless of 
treatment dose delays) until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs first, 
regardless of whether patients start a new anti-cancer therapy.
In case of an early termination of the study, patients who are deriving clinical benefit 
from treatment with atezolizumab will be permitted to continue treatment with 
atezolizumab at the discretion of the investigator.


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Figure 1
Study Schema
ECOG PSEastern Cooperative Oncology Group performance status; SCLCsmall cell lung 
cancer; RECIST Response Evaluation Criteria in Solid Tumors.
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 after a minimum 
of 12 patients have been enrolled into each treatment arm and have received treatment 


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for two cycles.  Subsequently, the iDMC will review safety data approximately every 
6 months.
The safety data will include disposition, demographic data, adverse events, serious 
adverse events, and relevant laboratory data.
The Sponsor will remain blinded to the efficacy results until the primary PFS analysis.  
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 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 AND LENGTH OF STUDY
The end of study will occur when all of the following criteria have been met:

The last patient last visit (LPLV) has occurred (i.e., last patient in the global 
 
). 

Approximately 306 deaths have been observed among the randomized patients in 
the global enrollment phase.

 
 (see Section 6.1.1).
Additionally, the Sponsor may decide to terminate the study at any time.  If the Sponsor 
decides to terminate the study, patients who are still receiving study treatment or 
undergoing survival follow-up may be enrolled in an extension study or a non-
interventional study.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 31 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Testing Atezolizumab in Combination with 
Carboplatin and Etoposide in Patients with ES-SCLC
Despite the initial response rates observed with first-line chemotherapy regimens, the 
prognosis for patients with ES-SCLC remains dismal, with a median OS of 
approximately 911 months.  There is a significant need for new agents with novel 


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mechanisms of action and non-overlapping toxicity, which can be combined with 
established treatments.
Results from Study PCD4989g provide evidence of an acceptable safety profile and 
encouraging single-agent activity of atezolizumab in patients with SCLC.  In addition, 
efficacy results from the POPLAR (GO28753) study demonstrate an OS benefit of 
single-agent atezolizumab compared with docetaxel in patients with advanced NSCLC.  
In the Phase Ib Study GP28328 evaluating atezolizumab in combination with 
carboplatin-based chemotherapy, ORRs ranging from 50%75% were observed in 
patients with NSCLC at all levels of PD-L1 expression.  No additive adverse effects were 
observed when atezolizumab was administered with chemotherapy.
On the basis of this, Study GO30081 will evaluate atezolizumab in combination with 
carboplatin and etoposide for patients with ES-SCLC.  TC killing by cytotoxic 
chemotherapy may expose the immune system to high levels of tumor antigens, and 
invigorating tumor-specific T-cell immunity in this setting by inhibiting PD-L1/PD-1 
signaling may result in deeper and more durable responses compared with standard 
chemotherapy alone (Merritt et al. 2003; Apetoh et al. 2007), and this may reasonably 
occur in tumors regardless of PD-L1 expression.
3.3.2
Rationale for Control Arm
The current standard-of-care in the first-line treatment for ES-SCLC is platinum-based 
chemotherapy plus etoposide.  In this study, patients in the control arm will receive 
four cycles of placebocarboplatinetoposide, followed by placebo until disease 
progression per RECIST v1.1.  During the maintenance phase, prophylactic cranial 
irradiation is permitted as per local standard-of-care.  This control arm treatment is 
recognized as a standard-of-care for the first-line treatment of ES-SCLC (see 
Section 1.1).
3.3.3
Rationale for Progression-Free Survival and Overall Survival 
as Co-Primary Endpoints
Investigator-assessed PFS and OS are the co-primary endpoints for this study.
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; additionally, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents a 
direct clinical benefit or a surrogate for clinical benefit depends upon the magnitude of 
the effect and the benefit-risk of the new treatment compared with available therapies 
(Guidance for Industry 2007; European Medicines Agency 2012).  The PFS HR that will 
be targeted in the ITT population constitutes a clinically meaningful benefit in this patient 
population.
To ensure the validity of investigator-assessed PFS as the primary endpoint, a number 
of measures have been implemented:  a substantial target magnitude of benefit and 


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study assessments that will allow a robust evaluation of benefit-risk (conventional 
RECIST v1.1 criteria to define radiographic disease progression with fixed assessment 
intervals that are identical in both treatment arms and a robust definition of PFS and 
prospectively-defined methods to assess, quantify, and analyze PFS, including 
sensitivity analyses).
OS is a co-primary endpoint in this study.  Improvement in OS is generally accepted as 
the best measure of clinical benefit for patients with advanced/unresectable or 
metastatic lung cancer.  In the randomized Phase II Study GO28753 (POPLAR) in 
patients with advanced NSCLC, an OS benefit in the atezolizumab arm was observed 
compared with the docetaxel arm (Fehrenbacher et al. 2016).
New treatment modalities, such as targeted therapies and immunotherapy, are emerging 
as highly effective regimens that are providing improvements in patient outcomes 
beyond what has been previously achieved (Ellis et al. 2014).  In particular, 
immunotherapy has been correlated or associated with durable responses, prolongation 
of OS, and improvement of quality of life.  
3.3.4
Rationale for Allowing Selected Patients to Continue Treatment 
beyond Radiographic Disease Progression per RECIST v1.1
Patients with ES-SCLC experience rapid tumor growth, fast clinical deterioration, and 
have an overall poor prognosis.  First-line therapy with a platinum agent and etoposide 
has consistently demonstrated high response rates and significant clinical benefit.  
However, after disease progression, treatment options are limited and such options have 
shown limited efficacy and significant toxicity (see Section 1.1.1).  Given that the highest 
opportunity to achieve a clinically significant benefit from therapy is in the front-line 
setting and given the poor efficacy and high toxicity profile of second-line therapies, 
patients may be considered for treatment beyond radiographic disease progression per 
RECIST v1.1 at the discretion of the investigator and after appropriate discussion with 
the patient and obtaining informed consent, only if they meet all of the criteria described 
in Section 3.1. 
In addition, 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 to remain on 
treatment after apparent radiographic disease progression per RECIST v1.1, provided all 
criteria in Section 3.1 are met.  Patients who continue treatment beyond radiographic 
disease progression per RECIST v1.1 should be closely monitored clinically and with a 
follow-up scan in 6 weeks, or sooner if symptomatic deterioration occurs.  Treatment 
should be discontinued if clinical deterioration due to disease progression occurs at any 
time or if persistent disease growth is confirmed in a follow-up scan.  In addition, patients 
should be discontinued for unacceptable toxicity or for any other signs or symptoms of 


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deterioration attributed to disease progression as determined by the investigator after an 
integrated assessment of radiographic data and clinical status (see Section 3.1). 
3.3.5
Rationale for Patient-Reported Outcome Assessments
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on health-related quality 
of life (HRQoL) (Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).  
This is especially true for studies that have 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 lung cancer.  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 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, physical functioning, and symptom severity.
The EQ-5D-5L (see Appendix 8) is also included in this study to generate utility scores 
for use in economic models for reimbursement.  Results from the EQ-5D-5L are not 
planned to be used for market authorization.
3.3.6
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to antiPDL-1/antiPD-1 therapy (Herbst et al. 2014; Topalian et al. 2012).  
This correlation was also observed with atezolizumab in Study PCD4989g and Study 
GO28753 (POPLAR) (Horn et al. 2015; Spira et al. 2015).  
This study will allow for the evaluation of the efficacy of atezolizumab in the ITT 
population, as well as an exploratory analysis of the efficacy of atezolizumab in patients 
with PD-L1expressing tumors (defined by expression of PD-L1 in TCs and/or 
tumor-infiltrating immune cells [ICs]).  Therefore, in this study, pre-treatment archival 
and/or fresh tumor specimens must be submitted. 
The assessment of other exploratory biomarkers as potential predictive and prognostic 
markers related to the clinical benefit and safety of atezolizumab, tumor immunobiology, 


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mechanisms of resistance, or tumor type, may also be analyzed.  DNA, RNA, or other 
biological molecules may be extracted and analyzed to increase understanding of 
disease pathobiology.
3.3.7
Rationale for Blood Biomarker Assessments
An exploratory objective of this study is to evaluate blood-based biomarkers including 
plasma, serum, whole blood, and extracts thereof.  Evaluation of blood biomarkers may 
provide evidence for biologic activity of atezolizumab in patients with SCLC and may 
allow for the development of blood-based biomarkers to help predict which patients may 
benefit from atezolizumab.  These samples may also be used to evaluate the effects, if 
any, of chemotherapy on T cells, other immune cells, or related constituents of 
peripheral blood. 
In addition, potential correlations of these biomarkers with the safety and activity of 
atezolizumab may be explored.
3.3.8
Rationale for the Collection of Tumor Specimens at 
Radiographic Progression
Anti-tumor immune responses, such as those associated with atezolizumab, may result 
in objective responses that are delayed and can be preceded by initial apparent 
radiographic progression.  This initial apparent progression may occur as a result of 
either delayed anti-tumor activity and/or robust immune infiltration of the tumor 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, it is recommended that a tumor biopsy be performed at the time of 
radiographic progression in order to better understand the biological changes that drive 
the increase in size of the radiographically progressing lesion.  In addition, mechanisms 
relating to progression, resistance, predictive, prognostic, and pharmacodynamic 
relationships in tumor biomarkers (including but not limited to PD-L1, CD8, mutation 
status, and others) and their efficacy will be evaluated.  DNA and/or RNA extraction may 
be performed to enable NGS to identify somatic mutations that are associated with 
disease progression or acquired resistance to atezolizumab and to increase 
understanding of disease pathobiology.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
3.4.1.1
Primary Efficacy Outcome Measures
The primary efficacy outcome measures for this study are:

PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator using RECIST v1.1 or death from any 
cause, whichever occurs first. 


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
OS, defined as the time from randomization to death from any cause.
3.4.1.2
Secondary Efficacy Outcome Measures
The secondary efficacy outcome measures for this study are:

Objective response, defined as PR or CR as determined by the investigator 
according to RECIST v1.1 

DOR, defined as the time interval from first occurrence of a documented objective 
response to the time of disease progression as determined by the investigator using 
RECIST v1.1 or death from any cause, whichever comes first

PFS rates at 6 months and at 1 year

OS rates at 1 and 2 years

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 maintained for two assessments or 
one assessment followed by death from any cause within 3 weeks
3.4.2
Safety Outcome Measures
The safety outcome measures for this study are:

Incidence, nature, and severity of adverse events graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v4.0

Changes in vital signs, physical findings, and clinical laboratory results during and 
following study treatment administration

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters
3.4.3
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are:

Maximum observed serum atezolizumab concentration (Cmax) after infusion 

Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at 
selected cycles, at treatment discontinuation, and at 120 days (30 days) after the 
last dose of atezolizumab

Plasma concentrations for carboplatin 

Plasma concentrations for etoposide 
See Appendix 2 for specific sample collection times.
3.4.4
Exploratory Outcome Measures
The exploratory outcome measures for this study are:

Objective response, PFS, and DOR as determined by the investigator according to 
modified RECIST


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
Status of PD-L1-, immune-, and SCLC-related and other exploratory biomarkers in 
archival and/or freshly obtained tumor tissues, and blood (or blood derivatives) 
collected before, during, or after treatment with atezolizumab or at progression and 
association with disease status and/or response to atezolizumab

Utility scores of the EQ-5D-5L

Change from baseline in PROs of health-related quality of life, lung cancerrelated 
symptoms, physical functioning, and health status as assessed by the 
EORTC QLQ-C30 and QLQ-LC13

Changes in levels and type of peripheral and tumor-specific T-cell populations 
during and after induction therapy and its relationship to efficacy and safety 
outcomes
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients may be eligible if they are chemotherapy-naive and have ES-SCLC.
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 9)

Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration 
Lung Study Group (VALG) staging system; (Micke et al. 2002; Appendix 3)

No prior systemic treatment for ES-SCLC

Patients who have received prior chemoradiotherapy for limited-stage SCLC must 
have been treated with curative intent and experienced a treatment-free interval of 
at least 6 months since last chemotherapy, radiotherapy, or chemoradiotherapy 
cycle from diagnosis of extensive-stage SCLC

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 evidence of interim progression between the completion of CNS-directed 
therapy and randomization
Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases.  
Following treatment, these patients may then be eligible without the need for an 
additional brain scan prior to randomization, if all other criteria are met.


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
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 
test 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

Patients must submit a pre-treatment tumor tissue sample.  Any available tumor 
tissue sample can be submitted.  The tissue sample should be submitted before or 
within 4 weeks after randomization; however, patients may be enrolled into the 
study before the pre-treatment tumor tissue sample is submitted.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 5 months after the last 
dose of study treatment.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices.


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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, as defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during treatment with chemotherapy 
(i.e., carboplatin and etoposide) and for at least 6 months after the last dose of 
chemotherapy to avoid exposing the embryo. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

4.1.2
Exclusion Criteria
Patients who meet any of the criteria below will be excluded from study entry:

Active or untreated CNS metastases as determined by computed tomography (CT) 
or magnetic resonance imaging (MRI) evaluation during screening and prior 
radiographic assessments

Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 1 week prior to randomization

Leptomeningeal disease

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 regardless of 
drainage frequency.

Uncontrolled or symptomatic hypercalcemia 
Patients who are receiving denosumab prior to randomization must be willing 
and eligible to discontinue its use and replace it with a bisphosphonate while in 
the study.

Malignancies other than SCLC 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)


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
Women who are pregnant, lactating, or intending to become pregnant during the 
study

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 11 for 
a more comprehensive list of autoimmune diseases)
Patients with a history of autoimmune-related hypothyroidism on thyroid 
replacement hormone therapy are eligible.
Patients with controlled Type I diabetes mellitus on an insulin regimen are 
eligible.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are eligible for the study provided that they meet the following 
conditions: 
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and only requires low potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, high potency, or oral 
steroids)

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive test result for HIV
All patients must be tested for HIV; patients who test positive for HIV will be 
excluded.

Patients with active hepatitis B (chronic or acute; defined as having a positive 
hepatitis B surface antigen [HBsAg] test result at screening) or hepatitis C virus 
(HCV)
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.  HBV DNA should be obtained in these patients prior to 
randomization.
Patients positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA.

Active tuberculosis


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
Severe infections at the time of randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction, or cerebrovascular accident 
within 3 months prior to randomization, unstable arrhythmias, or unstable angina
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or left ventricular ejection fraction 50% must be on 
a stable medical regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist if appropriate.

Major surgical procedure other than for diagnosis within 28 days prior to 
randomization or anticipation of need for a major surgical procedure during the 
course of the study

Prior allogeneic bone marrow transplantation or solid organ transplant

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk for treatment 
complications

Patients with illnesses or conditions that interfere with their capacity to understand, 
follow, and/or comply with study procedures

Treatment with any other investigational agent with therapeutic intent within 28 days 
prior to randomization

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
Patients must not receive live, attenuated influenza vaccines (e.g., FluMist®) 
within 4 weeks prior to randomization, during treatment, and for 5 months 
following the last dose of atezolizumab/placebo.

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunosuppressive medications (including, but not limited 
to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [anti-TNF] agents) within 1 week prior to randomization
Patients who have received acute systemic immunosuppressant medications 
(e.g., use of corticosteroids for nausea, vomiting, or management of or 
premedication for allergic reactions) may be enrolled in the study after 
discussion with and approval by the Medical Monitor.  In those patients, the 
need and length of the washout period prior to randomization will also be 
established in conjunction with the Medical Monitor.
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical 
insufficiency are allowed.


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
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 allergic reactions to carboplatin or etoposide
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is a randomized, double-blind, placebo-controlled study. 
After written informed consent has been obtained, all screening procedures and 
assessments have been completed, and eligibility has been established, the study site 
will obtain the patient’s identification number and treatment assignment from the 
interactive voice or Web response system (IxRS) for eligible patients. 
Randomization will occur in a 1:1 ratio using a permuted-block randomization method.  
Patients will be randomized to one of two treatment arms:  A) atezolizumabcarboplatin
etoposide or B) placebocarboplatinetoposide.  The randomization scheme is
designed to ensure that an approximately equal number of patients will be enrolled in 
each treatment arm within the baseline characteristics of the following stratification 
factors:

Sex (male vs. female)

ECOG performance status (0 vs. 1)

Presence of brain metastases (yes vs. no)
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.
The Sponsor and its agents (with the exception of the IxRS service provider [the external 
independent statistical coordinating center responsible for verifying patient 
randomization and study treatment kit assignments], PK/pharmacodynamic laboratory 
personnel, and the iDMC members); the study site personnel, including the investigator; 
and the patient will be blinded to treatment assignment (see Sections 4.2.1 and 4.2.2).
While PK and ATA samples must be collected from patients assigned to the comparator 
arm to maintain the blinding of treatment assignment, PK and ATA assay results for 
atezolizumab in these patients are generally not needed for the safe conduct or proper 
interpretation of this study.  Sponsor personnel responsible for performing PK and ATA 
assays will be unblinded to patients’ treatment assignment to identify appropriate 
samples to be analyzed.  Samples from patients assigned to the comparator arm will not 
be analyzed for atezolizumab concentration except by request (e.g., to evaluate a 
possible error in dosing).  Atezolizumab ATA samples collected on Day 1 of Cycle 1 may 


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be analyzed for all patients, while subsequent samples from patients assigned to the 
comparator arm will not be analyzed for ATA unless requested.
 
4.2.1
Unblinding at the Patient Level
4.2.1.1
Emergency Unblinding
Study treatment assignment may be unblinded for serious, unexpected study 
drugrelated toxicity (as part of the Investigational New Drug [IND] application safety 
reporting process).  
If unblinding is necessary for patient management in the case of an adverse event for 
which patient management might be affected by knowledge of treatment assignment, the 
investigator will be able to break the treatment code via the IxRS.  Emergency unblinding 
should be a last resort performed only in cases where knowledge of treatment 
assignment will affect ongoing treatment of the toxicity.  Investigators are encouraged to 
consult with the Medical Monitor prior to performing emergency unblinding.  The reason 
and date of unblinding should be documented in the electronic data capture (EDC) 
system.
4.2.2
Unblinding at the Study Level
For regulatory reporting purposes, if required by local health authorities, the Sponsor will 
break the treatment code for all serious, unexpected adverse reactions that are 
considered by the investigator or Sponsor to be related to study drug.
Treatment assignment will be unblinded to the Sponsor at the time of the primary 
analysis of PFS.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab and Placebo
For information on the formulation, packaging, and handling of atezolizumab and 
placebo, refer to the Atezolizumab Pharmacy Manual and Investigator’s Brochure.
Atezolizumab and placebo will be supplied by the Sponsor.
4.3.1.2
Carboplatin and Etoposide
Carboplatin and etoposide are background treatment and are considered 
non-investigational medicinal products (NIMPs).  Carboplatin and etoposide will be used 
in the commercially available formulation. 
For information on the formulation, packaging, and handling of carboplatin and etoposide, 
refer to the 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 cycles of atezolizumab/placebo plus 
chemotherapy, with each cycle being 21 days in duration.  On Day 1 of each cycle, all 
eligible patients will be administered study drug infusions in the following order:
Arm A:  atezolizumab carboplatin etoposide 
Arm B:  placebo carboplatin etoposide
For Cycle 1, premedication administered for atezolizumab/placebo is not permitted.  
Patients should receive anti-emetics and IV hydration for carboplatin and etoposide 
according to the local standard-of-care and manufacturer’s instruction.  However, 
because of the immunomodulatory effects of steroids, premedication with steroids 
should be minimized to the extent that is clinically feasible (see Section 4.4.2).  All 
medications must be recorded on the appropriate Concomitant Medications eCRF.
During the induction phase, study treatment should be administered in the following 
manner on Day 1:
1.
Atezolizumab/placebo administered intravenously over 60 (15) minutes (for the 
first infusion and shortening to 30 [10] minutes for subsequent infusions) (see 
Table 6), followed by
2.
Carboplatin administered intravenously over 3060 minutes to achieve an initial 
target area under the concentrationtime curve (AUC) of 5 mg/mL/min (Calvert 
formula dosing), followed by
3.
Etoposide (100 mg/m2) administered intravenously over 60 minutes 
During the induction phase, etoposide (100 mg/m2) will be administered intravenously 
over 60 minutes on Days 2 and 3.
Cycles in which no chemotherapy is given do not count toward the total number of 
induction chemotherapy cycles.
After the induction phase, patients will begin maintenance therapy with 
atezolizumab/placebo. 
During treatment (induction or maintenance), upon radiographic disease progression per 
RECIST v1.1, patients may be considered for treatment beyond radiographic disease 
progression per RECIST v1.1, provided all criteria specified in Section 3.1 are met. 
The suggested infusion times for carboplatin and etoposide may be adapted in 
accordance with local standard-of-care.
For patients undergoing additional PK assessments for carboplatin and etoposide, refer 
to Appendix 2 for the schedule of PK sampling.


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Guidelines for dose modification and treatment interruption or discontinuation for 
carboplatin and etoposide are provided in Sections 5.1.5.1 and Section 5.1.7.
4.3.2.1
Atezolizumab/Placebo
Patients will receive atezolizumab/placebo 1200 mg (equivalent to an average body 
weight-based dose of 15 mg/kg) administered by IV infusion every 21 (3) days in a 
monitored setting where there is immediate access to trained personnel and adequate 
equipment/medicine to manage potentially serious reactions.  
Atezolizumab/placebo infusions will be administered per the instructions outlined in 
Table 6.


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Table 6
Administration of First and Subsequent Infusions of 
Atezolizumab/Placebo
First Infusion
Subsequent Infusions
No premedication is allowed. 
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.
Infuse atezolizumab/placebo (1200 mg in a 
250 mL 0.9% NaCl intravenous infusion bag) 
over 60 (15) minutes.
If clinically indicated, record patient’s vital 
signs (pulse rate, respiratory rate, blood 
pressure, and temperature) during the 
infusion at 15, 30, 45, and 60 minutes 
(5-minute windows are allowed for all time 
points).
If clinically indicated, record patient’s vital 
signs (pulse rate, respiratory rate, blood 
pressure, and temperature) at 30 (10) 
minutes after the infusion.
Patients will be informed about the possibility 
of delayed post-infusion symptoms and 
instructed to contact their study physician if 
they develop such symptoms.
If the patient experienced an 
infusion-related reaction during any 
previous infusion, premedication with 
antihistamines may be administered for 
Cycles 2 at the discretion of the treating 
physician.
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.
If the patient tolerated the first infusion well, 
without infusion-associated adverse events, 
the second infusion may be administered 
over 30 (10) minutes.
If no reaction occurs, subsequent infusions 
may be administered 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 administered 
over 60 (15) minutes.
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion if 
clinically indicated or if patient 
experienced symptoms during the 
previous infusion. 
Record patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) 30 (10) minutes after the 
infusion if clinically indicated or if patient 
experienced symptoms during previous 
infusion.
NaClsodium chloride.
Dose modifications to atezolizumab/placebo are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are 
provided in Sections 5.1.5.2 and 5.1.6.
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.


