Conditions: Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 453
Healthy volunteers: no

Brief summary:
This Phase III, global, multicenter, open-label, randomized, controlled study will evaluate the efficacy and safety of atezolizumab (an anti-programmed death-ligand 1 \[anti-PD-L1\] antibody) compared with a single agent chemotherapy regimen by investigator choice (vinorelbine or gemcitabine) in treatment-naïve participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are deemed unsuitable for any platinum-doublet chemotherapy due to poor performance status (Eastern Cooperative Oncology Group \[ECOG\] performance status of 2-3).

Detailed description:

Arms:
arm 1: Participants will receive atezolizumab 1200 milligrams (mg) intravenous (IV) infusion on Day 1 of each 21-day cycle until loss of clinical benefit, unacceptable toxicity, participant or physician decision to discontinue, or death. arm 2: Participants will receive single agent chemotherapy; either vinorelbine oral or IV, or gemcitabine IV, according to the label based on investigator's choice.

Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody intervention 2: Vinorelbine intervention 3: Gemcitabine
Intervention descriptions: intervention 1: Atezolizumab will be administered via IV infusion once every three weeks (QW3). intervention 2: Vinorelbine will be administered per relevant local guidelines and Summary of Product Characteristics (SmPC) management. intervention 3: Gemcitabine will be administered per relevant local guidelines and SmPC management.

Protocol document:
Prot_002.pdf: 
 
Official Title: 
A Phase III, Open-Label, Multicenter, Randomized Study to 
Investigate the Efficacy and Safety of Atezolizumab Compared With 
Chemotherapy in Patients With Treatment Naïve Advanced or 
Recurrent (Stage IIIb Not Amenable for Multimodality Treatment) or 
Metastatic (Stage IV) Non-Small Cell Lung Cancer Who Are Deemed 
Unsuitable for Platinum-Containing Therapy 
NCT Number: 
NCT03191786 
Document Date: 
Protocol Amendment Version 8: 09-May-2023 
 
 
 


 
 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 MO29872, Version 8 
PROTOCOL 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
COMPARED WITH CHEMOTHERAPY IN PATIENTS 
WITH TREATMENT-NAÏVE ADVANCED OR 
RECURRENT (STAGE IIIB NOT AMENABLE FOR 
MULTIMODALITY TREATMENT) OR METASTATIC 
(STAGE IV) NON-SMALL CELL LUNG CANCER 
WHO ARE DEEMED UNSUITABLE FOR 
PLATINUM-CONTAINING THERAPY 
PROTOCOL NUMBER: MO29872 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2015-004105-16 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT03191786 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and stamp date on the final 
page of this document. 
 
 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol MO29872, Version 8  
 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
8 
See electronic date stamp on the final 
page of this document. 
7 
22 Dec 2021 
6 
03 Feb 2021 
5 
19 Dec 2019 
4 
14 Jan 2019 
3 
16 Jan 2018 
2 
29 Jun 2017 
1 
13 Feb 2017 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol MO29872, Version 8  
PROTOCOL AMENDMENT, VERSION 8 
RATIONALE 
Protocol MO29872 has been amended to include updates following the Atezolizumab 
Investigator's Brochure, Version 19, release.  Substantive changes to the protocol, along 
with a rationale for each change, are summarized below:  
 
The medical term “Wegener granulomatosis” has been replaced by the 
term “granulomatosis with polyangiitis” to align with the updated preferred term in 
MedDRA (Section 4.1.2.2). In addition, this term has also been added to 
Appendix 11. 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with Roche practices (Section 8.4). 
 
Benefit-risk assessment and guidance on concomitant administration of severe 
acute respiratory syndrome coronavirus 2 vaccines with atezolizumab has been 
added (Sections 1.8 and 4.4.1.1). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.11.6). 
 
Personal identifiable information (i.e., name and telephone number) for the Medical 
Monitors has been removed from the protocol (front matter and Section 5.4.1).  
Medical Monitor contact information has been replaced with a sentence indicating 
that this information will be provided separately to sites. 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 9.5). 
 
The list of identified risks for atezolizumab has been revised to include myelitis and 
facial paresis (Section 5.1.1.1). 
 
Hemophagocytic lymphohistiocytosis (HLH) has been updated from a potential risk 
to an identified risk associated with atezolizumab and language has been revised 
accordingly (Section 5.1.1.1). 
 
The list of adverse events of special interest has been revised to include myelitis 
and facial paresis (Section 5.2.3). 
 
Appendix 11 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a pericardial 
disorder while receiving another immunostimulatory anti-cancer agent. 
 
Appendix 11 has been revised to include autoimmune myelitis. 
 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 19 and Addendum 1 and 2 to the 
Atezolizumab Investigator’s Brochure, Version 19 (Appendix 13). 
Additional minor changes have been made to improve clarity and 
consistency.  Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND ............................................................................ 30 
1.1 
Background on Non-Small Cell Lung Cancer .......................... 30 
1.2 
First-Line Treatment for NSCLC .............................................. 31 
1.2.1 
First-Line Therapy for NSCLC Patients with Poor 
Performance Status ................................................................. 34 
1.2.2 
Platinum-Based Regimen for First-Line NSCLC ...................... 37 
1.2.3 
Non-Platinum Based Chemotherapy for NSCLC PS2 
Patients .................................................................................... 38 
1.2.3.1 
Pemetrexed Monotherapy........................................................ 39 
1.2.3.2 
Docetaxel Monotherapy ........................................................... 40 
1.2.3.3 
Gemcitabine Monotherapy ....................................................... 41 
1.2.3.4 
Vinorelbine Monotherapy (Intravenous and Oral) .................... 41 
1.3 
Targeted Therapy for NSCLC .................................................. 42 
1.4 
Second-Line Treatment for NSCLC ......................................... 43 
1.5 
Immunotherapy in Metastatic NSCLC ...................................... 44 
1.6 
Background on Atezolizumab .................................................. 45 
1.6.1 
Summary of Nonclinical Studies .............................................. 46 
1.7 
Clinical Experience with Atezolizumab .................................... 47 
1.7.1 
Clinical Studies in NSCLC ....................................................... 47 
1.7.2 
Clinical Safety .......................................................................... 48 
1.7.2.1 
Single-Agent Clinical Safety in Patients with Non-Small 
Cell Lung Cancer in Study PCD4989g ..................................... 48 
1.7.2.2 
Single-Agent Clinical Safety in Patients with Non-Small 
Cell Lung Cancer in Study GO28753 (POPLAR) ..................... 50 
1.7.2.3 
Single-Agent Clinical Safety in Patients with Non-Small 
Cell Lung Cancer in Study GO28754 (BIRCH) ........................ 51 
1.7.2.4 
Atezolizumab as a Combination Agent .................................... 52 
1.7.3 
Clinical Activity ......................................................................... 52 
1.7.3.1 
Single-Agent Clinical Activity in Patients with NSCLC in 
Study PCD4989g ..................................................................... 52 


 
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1.7.3.2 
Single-Agent Clinical Activity in Patients with NSCLC in 
Study GO28753 (POPLAR) ..................................................... 53 
1.7.3.3 
First Phase III Study of Atezolizumab in Previously-treated 
NSCLC in Study GO28915 (OAK) ........................................... 55 
1.7.3.4 
Single-Agent Clinical Activity in Patients with NSCLC in 
Study GO28625 (FIR) .............................................................. 55 
1.7.3.5 
Clinical Pharmacokinetics ........................................................ 58 
1.7.3.6 
Immunogenicity ........................................................................ 59 
1.8 
Study Rationale and Benefit-Risk Assessment ........................ 59 
2. 
OBJECTIVES ................................................................................ 62 
2.1 
Efficacy Objectives .................................................................. 62 
2.1.1 
Primary Efficacy Objective ....................................................... 62 
2.1.2 
Secondary Efficacy Objectives ................................................ 63 
2.2 
Safety Objectives ..................................................................... 63 
2.3 
Patient-Reported Outcome Objective ...................................... 63 
2.4 
Exploratory Objectives ............................................................. 64 
3. 
STUDY DESIGN ........................................................................... 64 
3.1 
Description of the Study ........................................................... 64 
3.1.1 
Overview of Study Design........................................................ 66 
3.1.2 
Independent Data Monitoring Committee ................................ 68 
3.2 
End of Study and Length of Study ........................................... 68 
3.3 
Rationale for Study Design ...................................................... 69 
3.3.1 
Rationale for Patient Population .............................................. 69 
3.3.2 
Rationale for Control Arm ........................................................ 70 
3.3.3 
Rationale for Atezolizumab Dosing .......................................... 71 
3.3.4 
Rationale for Open-Label Study ............................................... 72 
3.3.5 
Rationale for Primary and Secondary Endpoints ..................... 72 
3.3.6 
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment until Loss of Clinical Benefit .................................... 73 
3.3.7 
Rationale for Patient-Reported Outcome Assessments ........... 73 
3.3.8 
Rationale for Assessment of Response using Modified 
(Immune-Mediated) RECIST Criteria ....................................... 74 
3.3.9 
Rationale for Biomarker Assessments ..................................... 75 


 
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3.3.9.1 
Tumor Tissue Specimens for Patient Stratification 
According to PD-L1 IHC Status and Exploratory Biomarker 
Analyses .................................................................................. 75 
3.3.9.2 
Blood Sample .......................................................................... 75 
3.4 
Outcome Measures ................................................................. 75 
3.4.1 
Efficacy Outcome Measures .................................................... 75 
3.4.1.1 
Primary Efficacy Outcome Measure ........................................ 75 
3.4.1.2 
Secondary Efficacy Outcome Measures .................................. 75 
3.4.2 
Safety Outcome Measures ...................................................... 76 
3.4.3 
Patient-Reported Outcome Measures ..................................... 76 
3.4.4 
Exploratory Outcome Measures .............................................. 76 
4. 
MATERIALS AND METHODS ...................................................... 76 
4.1 
Patients .................................................................................... 76 
4.1.1 
Inclusion Criteria ...................................................................... 77 
4.1.2 
Exclusion Criteria ..................................................................... 79 
4.1.2.1 
Cancer-Specific Exclusion Criteria ........................................... 79 
4.1.2.2 
General Medical Exclusion Criteria .......................................... 80 
4.1.2.3 
Exclusion Criteria Related to Atezolizumab ............................. 82 
4.1.2.4 
Exclusion Criteria Related to Chemotherapy ........................... 83 
4.2 
Method of Treatment Assignment and Blinding ....................... 83 
4.3 
Study Treatment ...................................................................... 84 
4.3.1 
Formulation, Packaging, and Handling .................................... 84 
4.3.1.1 
Atezolizumab ........................................................................... 84 
4.3.1.2 
Vinorelbine, Gemcitabine ......................................................... 85 
4.3.2 
Dosage, Administration, and Compliance ................................ 85 
4.3.2.1 
Atezolizumab ........................................................................... 85 
4.3.2.2 
Vinorelbine ............................................................................... 86 
4.3.2.3 
Gemcitabine ............................................................................. 87 
4.3.3 
Additional Required Medication ............................................... 87 
4.3.3.1 
Atezolizumab ........................................................................... 87 
4.3.3.2 
Vinorelbine ............................................................................... 88 
4.3.3.3 
Gemcitabine ............................................................................. 88 
4.3.4 
Investigational Medicinal Product Accountability ..................... 88 