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4.3.2.2
CarboplatinEtoposide
Carboplatin
Carboplatin will be administered after completion of atezolizumab/placebo by IV infusion 
over 3060 minutes to achieve an initial target AUC of 5 mg/mL/min (Calvert formula 
dosing) with standard anti-emetics per local practice guidelines.  Because the effects of 
corticosteroids on T-cell proliferation have the potential to attenuate atezolizumab-
mediated anti-tumor immune activity, premedication with corticosteroids should be 
minimized to the extent that is clinically feasible (see Section 4.4.2).  Carboplatin 
infusion times may be adapted in accordance with local standard-of-care.
The carboplatin dose of AUC 5 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 the GFR 
through use of a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 
125 mL/min.
If a patient’s GFR is estimated based on serum creatinine measurements by the isotope 
dilution mass spectroscopy method, the 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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 with use of the following 
Web site for more details:
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/
ucm228974.htm
Etoposide
During the induction phase, on Day 1 of each cycle, etoposide (100 mg/m2) will be 
administered by IV infusion over 60 minutes following carboplatin administration.  On 
Days 2 and 3 of each cycle, etoposide (100 mg/m2) will be administered by IV infusion 
over 60 minutes.  Premedication should be administered according to local standard-of-
care.  Because the effects of corticosteroids on T-cell proliferation have the potential to 
attenuate atezolizumab-mediated anti-tumor immune activity, premedication with 
corticosteroids should be minimized to the extent that is clinically feasible (see 
Section 4.4.2).  Etoposide infusion times may be adapted in accordance with local 
standard-of-care.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab/placebo) will be provided by 
the Sponsor where required by local health authorities.  The study site will acknowledge 
receipt of the IMPs using IxRS to confirm shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Atezolizumab
The Sponsor will evaluate the appropriateness of continuing to provide atezolizumab to 
patients assigned to this treatment after evaluating the primary and secondary efficacy 
outcome measures and safety data gathered in the study and in accordance with the 
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


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These analyses may be conducted prior to completion of the study.
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs or homeopathic remedies, nutritional supplements) used by a patient from 7 days 
prior to screening until the treatment discontinuation visit. All such medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy
Premedication with antihistamines may be administered for any atezolizumab/placebo 
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/placebo during palliative 
radiotherapy

Inactive influenza vaccinations 

Megestrol administered as an appetite stimulant 

Inhaled corticosteroids for chronic obstructive pulmonary disease

Mineralocorticoids (e.g., fludrocortisone) 

Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2 receptor antagonist per standard 
practice (for sites outside the United States, equivalent medications may be substituted 
per local practice).  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 10). 


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All concomitant medications must be recorded on the appropriate Concomitant 
Medications 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 clinically appropriate, 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.  
Refer to Appendix 12 for additional information on the management of adverse events
associated with atezolizumab.
4.4.3
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited for various time periods prior to 
starting study treatment, depending on the anti-cancer agent (see Section 4.1.2), and 
during study treatment until disease progression is documented and the patient has 
discontinued study treatment.  This includes, but is not limited to chemotherapy, 
hormonal therapy, immunotherapy, radiotherapy, non-approved experimental agents, or 
herbal therapy (unless otherwise noted).
The following medications are prohibited 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

Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to randomization, 
during treatment, and for 5 months following the last dose of atezolizumab/placebo

Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, non-contrast CT scans of the chest and non-contrast CT scans or 
MRIs of the abdomen and pelvis should be performed 
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 


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investigator, provided that there are no known interactions with any study treatment.  As 
noted above, herbal therapies intended for the treatment of cancer are prohibited.
4.5
STUDY ASSESSMENTS
The schedules of study assessments are provided in Appendix 1 and Appendix 2.
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient.
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
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 show radiographic disease progression per RECIST v1.1 may be 
considered for treatment beyond radiographic disease progression, provided all criteria 
specified in Section 3.1 are met, and patients must sign consent at that time to 
acknowledge deferring other treatment options in favor of continuing study treatment.
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. 
SCLC cancer history will include prior cancer therapies and procedures.
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 


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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 pulse rate, respiratory rate, and systolic and 
diastolic blood pressures while the patient is in a seated position and temperature.
Vital signs will be measured and recorded at screening and as described in Table 7.
Table 7
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/placebo infusion

During the atezolizumab/placebo infusion (every 
15 [5] minutes) and within 30 (10) minutes after 
atezolizumab/placebo infusion, if clinically indicated

During the carboplatin and etoposide infusions and within 
30 (10) minutes after etoposide infusion, if clinically indicated
Subsequent Cycles
Treatment Arm
Timepoints
Arms A and B 

Within 60 minutes prior to atezolizumab/placebo infusion

During and within 30 (10) minutes after atezolizumab/placebo 
infusion if clinically indicated or symptoms occurred during the 
prior infusion

During the carboplatin and etoposide infusions and within 
30 (10) minutes after etoposide infusion if clinically indicated 
or if symptoms occurred during the prior infusion
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 evaluate CNS metastasis in all patients.  An MRI scan of the brain is 


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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).
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 reassessed at each subsequent 
tumor evaluation.  The same radiographic procedure used to assess disease sites at 
screening should be used throughout the study (e.g., the same contrast protocol for 
CT scans).  Response will be assessed by the investigator using RECIST v1.1 (see 
Appendix 4) and modified RECIST criteria (see Appendix 5).  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. 
Patients will undergo tumor assessments at baseline and every 6 weeks (7 days) for 
48 weeks following Cycle 1, Day 1, regardless of treatment dose delays.  After 
completion of the Week 48 tumor assessment, tumor assessments will be required every 
9 weeks (7 days) thereafter, regardless of treatment dose delays.  Patients will
undergo tumor assessments until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs first.  
Patients who continue treatment beyond radiographic disease progression per RECIST 
v1.1 will continue to undergo tumor assessments every 6 weeks (7 days), or sooner if 
symptomatic deterioration occurs.  For these patients, tumor assessments will continue 
every 6 weeks (7 days) regardless of time in the study, until study treatment is 
discontinued. 
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 at the same frequency as would have been followed if the 
patient had remained on study treatment (i.e., every 6 weeks [7 days] for 48 weeks 
following Cycle 1, Day 1 and then every 9 weeks [7 days] thereafter, regardless of 
treatment dose delays) until radiographic disease progression per 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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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 if considered standard of care in the 
region, calcium, phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, LDH, 
total protein, and albumin)

Coagulation (aPTT or INR)

Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed at Day 1 of each 
cycle during treatment prior to administration of study treatment.  If a urine 
pregnancy test result is positive, it must be confirmed by a serum pregnancy test.
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being postmenopausal 
(12 months of amenorrhea). 

Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood); dipstick 
permitted

Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4)
Total T3 will be tested only at sites where free T3 is not performed.

HBV serology:  HBsAg, antibodies against HBsAg, total HBcAb
HBV DNA should be obtained prior to randomization if the patient has a 
negative serology for HbsAg and a positive serology for HBcAb

HCV serology:  HCV antibody (anti-HCV)
HCV RNA must be obtained prior to randomization if 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 study
A central laboratory will coordinate the sample collection of tissue and blood samples for 
research-related testing at central laboratories or at the Sponsor. Instruction manuals 
and supply kits will be provided for all central laboratory assessments.  Samples for the 
following laboratory tests will be sent to one or several central laboratories or to the 
Sponsor for analysis:

ATA assays


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Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of validated immunoassays.  Accompanying PK samples will be collected 
at the same timepoints.

PK assays
Blood samples for PK assessments will be obtained according to the schedule 
in Appendix 2.
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.
At select sites, a subset of approximately 40 patients will undergo additional PK 
assessments for carboplatin and etoposide.  
Plasma carboplatin and etoposide 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 SCLC or tumor immune biology) from 
all eligible patients according to the schedule in Appendix 1 and Appendix 2.  
Samples will be processed to obtain plasma and serum for the determination of 
changes in blood-based biomarkers (e.g., circulating tumor DNA).  Whole blood 
samples may be processed to obtain their derivatives (e.g., RNA, DNA, and 
other biological molecules) and evaluated for immune-related, tumor 
typerelated, and other exploratory biomarkers (e.g., alterations in gene 
expression or single nucleotide polymorphisms).

For patients who consent to the optional collection of samples for the Roche Clinical 
Repository (RCR), any leftover material from the above sample collection will be 
stored and used for exploratory analyses as indicated in Section 4.5.11.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
4.5.7
Tumor Tissue Samples
4.5.7.1
Archival and Freshly Collected Tumor Tissue Samples 
Patients may enroll into the study before submitting a pre-treatment tumor tissue sample.  
A pre-treatment tumor tissue (archival or freshly obtained) sample should be submitted 
before or within 4 weeks after randomization. 
This specimen must be accompanied by the associated pathology report.  Although any 
available tumor tissue sample can be submitted, it is strongly encouraged that 
representative tumor specimens in paraffin blocks (preferred) or 10 (or more) serial, 
freshly cut, unstained slides be submitted for exploratory biomarker analysis (including, 
but not limited to PD-L1 status, markers related to immune- or SCLC-biology such as 


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T-cell markers or non-inherited biomarkers identified through NGS on extracted DNA, 
RNA, or other biological molecules).
Preferred sample types include:

Formalin-fixed paraffin-embedded (FFPE) samples prepared from resections, core 
needle, excisional, incisional, punch, or forceps biopsies.  If these sample types are 
not available, any type of specimen (including fine-needle aspiration, cell pellet 
specimens [e.g., from pleural effusion and lavage samples]) is acceptable. 
Tumor tissue should be of good quality based on total and viable tumor content.  Tumor 
tissue from bone metastases that is subject to decalcification is not advisable.  
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 
into the study will be returned no later than 6 weeks after eligibility determination.
NGS may be performed by Foundation Medicine on evaluable pre-treatment tissue 
(e.g., with adequate tumor content) if requested by the investigator.  If performed by 
Foundation Medicine, the investigator can obtain results from the pre-treatment samples 
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 health authorities.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions.
4.5.7.2
Optional Tumor Samples after Completion of Induction 
Treatment
If clinically feasible, and if the patient signs the Optional Biopsy Consent, an optional 
tumor biopsy after the completion of induction treatment may be obtained.  Preferred 
sample types include: FFPE samples prepared from resections, core needle, excisional, 
incisional, punch, or forceps biopsies.  If these sample types are not available, any type 
of specimen (including fine-needle aspiration, cell pellet specimens [e.g., from pleural 
effusion and lavage samples]) is acceptable.  
The status of immune-related, tumor typerelated, and other exploratory biomarkers 
(including, but not limited to T-cell markers and non-inherited biomarkers on fixed tissue 
identified through NGS on extracted DNA and/or RNA or identified through other 
methods on extracted DNA, RNA, or other biological molecules) in tumor tissue samples 
may be evaluated.  
NGS may be performed by Foundation Medicine on evaluable tissue (e.g., with 
adequate tumor content) if requested by the investigator.  If performed by Foundation 
Medicine, the investigator can obtain results from the post-induction treatment samples 
in the form of an NGS report, which is available upon request directly from Foundation 


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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 health authorities.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions.
4.5.7.3
Optional Tumor Samples at the Time of Radiographic 
Progression
If clinically feasible, and if the patient signs the Optional Biopsy Consent, it is 
recommended that a tumor biopsy be performed to obtain a tumor sample at the time of 
radiographic disease progression (preferably within 40 days of radiographic progression 
or prior to start of the next anti-cancer treatment, whichever is sooner).  Preferred 
sample types include: FFPE samples prepared from resections, core needle, excisional, 
incisional, punch, or forceps biopsies.  If these sample types are not available, any type 
of specimen (including fine-needle aspiration, cell pellet specimens [e.g., from pleural 
effusion and lavage samples]) is acceptable. 
The status of immune-related, tumor typerelated and other exploratory biomarkers 
(including but not limited to T-cell markers and non-inherited biomarkers identified 
through NGS on extracted DNA and/or RNA) in tumor tissue samples may be evaluated.
NGS may be performed by Foundation Medicine on evaluable tissue (e.g., with 
adequate tumor content) if requested by the investigator.  If performed by Foundation 
Medicine, the investigator can obtain results from the disease progression samples 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 health authorities.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions.
4.5.7.4
Tumor Samples at Other Timepoints
If a patient undergoes a medically indicated procedure (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) any time during the course of the study 
that has the likelihood of yielding tumor tissue, any remaining samples or a portion of the 
sample not necessary for medical diagnosis (leftover tumor tissue) may be obtained 
for exploratory analysis.
Patients with additional tissue samples from procedures performed at different times 
during the course of their study participation (during treatment and during survival 
follow-up) who have signed the RCR optional consent will be requested (but not required) 
to also submit these optional fresh tumor biopsy samples for central testing.  Tumor 
tissue samples collected at the time of clinical events (e.g., clinical response, etc.) are 
preferred.  Tissue samples obtained at multiple times for individual patients will greatly 
contribute to an improved understanding of the dynamics of PD-L1 expression and 
relationship with intervening anti-cancer therapy.


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4.5.7.5
Use and Storage of Remaining Samples from Study-Related 
Procedures
The remainder of samples obtained for study-related procedures will be destroyed no 
later than 5 years after the end of the study or earlier depending on local regulations.  If 
the patient provides optional consent for storing samples in the RCR for future research 
(see Section 4.5.11), the samples will be destroyed no later than 15 years after the date 
of final closure of the clinical database.
Serum samples collected for PK and immunogenicity analysis that may be used for 
additional method development, assay validation, and characterization will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
4.5.8
Anti-Therapeutic Antibody Testing
Treatment with atezolizumab may elicit an immune response.  Patients with signs of any 
potential immune response to atezolizumab will be closely monitored.  Validated 
screening and confirmatory assays will be employed to detect ATAs at multiple 
timepoints before, during, and after treatment with atezolizumab (see Appendix 1 and 
Appendix 2 for the schedule).  The immunogenicity evaluation will utilize a risk-based 
immunogenicity strategy (Rosenberg and Worobec 2004; Koren et al. 2008) to 
characterize ATA responses to atezolizumab in support of the clinical development 
program.  This tiered strategy will include an assessment of whether ATA responses 
correlate with relevant clinical endpoints.  Implementation of ATA characterization 
assays will depend on the safety profile and clinical immunogenicity data.
4.5.9
Electrocardiograms
Twelve-lead ECG is required at screening and as clinically indicated.  ECGs should be 
obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.
4.5.10
Patient-Reported Outcomes
PRO data will be collected via the EORTC QLQ-C30, the EORTC QLQ-LC13, and the 
EQ-5D-5L to more fully characterize the clinical profile of atezolizumab.
The questionnaires will be translated into the local language as required.  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.


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Patients will use an electronic PRO (ePRO) device to capture PRO data.  The ePRO 
device and/or instructions for completing the PRO questionnaires electronically will be 
provided by the investigator staff.  The data will be transmitted via a prespecified 
transmission method (e.g., Web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the internet.
The EORTC QLQ-C30 (see Appendix 6) 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 (30 days) and 6 months 
(30 days) following radiographic disease progression per RECIST v1.1 (or at 3 months 
[30 days] and 6 months [30 days] after treatment is discontinued for patients who 
continue treatment after disease progression per RECIST v1.1). 
The EORTC QLQ-LC13 (see Appendix 7) 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 (30 days) and 6 months (30 days) following 
radiographic disease progression per RECIST v1.1 (or at 3 months (30 days) and 
6 months (30 days) after treatment is discontinued for patients who continue treatment 
after disease progression per RECIST v1.1). 
The EQ-5D-5L 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 8).  The EQ-5D-5L 
takes approximately 2 minutes to complete.  The EQ-5D-5L 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 at 
3 months (30 days) and 6 months (30 days) following radiographic disease 
progression per RECIST v1.1 (or at 3 months (30 days) and 6 months (30 days) after 
treatment is discontinued for patients who continue treatment after disease progression 
per RECIST v1.1). 
Patients who discontinue study treatment for any reason other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete 
EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L at each tumor assessment visit 


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until radiographic disease progression per RECIST v1.1, unless the patient withdraws 
consent or the Sponsor terminates the study, whichever occurs first.
The Sponsor will not derive adverse events reports from PRO data (see 
Section 5.3.5.13).
Patients whose native language is not available on the ePRO device or who are deemed 
by the investigator incapable of inputting their ePRO assessment after undergoing 
appropriate training are exempted from completing all ePRO assessments.
4.5.11
Samples for Roche Clinical Repository
4.5.11.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RCR sampling, this section of the protocol 
(Section 4.5.11) will not be applicable at that site.
4.5.11.3
Sample Collection
The following samples may be collected for patients who have signed the RCR optional 
consent:

Optional fresh biopsy samples

Leftover tumor tissue samples


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
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
The following sample will be used for identification of genetic (inherited) biomarkers:

Whole blood sample for DNA extraction (6 mL) (see Appendix 1 and Appendix 2)
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens collected for the RCR will 
undergo additional processes to ensure confidentiality as described below.
4.5.11.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request 
by representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.


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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.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  A
separate, specific signature will be required to document a patient's agreement to 
provide optional RCR specimens.  Patients who decline to participate will not provide a 
separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.11.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  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.  The patient will be provided 
with instructions on how to withdraw consent after the study is closed.  A patient's 
withdrawal from Study GO30081 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 GO30081. If a patient wishes to withdraw consent to the testing 
of his or her RCR samples after closure of the site, the investigator must inform the 
Sponsor by emailing the study number and patient number to the following email 
address:


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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, pharmacodynamic, ATA, and biomarker sampling.
4.5.12.2
Assessments during Treatment
All treatment 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 administered 21 days from the previous dose 
administration; two consecutive 28 cycles are not permitted.  If a dose modification is 
required due to toxicity, refer to Section 5.1.
Tumor assessments will occur every 6 weeks (7 days) for 48 weeks following Cycle 1, 
Day 1 and every 9 weeks (7 days) thereafter after the completion of the Week 48 tumor 
assessment, regardless of treatment dose delays, until radiographic disease progression 
per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, 
whichever occurs first.  Patients who continue treatment beyond radiographic disease 


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progression per RECIST v1.1 will continue to undergo tumor assessments every 6 
weeks (7 days), or sooner if symptomatic deterioration occurs.  For these patients, 
tumor assessments will continue every 6 weeks (7 days) regardless of time on study, 
until study treatment is discontinued.
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 at the same frequency as would have been followed if the 
patient had remained on study treatment (i.e., every 6 weeks [7 days] for the 48 weeks 
following Cycle 1, Day 1 and then every 9 weeks [7 days]) thereafter, regardless of 
treatment dose delays) until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first, 
regardless of whether patients start a new anti-cancer therapy.
The 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 
last treatment for a study drug discontinuation visit.  The visit at which the decision is 
made to discontinue treatment (e.g., disease progression occurs) may be used as the 
study-drug discontinuation visit.
See Appendix 1 and Appendix 2 for the schedule of follow-up assessments.
4.5.12.4
Follow-Up Assessments
After the study drug discontinuation visit, adverse events should be followed as outlined 
in Section 5.3.1.
For patients who discontinue study treatment for any reason other than radiographic 
progressive disease per RECIST v1.1, tumor assessments will continue at the same 
frequency as would have been followed if the patient had remained on study treatment 
until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, 
or study termination by the Sponsor, whichever occurs first.


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Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 will continue 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.  EORTC QLQ-C30, EORTC QLQ-LC13, 
and EQ-5D-5L will be completed at the site on the ePRO tablet at 3 months (30 days) 
and 6 months (30 days) after disease progression per RECIST v1.1 (or at 3 months 
(30 days) and 6 months (30 days) after treatment is discontinued for patients who 
continue treatment after disease progression per RECIST v1.1).  Patients who 
discontinue study treatment for any reason other than radiographic disease progression 
per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete the EORTC 
QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L at each tumor assessment visit until
radiographic disease progression per RECIST v1.1, unless the patient withdraws 
consent or the Sponsor terminates the study, whichever occurs first.
Adverse events will be followed as described in Section 5.5. 
Survival follow-up information will be collected via telephone calls, patient medical 
records, and/or clinic visits every 3 months or more frequently until death, loss to follow-
up, or study termination by the Sponsor, whichever occurs first.  All patients will be 
periodically contacted for survival and new anti-cancer therapy information unless the 
patient requests to be withdrawn from the study (this request must be documented in the 
source documents and signed by the investigator).  If the patient withdraws from the 
study, the study staff may use a public information source (e.g., county records) when 
permissible, to obtain information about survival status only.
See Appendix 1 and Appendix 2 for the schedule of follow-up assessments.
4.5.12.5
Assessments at Unplanned Visits
Assessments for unscheduled visits related to a patient’s underlying SCLC, 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


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
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. Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results if 
available, and the patient’s 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 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 
However, to better accommodate standard clinical practice which is guided by the fact 
that patients with ES-SCLC whose disease progresses after first-line treatment have 
limited treatment options and such options also have limited efficacy and significant 
toxicity, patients may be considered for treatment beyond radiographic progression per 
RECIST v1.1 at the discretion of the investigator and after appropriate discussion with 
the patient and obtaining informed consent, only if all of the following criteria are met:

Evidence of clinical benefit as assessed by the investigator

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Patients must provide written consent to acknowledge deferring other treatment 
options in favor of continuing study treatment at the time of initial progression.
Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 should be closely monitored clinically and a follow-up scan should be 


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performed in 6 weeks, or sooner if symptomatic deterioration occurs.  Treatment should 
be discontinued if clinical deterioration due to disease progression occurs at any time or 
if persistent disease growth is confirmed in a follow-up scan.  In addition, patients should 
be discontinued for unacceptable toxicity or for any other signs or symptoms of 
deterioration attributed to disease progression as determined by the investigator after an 
integrated assessment of radiographic data and clinical status.
Figure 2
Criteria for Continuing Treatment in the Presence of Increased 
Radiographic Tumor Size
ECOG PSEastern Cooperative Oncology Group performance status; RECIST v1.1Response 
Evaluation Criteria in Solid Tumors, Version 1.1.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.


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
Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on 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 important safety risks for atezolizumab are provided below.  Refer to the 
Atezolizumab Investigator’s Brochure for a complete summary of safety information. 
5.1
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria (see Sections 4.1.1
and 4.1.2) and close monitoring (as indicated below and in Section 4.5).  See 
Section 5.3 (Methods and Timing for Capturing and Assessing Safety Parameters) for 
complete details regarding safety reporting for this study.  An iDMC has also been 
incorporated into the study design to periodically review safety data (see the iDMC 
Charter for a detailed monitoring plan).
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 until the initiation of new systemic anti-cancer 
therapy after the last dose of study treatment, whichever occurs first. 
After the adverse event reporting period, all deaths should continue to be reported.  In 
addition, the Sponsor should be notified if the investigator becomes aware of any 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).  These events should be reported 
through use of the Adverse Event eCRF.  However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 


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by faxing or by scanning and e-mailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or e-mail 
address provided to investigators.
The potential safety issues anticipated in this study, as well as measures intended to 
avoid or minimize such toxicities, are outlined in the following sections.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-related hypothyroidism, hyperthyroidism, adrenal insufficiency, Type 1 diabetes 
mellitus, pancreatitis, hepatitis, pneumonitis, colitis, meningoencephalitis, myasthenia 
gravis or myasthenic syndrome, Guillain-Barré syndrome, hypophysitis, myocarditis, 
and nephritis. In addition, systemic immune activation is considered a potential risk 
for atezolizumab. Refer to Appendix 12 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 Etoposide
Etoposide is known to cause bone marrow suppression including myelosuppression, 
anemia, thrombocytopenia, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), 
hepatotoxicity, and alopecia.  Etoposide-based chemotherapy is considered to be 
moderately emetogenic.  Etoposide carries a risk of secondary hematologic malignancy.  
Patients will be monitored for etoposide-related adverse events.
For more details regarding the safety profile of etoposide, refer to the etoposide 
prescribing information.
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 carboplatin 
prescribing information.
5.1.4
Management of Patients Who Experience Specific Adverse 
Events
5.1.4.1
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.


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General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts 
(see Appendix 1 for the list and timing of study assessments).
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.
All serious adverse events and protocol-defined events of special interest (see 
Sections 5.2.2 and 5.2.3) will be reported in an expedited fashion (see Section 5.4.2).  In 
addition, the iDMC and Medical Monitor will review and evaluate observed adverse 
events on a regular basis.
Patients will be followed for adverse events (including deaths, serious adverse events, 
and adverse events of special interest during and after the adverse event reporting 
period as described in Sections 5.3.1, 5.3.5.8, 5.5, and 5.6.  
5.1.5
Dose Modification
5.1.5.1
General Notes Regarding Dose Modification
Reasons for dose modifications including dose 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.

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 and the dose or administration of that component
is delayed or modified, the dose or administration of the other study treatment
components do not require modification and may be administered if there is no
contraindication.

When treatment is temporarily interrupted because of toxicity caused by
atezolizumab/placebo, carboplatin, or etoposide, the treatment cycles should be
restarted such that the atezolizumab/placebo infusions remain synchronized and
aligned with the chemotherapy schedule.

If, in the opinion of the investigator, a toxicity is considered to be due solely to
one chemotherapy drug, the dose of the other chemotherapy drug does not
require modification.
The investigator may use discretion in modifying or accelerating the dose modification 
guidelines described below depending on the severity of toxicity and an assessment of 
the risk versus benefit for the patient, with the goal of maximizing patient compliance and 
access to supportive care.


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5.1.5.2
Atezolizumab Dose Modification, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events
There will be no dose reduction for atezolizumab/placebo in this study.  Patients may 
temporarily suspend study treatment with atezolizumab/placebo for up to 105 days 
beyond the last dose if they experience an adverse event that requires a dose to be 
withheld.  If atezolizumab/placebo is withheld because of adverse events for more than 
105 days beyond the last dose, then the patient will be discontinued from 
atezolizumab/placebo treatment.  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.
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Medical Monitor approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor.
5.1.6
Management of Atezolizumab-Specific Adverse Events
Refer to Appendix 12 for details on the management of atezolizumab-specific adverse 
events, including systemic immune activation.  See Appendix 10 for precautions for 
anaphylaxis.
5.1.7
Chemotherapy Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events
Dose modifications for carboplatin and etoposide are permitted for toxicity according to 
the prescribing information and local standard-of-care.  
Dose modification guidelines are provided below.  Once reduced, the dose cannot be 
increased back to 100%.  
Treatment with carboplatin or etoposide should be discontinued if a patient experiences 
any hematologic or non-hematologic Grade 3 or Grade 4 toxicity after two dose 
reductions or treatment is delayed for more than 63 days due to toxicities. 
Hematologic Toxicity
At the start of each cycle, the ANC should be 1500/L and the platelet count should be 
100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time for
recovery.  Growth factors may be used in accordance with American Society of Clinical
Oncology (ASCO) and NCCN guidelines (Smith et al. 2006; NCCN 2015).  Upon


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recovery, dose adjustments at the start of a subsequent cycle will be made on the basis 
of the lowest platelet and neutrophil values from the previous cycle (see Table 8).
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose.
Table 8
Chemotherapy Dose Modification for Hematologic Toxicities
Toxicity a
Dose
ANC 500/L and platelets 50,000/L
75% of previous dose
Platelets 25,000/L, regardless of ANC
75% of previous dose
Platelets 50,000/L with Grade 2 bleeding, regardless of ANC
50% of previous dose
ANC 1000/L plus fever of 38.5°C
75% of previous dose
a Nadir of prior cycle.
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity.
If chemotherapy is withheld because of hematologic toxicity, full blood counts (including 
differential WBC) should be obtained weekly until the counts reach the lower limits for 
treatment as outlined.  The treatment can then be resumed.
No dose reductions are recommended for anemia.  Patients should be supported per the 
investigator’s institution’s guidelines.
Non-Hematologic Toxicity
For a non-hematologic toxicity (see Table 9), treatment should be delayed for up to 
63 days until resolution to less than or equal to the patient’s baseline value (or Grade 1 
if the patient did not have that toxicity at baseline).  Dose reductions at the start of the 
subsequent cycle should be made on the basis of non-hematologic toxicities from the 
dose administered in the preceding cycle.  Table 9 provides recommended dose 
modifications for non-hematologic toxicities.


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Table 9
Dose Modifications or Treatment Discontinuation for 
Non-Hematologic Toxicities 
Toxicity
Adjusted Dose as % 
of Previous Dose a
Diarrhea
Grade 3 or 4 b
75%
Nausea/vomiting
Grade 3 or 4 c
75%
Neurotoxicity
Grade 2
75%
Grade 3 or 4
50% or permanent 
discontinuation
Transaminase elevation
Grade 3
75%
Grade 4
Discontinue
Other 
Grade 3 or 4
75%
AUCarea under the concentrationtime curve.
a If deemed appropriate by the investigator, adjust carboplatin dose to the 
specified percentage of the previous AUC.
b Grade 3 or 4 diarrhea that occurs on adequate anti-diarrhea medication 
or any grade of diarrhea requiring hospitalization.
c Despite the use of anti-emetics.
Diarrhea should be controlled with adequate anti-diarrhea medication.  Nausea and/or 
vomiting may be controlled with adequate anti-emetics.  For Grade 3 or 4 neurotoxicity 
chemotherapy should be resumed at 50% of the previous dose upon improvement or 
discontinued immediately (based on investigator’s clinical judgment).
Suggested recommendations for dose modification of etoposide for renal impairment are 
provided in Table 10. 
Table 10 Etoposide Dose Modification for Renal Impairment
Creatinine clearance 
(mL/min)
Etoposide Dose
50
100%
1550
75% of dose
5.1.8
Potential Overlapping Toxicities
The risk of overlapping toxicities between atezolizumab, carboplatin, and etoposide 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 be ambiguous when the agents are administered 
together.  It is theoretically possible that allergic or inflammatory adverse events 
associated with carboplatin and etoposide (e.g., dermatitis, infusion-associated 
symptoms) could be exacerbated by the immunostimulatory activity of atezolizumab. 


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Toxicities should initially be managed according to the recommendations in 
Sections 5.1.6 and 5.1.7 and Appendix 12, 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 held for a maximum of 105 days beyond the last infusion
(see Section 5.1.5.2).  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 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 non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug


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
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported 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:

The following confirmed treatment-emergent autoimmune conditions:
Pneumonitis


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Colitis
Endocrinopathies:  diabetes mellitus, pancreatitis, or adrenal insufficiency or 
hyperthyroidism
Hepatitis
Transaminitis: Grade 2 (AST or ALT3ULN and bilirubin 2ULN) OR 
AST/ALT 10ULN
Systemic lupus erythematosus
Neurologic: Guillain-Barré syndrome, myasthenia gravis, meningoencephalitis
Nephritis

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response syndrome (SIRS), systemic immune activation, or 
infusion-reaction syndromes

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained, but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).


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After initiation of study drug, all serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new systemic anti-cancer therapy after the last 
dose of study treatment, whichever occurs first.  All other adverse events, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of study drug 
or initiation of new 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 11 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 11 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
5
Death related to adverse event
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 refers 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.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Causality will be assessed individually for each protocol-mandated therapy.


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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
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after the end of study drug infusion 
and are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences 
both a local and systemic reaction to the same dose of study drug, each reaction should 
be recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated Infusion-Related Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For 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.
5.3.5.3
Adverse Events that are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If 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.


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All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity) of the event will be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, the 
most extreme intensity should also be recorded on the Adverse Event eCRF.  If the 
event becomes serious, it should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning that the event became serious; see Section 5.4.2 for 
reporting instructions).  The Adverse Event eCRF should be updated by changing the 
event from "non-serious" to "serious," providing the date that the event became serious, 
and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it 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 


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be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it 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.
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of SCLC should be recorded only on the Death 
Attributed to Progressive Disease eCRF.  All other deaths occurring during the adverse 
event reporting period, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  The 
iDMC will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "Death due to Unknown Cause" should be recorded on the Adverse Event 
eCRF.  If the cause of death later becomes available (e.g., after autopsy), the event 
should be replaced by the established cause of death.  The term "sudden death" should 
not be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches" or “worsened headache”).
5.3.5.10
Lack of Efficacy or Worsening of SCLC
Events that are clearly consistent with the expected pattern of progression of SCLC 
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 criteria.  In rare cases, the determination of clinical progression will be based 


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on symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or to perform an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization 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
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An 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 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).


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5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Sites are not expected to review the 
PRO data for adverse events. 
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor:
, M.D.
Telephone No.:
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators. 


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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained, but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to Roche or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and e-mailing the form with use of the fax number or e-mail address 
provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment or initiation of 
new systemic anti-cancer therapy after the last dose of study drug, whichever occurs 
first.  All other adverse events, regardless of relationship to study drug, will be reported 
until 30 days after the last dose of study treatment or initiation of new systemic 
anti-cancer therapy after the last dose of study drug, whichever occurs first.
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the 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 e-mailing the form with use of 
the fax number or e-mail 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 study treatment.  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 e-mailing 
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 


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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 female partner becomes pregnant during chemotherapy 
study treatment (i.e., carboplatin and etoposide) or within 6 months after the last dose of 
chemotherapy study treatment.  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 e-mailing 
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 drug.  The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will 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 the 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, regardless of cause, should be reported through use of the Long-Term Survival 
Follow-up eCRF.  
In addition, if the investigator becomes aware of a serious adverse event or adverse 
event of special interest that is believed to be related to prior exposure to study 
treatment, the event should be reported through use of the Adverse Event eCRF.  
However, if the EDC system is not available, the investigator should report these events
directly to the Sponsor or its designee, either by faxing or by scanning and e-mailing the 
paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form using the fax number or e-mail address provided to investigators.


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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 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 Atezolizumab Investigator's 
Brochure for atezolizumab.
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 I/III, global, double-blind, placebo-controlled study designed 
to evaluate the safety and efficacy of atezolizumab in combination with 
carboplatinetoposide compared with treatment with placebo and 
carboplatinetoposide in patients who have ES-SCLC and are chemotherapy-naive for 
their extensive-stage disease.
All analyses discussed in this section will be restricted to the patients enrolled in the 
global enrollment phase only
 unless 
otherwise noted. The analysis populations used in this section, such as the ITT (i.e., all 
randomized patients) and the PD-L1selected populations will not 
 
 unless otherwise noted.
The analyses of PFS and OS will be performed on all randomized patients (ITT), with 
patients grouped according to the treatment assigned at randomization, regardless of 
whether they receive any assigned study drug.  ORR will be analyzed using all 
randomized patients who have measurable disease at baseline.  DOR will be assessed 
in patients who have an objective response.  TTD analyses will be conducted on all 
patients with a non-missing baseline PRO assessment.  Change from baseline analysis 
on PROs will be performed using patients who have both a non-missing baseline 


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assessment and at least one post-baseline assessment with patients grouped according 
to the treatment assigned at randomization.
Safety analyses will be performed on all randomized patients who received any amount 
of study drug, with patients grouped according to whether any full or partial dose of 
atezolizumab was received.
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 400 patients will be randomized into the global enrollment phase of this 
study to the atezolizumabcarboplatinetoposide arm and the 
placebocarboplatinetoposide arm in a 1:1 ratio.
There are two co-primary efficacy endpoints: PFS and OS. To control the overall 
two-sided Type I error rate at 0.05, the two-sided significance levels of 0.005 and 
0.045 are allocated to the primary comparisons for PFS and OS, respectively.
The following sample size calculation applies to the global enrollment phase, 
 
 unless otherwise noted.
The sample size of the study is determined by the analysis of OS. To detect an 
improvement of HR0.68 in OS using a log-rank test, approximately 306 deaths in the 
ITT population will be required to achieve 91% power at a two-sided significance level of 
0.045. One OS interim analysis will be performed when approximately 240 OS events in 
the ITT population are observed, which by estimation will occur at approximately 
25 months after the first patient is randomized. 
The primary analysis of PFS is planned to be conducted at the time of the OS interim 
analysis, and is estimated to be when approximately 295 PFS events in the ITT 
population have occurred, which is expected at approximately 25 months after the first 
patient is randomized. This provides 99% power to detect an improvement of HR0.55 
in PFS at a two-sided significance level of 0.005.   There will be no interim analysis for 
PFS. 
By a group sequential Holm procedure (Ye et al., 2011), if the primary analysis of PFS is 
significant, then the two-sided 0.005 alpha will be recycled to OS; the detailed testing 
boundary is provided in Section 6.8.1. Otherwise, if the OS analysis at either interim or 
final is significant, the allocated test mass of two-sided 0.045 alpha can be returned to 
PFS so PFS primary analysis can be tested at a two-sided 0.05 level (see Figure 3). 
Additional details will be provided in the Statistical Analysis Plan. 


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Figure 3
Group Sequential Holm Procedure
The final analysis of OS will be performed when approximately 306 OS events in the ITT 
population have been observed, which is expected at approximately 36 months after the 
first patient is randomized.
The calculation of sample size and estimates of the analysis timelines are based on the 
following assumptions:

PFS and OS are exponentially distributed.

The median duration of PFS in the control arm is 6 months.

The median duration of OS in the control arm is 10 months.

The interim and final analyses of OS use the Lan-DeMets alpha spending function
to approximate the O’Brien-Fleming boundary.

The dropout rate is 5% over 12 months for PFS and OS.
6.1.1
OS (=0.045)
2-sided =0.05
PFS (=0.005)
if rejected, =0.005 will 
be passed to OS 
if rejected, =0.045 will 
be passed to PFS


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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 ITT 
population.  Major protocol deviations, including major deviations of inclusion/exclusion 
criteria, will be reported and summarized by treatment arm for the ITT population.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG performance status) will be summarized by treatment arm 
for the ITT population.  Descriptive statistics (mean, median, SD, and range) will be 
presented for continuous data, and frequencies and percentages will be presented for 
categorical data.
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of protocol treatment.
6.4
EFFICACY ANALYSES
The stratification factors will be those used for randomization from the IxRS (i.e., sex, 
ECOG performance status, and brain metastases). Due to the potential risk of over-
stratification (Akazawa et al. 1997), if at least one stratum (i.e., a combination of 
stratification factor levels across sex [male vs female], ECOG performance status [0 vs 
1], and brain metastasis [Yes vs No] per IxRS) has less than 10 events (PFS or OS 
events), the stratification factor (one of 3 stratification factors: sex, ECOG performance 
status, and brain metastasis per IxRS) which contains the level with the smallest 
number of patients will be removed from the stratified analyses. The removal of the 
stratification factor will continue until there is no stratum with less than 10 events 
(PFS or OS events). The final set of stratification factors used in stratified analyses 
will be applied to all endpoints where stratified analyses are planned. Analyses based on 
stratification factors recorded on the electronic Case Report Form (eCRF) will also be 
provided if considerable discrepancy is observed between IxRS and eCRF records.
6.4.1
Primary Efficacy Endpoints
To adjust for multiplicity due to having two co-primary endpoints, a group sequential 
Holm’s procedure will be implemented: initially the hypothesis test for PFS will be
conducted at a two-sided alpha of 0.005 and OS will be tested at a two-sided alpha of 
0.045. Once a null hypothesis is rejected, the test mass predefined for that endpoint 
becomes available and can be recycled to the other unrejected test. 


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The null and alternative hypotheses regarding PFS or OS in the ITT population can be 
phrased in terms of the PFS or OS survival functions SA(t) and SB(t) for Arm A 
(atezolizumabcarboplatinetoposide) and Arm B (placebocarboplatinetoposide), 
respectively:
H0: SA(t) SB(t) versus H1: SA(t) ≠SB(t)
One of the co-primary efficacy endpoints is PFS as assessed by the investigator using 
RECIST v1.1.  PFS is defined as the time between the date of randomization and the 
date of first documented disease progression or death, whichever occurs first.  Patients 
who have not experienced disease progression or death at the time of analysis will be 
censored at the time of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored at the date of randomization plus 1 day.
The stratified log-rank test, will be used as the primary analysis to compare PFS 
between the two treatment arms.  The results from the unstratified log-rank will also be 
provided. 
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm.  
The Brookmeyer-Crowley methodology (Brookmeyer and Crowley 1982) will be used to 
construct the 95% CI for the median PFS for each treatment arm.  Cox 
proportional-hazards models will be used to estimate the stratified HR and its 95% CI.  
The unstratified HR will also be presented.
OS, the other co-primary efficacy endpoint, is defined as the time from the date of 
randomization to the date of death from any cause.  Patients who are alive at the time of 
the analysis data cutoff will be censored at the last date they were known to be alive.  
Patients with no post-baseline information will be censored at the date of randomization 
plus 1 day. Methods for OS analyses are similar to those described for the PFS 
endpoint.
The final analysis of OS will occur after approximately 306 OS events in the ITT 
population have occurred.  One interim analysis of OS will be conducted at the time that 
approximately 240 OS events or approximately 295 PFS events have occurred in the ITT 
population, whichever occurs later. It is projected that approximately 220 OS events in 
the ITT population will be observed at 25 months after the first patient is randomized.  To 
control the two-sided significance level at 0.045 for the OS interim and final analyses, 
the Lan-DeMets alpha spending function will be used to approximate the O’Brien-
Fleming boundary (DeMets and Lan 1994). See Section 6.8.1 (Planned Interim Analysis) 
for additional information.


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6.4.2
Secondary Efficacy Endpoints
6.4.2.1
Objective Response Rate
An objective response is defined as either an unconfirmed CR or a PR, as determined
by the investigator using RECIST v1.1.  Patients not meeting these criteria, including 
patients without any post-baseline tumor assessment, will be considered 
non-responders.
ORR is defined as the proportion of patients who had an objective response.  The
analysis population for ORR will be all randomized patients with measurable disease at 
baseline.  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.
6.4.2.2
Duration of Response
DOR will be assessed in patients who had an objective response as determined by the 
investigator using RECIST v1.1.  DOR is defined as the time interval from the date of the 
first occurrence of a CR or PR (whichever status is recorded first) until the first date that 
progressive disease or death is documented, whichever occurs first.  Patients who have 
not progressed and who have not died at the time of analysis will be censored at the 
time of last tumor assessment date.  If no tumor assessments were performed after the 
date of the first occurrence of a CR or PR, DOR will be censored at the date of the 
first occurrence of a CR or PR plus 1 day.  DOR is based on a non-randomized subset 
of patients (specifically, patients who achieved an objective response); therefore, formal 
hypothesis testing will not be performed for this endpoint.  Comparisons between 
treatment arms will be made for descriptive purposes.  The methodologies detailed for 
the PFS analysis will be used for the DOR analysis.
6.4.2.3
Landmark Analysis on Progression-Free Survival and Overall 
Survival
The PFS rates 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 
the standard error derived from Greenwood’s formula.  The 95% CI for the difference in 
PFS rates between the two treatment arms will be estimated using the normal 
approximation method.
Similar analyses will be performed for the OS rates at 1 and 2 years after randomization.
6.4.2.4
Patient-Reported Outcomes
TTD using EORTC is defined as the time from baseline to the first time the patient’s 
score shows a 10-point increase above baseline in any of the following 
EORTC-transformed symptom subscale scores (whichever occurs first):  cough, 
dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain, 
whichever occurs first.  The linear transformation gives each individual symptom 


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subscale a possible score of 0100.  In order for the symptom to be considered 
“deteriorated,” a score increase of 10 points above baseline must be held for at least 
two consecutive assessments or an initial score increase of 10 points is followed by 
death within 3 weeks from the last assessment.  A 10-point change in the symptoms 
subscale score is perceived by patients 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 using the EORTC scale will be 
analyzed using the same methods as for PFS.  The analysis populations for TTD will be 
all randomized patients with a non-missing baseline PRO assessment.
PROs of HRQoL, lung cancerrelated symptoms, and health status will be measured 
using EORTC QLQ-C30 and EORTC QLQ-LC13.  Summary statistics (mean, SD, 
median, 25th and 75th percentiles, and range) and the mean change from baseline of 
linear-transformed scores will be reported for all of the items and subscales of the 
EORTC QLQ-C30 questionnaire and the QLQ-LC13 according to the EORTC scoring 
manual guidelines.  Completion and compliance rates will be summarized at each 
timepoint by treatment arm.  The analysis populations for PRO changes will be all 
randomized patients with a non-missing baseline assessment and at least 
one non-missing post-baseline assessment.
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.  
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 CR or PR plus 1 day.
For TTD with use of the 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.