 
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4.3.5 
Continued Access to Atezolizumab ......................................... 89 
4.4 
Concomitant Therapy .............................................................. 90 
4.4.1 
Atezolizumab Concomitant Therapy ........................................ 90 
4.4.1.1 
Permitted Therapy with Atezolizumab ..................................... 90 
4.4.1.2 
Cautionary Therapy for Atezolizumab-Treated Patients .......... 91 
4.4.1.3 
Prohibited Therapy with Atezolizumab ..................................... 91 
4.4.2 
Chemotherapy Concomitant Therapy ...................................... 92 
4.4.2.1 
Vinorelbine Concomitant Therapy ............................................ 92 
4.4.2.2 
Gemcitabine Concomitant Therapy ......................................... 92 
4.5 
Study Assessments ................................................................. 93 
4.5.1 
Informed Consent Forms and Screening Log .......................... 93 
4.5.2 
Medical History and Demographic Data .................................. 93 
4.5.3 
Physical Examinations ............................................................. 93 
4.5.4 
Vital Signs ................................................................................ 94 
4.5.5 
Tumor and Response Evaluations ........................................... 94 
4.5.6 
Determination of EGFR and ALK Status .................................. 95 
4.5.7 
Tumor Tissue Requirements for Central PD-L1 Analysis 
(Stratification) ........................................................................... 96 
4.5.8 
Laboratory Assessments and Biomarker Samples .................. 96 
4.5.9 
Electrocardiograms .................................................................. 99 
4.5.10 
Patient-Reported Outcomes .................................................. 100 
4.5.11 
Samples for Research Biosample Repository (RBR) ............. 101 
4.5.11.1 
Overview of the Research Biosample Repository .................. 101 
4.5.11.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................. 101 
4.5.11.3 
Sample Collection .................................................................. 101 
4.5.11.4 
Confidentiality ........................................................................ 102 
4.5.11.5 
Consent to Participate in the Research Biosample 
Repository.............................................................................. 102 
4.5.11.6 
Withdrawal from the Research Biosample Repository ........... 103 
4.5.11.7 
Monitoring and Oversight ....................................................... 103 
4.5.12 
Timing of Assessments .......................................................... 103 
4.5.12.1 
Screening/Baseline Assessments .......................................... 103 
4.5.12.2 
Assessments During Study Treatment .................................. 104 


 
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4.5.12.3 
Assessments at Treatment Discontinuation Visit ................... 105 
4.5.12.4 
Assessments After Treatment Discontinuation Until 
Disease Progression .............................................................. 105 
4.5.12.5 
Follow-Up Assessments ........................................................ 105 
4.5.12.6 
Assessments at Unscheduled Visits ...................................... 106 
4.6 
Patient, Treatment, Study, and Site Discontinuation .............. 106 
4.6.1 
Patient Discontinuation .......................................................... 106 
4.6.2 
Study Treatment Discontinuation ........................................... 106 
4.6.3 
Study and Site Discontinuation .............................................. 107 
5. 
ASSESSMENT OF SAFETY ....................................................... 108 
5.1 
Safety Plan ............................................................................ 108 
5.1.1 
Risks Associated with Investigational Medicinal Products ..... 109 
5.1.1.1 
Risks Associated with Atezolizumab ...................................... 109 
5.1.1.2 
Risks Associated with Vinorelbine ......................................... 109 
5.1.1.3 
Risks Associated with Gemcitabine ....................................... 115 
5.1.2 
General Plan to Manage Safety Concerns ............................ 118 
5.1.2.1 
Monitoring .............................................................................. 118 
5.1.3 
Dose Modifications and Management of Special Adverse 
Events .................................................................................... 119 
5.1.3.1 
General Notes Regarding Dose Modification ......................... 119 
5.1.3.2 
Atezolizumab Dose Modification ............................................ 119 
5.1.3.3 
Management of Atezolizumab-Specific Adverse Events ........ 120 
5.1.3.4 
Vinorelbine Dose Modification and Management of 
Specific Adverse Events ........................................................ 120 
5.1.3.5 
Gemcitabine Dose Modification and Management of 
Specific Adverse Events ........................................................ 123 
5.2 
Safety Parameters and Definitions ........................................ 125 
5.2.1 
Adverse Events ...................................................................... 125 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 126 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 127 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 128 
5.3.1 
Adverse Event Reporting Period ............................................ 128 