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6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety-evaluable population, which is defined 
as all randomized patients who receive any amount of any component of protocol 
treatment.  Patients will be allocated according to whether any full or partial dose of 
atezolizumab was received.
Drug exposure will be summarized to include treatment duration, number of doses, and 
dose intensity.
Verbatim description of adverse events will be mapped to thesaurus terms and graded 
according to NCI CTCAE v4.0.  All adverse events occurring during or after the first 
study drug dose will be summarized by treatment arm and NCI CTCAE grade.  In 
addition, serious adverse events, severe adverse events (Grade 3), 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 will be summarized by treatment arm.
6.6
PHARMACOKINETIC ANALYSES
PK samples will be collected in this study as outlined in Appendix 2.  Atezolizumab 
serum concentration data (Cmin and Cmax) will be tabulated and summarized.  Descriptive 
statistics will include means, medians, ranges, and SDs, as appropriate.
Plasma concentrations of carboplatin and etoposide will be collected in this study as 
outlined in Appendix 2.  The concentrations of carboplatin and etoposide 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
Objective Response Rate, Duration of Response, and
Progression-Free Survival per Modified RECIST
Analyses using modified RECIST criteria (see Appendix 5) for ORR, DOR, and PFS, as 
determined by the investigator will also be conducted (for atezolizumab-treated patients
only).  Comparisons between the treatment arms will not be made.  The methods 
outlined for the primary and secondary efficacy endpoint analyses to estimate the 
median PFS or ORR for each treatment arm will be used for these analyses. 


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6.7.2
Exploratory Analyses of Progression-Free Survival
6.7.2.1
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 treatment arms in which patients who 
receive nonprotocol-specified anti-cancer therapy before a PFS event will be censored 
at the last tumor assessment date before receipt of nonprotocol-specified anti-cancer 
therapy.
6.7.2.2
Subgroup Analysis
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG 
performance status, smoking status, presence of brain metastases), 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 treatment arms.
6.7.2.3
Sensitivity Analyses
One sensitivity analysis 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.
If a patient misses two or more assessments scheduled immediately prior to the date of 
the PFS event, the patient will be counted as having progressed on the date of the first 
of these missing assessments.
Another sensitivity analysis is that data for patients with a PFS event who missed two or 
more scheduled assessments immediately prior to the PFS event will be censored at the 
last tumor assessment prior to the missed visits.  
The imputation rule will be applied to patients in both treatment arms.  Statistical 
methodologies that are analogous to those used in the primary analysis of PFS as 
specified in Section 6.4.1 will be used for this sensitivity analysis.
The impact of non-protocol-specified anti-cancer therapy on OS will be assessed, in 
which data from patients who receive non-protocol-specified anti-cancer therapy before 
a PFS event will be censored at the date before receipt of non-protocol-specified anti-
cancer therapy.


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6.7.3
Exploratory Analyses of Overall Survival
6.7.3.1
Subgroup Analysis
To assess the consistency of the study results in subgroups defined by demographics 
(e.g., age, sex, and race/ethnicity), baseline prognostic characteristics (e.g., ECOG 
performance status, smoking status, presence of brain 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 
treatment arms.
6.7.4
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.
6.8
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. 
One interim efficacy analysis of OS is planned when approximately 240 OS events have 
been observed.  The primary analysis of PFS will be conducted at the same time of the 
interim OS analysis and is estimated to occur when approximately 295 PFS events in
the ITT population have occurred, which is expected at approximately 25 months after 
the first patient is randomized.
The final OS analysis will be conducted when approximately 306 OS events in the ITT 
population have been observed.  This is expected to occur approximately 36 months
after the first patient is randomized, but the exact timing of this analysis will depend on 
the actual number of OS events.  
To control the type I error for OS, the stopping boundaries for OS interim and final 
analyses are to be computed with use of the Lan-DeMets approximation to the 
O’Brien-Fleming boundary (DeMets and Lan 1994) as shown in Table 12.


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Table 12 Analysis Timing and Stopping Boundary of Overall Survival
Analysis Timing
Information 
Fraction
(Number of 
Events)
Estimated
Stopping Boundary in HR (p-value)
Time from 
First 
Patient In 
(months)
PFS is 
Statistically 
Significant
PFS is Not 
Statistically 
Significant
25
HR0.7453
(p0.0228)
HR0.7405
(p 0.02)
OS interim analysis 
78.4%(240) 
OS final analysis 
100% (306)
36
HR0.7937
(p0.0433)
HR0.7899
(p 0.039)
HRhazard ratio; OSoverall survival; PFSprogression-free survival.
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.
If an interim analysis is conducted, the Sponsor will remain blinded. The interim analysis 
will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
Charter.
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC Charter will document potential recommendations the iDMC 
can make to the Sponsor as a result of the analysis (e.g., stop the study for positive 
efficacy, stop the study for futility), and the iDMC Charter will also be made available to 
relevant health authorities.
6.9


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
Patient-reported data will be collected electronically through use of electronic devices 
provided by an ePRO vendor.  The electronic device is designed for entry of data in a 
way that is attributable, secure, and accurate, in compliance with the FDA regulations for 
electronic records (21 Code of Federal Regulations, Part 11).  The data will be 
transmitted to a centralized database at the ePRO vendor.  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 data, audit trail, and study and system documentation 
will be archived.  The investigator will receive patient data for the site in both human-
and machine-readable formats on an archival-quality compact disc that must be kept 


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with the study records as source data.  Acknowledgement of receipt of the compact disc 
is required.  In addition, the Sponsor will receive all data in a machine-readable format 
on a compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical study.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification, 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.


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7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. IND 
application will comply with the 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) and applicable local, regional, and 
national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Form 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 


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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 who meet all of the criteria specified in Section 3.1 and 
continue treatment beyond radiographic disease progression per RECIST v1.1.  
This separate consent is to be signed after initial radiographic disease progression 
has occurred and patients have discussed other available treatment options and the 
potential risks of continuing treatment.

A signature page for patients to sign to consent to undergoing optional tumor 
biopsies during the study (after induction completion of induction treatment or after 
radiographic disease progression per RECIST v1.1). 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.


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8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 150 sites globally will participate in the study and approximately 
400 patients will be randomized during the initial global enrollment phase of the study.   
Randomization will occur through use of an IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests and PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 


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


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10.
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AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Assessments
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation Visit
Survival Follow-Up
Days 28
to 1
Induction Phase
(Cycles 14)
Maintenance
Phase
30 Days after Last 
Dose of Study Treatment
Every 3 Months after 
Disease Progression 
Every 21 Days
(3 Days) b
Every 21 Days
(3 Days) 
Informed consent
x
Pre-treatment tumor tissue specimen for biomarker 
testing 
x c
x c
x c
Demographic data
x
Medical history and baseline conditions
x
SCLC cancer history
x
Vital signs d
x
x
x
x
Weight
x
x
x
x
Height
x
Complete physical examination
x
Limited physical examination e
x
x
x
ECOG performance status
x
x
x
x
12-lead ECG
x
x f
x f
x f
Hematology g
x h
x
x
x
Serum chemistry i
x h
x
x
x
Coagulation test (aPTT or INR)
x h
x


Appendix 1
Schedule of Assessments (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
133/Protocol GO30081, Version 7
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation Visit
Survival Follow-Up
Days 28
to 1
Induction Phase
(Cycles 14)
Maintenance
Phase
30 Days after Last 
Dose of Study Treatment
Every 3 Months after 
Disease Progression 
Every 21 Days
(3 Days) b
Every 21 Days
(3 Days) 
Pregnancy test (women of 
childbearing-potential only)
x j
x k
x k
x k
TSH, free T3, free T4 l
x
x m
x m
x
HIV, HBV, HCV serology n
x
Urinalysis o
x o
x o
x o
x o
Induction treatment administration
Arm A:  atezolizumabetoposidecarboplatin
Arm B:  placeboetoposidecarboplatin
x p
Maintenance treatment administration
Arm A:  atezolizumab
Arm B:  placebo
x p
Prophylactic cranial irradiation
x q
Tumor response assessment
x r
x s
x s
x t
Serum sample for atezolizumab ATA assessment u
x
x
x
120 (30) days after last 
dose of atezolizumab
Serum sample for atezolizumab PK sampling u
x
x
x
120 (30) days after last 
dose of atezolizumab
Carboplatin and etoposide PK sampling u
x


Appendix 1
Schedule of Assessments (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
134/Protocol GO30081, Version 7
Procedure
Screening
All Treatment Cycles a
Treatment 
Discontinuation Visit
Survival Follow-Up
Days 28
to 1
Induction Phase
(Cycles 14)
Maintenance
Phase
30 Days after Last 
Dose of Study Treatment
Every 3 Months after 
Disease Progression 
Every 21 Days
(3 Days) b
Every 21 Days
(3 Days) 
Blood samples for PD biomarkers u
x
x
x
120 (30) days after last 
dose of atezolizumab
Optional tumor biopsy after induction treatment (if 
patient signs consent)
After induction treatment
Optional tumor biopsy at time of radiographic 
progression (if patient signs consent) v
At time of initial radiographic 
progression
Optional tumor biopsy at other time points 
(RCR only)
Any time during study treatment or during survival follow-up
Optional blood for DNA extraction (RCR only) u, w
x
Adverse events
x
x
x
x x
x x
Concomitant medications
x y
x y
x y
x y
Patient-reported outcomes (EORTC QLQ-C30, 
EORTC QLQ-LC13, and EQ-5D-5L) z
x z
x z
x z
Survival and anti-cancer therapy follow-up
x aa


Appendix 1
Schedule of Assessments (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
135/Protocol GO30081, Version 7
ATAanti-therapeutic antibody; CT computed tomography; ECOG Eastern Cooperative Oncology Group; eCRF electronic case report form; 
EORTCEuropean Organization for Research and Treatment of Cancer; ePRO electronic Patient-Reported Outcome; EQ-5D-5LEuroQoL 5 
Dimensions 5-Level Version; FFPEformalin-fixed paraffin-embedded; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen;
HBVhepatitis B virus; HCVhepatitis C virus; MRImagnetic resonance imaging; NSCLCnonsmall cell lung cancer; PCIprophylactic cranial 
irradiation; PCR polymerase chain reaction; PDpharmacodynamic; PD-L1programmed deathligand 1; PKpharmacokinetic; 
PROPatient-Reported Outcome; QLQ-C30Quality-of-Life Questionnaire Core 30; QLQ-LC13Quality-of-Life Questionnaire Lung Cancer module; 
RCRRoche Clinical Repository; RECIST Response Evaluation Criteria in Solid Tumors; SCLCsmall cell lung cancer; TSHthyroid-stimulating 
hormone.
a Assessments should be performed before study drug infusion unless otherwise noted.
b Cycle 1 must be performed within 5 days after the patient is randomized.  Screening assessments performed 96 hours before Cycle 1, Day 1 are 
not required to be repeated for Cycle 1, Day 1.  In addition, ECOG performance status, limited physical examination, and local laboratory tests may 
be performed 96 hours before Day 1 of each cycle as specified in Section 4.5.12.2.
c A pre-treatment tumor tissue (archival or freshly obtained) sample should be submitted before or within 4 weeks after randomization.  This specimen 
must be accompanied by the associated pathology report.  Although any available tumor tissue sample can be submitted, it is strongly encouraged 
that representative tumor specimens in paraffin blocks (preferred) or 10 (or more) serial, freshly cut, unstained slides be submitted.  See 
Section 4.5.7.1 for details.
d Vital signs include pulse rate, respiratory rate, blood pressures, and temperature.  Vital signs should be recorded as described in Section 4.5.4.
e Symptom-directed physical examinations; see Section 4.5.3 for details.
f
ECG recordings will be obtained when clinically indicated.
g Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, basophils, and other cells), and platelet count. 
h At screening, the patient must have adequate hematologic and end-organ function defined by laboratory test results obtained within 14 days prior to 
randomization. See Section 4.1.1 for details.
I
Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2 if considered standard of care 
in the region, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.
j
Serum pregnancy test within 14 days before Cycle 1, Day 1.
k Urine pregnancy tests; if a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test.
l
Total T3 will be tested only at sites where free T3 is not performed.
m Thyroid function testing (TSH, free T3, free T4) collected on Day 1 of Cycles 1, 4, 8, and 12, and every fourth cycle thereafter.


Appendix 1
Schedule of Assessments (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
136/Protocol GO30081, Version 7
n All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the study.  Patients with active 
hepatitis B (chronic or acute; defined as having a positive HBsAg test result at screening) will be excluded from the study.  Patients with past or 
resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible; HBV DNA should be obtained in these patients prior 
to randomization.  Patients with HCV will be excluded from the study; patients who test positive for HCV antibody are eligible only if PCR is negative 
for HCV RNA. 
o Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood).  Urinalysis is required at screening and will be obtained when 
clinically indicated.
p For atezolizumab/placebo, the initial dose will be administered over 60 (15) minutes.  If the first infusion is well tolerated, subsequent infusions may 
be administered over 30 (10) minutes.  For carboplatin and etoposide, study drug will be administered as described in Section 4.3.2.
q During the maintenance phase, PCI is permitted as per local standard-of-care and will be reported on the Prophylactic Cranial Irradiation eCRF.
r CT scans (with oral/IV contrast unless contraindicated) or MRI scans 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.
s Perform every 6 weeks (7 days) for 48 weeks following Cycle 1, Day 1 and then every 9 weeks (7 days) thereafter, after completion of the Week 
48 tumor assessment, regardless of treatment delays, until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.  Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 will 
continue to undergo tumor assessments every 6 weeks (7 days) or sooner if symptomatic deterioration occurs.  For these patients, tumor 
assessments will continue every 6 weeks (7 days), regardless of time on study, until study treatment is discontinued.  See Section 4.5.5 for details.
t
If the patient discontinued 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 
(i.e., every 6 weeks [7 days] for 48 weeks following Cycle 1, Day 1 and then every 9 weeks [7 days] thereafter) until radiographic disease 
progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if the patient starts 
another anti-cancer therapy after study treatment discontinuation, unless consent is withdrawn.  See Section 4.5.5 for details.
u See Appendix 2 for detailed schedule.
v Optional tumor biopsy at radiographic disease progression, if clinically feasible, preferably within 40 days of radiographic progression or prior to start 
of the next anti-cancer therapy, whichever occurs is sooner.
w 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.
x All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the last 
dose of study drug or initiation of new systemic anti-cancer therapy after the last dose of study drug, whichever occurs first.  All other adverse events, 


Appendix 1
Schedule of Assessments (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
137/Protocol GO30081, Version 7
regardless of relationship to study drug, will be reported until 30 days after the last dose of study drug or initiation of new systemic anti-cancer therapy 
after the last dose of study drug, whichever occurs first.  After this period, all deaths should continue to be reported.  In addition, the Sponsor should 
be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that is believed to be related to prior 
exposure to study treatment (see Section 5.6). These events should be reported through use of the Adverse Event eCRF.  
y From 7 days before screening until the treatment discontinuation visit.  All such medications should be reported to the investigator and recorded on 
the Concomitant Medications eCRF.
z EORTC QLQ-C30, EORTC QLQ-LC13, and the EQ-5D-5L questionnaires will be completed by the patients on the ePRO tablet at each scheduled 
study visit prior to administration of study drug and prior to any other study assessment(s).  During survival follow-up, the EORTC QLQ-C30, EORTC 
QLQ-LC13, and EQ-5D-5L questionnaires will be completed at 3 months (30 days) and 6 months (30 days) following radiographic disease 
progression per RECIST v1.1 (or at 3 months [30 days] and 6 months [30 days] after treatment is discontinued for patients who continue 
treatment after disease progression per RECIST v1.1).  Patients who discontinue study treatment for any reason other than radiographic 
disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L 
at each tumor assessment visit until radiographic disease progression per RECIST v1.1, unless the patient withdraws consent or the Sponsor 
terminates the study, whichever occurs first.  Study personnel should review all questionnaires for completeness before the patient leaves the 
investigational site.  Patients whose native language is not available in the ePRO device or who are deemed by the investigator incapable of inputting 
their ePRO assessment after undergoing appropriate training are exempt from all ePRO assessments.
aa 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.


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Appendix 2
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Therapeutic Antibody Assessments
Study Visit
Time
Atezolizumab/Placebo
CarboplatinEtoposide
Cycle 1, Day 1 a
Predose (same day as treatment 
administration) (for biomarker 
sampling, prior to first dose of 
steroids)
Atezolizumab ATA
Atezolizumab PK
Carboplatin PK b
Etoposide PK b
Biomarkers c
30 (10) minutes after end of 
atezolizumab infusion
Atezolizumab PK
510 minutes before the end of 
carboplatin infusion b
Carboplatin PK b
1 hour (15 minutes) after end of 
carboplatin infusion b
Carboplatin PK b
510 minutes before the end of 
etoposide infusion b
Etoposide PK b
1 hour (15 minutes) after end of 
etoposide infusion b
Etoposide PK b
4 hours (30 minutes) after end of 
etoposide infusion b
Etoposide PK b
Cycle 2, Day 1
Predose (same day as treatment 
administration)
Atezolizumab ATA
Atezolizumab PK
Biomarkers d
Cycle 3, Day 1
Predose (same day as treatment 
administration)

Atezolizumab ATA

Atezolizumab PK

Carboplatin PK b

Etoposide PK b

Biomarkers c


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Appendix 2
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Therapeutic Antibody Assessments (cont.)
Study Visit
Time
Atezolizumab/Placebo
CarboplatinEtoposide
Cycle 3, Day 1
510 minutes before the end of 
carboplatin infusion b
Carboplatin PK b
1 hour (15 minutes) after end 
of carboplatin infusion b
Carboplatin PK b
510 minutes before the end of 
etoposide infusion b
Etoposide PK b
1 hour (15 minutes) after end 
of etoposide infusion b
Etoposide PK b
4 hours (30 minutes) after end 
of etoposide infusion b
Etoposide PK b
Cycles 4, 8, and 16, Day 1
Predose (same day as treatment 
administration)

Atezolizumab ATA

Atezolizumab PK
Biomarkers d
After Cycle 16, every 8th 
cycle, Day 1
Predose (same day as treatment 
administration)

Atezolizumab ATA

Atezolizumab PK
Biomarkers d
At time of fresh biopsy 
(on-treatment including 
during follow-up)
At visit
Biomarkers d
Treatment discontinuation 
visit
At visit

Atezolizumab ATA

Atezolizumab PK
Biomarkers d
120 (30 days) after last 
dose of 
atezolizumab/placebo
At visit

Atezolizumab ATA

Atezolizumab PK
Biomarkers d
Any time point during the 
study (RCR consent 
required)
Optional RCR blood (DNA 
extraction) e
ATAanti-therapeutic antibody; PKpharmacokinetic; RCRRoche Clinical Repository.
Note:  Serum PK samples for atezolizumab; plasma PK samples for carboplatin and etoposide.
a Biomarker sampling before Cycle 1, Day 1 should be performed before patients are treated 
with first dose of steroids.
b At select sites, a subset of approximately 40 patients will undergo the additional PK 
assessments for carboplatin and etoposide.  The additional PK assessments should be taken 
only if the patient is receiving both carboplatin and etoposide at the cycle.  
c Plasma, serum, whole blood for biomarkers.
d Plasma and serum for biomarkers.
e The optional RCR blood sample (for DNA extraction) requires an additional informed consent 
and can be collected at any time during the course of the study.


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Appendix 3
Veterans Administration Lung Study Group (VALG) Staging 
System for SCLC
Stage
Characteristics
Limited SCLC

Disease confined to one hemithorax, although local 
extensions may be present; 

No extrathoracic metastases except for possible ipsilateral, 
supraclavicular nodes if they can be included in the same 
portal as the primary tumor; and 

Primary tumor and regional nodes that can be adequately 
treated and totally encompassed in every portal
Extensive SCLC

Inoperable patients who cannot be classified as having 
limited disease
SCLCsmall cell lung cancer.
Source:  Micke et al. 2002.


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Appendix 4
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows.
a.
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resolution imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
b.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:22847.
2
For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


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


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
Chest X-Ray.  Chest CT scan is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, particularly 
in identifying new lesions.  However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT scan or MRI scan (without IV contrast) will be used to 
evaluate the patient at baseline and during the study should be guided by the tumor type 
under investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after a baseline contrast CT scan is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) scan will be performed 
should also be based on the tumor type and the anatomic location of the disease 
and should be optimized to allow for comparison with the prior studies if possible.  
Each case should be discussed with the radiologist to determine if substitution of these 
other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward.  Care must be taken in measurement of target lesions on a 
different modality and interpretation of non-target disease or new lesions since the same 
lesion may appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.


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


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


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


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


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
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change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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Table 1
Timepoint Response:  Patients with Target Lesions (with or 
without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not 
all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
b.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen 


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


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


Appendix 4
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
152/Protocol GO30081, Version 7
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1Table 3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.


AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 5
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment.
Modified Response Evaluation Criteria in Solid Tumors (RECIST) is derived from 
RECIST, Version 1.1 (v1.1) conventions3, 4, 5 and immune-related response criteria5, 6, 7
(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.
                                           
3
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.
4
Topalian et al. Safety activity, and immune correlates of antiPD-L1 antibody in cancer. N Engl 
J Med 2012;366:244354.
5
Wolchok JD,  Hoos A, O’Day S, et al. Guidelines for the evaluation of immunetherapy activity 
in solid tumors: immune-related response criteria Clin Can Res 2009;15:741220.
6
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response 
assessment: does reducing the number of lesions impact response assessment in melanoma 
patients treated with ipilimumab. J Immunother Can 2014;2:17.
7
Nishino M, Giobbie-Hurder A, Gargano M et al. Developing a common language for tumor 
response to immuno therapy: immune-reated response criteria using unidimensional 
measurements. Clin Can Res 2013;19:393643.


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
154/Protocol GO30081, Version 7
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.  
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 


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
155/Protocol GO30081, Version 7
considered as 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 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-measurable 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.


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
156/Protocol GO30081, Version 7
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, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm but 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of 10 mm are considered non-pathological and should not be 
recorded or followed.
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions.
Non-Target Lesions
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required.
It is possible to record multiple non-target lesions involving the same organ as a single 
item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).
After baseline, changes in non-target lesions will contribute only in the assessment 
of CR (i.e., a CR is attained only with the complete disappearance of all tumor lesions, 
including non-target lesions) and will not be used to assess progressive disease.
New Lesions
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints. New lesions will also be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST, (e.g., nonlymph node lesions must be 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.


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
157/Protocol GO30081, Version 7
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. 
B.2 CALCULATION OF SUM OF THE DIAMETERS
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden.
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses.
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1.
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions selected at 
baseline and up to five new measurable lesions (with a maximum of two new lesions per 
organ) that have emerged after baseline will contribute to the sum of the diameters at 
tumor assessment.  Hence, each net percentage change in tumor burden per 
assessment with use of modified RECIST accounts for the size and growth kinetics of 
both old and new lesions as they appear.
Note:  In the case of new lymph nodes, RECIST v1.1 criteria for measurability 
(equivalent to baseline target lesion selection) will be followed.  That is, if at first 
appearance the short axis of a new lymph node lesion 15 mm, it will be considered a 
measureable new lesion and will be tracked and included in the SLD.  Thereafter, the 
lymph node lesion will be measured at subsequent timepoints and measurements will be 
included in the SLD, even if the short axis diameter decreases to 15 mm (or even 
10 mm).  However, if it subsequently decreases to 10 mm, and all other lesions are 
no longer detectable (or have also decreased to a short axis diameter of 10 mm if 
lymph nodes), then a response assessment of CR may be assigned.
If at first appearance the short axis of a new lymph node is 10 mm and 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion. It 
will not be included in the SLD unless it subsequently becomes measurable (short axis 
diameter 15 mm).
The appearance of new lymph nodes with diameter 10 mm should not be considered 
pathological and not considered a new lesion.


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
158/Protocol GO30081, Version 7
B.3 RESPONSE CRITERIA
Timepoint Response
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
Complete Response (CR):  Disappearance of all target and non-target lesions.  Lymph 
nodes that shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
Note: the appearance of new measurable lesions is factored into the overall tumor 
burden, but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and selected new measurable lesions, taking as reference the smallest sum on 
study (nadir SLD; this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution to 
total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response.
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is 
considered not evaluable (NE) at that timepoint.  If only a subset of lesion 
measurements are made at an assessment, usually the case is also considered NE at 
that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This 
would only happen in the case of PD.  For example, if a patient had a baseline sum of 
50 mm with three measured lesions and at follow-up only two lesions were assessed but 


Appendix 5
Modified Response Evaluation Criteria in Solid Tumors (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
159/Protocol GO30081, Version 7
those gave a sum of 80 mm, the patient will be assigned PD status, regardless of the 
contribution of the missing lesion.
Table 1
Modified RECIST Timepoint Response Definitions
% Change in Sum of the Diameters a
Non-Target Lesion 
Response 
Assessment
Overall Modified RECIST 
Timepoint Response
100% from baseline b
CR
CR
100% from baseline b
Non-CR or not all 
evaluated
PR
30% from baseline
Any
PR
30% to 20%
Any
SD
Not all evaluated
Any
NE
20%from nadir SLD
Any
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
RECIST Response Evaluation Criteria in Solid Tumors; SD stable disease; SLDsum of the 
longest diameter.
a Percent change in sum of the diameters (including measurable new lesions when present).
b When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if CR criteria are met, since a normal lymph node is 
defined as having a short axis of 10 mm.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 10 mm in order to meet the definition of 
CR.


AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 6
EORTC QLQ-C30


AtezolizumabF. Hoffmann-La Roche Ltd
161/Protocol GO30081, Version 7
Appendix 6
EORTC QLQ-C30 (cont.)


AtezolizumabF. Hoffmann-La Roche Ltd
162/Protocol GO30081, Version 7
Appendix 7
EORTC QLQ-LC13


AtezolizumabF. Hoffmann-La Roche Ltd
163/Protocol GO30081, Version 7
Appendix 8
EQ-5D-5L


AtezolizumabF. Hoffmann-La Roche Ltd
164/Protocol GO30081, Version 7
Appendix 8
EQ-5D-5L (cont.)


AtezolizumabF. Hoffmann-La Roche Ltd
165/Protocol GO30081, Version 7
Appendix 8
EQ-5D-5L (cont.)


AtezolizumabF. Hoffmann-La Roche Ltd
166/Protocol GO30081, Version 7
Appendix 9
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead


AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 10
Anaphylaxis Precautions
EQUIPMENT NEEDED

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, 
the following procedures should be performed:
1.
Stop the study drug infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.


AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 11
Preexisting Autoimmune Diseases
Subjects should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Subjects with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be subjects with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on thyroid replacement hormone therapy are 
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


AtezolizumabF. Hoffmann-La Roche Ltd
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Appendix 12
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-related 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-related 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-related 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 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
170/Protocol GO30081, Version 7
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary event, 
Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 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

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 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.
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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
171/Protocol GO30081, Version 7
HEPATIC EVENTS
Immune-related 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 or to 
baseline values. 
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 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
LFT liver function tests.
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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
172/Protocol GO30081, Version 7
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic injury. 

Initiate treatment with 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.
LFT liver function tests.
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-related 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
173/Protocol GO30081, Version 7
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with 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
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 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 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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
174/Protocol GO30081, Version 7
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with 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 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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
175/Protocol GO30081, Version 7
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and thyroid 
function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and thyroid 
function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-related 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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
176/Protocol GO30081, Version 7
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 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 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.

Investigate for diabetes.  If patient has Type 1 diabetes, treat as a 
Grade 3 event.  If patient does not have Type 1 diabetes, treat as 
per institutional guidelines.

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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
177/Protocol GO30081, Version 7
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone 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 corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone 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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
178/Protocol GO30081, Version 7
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor.
c

Refer patient to ophthalmologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.  

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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
179/Protocol GO30081, Version 7
IMMUNE-RELATED MYOCARDITIS
Immune-related myocarditis has been associated with the administration of atezolizumab.  
Immune-related myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
180/Protocol GO30081, Version 7
Table 6
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-related 
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 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 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-related 
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 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 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 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-related 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.
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) with Cycle 1 of atezolizumab 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
181/Protocol GO30081, Version 7
may receive premedication with antihistamines or antipyretics/analgesics (e.g., 
acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7.  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.
Table 7
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of event 
onset.

After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to the 
original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids).

After symptoms have resolved to baseline, resume infusion at half the 
rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids).

Permanently discontinue atezolizumab and contact Medical 
Monitor. a
IRR infusion-related reaction.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
182/Protocol GO30081, Version 7
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup 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
Amylase and/or lipase 1.52.0 ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone.
Asymptomatic with amylase and/or lipase 2.05.0 ULN:

Treat as a Grade 3 event.
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 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

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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
183/Protocol GO30081, Version 7
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-related pancreatitis, 
Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate 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 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-related pancreatitis, 
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate 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 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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
184/Protocol GO30081, Version 7
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of 
rash were mild in severity and self limited, with or without pruritus.  A dermatologist 
should evaluate persistent and/or severe rash or pruritus.  A biopsy should be considered 
unless contraindicated.  Management guidelines for dermatologic events are provided in 
Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, 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 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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
185/Protocol GO30081, Version 7
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup 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-related 
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-related 
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-related 
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 corticosteroids equivalent to 12 mg/kg/day 
oral or IV prednisone.
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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
186/Protocol GO30081, Version 7
IMMUNE-RELATED MENINGOENCEPHALITIS
Immune-related meningoencephalitis is an identified risk associated with the administration 
of atezolizumab.  Immune-related 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-Related Meningoencephalitis
Event
Management
Immune-related 
meningoencephalitis, all 
grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate 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 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-related 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-related nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal renal 
function should be evaluated and treated for other more common etiologies (including 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
187/Protocol GO30081, Version 7
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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
188/Protocol GO30081, Version 7
IMMUNE-RELATED MYOSITIS
Immune-related 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-Related Myositis
Event
Management
Immune-related 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-related 
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-related 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 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
189/Protocol GO30081, Version 7
Table 13
Management Guidelines for Immune-Related Myositis (cont.)
Immune-related 
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-related
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-related 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 12 
 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
190/Protocol GO30081, Version 7 
SYSTEMIC IMMUNE ACTIVATION 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk for atezolizumab. 
Recommendations regarding early identification and management of systemic immune 
activation are provided below.  In the event of suspected systemic immune activation, 
atezolizumab should be withheld and clinical specialists (e.g., rheumatology, clinical 
immunology, or solid organ or hematopoietic stem cell transplant specialists) and the 
Medical Monitor should be consulted for additional guidance. 
Early disease recognition is critical, and systemic immune activation should be suspected if, 
in the absence of an alternative etiology, the patient meets two or more of the following 
criteria: 
 
Hypotension that is refractory to aggressive IV fluid challenge 
Vasopressor support may be required. 
 
Respiratory distress that requires aggressive supportive care 
Supplemental oxygen and intubation may be required. 
 
Fever  38.5C 
 
Acute renal or hepatic failure 
 
Bleeding from coagulopathy 
 
Any of the following unexplained laboratory abnormalities (change from baseline):  
cytopenias (in two or more lineages), significant transaminitis, or coagulopathy 
 
For patients with suspected systemic immune activation, an initial evaluation should 
include the following: 
 
CBC with peripheral smear 
 
PT, PTT, fibrinogen, and D-dimer 
 
Ferritin 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) 
 
Triglycerides 
 
AST, ALT, and direct bilirubin 
 
LDH 
 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 


Appendix 12 
 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.) 
AtezolizumabF. Hoffmann-La Roche Ltd 
191/Protocol GO30081, Version 7 
Laboratory tests with normal results should be repeated frequently in patients for whom a 
high clinical suspicion of systemic immune activation exists. 
If neurologic abnormalities are present, consider cerebrospinal fluid analysis and/or an MRI 
of the brain. 
If cytopenias are present (Grade  2 in two or more lineages) or ferritin is  3000 ng/mL, the 
following evaluations should also be performed:   
 
Bone marrow biopsy and aspirate (assess for evidence of hemophagocytosis) 
 
Adenovirus, cytomegalovirus, Epstein-Barr virus, herpes-simplex virus, and human 
herpesvirus 6, 7, and 8 evaluation (for reactivated or active disease) 
 
Diagnostic criteria and recommended management for systemic immune activation are 
provided in Table 14.  The diagnostic criteria apply only when alternative etiologies have 
been excluded. 
An adverse event of systemic immune activation should be reported on the Adverse Event 
eCRF if it meets the criteria for "consistent with systemic immune activation" or "probable 
systemic immune activation" as outlined in Table 14. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
192/Protocol GO30081, Version 7
Table 14
Diagnostic Criteria and Recommended Management for Systemic 
Immune Activation
Systemic Immune Activation Diagnostic Criteria 
(applicable only when alternative etiologies have been excluded)
Major Criteria
Minor Criteria

Fever 38.5C on more than one occasion

Ferritin 3000 ng/mL

Cytopenias (Grade 2 in two or more 
lineages)

Age-adjusted soluble interleukin-2 receptor 
elevated by 2 standard deviations

Severe (Grade 3) or progressive dysfunction 
in two or more organs

Decreased fibrinogen

Splenomegaly 

Hemophagocytosis in bone marrow, spleen, or 
lymph nodes

Elevated -glutamyl transpeptidase (GGT) or liver 
function tests (AST, ALT, or direct bilirubin)

Elevated triglycerides

Elevated LDH

Decreased natural killer cell activity
Diagnosis and Management of Systemic Immune Activation
Number of Criteria
Diagnosis
Action to Be Taken
4 major criteria
Consistent 
with systemic 
immune 
activation
Permanently discontinue atezolizumab.
Consider treatment with an immunosuppressive agent 
(i.e., cytokine inhibitors) and IV corticosteroids 
(i.e., methylprednisolone 1 g once daily or equivalent, or 
dexamethasone 10 mg/m2 once daily if neurologic abnormalities 
are present).
Contact the Medical Monitor for additional recommendations.
Consider HLH-2004 protocol (Henter et al. 2007) if there is no 
clinical improvement.
3 major criteria
OR
2 major plus 
3 minor criteria
Probable 
systemic 
immune 
activation
Depending on clinical severity, follow guidelines for “Consistent 
with systemic immune activation” or “Possible systemic immune 
activation” diagnosis.
Clinical specialists and the Medical Monitor may be contacted for 
recommendations.
2 major plus 
2 minor criteria
OR
1 major plus 
4 minor criteria
Possible 
systemic 
immune 
activation
Withhold atezolizumab.
Consider treatment with IV corticosteroids.
Clinical specialists and the Medical Monitor may be contacted for 
additional recommendations.
Follow guidelines for “Consistent with systemic immune 
activation” diagnosis if there is no clinical improvement or if 
clinical worsening occurs.
If clinical improvement occurs, atezolizumab may be resumed 
following a benefit-risk assessment by the Medical Monitor.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
AtezolizumabF. Hoffmann-La Roche Ltd
193/Protocol GO30081, Version 7
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria in the 
positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 2014).
Grades are based on National Cancer Institute Common Terminology Criteria for Adverse Events.
These recommendations do not replace clinical judgment and are intended as suggested guidance.
REFERENCES
Hejblum G, Lambotte O, Galicier L, et al. A web-based Delphi study for eliciting helpful 
criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. PLoS 
ONE 2014;9(4):e94024. doi: 10.1371/journal.pone.0094024.
Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for 
hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:12431.


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO30081 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE I/III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF CARBOPLATIN PLUS 
ETOPOSIDE WITH OR WITHOUT ATEZOLIZUMAB 
(MPDL3280A, ANTI−PD-L1 ANTIBODY) IN PATIENTS WITH 
UNTREATED EXTENSIVE-STAGE SMALL CELL LUNG 
CANCER 
PROTOCOL NUMBER: 
GO30081 
STUDY DRUG: 
Atezolizumab 
VERSION NUMBER: 
3 
IND NUMBER: 
117296 
EUDRACT NUMBER: 
2015­004861-97 
SPONSOR: 
F. Hoffmann-La Roche Ltd. 
PLAN PREPARED BY: 
, Ph.D. 
DATE FINAL: 
1 December 2017 
DATE AMENDED: 
See electronic date stamp below 
Name                                                             Reason for Signing                              Date and Time
(UTC)
14-May-2018 19:00:15
Company Signatory




Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan GO30081 
 
TABLE OF CONTENTS 
 
1. 
BACKGROUND ............................................................................................ 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Protocol Synopsis .................................................................... 9 
2.2 
Outcome Measures ............................................................... 10 
2.2.1 
Primary Efficacy Outcome Measures .................................... 10 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 10 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 10 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures ...................... 11 
2.2.5 
Safety Outcome Measures .................................................... 11 
2.3 
Determination of Sample Size ............................................... 11 
2.4 
Interim and Final Analyses Timing ......................................... 14 
3. 
STUDY CONDUCT ..................................................................................... 14 
3.1 
Randomization ....................................................................... 14 
3.2 
Data Monitoring ..................................................................... 15 
4. 
STATISTICAL METHODS .......................................................................... 15 
4.1 
Analysis Populations ............................................................. 15 
4.1.1 
Intent-to-Treat Population ...................................................... 15 
4.1.2 
Pharmacokinetic-Evaluable Population ................................. 15 
4.1.3 
Safety Population .................................................................. 15 
4.2 
Analysis of Study Conduct ..................................................... 15 
4.3 
Analysis of Treatment Group Comparability .......................... 16 
4.4 
Efficacy Analysis .................................................................... 16 
4.4.1 
Primary Efficacy Endpoint ...................................................... 16 
4.4.1.1 Progression-Free Survival .................................................... 16 
4.4.1.2 Overall Survival .................................................................... 17 
4.4.2 
Secondary Efficacy Endpoints ............................................... 17 
4.4.2.1 Objective Response Rate ..................................................... 17 
4.4.2.2 Duration of Response ........................................................... 18 
4.4.2.3 Overall Survival Rate at 1 year and 2 years, and 
Progression-Free Survival Rate at 6 months and 1 year .................... 18 


Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan GO30081 
4.4.2.4 Patient-Reported Outcomes of Lung-Disease 
Related Symptoms ............................................................................. 19 
4.4.3 
Exploratory Efficacy Endpoints .............................................. 20 
4.4.3.1 Objective Response Rate, Duration of 
Response, and Progression-Free Survival per Immune-
Modified RECIST ................................................................................ 20 
4.4.3.2 Biomarker Analysis ............................................................... 21 
4.4.3.3 Patient-Reported Outcomes of Health-Related 
Quality of Life ..................................................................................... 21 
4.4.4 
Sensitivity Analyses ............................................................... 21 
4.4.5 
Subgroup Analyses ............................................................... 23 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 23 
4.6 
Safety Analyses ..................................................................... 24 
4.6.1 
Exposure of Study Medication ............................................... 24 
4.6.2 
Adverse Events ..................................................................... 24 
4.6.3 
Laboratory Data ..................................................................... 24 
4.6.4 
Vital Signs .............................................................................. 24 
4.6.5 
Anti-Drug Antibody ................................................................ 25 
4.7 
Missing Data .......................................................................... 25 
4.8 
Interim Analyses .................................................................... 25 
4.8.1 
Optional Interim Analysis ....................................................... 25 
5. 
 ....................................................... 25 
6. 
REFERENCES ........................................................................................... 26 
 
 
LIST OF TABLES 
Table 1 
Study GO30081 Treatment Arms .................................................. 8 
Table 2 
Power and Minimum Detectable Difference for the Proposed 
Design of Each Primary Endpoint ............................................... 13 
Table 3 
Analysis Timing and Stopping Boundary of Overall Survival....... 14 


Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan GO30081 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................... 7 
Figure 2 
Group Sequential Weighted Holm Procedure ............................. 12 
 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 27 
Appendix 2 
Schedule of Assessments ........................................................... 38 
Appendix 3 
Schedule of Pharmacokinetic, Pharmacodynamic, 
Biomarker, and Anti-Therapeutic Antibody Assessments ........... 44 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Statistical Analysis Plan GO30081 
1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) is based on Protocol GO30081 (IMpower133), “A 
Phase I/III, Randomized, Double-Blind, Placebo-Controlled Study of Carboplatin plus 
Etoposide with or without Atezolizumab (Anti−PD-L1 Antibody) in Patients with 
Untreated Extensive-Stage Small Cell Lung Cancer”.  This SAP provides details of the 
planned analyses and statistical methods for Study GO30081 to support potential 
registration for carboplatin plus etoposide with atezolizumab as first-line treatment for 
patients with extensive-stage small cell lung cancer (ES-SCLC).  The background for the 
study can be found in the study protocol.  Any analyses that are beyond those outlined in 
the protocol are delineated in this document. 
In this study, the global population will include all patients enrolled during the global 
enrollment phase 
 
 
 
 
 
 
2. 
STUDY DESIGN 
This is a randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study 
designed to evaluate the safety and efficacy of atezolizumab in combination with 
carboplatin + etoposide compared with placebo + carboplatin + etoposide in patients who 
have ES-SCLC and who are chemotherapy-naive for their extensive-stage disease.  
Figure 1 illustrates the study design. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Statistical Analysis Plan GO30081 
Figure 1 Study Schema 
 
ECOG PS = Eastern Cooperative Oncology Group performance status; SCLC = small cell lung 
cancer; RECIST = Response Evaluation Criteria in Solid Tumors. 
 
Eligible patients are stratified by sex (male vs. female), Eastern Cooperative Oncology 
Group (ECOG) performance status (0 vs. 1), and presence of brain metastases  


Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Statistical Analysis Plan GO30081 
(yes vs. no) and randomized 1:1 to receive one of the following treatment regimens as 
shown in Table 1. 
Table 1 
Study GO30081 Treatment Arms 
Treatment Arm 
Induction 
(Four 21-Day Cycles) 
Maintenance 
(21-Day Cycles) 
A 
atezolizumab + carboplatin + etoposide 
atezolizumab 
B 
placebo + carboplatin + etoposide 
placebo 
Induction treatment was administered on a 21-day cycle for four cycles. 
Following the induction phase, patients continued on maintenance therapy with either 
atezolizumab or placebo. 
 
Patients undergo tumor assessments at baseline and every 6 weeks (±7 days) for 
48 weeks following Cycle 1, Day 1, regardless of treatment dose delays.  After 
completion of the Week 48 tumor assessment, tumor assessments are required every 
9 weeks (±7 days) thereafter, regardless of treatment dose delays.  Patients will undergo 
tumor assessments until radiographic disease progression per Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), withdrawal of consent, study 
termination by the Sponsor, or death, whichever occurs first. 
Treatment is discontinued in all patients (in both treatment arms) who exhibit evidence of 
disease progression per RECIST v1.1.  However, patients may be considered for 
treatment beyond radiographic disease progression per RECIST v1.1, at the discretion 
of the investigator and after appropriate discussion with the patient and obtaining 
informed consent, only if all of the following criteria are met: 
• 
Evidence of clinical benefit as assessed by the investigator 
• 
No decline in ECOG performance status that can be attributed to disease 
progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
• 
Patients must provide written consent to acknowledge deferring other treatment 
options in favor of continuing study treatment at the time of initial progression 
Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 should be closely monitored clinically and with a follow-up scan in 6 weeks 
or sooner if symptomatic deterioration occurs.  Treatment should be discontinued if 
clinical deterioration due to disease progression occurs at any time, or if persistent 
disease growth is confirmed in a follow-up scan.  In addition, patients should be 
discontinued for unacceptable toxicity or for any other signs or symptoms of deterioration 
attributed to disease progression as determined by the investigator after an integrated 
assessment of radiographic data and clinical status. 


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Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 will continue to undergo tumor assessments every 6 weeks (±7 days), 
regardless of time in the study, or sooner if symptomatic deterioration occurs, until study 
treatment is discontinued. 
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 at the same frequency as would have been followed if the 
patient had remained on study treatment (i.e., every 6 weeks [±7 days] for 48 weeks 
following Cycle 1, Day 1 and then every 9 weeks [±7 days] thereafter, regardless of 
treatment dose delays) until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs first, 
regardless of whether patients start a new anti-cancer therapy. 
The co-primary efficacy endpoints are progression-free survival (PFS) as assessed by 
the investigator according to RECIST v1.1 and overall survival (OS).  See Section 2.2 for 
further details on the co-primary efficacy endpoints, as well as secondary and other 
safety, pharmacokinetic (PK), and exploratory endpoints. 
There are no interim analyses planned for PFS and one interim analysis planned for OS 
in this study.  See Section 2.4 for detailed analysis timing. 
An external independent Data Monitoring Committee (iDMC) was set up to evaluate 
safety data on an ongoing basis. 
 