 
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5.3.2 
Eliciting Adverse Event Information ....................................... 128 
5.3.3 
Assessment of Severity of Adverse Events ........................... 129 
5.3.4 
Assessment of Causality of Adverse Events.......................... 129 
5.3.5 
Procedures for Recording Adverse Events ............................ 130 
5.3.5.1 
Infusion-Related Reactions .................................................... 130 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................. 130 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 130 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 131 
5.3.5.5 
Abnormal Laboratory Values ................................................. 131 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 132 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 132 
5.3.5.8 
Deaths ................................................................................... 133 
5.3.5.9 
Preexisting Medical Conditions .............................................. 133 
5.3.5.10 
Lack of Efficacy or Worsening of Non-Small Cell Lung 
Cancer ................................................................................... 134 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 134 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 134 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 136 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 136 
5.4.1 
Emergency Medical Contacts ................................................ 137 
5.4.1.1 
Medical Monitor Contact Information for All Sites .................. 137 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 137 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 137 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 138 
5.4.3 
Reporting Requirements for Pregnancies .............................. 138 
5.4.3.1 
Pregnancies in Female Patients ............................................ 138 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 138 
5.4.3.3 
Abortions................................................................................ 139 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 139 
5.5 
Follow-Up of Patients after Adverse Events........................... 139 
5.5.1 
Investigator Follow-Up ........................................................... 139 


 
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5.5.2 
Sponsor Follow-Up ................................................................ 140 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 140 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 140 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 141 
6.1 
Determination of Sample Size ............................................... 141 
6.2 
Summaries of Conduct of Study ............................................ 142 
6.3 
Summaries of Treatment Group Comparability ...................... 142 
6.4 
Efficacy Analyses ................................................................... 142 
6.4.1 
Primary Efficacy Endpoint ...................................................... 143 
6.4.2 
Secondary Efficacy Endpoints ............................................... 143 
6.4.2.1 
Six-month, 12-month, 18-month and 24-month Landmark 
OS ......................................................................................... 143 
6.4.2.2 
Objective Response Rate ...................................................... 143 
6.4.2.3 
Progression-Free Survival ..................................................... 144 
6.4.2.4 
Duration of Response ............................................................ 144 
6.4.2.5 
OS and Investigator-assessed PFS in Patients with PD-L1 
Positive Status ....................................................................... 144 
6.5 
Safety Analyses ..................................................................... 144 
6.6 
Patient-Reported Outcome Analyses ..................................... 145 
6.7 
Exploratory Analyses ............................................................. 145 
6.8 
Interim and Final Analyses .................................................... 146 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 147 
7.1 
Data Quality Assurance ......................................................... 147 
7.2 
Electronic Case Report Forms ............................................... 147 
7.3 
Electronic Patient-Reported Outcome Data ........................... 147 
7.4 
Source Data Documentation .................................................. 148 
7.5 
Use of Computerized Systems .............................................. 149 
7.6 
Retention of Records ............................................................. 149 
8. 
ETHICAL CONSIDERATIONS .................................................... 149 
8.1 
Compliance with Laws and Regulations ................................ 149 
8.2 
Informed Consent .................................................................. 149 


 
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8.3 
Institutional Review Board or Ethics Committee .................... 151 
8.4 
Confidentiality ........................................................................ 151 
8.5 
Financial Disclosure ............................................................... 152 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 152 
9.1 
Study Documentation ............................................................ 152 
9.2 
Protocol Deviations ................................................................ 152 
9.3 
Site Inspections ..................................................................... 153 
9.4 
Administrative Structure ......................................................... 153 
9.5 
Dissemination of Data and Protection of Trade Secrets ........ 153 
9.6 
Protocol Amendments ........................................................... 154 
10. 
REFERENCES............................................................................ 155 
 
LIST OF TABLES 
Table 1 
Summary of Trials Assessing First- and Second-line 
Treatment of Metastatic Non-Squamous NSCLC Patients 
Lacking an Actionable Mutation .................................................. 33 
Table 2 
Summary of Trials Assessing First- and Second-line 
Treatment of Metastatic Squamous NSCLC Patients Lacking 
an Actionable Mutation ............................................................... 34 
Table 3 
Overall Survival in PS2 Patients Treated with Gemcitabine, 
Docetaxel, Pemetrexed and Vinorelbine or Gemcitabine, 
respectively ................................................................................. 39 
Table 4 
Nivolumab and Pembrolizumab Immunotherapy in Advanced 
NSCLC ........................................................................................ 45 
Table 5 
Adverse Events Reported in ≥ 10% of Patients in Study 
PCD4989g .................................................................................. 50 
Table 6 
Treatment-Related Adverse Events Reported in at Least 
10% of Patients in Either Treatment Arm in Study GO28753 
(POPLAR) ................................................................................... 51 
Table 7 
Study PCD4989g: Investigator-Assessed ORR and DOR per 
RECIST v1.1 in Efficacy-Evaluable Patients with NSCLC by 
PD-L1 Expression Subgroup and All Patients ............................. 53 
Table 8 
Study GO28625 (FIR): Investigator-Assessed ORR per 
RECIST v1.1 and Immune-Modified RECIST ............................. 57 
Table 9 
Safety Profile of Atezolizumab versus Docetaxel in Study 
GO28753 (POPLAR) .................................................................. 71 
Table 10 
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 85 