 
 
 
 
 
 See Section 5 for more details. 
2.1 
PROTOCOL SYNOPSIS 
The protocol synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
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2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Outcome Measures 
The co-primary efficacy outcome measures for this study are: 
• 
PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator using RECIST v1.1 or death from any 
cause, whichever occurs first 
• 
OS, defined as the time from randomization to death from any cause 
 
2.2.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are: 
• 
Objective response (OR), defined as complete response (CR) or partial response 
(PR) as determined by the investigator according to RECIST v1.1 
• 
Duration of response (DOR), defined as the time interval from first occurrence of a 
documented objective response to the time of disease progression as determined 
by the investigator using RECIST v1.1 or death from any cause, whichever comes 
first 
• 
PFS rates at 6 months and at 1 year, defined as the proportion of patients who are 
alive without disease progression 6 months and 1 year after randomization, 
respectively 
• 
OS rates at 1 and 2 years, defined as the proportion of patients who are alive 1 year 
and 2 years after randomization, respectively 
• 
Time to deterioration (TTD) in patient-reported lung cancer symptoms, defined as 
time from randomization to deterioration (10-point change) on each of the European 
Organization for the Research and Treatment of Cancer (EORTC QLQ-C30) and 
supplemental lung cancer module (QLQ-LC13) symptom subscales maintained for 
two assessments or one assessment followed by death from any cause within 
3 weeks 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
The exploratory efficacy outcome measures for this study are: 
• 
OR, PFS, and DOR as determined by the investigator according to 
immune-modified RECIST 
• 
Status of blood-based tumor mutational burden (bTMB), immune-, and SCLC-
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 
• 
Change from baseline in patient-reported outcome (PROs) of health-related quality 
of life, lung cancer−related symptoms, physical functioning, and health status as 
assessed by the EORTC QLQ-C30 and QLQ-LC13 


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• 
Changes in levels and type of peripheral and tumor-specific T-cell populations 
during and after induction therapy and its relationship to efficacy and safety 
outcomes 
 
2.2.4 
Pharmacokinetic Efficacy Outcome Measures 
The PK outcome measures for this study are: 
• 
Maximum observed serum atezolizumab concentration (Cmax) after infusion  
• 
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at 
selected cycles, at treatment discontinuation, and at 120 days (± 30 days) after the 
last dose of atezolizumab 
• 
Plasma concentrations for carboplatin  
• 
Plasma concentrations for etoposide 
 
2.2.5 
Safety Outcome Measures 
The safety outcome measures for this study are: 
• 
Incidence, nature, and severity of adverse events graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 4 
(NCI CTCAE v4.0) 
• 
Changes in vital signs, physical findings, and clinical laboratory results during and 
following study treatment administration 
• 
Incidence of anti-drug antibody (ADA) response to atezolizumab and potential 
correlation with PK, safety, and efficacy 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
Determination of sample size is based on patients enrolled during the global enrollment 
phase of this study to the atezolizumab + carboplatin + etoposide arm and the 
placebo + carboplatin + etoposide arm in a 1:1 ratio.  This study plans to randomize 
400 patients during the global enrollment phase. 
 
 
 
 
To control the overall two-sided type I error rate at 0.05 in the analyses of patients 
enrolled during the global enrollment phase, a group sequential weighted Holm 
procedure (Ye et al. 2011) will be used wherein the two-sided significance levels of 
0.005 and 0.045 are allocated to the primary comparisons for PFS and OS, respectively.  
If PFS in the intent-to-treat (ITT) population is statistically significant at the two-sided 
α level of 0.005, OS in the ITT population will be tested at a two-sided α level of 0.05.  
Additionally, if OS in the ITT population is statistically significant at the two-sided α level 
of 0.045, PFS in the ITT population will be tested at a two-sided α level of 0.05.  The 
overview of the type I error rate control strategy is shown in Figure 2. 


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Atezolizumab—F. Hoffmann-La Roche Ltd 
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Table 2 
Power and Minimum Detectable Difference for the Proposed 
Design of Each Primary Endpoint 
Primary 
Endpoint 
Expected No. 
of Events 
Target HR 
Two-Sided Type I 
Error 
Power 
MDD HR 
PFS 
295 
0.55 
0.005 
99% 
0.721 
PFS 
295 
0.55 
0.05 
99.9% 
0.796 
OS 
306 
0.68 
0.045 
91% 
0.790 a 
OS 
306 
0.68 
0.05 
92% 
0.794 a 
HR = hazard ratio; MDD = minimum detectable difference; PFS = progression-free survival; 
OS = overall survival. 
a At final analysis conditional on interim analysis with 78% information fraction. 
 
Sample Size 
 
After approximately 400 patients had been randomized into the study, the global 
enrollment will be closed.  
 
 
 
  
 
 
 
 
 
 
 


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2.4 
INTERIM AND FINAL ANALYSES TIMING 
There will be no interim analyses planned for PFS in this study. 
One interim efficacy analysis of OS is planned for when approximately 240 OS events 
have been observed.  The primary analysis of PFS will be conducted at the same time 
as the interim OS analysis, and the exact timing of the analysis depends on when 
240 OS events in the ITT population have occurred. 
The final OS analysis will be conducted when approximately 306 OS events in the 
ITT population have been observed.  This is expected to occur approximately 36 months 
after the first patient is randomized, but the exact timing of this analysis will depend on 
the actual number of OS events. 
To control the type I error for OS, the stopping boundaries for the OS interim and final 
analyses are to be computed with use of the LanDeMets approximation to the 
O’Brien-Fleming boundary (DeMets and Lan 1994) as shown in Table 3. 
Table 3 
Analysis Timing and Stopping Boundary of Overall Survival 
Analysis Timing 
Information 
Fraction 
(Number of 
Events) 
Estimated 
Stopping Boundary in HR  
(two-sided p-value) 
Time from 
First Patient 
In (months) 
PFS is Statistically 
Significant 
PFS is Not 
Statistically 
Significant 
OS interim analysis 
78.4% (240) 
25 
HR≤0.7453 
(p≤0.0228) 
HR≤0.7405 
(p≤0.02) 
OS final analysis 
100% (306) 
36 
HR≤0.7937 
(p≤0.0433) 
HR≤0.7899 
(p≤0.039) 
HR = hazard ratio; OS = overall survival; PFS = progression-free survival. 
 
 
 
 
 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Eligible patients will be randomized in a 1:1 ratio to receive either 
atezolizumab+carboplatin+etoposide or placebo+carboplatin+etoposide with the use of a 
stratified permuted-block randomization.  The randomization will be stratified for the 
following factors: 
• 
Sex (male vs. female) 


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• 
ECOG performance status (0 vs. 1) 
• 
Presence of brain metastases (yes vs. no) 
 
The same randomization method is implemented for the 
 
3.2 
DATA MONITORING 
An iDMC has been used to evaluate safety during the study on a regular basis.  All 
summaries and analyses by treatment arm for the iDMC review are prepared by an 
external independent Data Coordinating Center.  Members of the iDMC are external 
to the Sponsor and follow a separate iDMC Charter that outlines their roles and 
responsibilities, as well as a detailed monitoring plan.  Refer to the iDMC Charter 
for further details. 
4. 
STATISTICAL METHODS  
The analyses described in this SAP will override those specified in Protocol GO30081. 
 
 
 
 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The ITT population is defined as all randomized patients, regardless of whether the 
patient has received the assigned treatment.  ITT patients will be analyzed according to 
the treatment assigned at randomization by the interactive voice/Web response system 
(IxRS). 
4.1.2 
Pharmacokinetic-Evaluable Population 
PK analyses will be based on PK observations from all patients who have received 
atezolizumab, carboplatin, or etoposide treatment and who have provided at least one 
evaluable PK sample. 
4.1.3 
Safety Population 
The safety population is defined as patients who received any amount of study treatment.  
Patients who received any amount of atezolizumab will be analyzed as part of Arm A 
even if atezolizumab was given in error.  Patients who were randomized to the study but 
did not receive any study drug will not be included in the safety population. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Enrollment, major protocol deviations (including major deviations of inclusion and/or 
exclusion criteria), and reasons for discontinuation from the study will be summarized 
by treatment arm for the ITT population.  Study treatment administration and reasons 


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for discontinuation from study treatment will be summarized by treatment arm for the 
safety population. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics, such as age and race/ethnicity, and baseline disease 
characteristics, current disease status, and stratification factors (i.e., sex, ECOG 
performance status, and brain metastases), will be summarized by treatment arm for the 
ITT population. 
Baseline values are the last available data obtained prior to a patient receiving the 
first dose of any study treatment on Cycle 1, Day 1 visits unless otherwise noted.  
Descriptive statistics (mean, median, SD, range) will be presented for continuous 
variables, and frequencies and percentages will be presented for categorical variables. 
4.4 
EFFICACY ANALYSIS 
The primary PFS and OS analyses will be conducted on the ITT population.  
 
  
Patients will be grouped according to the treatment assigned at randomization by IxRS.  
Analysis populations for other efficacy endpoints will be described in later sections.  
The stratification factors will be those used for randomization from the IxRS (i.e., sex, 
ECOG performance status, and brain metastases).  
 
(
 if at least one stratum (i.e., a combination of 
stratification factor levels across sex [male vs female], ECOG performance status [0 vs 
1], and brain metastasis [Yes vs No] per IxRS) has less than 10 events (PFS or OS 
events), the stratification factor (one of 3 stratification factors: sex, ECOG performance 
status, and brain metastasis per IxRS) which contains the level with the smallest number 
of patients will be removed from the stratified analyses.  The removal of the stratification 
factor will continue until there is no stratum with less than 10 events (PFS or OS events).  
The final set of stratification factors used in stratified analyses will be applied to all 
endpoints where stratified analyses are planned.  Analyses based on stratification 
factors recorded on the electronic Case Report Form (eCRF) will also be provided if 
considerable discrepancy is observed between IxRS and eCRF records. 
4.4.1 
Primary Efficacy Endpoint 
4.4.1.1 
Progression-Free Survival 
One of the co-primary endpoints for this study is PFS.  PFS is defined as the time from 
randomization to the first occurrence of disease progression as determined by the 
investigator using RECIST v1.1 or death from any cause, whichever occurs first.  
Patients who have not experienced disease progression or death at the time of analysis 
will be censored at the time of the last tumor assessment.  Patients with no 
post-baseline tumor assessment will be censored at the date of randomization plus 
1 day. 


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Treatment comparisons will be based on the stratified log-rank test.  If the null 
hypothesis of the OS testing is rejected at a two-sided significance level of 0.045, PFS 
will be tested at the two-sided significance level of 0.05.  Otherwise, PFS will be tested 
at the two-sided significance level of 0.005. 
The null and alternative hypotheses can be phrased in terms of the survival functions 
SPFS_A (t) and SPFS_B (t) in Arm A and Arm B, respectively: 
H0:  SPFS_A (t) = SPFS_B (t) versus H1:  SPFS_A (t)  ≠ SPFS_B (t) 
Kaplan-Meier methodology will be used to estimate median PFS for each treatment 
arm and to construct survival curves for each treatment arm.  The Brookmeyer-Crowley 
methodology and log-log transformation for normal approximation will be used 
to construct the 95% CI for the median PFS for each treatment arm 
(Brookmeyer and Crowley 1982). 
The HR, λPFS_A/λPFS_B, where λPFS_A and λPFS_B represent the hazard of the PFS event in 
Arm A and Arm B, respectively, will be estimated with a stratified Cox regression model 
and the same stratification variables used for the stratified log-rank test and the 95% CI 
will be estimated by normal approximation. 
Results from an unstratified analysis will also be provided. 
4.4.1.2 
Overall Survival 
The other co-primary endpoint for this study is OS, which is defined as the time from 
randomization to death from any cause.  Patients who are not reported as having died 
will be censored at the date when they were last known to be alive.  Patients who do not 
have post-baseline information will be censored at the date of randomization plus 1 day. 
OS will be analyzed with the same methodologies as PFS.  Treatment comparisons will 
be based on the stratified log-rank test, and as described in Section 2.3, if the null 
hypothesis of the PFS testing is rejected at a two-sided significance level of 0.005, 
OS will be tested at the two-sided significance level of 0.05.  Otherwise, OS will be 
tested at the two-sided significance level of 0.045.  As described in Section 2.4, two 
analyses for OS are planned, including one interim analysis.  If the two-sided p-value 
corresponding to the stratified log-rank test is less than or equal to the two-sided level of 
significance at the corresponding analysis, the null hypothesis will be rejected.  The null 
and alternative hypotheses can be phrased in terms of the survival functions SOS_A (t) 
and SOS_B (t) in Arm A and Arm B, respectively: 
H0:  SOS_A (t) = SOS_B (t) versus H1:  SOS_A (t) ≠ SOS_B (t) 
 
4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients who had an 
objective response by the investigator using RECIST v1.1.  The analysis population for 
ORR will be all randomized patients with measurable disease at baseline.  An estimate 


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of ORR and its 95% CI will be calculated with the Clopper Pearson method (Clopper and 
Pearson 1934) for each treatment arm.  CIs for the difference in ORRs between the two 
treatment arms will be determined with use of the normal approximation to the binomial 
distribution. 
Confirmation of response according to RECIST v1.1 will not be required, but for the 
exploratory purposes, ORR with confirmation will be reported as needed. 
4.4.2.2 
Duration of Response 
DOR will be assessed for patients who had an objective response as determined by the 
investigator using RECIST v1.1.  Patients whose disease has not progressed and who 
have not died at the time of analysis will be censored at the time of last tumor 
assessment date.  If no tumor assessments were performed after the date of the first 
occurrence of a CR or PR, DOR will be censored at the date of the first occurrence of a 
CR or PR plus 1 day.  DOR is based on a non-randomized subset of patients 
(specifically, patients who achieved an objective response); therefore, formal hypothesis 
testing will not be performed for this endpoint.  Comparisons between treatment arms 
will be made for descriptive purposes.  The methodologies detailed for the PFS analysis 
will be used for the DOR analysis. 
4.4.2.3 
Overall Survival Rate at 1 year and 2 years, and 
Progression-Free Survival Rate at 6 months and 1 year 
The OS rates at 1 and 2 years will be estimated with the use of Kaplan-Meier 
methodology for each treatment arm, along with 95% CIs calculated with the standard 
error derived from Greenwood’s formula.  The 95% CI for the difference in OS rates 
between the two treatment arms will be estimated with the normal approximation method. 
Similar analyses will be performed for the PFS rates at 6 months and 1 year after 
randomization. 


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4.4.2.4 
Patient-Reported Outcomes of Lung-Disease Related 
Symptoms 
PROs of HRQoL, lung cancer−related symptoms will be measured using EORTC QLQ-
C30 and EORTC QLQ-LC13. 
The ITT population will be used for TTD analyses and to document completion rates. 
Missing PRO scores will not be imputed.  Patients whose symptoms have not 
deteriorated before the last PRO assessment is completed will be censored at the date 
of the last PRO assessment.  Patients with no baseline assessment or post-baseline 
assessments will be censored at the date of randomization plus 1 day. 
TTD according to the EORTC QLQ-C30 and EORTC QLQ-LC13 measures will be 
evaluated in each of the following linearly transformed symptom scores:  cough, 
dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain.  
The linear transformation gives each individual symptom subscale a possible score of 
0 to 100.  For the symptom to be considered “deteriorated,” a score increase of ≥ 10 
points above baseline must be held for at least two consecutive assessments or an initial 
score increase of ≥10 points is followed by death within 3 weeks from the last 
assessment.  A ≥ 10-point change in the symptoms subscale score is perceived by 
patients as clinically significant (Osoba et al. 1998).  The methodologies outlined for the 
analysis of PFS will be used for the analyses of TTD of the pre-specified symptoms of 
the EORTC QLQ-C30 and EORTC QLQ-LC13 measures.  The estimated Kaplan-Meier 
plots will be provided for each symptom separately. 
In the ITT population, completion rates will be summarized by number and proportion of 
patients among those expected to complete the QLQ-C30 at each time point.  If 
collected, reasons for non-completion will be summarized at each time point by 
treatment arm. 
In addition, to interpret lung-disease related symptoms evolution over time and further 
support the clinical findings regarding delay in symptom deterioration, the following may 
be documented in population with all randomized patients with a non-missing baseline 
assessment and at least one non-missing post-baseline assessment until treatment 
discontinuation: 
• 
The mean change in symptom scores from baseline at each timepoint including end 
of treatment, and disease progression.  Repeated measures mixed-effect model will 
be used for comparing the aforementioned symptoms scale scores between 
treatment arms.  The model will include a term for intercept, a term for linear time 
trend, a term for treatment group, and a term of treatment-by-time interaction. 
Repeated measured over time will be accounted for by unstructured covariance 
structure.  
• 
The number and proportion of patients with a clinically meaningful change will be 
summarized by treatment arm for each of the symptom scores aforementioned, The 
95% CI around the proportion will be calculated using the Clopper-Pearson method 


Atezolizumab—F. Hoffmann-La Roche Ltd 
20/Statistical Analysis Plan GO30081 
for each treatment arm.  The difference in proportions between the two treatment 
arms will be presented with a two-sided 95% CI based on a normal approximation to 
the binomial distribution. 
• 
Cumulative distribution function (CDF) curves by treatment arm may be generated 
and used to evaluate absolute change in scores from baseline to RECIST-defined 
disease progression. 
4.4.3 
Exploratory Efficacy Endpoints 
4.4.3.1 
Objective Response Rate, Duration of Response, and 
Progression-Free Survival per Immune-Modified RECIST 
Analyses using immune-modified RECIST criteria (see Appendix 4 of the 
Protocol GO30081 for further details) for ORR, DOR, and PFS, as determined by the 
investigator, will also be conducted (for atezolizumab-treated patients only).  
Comparisons between the treatment arms will not be made. 
PFS by immune-modified RECIST is defined as the time from randomization to disease 
progression as determined by the investigator per immune-modified RECIST or death 
from any cause, whichever occurs first.  A patient is considered to have disease 
progression by immune-modified RECIST if either of the following conditions were met: 
a) Immune-modified RECIST for progression was met at a tumor assessment and no 
subsequent tumor assessment was performed. 
b) Immune-modified RECIST for progression was met at a tumor assessment, and at 
the subsequent tumor assessment, the criteria for progression by immune-modified 
RECIST were also met, i.e., confirmed. 
 
For patients who meet criterion a), the date of progression is the date of the tumor 
assessment that meets the criteria by immune-modified RECIST.  For patients who meet 
criterion b), the date of progression is the date of the tumor assessment at which the 
immune-modified RECIST for progression was first met.  Patients who did not meet 
either of these criteria are not considered to have had disease progression by 
immune-modified RECIST. 
The investigator-assessed ORR is defined as the proportion of patients whose best 
overall response is either a PR or CR per immune-modified RECIST. 
For patients who experienced objective response (CR or PR per immune-modified 
RECIST) as assessed by the investigator, DOR is defined as the time from the first 
tumor assessment that supports the patient’s objective response (CR or PR, whichever 
is recorded first) to disease progression per immune-modified RECIST or death from any 
cause, whichever occurs first.  Data for patients who are alive and who have not 
experienced disease progression at the time of analysis will be censored at the last 
tumor assessment date. 


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The methods outlined for the primary and secondary efficacy endpoint analyses to 
estimate the median PFS or ORR for each treatment arm will be used for these analyses. 
4.4.3.2 
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 bTMB using the cut-offs of 
≥10 and ≥16 separately (given data availability), and CD8, as defined by 
immunohistochemistry (IHC), quantitative reverse transcriptase−polymerase chain 
reaction (qRT−PCR), or other methods.  Additional pharmacodynamic analyses of 
predictive, prognostic, and 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 will be conducted as appropriate.  These exploratory 
analyses may be provided in a separate report. 
4.4.3.3 
Patient-Reported Outcomes of Health-Related Quality of Life 
Additional PROs of health-related quality of life (Global Health Status score), function 
(Physical function and Role function), and symptoms (i.e., Fatigue, Haemoptysis, Sore 
mouth, Peripheral neuropathy, Pain in chest, Pain in arm or shoulder and Pain in other 
parts), assessed according to the EORTC QLQ-C30 and EORTC QLQ-LC13 will be 
scored according to the EORTC scoring manual guidelines.  
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) and the 
mean change from baseline of linear-transformed scores will be reported for the 
aforementioned scales and scales detailed in Section 4.4.2.4). 
Similar longitudinal analyses (change from baseline and number and proportion of 
patients with a clinically meaningful change as described in Section 4.4.2.4) will be 
performed on patients with a non-missing baseline assessment and at least one non-
missing post-baseline assessment will be included in the analyses.  Missing PRO scores 
will not be imputed. 
4.4.4 
Sensitivity Analyses 
Impact of Missing Scheduled Tumor Assessments on Primary PFS 
The impact of missing scheduled tumor assessments on PFS will be assessed 
depending on the number of patients who missed consecutive assessments scheduled 
immediately prior to the date of disease progression per RECIST v1.1 or death.  If > 5% 
of patients missed two or more consecutive assessments scheduled immediately prior to 
the date of disease progression per RECIST v1.1 or death in any treatment arm, the 
following two sensitivity analyses may be performed: 
• 
Patients who missed two or more consecutive assessments scheduled immediately 
prior to the date of disease progression per RECIST v1.1 or death will be censored 
at the last tumor assessment prior to the first missed visit.  


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• 
Patients who missed two or more consecutive assessments scheduled immediately 
prior to the date of disease progression per RECIST v1.1 or death will be counted 
as having progressed on the date of the first of these missing assessments.  
The imputation rule will be applied to patients in both treatment arms. 
Impact of Non−Protocol-Specified Anti-Cancer Therapy 
The impact of non−protocol-specified anti-cancer therapy on PFS determined by the 
investigator may 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, patients who received non−protocol-specified anti-cancer therapy before 
a PFS event will be censored at the last tumor assessment date before they received 
non−protocol-specified anti-cancer therapy in PFS analyses that may be performed for 
the comparisons between treatment arms. 
The impact of subsequent NPT on OS may be assessed depending on the number of 
patients who received NPT.  If > 10% of patients received an NPT in the control arm, the 
following analysis may be performed to compare treatment arms. 
The discount method uses a “discounted” survival time after switching for patients who 
switch treatments based on a user-specified assumption for the effect on OS.  OS will be 
discounted in accordance with a range of possible effects on OS of the subsequent NPT 
after treatment switching occurred (e.g., 10%, 20%, 30%).  After adjustments are made 
for the effect of subsequent non−protocol-specified immunotherapy or anti-cancer 
therapy on OS, the methods outlined for the primary efficacy endpoint analyses will be 
used for these analyses. 
Delayed Clinical Effect 
If a delayed separation of the PFS and/or OS Kaplan-Meier curves is observed at the 
beginning of the curves and the delay is ≥3 months, the following analyses may be 
conducted to assess a potential delayed clinical effect for the treatment group.  The 
delayed clinical effect sensitivity analyses may not be included in the CSR.  
Milestone Analysis 
To assess the potential effect delayed clinical effects, a milestone analysis may be 
conducted (Chen 2015).  The milestone time points will be chosen such that the patients 
included in the analysis will achieve a certain patient-event ratio. 
The milestone analysis will be conducted only when the milestone duration has elapsed 
from the time the last patient entered the study, using the same methods as those 
specified for the primary analysis. 


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Restricted Mean Survival Time 
 
The restricted mean survival time (RMST) may be computed using the area under the 
curve from baseline to several timepoints.  RMST will be computed for each treatment 
arm and the difference with its 95% CI will be displayed. 
Weighted Log-Rank Analysis 
Where the delayed clinical effect is > 10% of the median time of the control group, an 
analysis may be performed using the weighted log-rank test based on the Rho-Gamma 
weight function family (Fleming and Harrington 1991) or piece-wise linear weight 
functions (Lin and Leon 2017) that weight more heavily on late events to account for the 
delayed clinical effect (Fine 2007).  In addition, hazard ratio estimates based on the 
corresponding Cox model (Lin and Leon 2017) using the piece-wise linear weight 
functions may also be provided to enhance clinical interpretation of the treatment effect 
that varies over time. 
Lost to Follow-Up 
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  If > 5% of patients are lost to follow-up for OS in either 
treatment arm, a sensitivity analysis will be performed for the comparisons between two 
treatment arms in which patients who are lost to follow-up will be considered as having 
died at the last date they were known to be alive. 
4.4.5 
Subgroup Analyses 
To assess the consistency of the study PFS and OS results, results in subgroups will be 
examined. The following subgroups will be considered: 
• 
Demographics (e.g., age, sex, and race/ethnicity etc) 
• 
Baseline prognostic characteristics (e.g., sex, ECOG performance status, smoking 
status, presence of brain metastases etc) 
Summaries of PFS and OS, including unstratified HRs estimated from Cox proportional 
hazards models, will be displayed in a forest plot (Lewis and Clarke 2001).  
Kaplan-Meier estimates of median PFS and OS will be produced separately for each 
level of the categorical variables for the comparisons between treatment arms. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
PK analyses will be performed for the pharmacokinetic-evaluable population.   
PK samples will be collected in this study as outlined in Appendix 3.  Atezolizumab 
serum concentration data (Cmin and Cmax) will be tabulated and summarized.  Descriptive 
statistics will include means, medians, ranges, and SDs, as appropriate. 
Plasma concentrations of carboplatin and etoposide will be collected in this study as 
outlined in Appendix 3.  The concentrations of carboplatin and etoposide will be 
summarized using descriptive statistics as described above. 


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Additional PK analyses will be conducted as appropriate, on the basis of the availability 
of data.  These additional PK analyses may not be included in the CSR. 
4.6 
SAFETY ANALYSES 
Unless specified otherwise, safety analyses described in this section will be conducted 
for the safety population, with patients grouped according to whether they received any 
atezolizumab treatment (i.e., patients who received any dose of atezolizumab will be 
included in the atezolizumab arm for the safety analyses). 
4.6.1 
Exposure of Study Medication 
Study drug exposure statuses, which include treatment duration, number of cycles, and 
dose intensity, will be summarized for each treatment arm with descriptive statistics. 
4.6.2 
Adverse Events 
Verbatim description of adverse events will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded by the investigator 
according to NCI CTCAE v4.0.  Treatment-emergent adverse events will be summarized 
by mapped term, appropriate thesaurus level, NCI CTCAE grade, and treatment arm.  In 
addition, serious adverse events, severe adverse events (Grade ≥ 3), adverse events of 
special interest, immune-related adverse events, and adverse events leading to study 
drug discontinuation or interruption will be summarized accordingly.  Multiple 
occurrences of the same event will be counted once at the maximum grade. 
For reporting purposes, “treatment emergent” is defined as adverse events occurring on 
or after the first dose of study drug is administered until the clinical cutoff date. 
All safety analyses of adverse events will also include all adverse events with onset on 
or after the first study drug treatment until the clinical cutoff date. 
Deaths reported during the study treatment period and the follow-up period after 
treatment completion and/or discontinuation will be summarized by treatment arm. 
4.6.3 
Laboratory Data 
Laboratory data will be summarized by treatment arm.  Values outside the normal 
ranges will be summarized by treatment arm.  In addition, selected laboratory data will 
be summarized by treatment arm and NCI CTCAE grade according to NCI CTCAE 
grade v4.0. 
4.6.4 
Vital Signs 
Changes in selected vital signs will be summarized by treatment arm and by change 
over time, which includes change from baseline.  Baseline is defined as the 
measurement obtained on Cycle 1, Day 1 before the first dose of study drug is 
administered. 


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4.6.5 
Anti-Drug Antibody 
Incidence of ADA against atezolizumab will be summarized.  The analyses of 
pharmacokinetics, key efficacy, and safety by ADA status will be conducted to explore 
the potential impact of immunogenicity. 
4.7 
MISSING DATA 
See Section 4.4.3.3  and Section 4.6 for methods for handling missing data for the 
primary and secondary endpoints. 
4.8 
INTERIM ANALYSES 
Please refer to Section 2.4 for details of planned interim analysis. 
4.8.1 
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 2.4.  Below are the specifications in place to 
ensure the study continues to meet the highest standards of integrity when an optional 
interim analysis is executed. 
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be amended in this SAP, and the SAP will be 
submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis. 
5. 
 
 
 
 
 
 
 
 
 
 
 
 


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6. 
REFERENCES 
Akazawa K, Nakamura T, Palesch Y. Power of Logrank Test and Cox Regression Model 
in Clinical Trials with Heterogeneous Samples. Statistics in Medicine 
1997;16:583-97. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29−41. 
Chen TT. Milestone survival: a potential intermediate endpoint for immune checkpoint 
inhibitors. J Natl Cancer Inst 2015;107:djv156. 
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika 1934;26:404−13. 
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341−52. 
Fine GD. Consequences of delayed treatment effects on analysis of time-to-event 
endpoints. Ther Innov Regul Sci 2007;41:535−9. 
Fleming TR, Harrington DP. Counting processes and survival analysis. New York: John 
Wiley & Sons, 1991. 
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479−80. 
Lin R, Leon L. Estimation of treatment effects in weighted log-rank tests. Contemporary 
Clinical Trials Communications 8 (2017) 147–155 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:139−44. 
Ye Y, Li A, Liu L, et al. A group sequential Holm precedure with multiple primary 
endpoints. Stat in Med 2011; 32(7):1112-24. doi: 10.1002/sim.5700


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Appendix 1  
Protocol Synopsis 
TITLE: 
A PHASE I/III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF CARBOPLATIN PLUS 
ETOPOSIDE WITH OR WITHOUT ATEZOLIZUMAB (ANTI−PD-L1 
ANTIBODY) IN PATIENTS WITH UNTREATED 
EXTENSIVE-STAGE SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
GO30081 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2015­004861-97 
IND NUMBER: 
117296 
TEST PRODUCT: 
Atezolizumab (MPDL3280A, RO5541267) 
PHASE: 
I/III 
INDICATION: 
Small cell lung cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
The following objective statements apply to the global enrollment phase
 
Efficacy Objectives 
Primary Efficacy Objectives 
The co-primary objectives of this study are the following: 
• 
To evaluate the efficacy of atezolizumab + carboplatin + etoposide compared with 
placebo + carboplatin + etoposide in the intent-to-treat (ITT) population as measured by 
investigator-assessed progression-free survival (PFS) according to Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v1.1) 
• 
To evaluate the efficacy of atezolizumab + carboplatin + etoposide compared with 
placebo + carboplatin + etoposide in the ITT population as measured by overall survival (OS) 
 
Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are: 
• 
To evaluate the efficacy of atezolizumab + carboplatin + etoposide compared with 
placebo + carboplatin + etoposide in the ITT population as measured by 
investigator-assessed objective response rate (ORR) according to RECIST v1.1 
• 
To evaluate the efficacy of atezolizumab + carboplatin + etoposide compared with 
placebo + carboplatin + etoposide in the ITT population as measured by 
investigator-assessed duration of response (DOR) according to RECIST v1.1  
• 
To evaluate the PFS rate at 6 months and at 1 year in each treatment arm for the ITT 
population 
• 
To evaluate the OS rate at 1 and 2 years in each treatment arm for the ITT population 


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• 
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, arm/shoulder pain, or fatigue using the European Organization for 
the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire−Core 
30 (QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) in patients treated 
with atezolizumab + carboplatin + etoposide compared with placebo + carboplatin + etoposide 
in the ITT population 
 
Safety Objectives 
The safety objectives for this study are: 
• 
To evaluate the safety and tolerability of atezolizumab in combination with 
carboplatin + etoposide compared with carboplatin + etoposide 
• 
To evaluate the incidence and titers of anti-drug antibodies (ADAs; equivalent to ATA) 
against atezolizumab and to explore the potential relationship of the immunogenicity 
response with pharmacokinetics, safety, and efficacy 
 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of 
atezolizumab, carboplatin, and etoposide in chemotherapy-naive patients with extensive-stage 
small cell lung cancer (ES-SCLC). 
Exploratory Objectives 
The exploratory objectives for this study are: 
• 
To evaluate investigator-assessed PFS, ORR, DCR, DOR, TIR, and TTR according to 
modified RECIST for the atezolizumab-containing treatment arm in the ITT population 
• 
To evaluate the relationship between tumor biomarkers (including but not limited to PD-L1, 
programmed death-1 (PD-1), somatic mutations, and others), as defined by 
immunohistochemistry (IHC) or quantitative reverse transcriptase−polymerase chain 
reaction (qRT-PCR), next generation sequencing (NGS), and/or other methods and 
measures of efficacy  
• 
To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival 
and/or fresh tumor tissue, blood, plasma and serum and their association with disease 
status, mechanisms of resistance, and/or response to study treatment 
• 
To evaluate and compare patient’s health status as assessed by the EuroQoL 
5 Dimensions 5-Level (EQ-5D-5L) questionnaire to generate utility scores for use in 
economic models for reimbursement 
• 
To determine the impact of atezolizumab + carboplatin + etoposide compared with 
placebo + carboplatin + etoposide as measured by change from baseline in patient-reported 
outcomes (PRO) of health-related quality of life, lung cancer−related symptoms, physical 
functioning, and health status as assessed by the EORTC QLQ-C30 and LC13 
• 
To evaluate the impact of chemotherapy (both carboplatin and etoposide) on peripheral and 
tumor-specific T-cell populations during and after induction therapy and its relationship to 
efficacy and safety outcomes 
 
Study Design 
Description of Study 
This is a randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study 
designed to evaluate the safety and efficacy of atezolizumab in combination with 
carboplatin + etoposide compared with treatment with placebo + carboplatin + etoposide in 
patients who have ES-SCLC and are chemotherapy-naive for their extensive-stage disease.   
Eligible patients will be stratified by sex (male vs. female), Eastern Cooperative Oncology Group 
(ECOG) performance status (0 vs. 1), and presence of brain metastases (yes vs. no) and 
randomized 1:1 to receive one of the following treatment regimens:  A) 
atezolizumab + carboplatin ± etoposide or B) placebo + carboplatin + etoposide. 


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Induction treatment will be administered on a 21-day cycle for four cycles. 
Following the induction phase, patients will continue maintenance therapy with either 
atezolizumab or placebo.  During the maintenance phase, prophylactic cranial irradiation is 
permitted as per local standard-of-care and will be reported on the Prophylactic Cranial 
Irradiation electronic Case Report Form (eCRF).  Thoracic radiation with curative intent or the 
intent to eliminate residual disease is not permitted.  Palliative thoracic radiation is allowed.    
Treatment should be discontinued in all patients (in both treatment arms) who exhibit evidence 
of disease progression per RECIST v1.1.  However, to better accommodate standard clinical 
practice which is guided by the fact that patients with ES-SCLC whose disease progresses after 
first-line treatment have limited treatment options and such options have limited efficacy and 
significant toxicity, patients may be considered for treatment beyond radiographic disease 
progression per RECIST v1.1, at the discretion of the investigator and after appropriate 
discussion with the patient and obtaining informed consent, only if all of the following criteria are 
met: 
• 
Evidence of clinical benefit as assessed by the investigator  
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
• 
Patients must provide written consent to acknowledge deferring other treatment options in 
favor of continuing study treatment at the time of initial progression 
 
Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 
should be closely monitored clinically and with a follow-up scan in 6 weeks or sooner if 
symptomatic deterioration occurs.  Treatment should be discontinued if clinical deterioration due 
to disease progression occurs at any time, or if persistent disease growth is confirmed in a 
follow-up scan.  In addition, patients should be discontinued for unacceptable toxicity or for any 
other signs or symptoms of deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic data and clinical status. 
If clinically feasible, it is recommended that the patient undergo a tumor biopsy sample 
collection at the time of radiographic disease progression.  These data will be used to explore 
whether radiographic findings are consistent with the presence of a tumor.  Additionally, these 
data will be analyzed to evaluate the association between changes in tumor tissue and clinical 
outcome and to further understand 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 will undergo tumor assessments at baseline and every 6 weeks (± 7 days) for 48 
weeks following Cycle 1, Day 1, regardless of treatment dose delays.  After completion of the 
Week 48 tumor assessment, tumor assessments will be required every 9 weeks (± 7 days) 
thereafter, regardless of treatment dose delays.  Patients will undergo tumor assessments until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, study termination by 
the Sponsor, or death, whichever occurs first.  
Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 will 
continue to undergo tumor assessments every 6 weeks (± 7 days), or sooner if symptomatic 
deterioration occurs.  For these patients, tumor assessments will continue every 6 weeks 
(± 7 days), regardless of time in the study, until study treatment is discontinued. 
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 at the same frequency as would have been followed if the patient had remained 
on study treatment (i.e., every 6 weeks [± 7 days] for 48 weeks following Cycle 1, Day 1 and 
then every 9 weeks [±7 days] thereafter, regardless of treatment dose delays) until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, study termination by the Sponsor, 
or death, whichever occurs first, regardless of whether patients start a new anti-cancer therapy. 
In case of an early termination of the study, patients who are deriving clinical benefit from 
treatment with atezolizumab will be permitted to continue treatment with atezolizumab at the 
discretion of the investigator. 


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Note:  After approximately 400 patients have been randomized into the study,
 
 
 
 
 
 
Number of Patients 
Approximately 400 patients will be randomized into the global enrollment phase of this study.  
 
 
 
 
Target Population 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry: 
• 
Signed Informed Consent Form 
• 
Male or female, 18 years of age or older 
• 
ECOG performance status of 0 or 1 
• 
Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration Lung 
Study Group (VALG) staging system 
• 
No prior systemic treatment for ES-SCLC 
• 
Patients who have received prior chemoradiotherapy for limited-stage SCLC must have 
been treated with curative intent and experienced a treatment-free interval of at least 
6 months since last chemotherapy, radiotherapy, or chemoradiotherapy cycle from 
diagnosis of extensive-stage SCLC  
• 
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 evidence of interim progression between the completion of CNS-directed therapy 
and randomization 
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. 
• 
Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease. 
• 
Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 14 days prior to randomization: 
ANC ≥ 1500 cells/µL without granulocyte colony-stimulating factor support 
Lymphocyte count ≥ 500/µL 
Platelet count ≥ 100,000/µL without transfusion 
Hemoglobin ≥ 9.0 g/dL 
Patients may be transfused to meet this criterion. 
INR or aPTT ≤ 1.5 × upper limit of normal (ULN) 


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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 
• 
Patients must submit a pre-treatment tumor tissue sample.  Any available tumor tissue 
sample can be submitted.  The tissue sample should be submitted before or within 4 weeks 
after randomization; however, patients may be enrolled into the study before the 
pre-treatment tumor tissue sample is submitted. 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% 
per year during the treatment period and for at least 5 months after the last dose of study 
treatment. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, as defined below: 
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during treatment with chemotherapy 
(i.e., carboplatin and etoposide) and for at least 6 months after the last dose of 
chemotherapy to avoid exposing the embryo.  
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical study and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• 
For patients enrolled in the extended China enrollment phase:  current resident of 
mainland China, Hong Kong, or Taiwan and of Chinese ancestry 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Active or untreated CNS metastases as determined by computed tomography (CT) or 
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments 
• 
Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for ≥ 1 week prior to randomization 
• 
Leptomeningeal disease 


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• 
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 regardless of drainage 
frequency. 
• 
Uncontrolled or symptomatic hypercalcemia 
Patients who are receiving denosumab prior to randomization must be willing and 
eligible to discontinue its use and replace it with a bisphosphonate while in the study. 
• 
Malignancies other than SCLC 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) 
• 
Women who are pregnant, lactating, or intending to become pregnant during the study 
• 
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism on thyroid replacement 
hormone therapy are eligible. 
Patients with controlled Type I diabetes mellitus on an insulin regimen are eligible. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are eligible 
for the study provided that they meet the following conditions: 
Rash must cover less than 10% of body surface area 
Disease is well controlled at baseline and only requires low potency topical 
steroids 
No acute exacerbations of underlying condition within the last 12 months (not 
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency, or oral steroids) 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Positive test result for HIV 
All patients must be tested for HIV; patients who test positive for HIV will be excluded.  
• 
Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test result at screening) or hepatitis C virus (HCV) 
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.  HBV DNA should be obtained in these patients prior to randomization. 
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 
• 
Active tuberculosis 
• 
Severe infections at the time of randomization, including but not limited to hospitalization for 
complications of infection, bacteremia, or severe pneumonia 
• 
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months 
prior to randomization, unstable arrhythmias, or unstable angina 
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or left ventricular ejection fraction < 50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
33/Statistical Analysis Plan GO30081 
• 
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 
• 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk for treatment complications 
• 
Patients with illnesses or conditions that interfere with their capacity to understand, follow, 
and/or comply with study procedures 
• 
Treatment with any other investigational agent with therapeutic intent within 28 days prior to 
randomization 
• 
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 
Patients must not receive live, attenuated influenza vaccines (e.g., FluMist) within 
4 weeks prior to randomization, during treatment, and for 5 months following the last 
dose of atezolizumab/placebo. 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, 
and anti−PD-L1 therapeutic antibodies 
• 
Treatment with systemic immunosuppressive medications (including, but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor [anti-TNF] agents) within 1 week prior to randomization 
Patients who have received acute systemic immunosuppressant medications (e.g., use 
of corticosteroids for nausea, vomiting, or management of or premedication for allergic 
reactions) may be enrolled in the study after discussion with and approval by the 
Medical Monitor.  In those patients, the need and length of the washout period prior to 
randomization will also be established in conjunction with the Medical Monitor. 
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed. 
• 
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 allergic reactions to carboplatin or etoposide 
 
End of Study 
The end of study is will occur when all of the following criteria have been met: 
• 
The last patient last visit (LPLV) has occurred (i.e., last patient in the global 
 
  
• 
Approximately 280 deaths have been observed among the randomized patients in the 
global enrollment phase.   
• 
 (see 
Section 6.1.1). 
 
Additionally, the Sponsor may decide to terminate the study at any time. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 31 months. 


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34/Statistical Analysis Plan GO30081 
Outcome Measures 
Efficacy Outcome Measures 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measures for this study are: 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression 
as determined by the investigator using RECIST v1.1 or death from any cause, whichever 
occurs first.  
• 
OS, defined as the time from randomization to death from any cause. 
 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are: 
• 
Objective response, defined as PR or CR as determined by the investigator according to 
RECIST v1.1  
• 
DOR, defined as the time interval from first occurrence of a documented objective response 
to the time of disease progression as determined by the investigator using RECIST v1.1 or 
death from any cause, whichever comes first 
• 
PFS rates at 6 months and at 1 year 
• 
OS rates at 1 and 2 years 
• 
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 maintained for two assessments or one assessment followed by death 
from any cause within 3 weeks 
 
Safety Outcome Measures 
The safety outcome measures for this study are: 
• 
Incidence, nature, and severity of adverse events graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 
• 
Changes in vital signs, physical findings, and clinical laboratory results during and following 
study treatment administration 
• 
Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters 
 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are: 
• 
Maximum observed serum atezolizumab concentration (Cmax) after infusion  
• 
Minimum observed serum atezolizumab concentration (Cmin) prior to infusion at selected 
cycles, at treatment discontinuation, and at 120 days (± 30 days) after the last dose of 
atezolizumab 
• 
Plasma concentrations for carboplatin  
• 
Plasma concentrations for etoposide  
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are: 
• 
Objective response, PFS and DOR as determined by the investigator according to modified 
RECIST 
• 
Status of PD-L1−, immune-, and SCLC-related and other exploratory biomarkers in archival 
and/or freshly obtained tumor tissues, and blood (or blood derivatives) collected before, 
during, or after treatment with atezolizumab or at progression and association with disease 
status and/or response to atezolizumab 
• 
Utility scores of the EQ-5D-5L 


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35/Statistical Analysis Plan GO30081 
• 
Change from baseline in PROs of health-related quality of life, lung cancer−related 
symptoms, physical functioning, and health status as assessed by the EORTC QLQ-C30 
and QLQ-LC13 
• 
Changes in levels and type of peripheral and tumor-specific T-cell populations during and 
after induction therapy and its relationship to efficacy and safety outcomes 
 
Investigational Medicinal Products 
The induction phase of the study will consist of four cycles of atezolizumab/placebo plus 
chemotherapy, with each cycle being 21 days in duration.  On Day 1 of each cycle, all eligible 
patients will receive drug infusions in the following order: 
Arm A:  atezolizumab → carboplatin → etoposide  
Arm B:  placebo → carboplatin → etoposide 
 
On Days 2 and 3, patients will receive etoposide alone.  
After the induction phase, patients will begin maintenance therapy with atezolizumab/placebo 
every 3 weeks.  
Test Product (Investigational Drug) 
The test products in this study are atezolizumab and atezolizumab placebo.  Patients will 
receive atezolizumab/placebo 1200 mg (equivalent to an average body weight-based dose of 
15 mg/kg) administered by IV infusion every 21 [± 2] days in a monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.  For information on the formulation, packaging, and handling of 
atezolizumab and atezolizumab placebo refer to the atezolizumab Pharmacy Manual and 
Investigator’s Brochure.  Atezolizumab and atezolizumab placebo will be supplied by the 
Sponsor. 
Non-Investigational Medicinal Products 
Carboplatin and etoposide are background treatment and are considered non-investigational 
medicinal products (NIMPs).  For information on the formulation, packaging, and handling of 
carboplatin and etoposide see the prescribing information for each drug. 
Carboplatin should be administered after completion of atezolizumab/placebo by IV infusion 
over 30−60 minutes to achieve an initial target area under the concentration-time curve (AUC) 
of 5 mg/mL/min (Calvert formula dosing) with standard anti-emetics per local practice guidelines. 
During the induction phase (Cycles 1−4), on Day 1 of each cycle, etoposide (100 mg/m2) should 
be administered intravenously over 60 minutes following carboplatin administration.  On 
Days 2 and 3 of each cycle, etoposide (100 mg/m2) should be administered intravenously over 
60 minutes.  Premedication should be administered according to local standard-of-care.   
Because the effects of corticosteroids on T-cell proliferation have the potential to attenuate 
atezolizumab-mediated anti-tumor immune activity, premedication with corticosteroids should 
be minimized to the extent that is clinically feasible. 
Statistical Methods 
All analyses will be restricted to the patients enrolled in the global enrollment phase only (i.e., 
 unless otherwise noted.  The analysis populations used 
in this section, such as the ITT (i.e., all randomized patients) and the PD-L1−selected 
populations will not
, unless otherwise noted. 
The analyses of PFS and OS will be performed on all randomized patients (ITT), with patients 
grouped according to the treatment assigned at randomization, regardless of whether they 
receive any assigned study drug.  ORR will be analyzed using all randomized patients who 
have measurable disease at baseline.  DOR will be assessed in patients who have an objective 
response.  TTD analyses will be conducted on all patients with a non-missing baseline PRO 
assessment.  Change from baseline analysis on PROs will be performed using patients who 
have both a non-missing baseline assessment and at least one post-baseline assessment with 
patients grouped according to the treatment assigned at randomization. 