 
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Table 11 
Management Guidelines for Infusion-related Reactions ............. 87 
Table 12 
Vital Signs Measurements at Cycle 1 and all Subsequent 
Cycles ......................................................................................... 94 
Table 13 
Proposed Biomarkers for Exploratory Research ......................... 99 
Table 14 
Adverse Reactions for Vinorelbine as Single Agent 
(Intravenous) ............................................................................. 110 
Table 15 
Adverse Reactions for Vinorelbine as Single Agent (Soft 
Capsule).................................................................................... 113 
Table 16 
Adverse Reactions for Gemcitabine Observed in Clinical 
Trials ......................................................................................... 116 
Table 17 
Intravenous Vinorelbine Dose Adjustments Based on 
Granulocyte Counts .................................................................. 121 
Table 18 
Intravenous Vinorelbine Dose Adjustments for Hepatic 
Insufficiency .............................................................................. 122 
Table 19 
Oral Vinorelbine Dose Adjustments during First Three 
Weeks Based on Neutrophils .................................................... 122 
Table 20 
Oral Vinorelbine Dose Adjustments beyond Fourth Week 
Based on Neutrophils ................................................................ 122 
Table 21 
Dose Modification Guidelines for Hematological Toxicities on 
Day 1 of Gemcitabine ............................................................... 124 
Table 22 
Dose Modification Guidelines for Hematological Toxicities at 
Week 3 of Gemcitabine ............................................................. 124 
Table 23 
Gemcitabine Dose Modification Guidelines for 
Non-Hematological Toxicities .................................................... 125 
Table 24 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 129 
Table 25 
Operating Characteristics for Proposed Study Design .............. 142 
Table 26 
Analysis Timing and Stopping Boundaries for Interim and 
Final Analysis for Overall Survival ............................................. 146 
 
 
 


 
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LIST OF FIGURES 
Figure 1 Study Schema ...................................................................................... 67 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ............................................................... 168 
Appendix 2 
 American Joint Committee on Cancer Non−Small Cell Lung 
Cancer Staging, 7th Edition ...................................................... 173 
Appendix 3 
 Response Evaluation Criteria in Solid Tumors:   Modified 
Excerpt from Original Publication .............................................. 175 
Appendix 4 
 Modified Response Evaluation Criteria in Solid Tumors .......... 187 
Appendix 5 
 Anti-PD-L1 Immunohistochemistry ........................................... 194 
Appendix 6 
 EORTC QLQ-C30 .................................................................... 195 
Appendix 7 
 EORTC QLQ-LC13 .................................................................. 197 
Appendix 8 
 EuroQoL 5 Dimension, 5 Level Questionnaire ......................... 198 
Appendix 9 
 Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 201 
Appendix 10 
 Anaphylaxis Precautions .......................................................... 202 
Appendix 11 
 Preexisting Autoimmune Diseases and Immune Deficiencies . 203 
Appendix 12 
 PD-L1 IHC Scoring Criteria ...................................................... 204 
Appendix 13 
 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 205 
  


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
COMPARED WITH CHEMOTHERAPY IN PATIENTS 
WITH TREATMENT-NAÏVE ADVANCED OR 
RECURRENT (STAGE IIIB NOT AMENABLE FOR 
MULTIMODALITY TREATMENT) OR METASTATIC 
(STAGE IV) NON-SMALL CELL LUNG CANCER 
WHO ARE DEEMED UNSUITABLE FOR 
PLATINUM-CONTAINING THERAPY 
PROTOCOL NUMBER: MO29872 
VERSION NUMBER: 
8  
EUDRACT NUMBER: 
2015-004105-16 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT03191786 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
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 as 
instructed by your local study monitor. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
COMPARED WITH CHEMOTHERAPY IN PATIENTS 
WITH TREATMENT-NAÏVE ADVANCED OR 
RECURRENT (STAGE IIIB NOT AMENABLE FOR 
MULTIMODALITY TREATMENT) OR METASTATIC 
(STAGE IV) NON-SMALL CELL LUNG CANCER WHO 
ARE DEEMED UNSUITABLE FOR PLATINUM-
CONTAINING THERAPY 
PROTOCOL NUMBER: 
MO29872 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2015-004105-16 
IND NUMBER: 
Not applicable 
NCT NUMBER: 
NCT03191786 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
PHASE: 
Phase III 
INDICATION: 
Non-small cell lung cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of atezolizumab compared with single agent 
chemotherapy with respect to antitumor effects in patients with treatment-naïve locally 
advanced or metastatic non-small cell lung cancer (NSCLC) who are deemed unsuitable for any 
platinum-doublet chemotherapy.  Specific objectives and corresponding endpoints for the study 
are outlined below. 
EFFICACY OBJECTIVES 
PRIMARY EFFICACY OBJECTIVE 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
compared with single agent chemotherapy in patients with treatment-naïve locally advanced or 
metastatic NSCLC who are deemed unsuitable for any platinum-doublet chemotherapy, as 
measured by overall survival (OS). 
SECONDARY EFFICACY OBJECTIVES 
The secondary efficacy objectives for this study are:  
 
To evaluate the efficacy of atezolizumab compared with single agent chemotherapy as 
measured by OS rates at 6, 12, 18 and 24 months 
 
To evaluate the efficacy of atezolizumab compared with single agent chemotherapy 
with respect to antitumor effects as measured by investigator-assessed ORR using 
RECIST v1.1  