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Primary Analysis 
To adjust for multiplicity due to having two co-primary endpoints, a group sequential Holm’s 
procedure will be implemented:  initially the hypothesis test for PFS will be conducted at a 
two-sided alpha of 0.005 and OS will be tested at a two-sided alpha of 0.045.  Once a null 
hypothesis is rejected, the test mass predefined for that endpoint becomes available and can be 
recycled to the other unrejected test. 
The null and alternative hypotheses regarding PFS or OS in the ITT population can be phrased 
in terms of the PFS or OS survival functions SA(t) and SB(t) for Arm A 
(atezolizumab + carboplatin + etoposide) and Arm B (placebo + carboplatin + etoposide), 
respectively: 
H0: SA(t)  = SB(t) versus H1: SA(t) ≠ SB(t) 
 
One of the co-primary efficacy endpoints is PFS as assessed by the investigator using 
RECIST v1.1.  PFS is defined as the time between the date of randomization and the date of 
first documented disease progression or death, whichever occurs first.  Patients who have not 
experienced disease progression or death at the time of analysis will be censored at the time of 
the last tumor assessment.  Patients with no post-baseline tumor assessment will be censored 
at the date of randomization plus 1 day. 
The two-sided log-rank test, stratified by sex (male vs. female), ECOG performance status 
(0 vs. 1), and presence of brain metastases (yes vs. no), as recorded in the interactive 
voice/Web response system (IxRS), will be used as the primary analysis to compare PFS 
between the two treatment arms.  The results from the unstratified log-rank test will also be 
provided.  
The Kaplan-Meier approach will be used to estimate median PFS for each treatment arm.  The 
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median PFS for 
each treatment arm.  Cox proportional hazards models, stratified by sex (male vs. female), 
ECOG performance status (0 vs. 1), and presence of brain metastases (yes vs. no) will be used 
to estimate the hazard ratio (HR) and its 95% CI.  The unstratified HR will also be presented. 
OS, the other co-primary efficacy endpoint, is defined as the time from the date of 
randomization to the date of death from any cause.  Patients who are alive at the time of the 
analysis data cutoff will be censored at the last date they were known to be alive.  Patients with 
no post-baseline information will be censored at the date of randomization plus 1 day.  Methods 
for OS analyses are similar to those described for the PFS endpoint. 
Determination of Sample Size   
Approximately 400 patients will be randomized into the global enrollment phase of this study to 
the atezolizumab + carboplatin + etoposide arm and the placebo + carboplatin + etoposide arm in 
a 1:1 ratio. 
There are two co-primary efficacy endpoints:  PFS and OS.  To control the overall two-sided 
Type I error rate at 0.05, the two-sided significance levels of 0.005 and 0.045 are allocated to 
the primary comparisons for PFS and OS, respectively. 
The following sample size calculation applies to the global enrollment phase, 
 
, unless otherwise noted. 
The sample size of the study is determined by the analysis of OS.  To detect an improvement of 
HR = 0.68 in OS using a log-rank test, approximately 280 deaths in the ITT population will be 
required to achieve 88% power at a two-sided significance level of 0.045.  One OS interim 
analysis will be performed when approximately 220 OS events in the ITT population are 
observed, which by estimation will occur at approximately 23 months after the first patient is 
randomized.   
The primary analysis of PFS is planned to be conducted at the time of the OS interim analysis, 
and is estimated to be when approximately 275 PFS events in the ITT population have occurred, 
which is expected at approximately 23 months after the first patient is randomized.  This 
provides 98% power to detect an improvement of HR = 0.55 in PFS at a two-sided significance 
level of 0.005.  There will be no interim analysis for PFS.   


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37/Statistical Analysis Plan GO30081 
By a group sequential Holm procedure, if the primary analysis of PFS is significant, then the 
two-sided 0.005 alpha will be recycled to OS.  Otherwise, iIf the OS analysis at either interim 
or final is significant, the allocated test mass of two-sided 0.045 alpha can be returned to PFS 
so PFS primary analysis can be tested at a two-sided 0.05 level.  Additional details will be 
provided in the SAP. 
The final analysis of OS will be performed when approximately 280 OS events in the ITT 
population have been observed, which is expected at approximately 31 months after the first 
patient is randomized. 
The calculation of sample size and estimates of the analysis timelines are based on the 
following assumptions: 
• 
PFS and OS are exponentially distributed. 
• 
The median duration of PFS in the control arm is 6 months. 
• 
The median duration of OS in the control arm is 10 months. 
• 
The two interim and final analyses of OS use the Lan-DeMets alpha spending function to 
approximate the O’Brien-Fleming boundary. 
• 
The dropout rate is 5% over 12 months for PFS and OS. 
 
The sample size of the
 
 
 
 
 
 
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.  Members of the iDMC will be external to the Sponsor 
and will follow a charter that outlines their roles and responsibilities.  Any outcomes of these 
safety reviews that affect study conduct will be communicated in a timely manner to the 
investigators for notification of the institutional review boards/ethics committees.  A detailed plan 
will be included in the iDMC Charter.  
One interim efficacy analysis of OS is planned when approximately 220 OS events have been 
observed.  The primary analysis of PFS will be conducted at the same time of the interim OS 
analysis, and the exact timing of the analysis depends on when approximiately 275 PFS 
events or approximately 220 OS events have occurred, whichever occurs later. 
The final OS analysis will be conducted when approximately 280 OS events in the ITT 
population have been observed.  This is expected to occur approximately 31 months after the 
first patient is randomized, but the exact timing of this analysis will depend on the actual number 
of OS events.   
To control the type I error for OS, the stopping boundaries for OS interim and final analyses are 
to be computed with use of the Lan-DeMets approximation to the O’Brien-Fleming boundary.


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38/Statistical Analysis Plan GO30081 
Appendix 2  
Schedule of Assessments 
Procedure 
Screening 
All Treatment Cycles a 
Treatment 
Discontinuation Visit 
Survival Follow-Up 
Days − 28 
to − 1 
Induction Phase 
(Cycles 1−4) 
Maintenance 
Phase 
≤ 30 Days after Last 
Dose of Study Treatment 
Every 3 Months after 
Disease Progression  
Every 21 Days 
(± 3 Days) b 
Every 21 Days 
(± 3 Days)  
Informed consent 
x 
 
 
 
 
Pre-treatment tumor tissue specimen for biomarker 
testing  
x c 
x c 
x c 
 
 
Demographic data 
x 
 
 
 
 
Medical history and baseline conditions 
x 
 
 
 
 
SCLC cancer history 
x 
 
 
 
 
Vital signs d 
x 
x  
x 
x  
 
Weight 
x 
x 
x 
x 
 
Height 
x 
 
 
 
 
Complete physical examination 
x 
 
 
 
 
Limited physical examination e 
 
x 
x 
x 
 
ECOG performance status 
x 
x 
x 
x 
 
12-lead ECG 
x 
x f 
x f 
x f 
 
Hematology g 
x  h 
x 
x 
x 
 
Serum chemistry i  
x h 
x 
x 
x 
 


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Appendix 2  
Schedule of Assessments (cont.) 
 
Procedure 
Screening 
All Treatment 
Cycles a 
All Treatment 
Cycles a 
Treatment 
Discontinuation Visit 
Survival Follow-Up 
Days − 28 
to − 1 
Induction Phase 
(Cycles 1−4) 
Maintenance 
Phase 
≤ 30 Days after Last 
Dose of Study Treatment 
Every 3 Months after 
Disease Progression  
Every 21 Days 
(± 3 Days) b 
Every 21 Days 
(± 3 Days) b 
Coagulation test (aPTT or INR) 
x h 
 
 
x 
 
Pregnancy test  (women of 
childbearing-potential only) 
x j 
x k 
x k 
x k 
 
TSH, free T3, free T4 l 
x 
x m 
x m 
x 
 
HIV, HBV, HCV serology n 
x 
 
 
 
 
Urinalysis o 
x o 
x o 
x o 
x o 
 
Induction treatment administration  
Arm A:  atezolizumab + etoposide + carboplatin  
Arm B:  placebo + etoposide + carboplatin  
 
x p 
 
 
 
Maintenance treatment administration 
Arm A:  atezolizumab   
Arm B:  placebo 
 
 
x p 
 
 
Prophylactic cranial irradiation 
 
 
x q 
 
 
Tumor response assessment  
x r 
x s 
x s 
 
x t 
Serum sample for atezolizumab ADA assessment u 
 
x 
x 
x 
120 (± 30) days after last 
dose of atezolizumab 
Serum sample for atezolizumab PK sampling u 
 
x 
x 
x 
120 (± 30) days after last 
dose of atezolizumab 


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40/Statistical Analysis Plan GO30081 
Appendix 2  
Schedule of Assessments (cont.) 
 
Procedure 
Screening 
All Treatment 
Cycles a 
All Treatment 
Cycles a 
Treatment 
Discontinuation Visit 
Survival Follow-Up 
Days − 28 
to − 1 
Induction Phase 
(Cycles 1−4) 
Maintenance 
Phase 
≤ 30 Days after Last 
Dose of Study Treatment 
Every 3 Months after 
Disease Progression  
Every 21 Days 
(± 3 Days) b 
Every 21 Days 
(± 3 Days) b 
Carboplatin and etoposide PK sampling u 
 
x 
 
 
 
Blood samples for PD biomarkers u 
 
x 
x 
x 
120 (± 30) days after last 
dose of atezolizumab 
Optional tumor biopsy after induction treatment (if 
patient signs consent) 
 
After induction treatment 
 
 
Optional tumor biopsy at time of radiographic 
progression (if patient signs consent) v 
 
At time of initial radiographic 
progression 
 
 
Optional tumor biopsy at other time points 
(RCR only) 
 
Any time during study treatment or during survival follow-up 
Optional blood for DNA extraction (RCR only) u, w 
 
x 
Adverse events 
x  
x 
x 
x x 
x x 
Concomitant medications  
x y 
x y 
x y 
x y 
 
Patient-reported outcomes (EORTC QLQ-C30, 
EORTC QLQ-LC13, and EQ-5D-5L) z 
 
x z 
x z 
 
x z 


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Appendix 2  
Schedule of Assessments (cont.) 
 
Procedure 
Screening 
All Treatment 
Cycles a 
All Treatment 
Cycles a 
Treatment 
Discontinuation Visit 
Survival Follow-Up 
Days − 28 
to − 1 
Induction Phase 
(Cycles 1−4) 
Maintenance 
Phase 
≤ 30 Days after Last 
Dose of Study Treatment 
Every 3 Months after 
Disease Progression  
Every 21 Days 
(± 3 Days) b 
Every 21 Days 
(± 3 Days) b 
Survival and anti-cancer therapy follow-up 
 
 
 
 
x aa 
 
ADA = anti-drug antibody; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; 
EORTC = European Organization for Research and Treatment of Cancer; ePRO = electronic Patient-Reported Outcome; EQ-5D-5L = EuroQoL 5 
Dimensions 5-Level Version; FFPE = formalin-fixed paraffin-embedded; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; HCV = hepatitis C virus; MRI = magnetic resonance imaging; NSCLC = non−small cell lung cancer; PCI = prophylactic cranial 
irradiation; PCR = polymerase chain reaction; PD = pharmacodynamic; PD-L1 = programmed death−ligand 1; PK = pharmacokinetic; 
PRO = Patient-Reported Outcome; QLQ-C30 = Quality-of-Life Questionnaire Core 30; QLQ-LC13 = Quality-of-Life Questionnaire Lung Cancer module; 
RCR = Roche Clinical Repository; RECIST = Response Evaluation Criteria in Solid Tumors; SCLC = small cell lung cancer; TSH = thyroid-stimulating 
hormone. 
a Assessments should be performed before study drug infusion unless otherwise noted. 
b Cycle 1 must be performed within 5 days after the patient is randomized.  Screening assessments performed ≤ 96 hours before Cycle 1, Day 1 are 
not required to be repeated for Cycle 1, Day 1.  In addition, ECOG performance status, limited physical examination, and local laboratory tests may 
be performed ≤ 96 hours before Day 1 of each cycle as specified in Section 4.5.12.2. 
c A pre-treatment tumor tissue (archival or freshly obtained) sample should be submitted before or within 4 weeks after randomization.  This specimen 
must be accompanied by the associated pathology report.  Although any available tumor tissue sample can be submitted, it is strongly encouraged 
that representative tumor specimens in paraffin blocks (preferred) or 10 (or more) serial, freshly cut, unstained slides be submitted.  See 
Section 4.5.7.1 for details. 
d Vital signs include pulse rate, respiratory rate, blood pressures, and temperature.  Vital signs should be recorded as described in Section 4.5.4. 
e Symptom-directed physical examinations; see Section 4.5.3 for details. 
f ECG recordings will be obtained when clinically indicated. 
g Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, eosinophils, 
monocytes, basophils, and other cells), and platelet count.  
h At screening, the patient must have adequate hematologic and end-organ function defined by laboratory test results obtained within 14 days prior to 


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42/Statistical Analysis Plan GO30081 
randomization. See Section 4.1.1 for details. 
I Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2 if considered standard of care 
in the region, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. 
j Serum pregnancy test within 14 days before Cycle 1, Day 1. 
k Urine pregnancy tests; if a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test. 
l Total T3 will be tested only at sites where free T3 is not performed. 
m Thyroid function testing (TSH, free T3, free T4) collected on Day 1 of Cycles 1, 4, 8, and 12, and every fourth cycle thereafter.   
n All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the study.  Patients with active 
hepatitis B (chronic or acute; defined as having a positive HBsAg test result at screening) will be excluded from the study.  Patients with past or 
resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible; HBV DNA should be obtained in these patients prior 
to randomization.  Patients with HCV will be excluded from the study; patients who test positive for HCV antibody are eligible only if PCR is negative 
for HCV RNA.  
o Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood).  Urinalysis is required at screening and will be obtained when 
clinically indicated. 
p For atezolizumab/placebo, the initial dose will be administered over 60 (± 15) minutes.  If the first infusion is well tolerated, subsequent infusions may 
be administered over 30 (± 10) minutes.  For carboplatin and etoposide, study drug will be administered as described in Section 4.3.2. 
q During the maintenance phase, PCI is permitted as per local standard-of-care and will be reported on the Prophylactic Cranial Irradiation eCRF. 
 r CT scans (with oral/IV contrast unless contraindicated) or MRI scans 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. 
s Perform every 6 weeks (± 7 days) for 48 weeks following Cycle 1, Day 1 and then every 9 weeks (± 7 days) thereafter, after completion of the Week 
48 tumor assessment, regardless of treatment delays, until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study 
termination by the Sponsor, whichever occurs first.  Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 will 
continue to undergo tumor assessments every 6 weeks (± 7 days) or sooner if symptomatic deterioration occurs.  For these patients, tumor 
assessments will continue every 6 weeks (± 7 days), regardless of time on study, until study treatment is discontinued.  See Section 4.5.5 for details. 
t If the patient discontinued 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 
(i.e., every 6 weeks [± 7 days] for 48 weeks following Cycle 1, Day 1 and then every 9 weeks [± 7 days] thereafter) until radiographic disease 
progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if the patient starts 
another anti-cancer therapy after study treatment discontinuation, unless consent is withdrawn.  See Section 4.5.5 for details. 
u See Appendix 2 for detailed schedule. 
v Optional tumor biopsy at radiographic disease progression, if clinically feasible, preferably within 40 days of radiographic progression or prior to start 
of the next anti-cancer therapy, whichever occurs is sooner. 


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w 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. 
x  All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the last 
dose of study drug or initiation of new systemic anti-cancer therapy after the last dose of study drug, whichever occurs first.  All other adverse events, 
regardless of relationship to study drug, will be reported until 30 days after the last dose of study drug or initiation of new systemic anti-cancer therapy 
after the last dose of study drug, whichever occurs first.  After this period, all deaths should continue to be reported.  In addition, the Sponsor should 
be notified if the investigator becomes aware of any serious adverse event or adverse event of special interest that is believed to be related to prior 
exposure to study treatment (see Section 5.6). These events should be reported through use of the Adverse Event eCRF.   
y From 7 days before screening until the treatment discontinuation visit.  All such medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF. 
z EORTC QLQ-C30, EORTC QLQ-LC13, and the EQ-5D-5L questionnaires will be completed by the patients on the ePRO tablet at each scheduled 
study visit prior to administration of study drug and prior to any other study assessment(s).  During survival follow-up, the EORTC QLQ-C30, EORTC 
QLQ-LC13, and EQ-5D-5L questionnaires will be completed at 3 months (± 30 days) and 6 months (± 30 days) following radiographic disease 
progression per RECIST v1.1 (or at 3 months [± 30 days] and 6 months [± 30 days] after treatment is discontinued for patients who continue 
treatment after disease progression per RECIST v1.1).  Patients who discontinue study treatment for any reason other than radiographic 
disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L 
at each tumor assessment visit until radiographic disease progression per RECIST v1.1, unless the patient withdraws consent or the Sponsor 
terminates the study, whichever occurs first.  Study personnel should review all questionnaires for completeness before the patient leaves the 
investigational site.  Patients whose native language is not available in the ePRO device or who are deemed by the investigator incapable of inputting 
their ePRO assessment after undergoing appropriate training are exempt from all ePRO assessments. 
aa 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. 


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Appendix 3  
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Therapeutic Antibody Assessments 
Study Visit 
Time 
Atezolizumab/Placebo + 
Carboplatin + Etoposide 
Cycle 1, Day 1 a 
Predose (same day as treatment 
administration) (for biomarker 
sampling, prior to first dose of 
steroids) 
• Atezolizumab ADA  
• Atezolizumab PK 
• Carboplatin PK b 
• Etoposide PK b 
• Biomarkers c 
 
30 (± 10) minutes after end of 
atezolizumab infusion 
Atezolizumab PK 
 
5−10 minutes before the end of 
carboplatin infusion 
b 
Carboplatin PK 
b 
 
1 hour (± 15 minutes) after end of 
carboplatin infusion 
b 
Carboplatin PK 
b 
 
5−10 minutes before the end of 
etoposide infusion 
b 
Etoposide PK 
b 
 
1 hour (± 15 minutes) after end of 
etoposide infusion 
b 
Etoposide PK 
b 
 
4 hours (± 30 minutes) after end of 
etoposide infusion b 
Etoposide PK b 
Cycle 2, Day 1 
Predose (same day as treatment 
administration) 
• Atezolizumab ADA 
• Atezolizumab PK 
• Biomarkers d 
Cycle 3, Day 1 
Predose (same day as treatment 
administration) 
• Atezolizumab ADA 
• Atezolizumab PK 
• Carboplatin PK 
b 
• Etoposide PK
 b 
• Biomarkers c  


Atezolizumab—F. Hoffmann-La Roche Ltd 
45/Statistical Analysis Plan GO30081 
Appendix 3  
Schedule of Pharmacokinetic, Pharmacodynamic, Biomarker, 
and Anti-Therapeutic Antibody Assessments (cont.) 
Study Visit 
Time 
Atezolizumab/Placebo + 
Carboplatin + Etoposide 
Cycle 3, Day 1 
5−10 minutes before the end of 
carboplatin infusion
 b 
Carboplatin PK b 
 
1 hour (± 15 minutes) after end of 
carboplatin infusion b 
Carboplatin PK b 
 
5−10 minutes before the end of 
etoposide infusion b 
Etoposide PK b 
 
1 hour (± 15 minutes) after end of 
etoposide infusion b 
Etoposide PK b 
 
4 hours (± 30 minutes) after end 
of etoposide infusion b 
Etoposide PK b 
Cycles 4, 8, and 16,  Day 1 
Predose (same day as treatment 
administration) 
• Atezolizumab ADA 
• Atezolizumab PK 
• Biomarkers d 
After Cycle 16, every 8th 
cycle, Day 1 
Predose (same day as treatment 
administration) 
• Atezolizumab ADA 
• Atezolizumab PK 
• Biomarkers d 
At time of fresh biopsy 
(on-treatment including during 
follow-up) 
At visit 
• Biomarkers d 
Treatment discontinuation 
visit 
At visit 
• Atezolizumab ADA 
• Atezolizumab PK 
• Biomarkers d 
120 (± 30 days) after last 
dose of atezolizumab/placebo 
At visit 
• Atezolizumab ADA 
• Atezolizumab PK 
• Biomarkers d 
Any time point during the 
study (RCR consent required) 
 
Optional RCR blood (DNA 
extraction) e 
ADA = anti-drug antibody; PK = pharmacokinetic; RCR = Roche Clinical Repository. 
Note:  Serum PK samples for atezolizumab; plasma PK samples for carboplatin and etoposide. 
a Biomarker sampling before Cycle 1, Day 1 should be performed before patients are treated 
with first dose of steroids. 
b At select sites, a subset of approximately 40 patients will undergo the additional PK 
assessments for carboplatin and etoposide.  The additional PK assessments should be taken 
only if the patient is receiving both carboplatin and etoposide at the cycle.   
c Plasma, serum, whole blood for biomarkers. 
d Plasma and serum for biomarkers. 
e The optional RCR blood sample (for DNA extraction) requires an additional informed consent 
and can be collected at any time during the course of the study.