 
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 
To evaluate the efficacy of atezolizumab compared with single agent chemotherapy 
with respect to antitumor effects as measured by investigator-assessed 
progression-free survival (PFS) using RECIST v1.1  
 
To evaluate the efficacy of atezolizumab compared with single agent chemotherapy 
with respect to antitumor effects as measured by investigator-assessed duration of 
response (DOR) using RECIST v1.1 
 
To evaluate the efficacy (OS and investigator-assessed PFS using RECIST v1.1) of 
atezolizumab compared with single agent chemotherapy in patients with PD-L1 
expression defined by the PD-L1 SP263 immunohistochemistry (IHC) assay 
SAFETY OBJECTIVE 
The safety objective for this study is: 
 
To evaluate the safety and tolerability of atezolizumab compared with single agent 
chemotherapy  
PATIENT-REPORTED OUTCOME OBJECTIVES 
The patient-reported outcome (PRO) objective for this study is  
 
To evaluate and compare PROs of lung cancer symptoms, patient functioning, and 
health-related quality of life (HRQoL) between treatment arms as measured by the 
European Organisation for Research and treatment of Cancer (EORTC) Quality-of-life 
Questionnaire Core 30 (QLQ C30) and its Lung Cancer Module (QLQ LC13)   
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are: 
 
To evaluate the efficacy of atezolizumab compared with single agent chemotherapy 
with respect to antitumor effects as measured by investigator-assessed ORR, PFS and 
DOR according to modified RECIST (immune-mediated response criteria; imRC) 
 
To evaluate and compare investigator-assessed disease control rates (DCR) between 
the two treatment arms using RECIST v1.1 
 
To evaluate the relationship between the main efficacy endpoints and tumor tissue 
programmed death-ligand 1 (PD-L1) expression   
 
To evaluate the relationship between the main efficacy endpoints and exploratory 
biomarkers in tumor tissue and plasma  
 
To evaluate the relationship between the main efficacy endpoints and the expression of 
immune markers in peripheral blood mononuclear cells (PBMCs)  
 
To generate utility scores for use in economic models for reimbursement by collecting 
patient’s health status data using the EuroQoL-5 Dimensions 5-level (EQ-5D-5L) 
questionnaire 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a Phase III, global, multicenter, open-label, randomized, controlled study designed to 
evaluate the efficacy and safety of atezolizumab compared with a single agent chemotherapy 
regimen by investigator choice (vinorelbine or gemcitabine) in treatment-naïve patients with 
locally advanced or metastatic NSCLC who are deemed unsuitable for any platinum-doublet 
chemotherapy due to poor performance status (Eastern Cooperative Oncology Group 
performance status [ECOG PS] of 2-3). 
However, patients ≥ 70 years of age who have an ECOG PS of 0 or 1 may be included if they 
are deemed unsuitable for platinum doublet chemotherapy by the investigator due to: 
a) 
substantial comorbidities 
b) 
contraindication(s) for platinum-doublet chemotherapy.  
Eligible patients will be stratified by (a) histologic subtype (non-squamous vs squamous), 
(b) PD-L1 immunohistochemistry (IHC) status (positive/negative/unknown) and (c) brain 
metastases (yes/no) and then randomized at a 2:1 ratio to receive either atezolizumab or single 
agent chemotherapy.  


 
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Eligible patients must therefore provide a tumor tissue specimen for central assessment of 
PD-L1 expression by IHC at a central laboratory.  The study will enroll all patients whose tissue 
is evaluable for PD-L1 analysis, regardless of PD-L1 expression status.   
Given the unique toxicities associated with chemotherapy (i.e., alopecia, neutropenia, febrile 
neutropenia) and the pre-medications required (i.e., steroid, anti-emetics, and potentially growth 
factor support), this will be an open-label study. 
No crossover will be allowed between treatment arms. 
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 
21-day cycle.  
Patients randomized to receive single agent chemotherapy (vinorelbine [oral or intravenous] or 
gemcitabine [intravenous]), based on investigator’s choice will receive chemotherapy per 
relevant local guidelines and summary of product characteristics (SmPC) management.  Doses 
and dose modifications for the selected single agent chemotherapy should be made per 
relevant local guidelines and SmPC management.   
At any time-point after RECIST v1.1 criteria for progressive disease are met, patients in the 
experimental arm who show evidence of clinical benefit, will be permitted to continue treatment 
with atezolizumab if they meet all of the following criteria: 
 
Evidence of clinical benefit (i.e., in the absence of symptomatic deterioration attributed 
to disease progression as determined by the investigator after an integrated 
assessment of radiographic data, biopsy results [if available], clinical status, and of 
laboratory values)  
 
Absence of unacceptable toxicity   
 
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 for whom approved therapies exist must provide written consent to 
acknowledge deferring these treatment options in favor of continuing study treatment at 
the time of initial progression.  
Tumor assessments will be performed at baseline, every 6 weeks (± 5 days) following 
randomization for 48 weeks, and every 9 weeks (± 5 days) thereafter, with additional scans as 
clinically indicated. Assessments will continue until disease progression per RECIST v1.1. 
Patients randomized to atezolizumab who continue to receive atezolizumab following disease 
progression will undergo tumor assessments until treatment discontinuation. Tumor 
assessments should continue regardless of whether patients discontinue study treatment or 
start new anti-cancer therapy in the absence of disease progression unless they withdraw 
consent. 
In all patients, response will be assessed by the investigator using RECIST v1 until disease 
progression.  Patients randomized to receive atezolizumab will additionally be assessed by 
modified RECIST criteria until treatment discontinuation.   
Follow-up data capture, including subsequent anticancer therapies, will continue for each 
patient until death, withdrawal of consent, loss to follow up, or study termination by Sponsor, 
whichever occurs first. 
In addition to PD-L1 analysis, exploratory research will be performed on histological tumor 
tissue samples pre-treatment.   
Patients will undergo blood sample collection for exploratory biomarker analyses using plasma 
and PBMCs as per schedule of assessments.  
Tissue and plasma samples will be analyzed for example by methods like IHC, quantitative 
reverse transcriptase PCR (qRT-PCR), next-generation sequencing (NGS) and/or other 
methods to study tumor biomarkers and changes thereof on DNA, RNA and/or protein (or other 
analytes).  These exploratory biomarker evaluations will not be used for any treatment-related 
decisions.  Exploratory analyses aim to study tumor-associated alterations to further understand 
disease pathobiology (including but not limited to mechanisms of disease progression, pseudo-
progression, acquired resistance), to evaluate surrogate biomarkers and to potentially allow for 
the development of blood-based and tissue-based diagnostic tests to help predict which 
patients may benefit from atezolizumab. 


 
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Primary imaging data used for tumor assessment may be collected by the Sponsor to enable 
centralized, independent review of response endpoints, if needed.   
Safety assessments will include the incidence, nature, and severity of adverse events and 
laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v4.0 and assessed by immune-mediated adverse events 
(imAEs) and immune-mediated adverse reactions (imARs) methods.  Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry. An external 
independent Data Monitoring Committee (iDMC) will be assembled and will be responsible for 
monitoring the safety of patients in the study in accordance with a pre specified iDMC charter.   
During the study, assessments will be performed according to the Schedule of Assessments. 
NUMBER OF PATIENTS 
Approximately 120 sites globally will participate in the study, and 441 patients are expected to 
be randomized. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Male or female, age ≥ 18 years 
3. Able to comply with the study protocol, in the investigator’s judgment 
4. Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American 
Joint Committee on Cancer (AJCC) 7th edition  
5. No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 
19 deletions) or anaplastic lymphoma kinase (ALK) fusion oncogene detected 
6. No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for 
multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th edition  
7. Life expectancy ≥ 8 weeks 
8. Deemed unsuitable for any platinum-doublet chemotherapy by the investigator due to poor 
performance status (ECOG PS of 2-3) 
However, patients ≥ 70 years of age who have an ECOG PS of 0 or 1 may be included due 
to: 
a) substantial comorbidities 
b) contraindication(s) for any platinum-doublet chemotherapy 
9. Representative formalin-fixed paraffin-embedded (FPPE) tumor tissue block obtained 
during course of disease (archival tissue) or at screening (tumor blocks are highly preferred 
for central analysis of PD-L1 expression and exploratory biomarkers)  
10. Patients with treated, asymptomatic central nervous system (CNS) metastases are eligible, 
provided they meet all of the following criteria: 
a) Measurable disease outside CNS 
b) Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord) 
c) No ongoing requirement for corticosteroids as therapy for CNS disease; 
anticonvulsants at a stable dose allowed 
d) No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior 
to randomization 
e) No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study 


 
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Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior to 
randomization, if all other criteria are met, including clinical confirmation of no evidence 
of interim disease progression. 
11. Measurable disease (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. 
12. Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 14 days prior to randomization: 
a) Absolute neutrophil count (ANC) ≥ 1500 cells/µL without granulocyte colony-stimulating 
factor support  
b) White blood cell (WBC) counts > 2500/µL 
c) Lymphocyte count ≥ 500/µL 
d) Serum albumin ≥ 2.5 g/dL 
e) Platelet count ≥ 100,000/µL without transfusion (without transfusion within 2 weeks of 
laboratory test used to determine eligibility) 
f) 
Hemoglobin ≥ 9.0 g/dL, patients may be transfused or receive erythropoietic treatment 
to meet this criterion 
g) International normalized ratio (INR) or activated partial thromboplastin time (aPTT) 
≤ 1.5 × upper limit of normal (ULN).  This applies only to patients who are not receiving 
therapeutic anticoagulation; patients receiving therapeutic anticoagulation must have an 
INR or aPTT within therapeutic limits for at least 1 week prior to randomization 
h) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline 
phosphatase ≤ 2.5 × ULN with the following exceptions:  
o 
 Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN 
o 
 Patients with documented liver or bone metastases: alkaline phosphatase 
≤ 5 × ULN 
i) 
Serum bilirubin ≤ 1.5 × ULN.  Patients with known Gilbert’s syndrome who have serum 
bilirubin level ≤ 3 × ULN may be enrolled  
j) 
Serum creatinine ≤ 1.5 × ULN 
13. For female patients of childbearing potential randomized to the atezolizumab treatment 
arm: agreement (by patient and/or partner) to remain abstinent (refrain from heterosexual 
intercourse) or to use highly effective form(s) of contraceptive methods that result in a 
failure rate of < 1% per year when used consistently and correctly during the treatment 
period and for at least 5 months after the last dose of atezolizumab. 
o 
A woman is considered to be of childbearing potential if she is postmenarchal, 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). 
o 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, and established, proper use of hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
o 
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 adequate methods of contraception. 


 
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14. Female patients of childbearing potential and male patients with partners of childbearing 
potential treated in the comparative single agent chemotherapy arm should continue 
contraception use for at least 6 months after the last dose of study treatment.  Such 
methods include: combined (estrogen and progestogen containing) hormonal 
contraception, progestogen-only hormonal contraception associated with inhibition of 
ovulation together with another additional barrier method always containing a spermicide, 
intrauterine device (IUD): intrauterine hormone-releasing system (IUS), bilateral tubal 
occlusion, vasectomized partner (on the understanding that this is the only one partner 
during the whole study duration), and sexual abstinence. Male patients should not donate 
sperm during this study and for at least 6 months after the last dose of comparative single 
agent chemotherapy treatment.  
o 
Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drug.  The same rules are valid for 
male patients involved in this clinical study if they have a partner of childbirth potential. 
Male patients must always use a condom.  
15. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusion Criteria 
1. Patients younger than 70 years who have an ECOG PS of 0 or 1. 
2. Active or untreated CNS metastases as determined by computed tomography (CT) or 
magnetic resonance imaging (MRI) evaluation of the brain during screening and prior 
radiographic assessments 
a) Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for > 2 weeks prior to randomization 
b) Leptomeningeal disease 
c) History of CNS metastases intracranial haemorrhage  
3. Uncontrolled tumor-related pain 
a) Patients requiring pain medication must be on a stable regimen at study entry. 
b) Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment. Patients 
should have recovered from the effects of radiation. There is no required minimum 
recovery period. 
c) Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment. 
4. 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. 
5. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L or 
calcium > 12 mg/dL or corrected serum calcium > ULN)  
6. History of other malignancy within 5 years prior to screening, 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 with curative intent, 
breast ductal carcinoma in situ treated surgically with curative intent)  


 
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7. NCI CTCAE (v4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) 
(excluding alopecia), which have not shown improvement and are strictly considered to 
interfere with current study medication 
8. Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or 
chemoradiotherapy with curative intent for non-metastatic disease must have experienced 
a treatment-free interval of at least 6 months from randomization since the last 
chemotherapy, radiotherapy, or chemoradiotherapy 
General Medical Exclusion Criteria 
9. Women who are pregnant or lactating or intending to become pregnant during the study.  
Women of childbearing potential including women who have had a tubal ligation, must have 
a negative serum pregnancy test result within 14 days prior to initiation of study drug 
10. 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, 
granulomatosis with polyangiitis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple 
sclerosis, vasculitis, or glomerulonephritis 
o 
Patients with a history of autoimmune-mediated hypothyroidism on a stable dose of 
thyroid-replacement hormone may be eligible for this study 
o 
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study 
11. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions: 
a) Rash must cover less than 10% of body surface area (BSA) 
b) Disease is well controlled at baseline and only requiring low potency topical steroids 
c) No acute exacerbations of underlying condition within the last 12 months requiring 
treatment with either psoralen plus ultraviolet radiation (PUVA), methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors or high potency or oral steroids 
12. History of idiopathic pulmonary fibrosis (IPF), 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 
13. Known positivity for human immunodeficiency virus (HIV) 
o 
Testing is not required in the absence of clinical symptoms and signs suggestive of HIV 
infection. 
o 
Patients with a past history of/or symptoms of HIV are eligible only if serological tests 
are negative. 
14. Known active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) or known active hepatitis C   
o 
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 test must be performed in these patients prior to randomization.  
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA 
15. Active tuberculosis 
16. Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
17. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to randomization, 
unstable arrhythmias, or unstable angina   


 
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o 
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or left ventricular ejection fraction (LVEF) < 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 
18. Major surgical procedure other than for diagnosis within 4 weeks prior to randomization or 
anticipation of need for a major surgical procedure during the course of the study 
19. Prior allogeneic bone marrow transplantation or solid organ transplant 
20. Any serious medical condition (including metabolic dysfunction, physical examination 
finding) or abnormality in clinical laboratory tests that, in the investigator’s judgment, 
precludes the patient’s safe participation in and completion of the study or that may affect 
the interpretation of the results or render the patient at high risk for treatment complications 
21. Patients with an illness or condition that may interfere with capacity or compliance with the 
study protocol, as per investigator's judgment  
22. Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 28 days prior to randomization 
Exclusion Criteria Related to Atezolizumab 
23. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
24. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation 
25. Oral or IV antibiotic treatment.  Patients will thus need to have recovered from any infection 
requiring antibiotics.  Patients receiving prophylactic antibiotics (e.g., for prevention of a 
urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
26. 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 
o 
Influenza vaccination is allowed but should be given during influenza season.  However, 
patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 
4 weeks prior to randomization, at any time during the study or within 5 months after the 
last atezolizumab dose 
27. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
anti-programmed death−1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies.  Patients 
who have had prior anti-cytotoxic T lymphocyte−associated antigen 4 (CTLA-4) treatment 
may be enrolled, provided the following requirements are met: 
a) Minimum of 6 weeks from the last dose of anti−CTLA-4 
b) No history of severe immune-mediated adverse effects from anti-CTLA-4 (NCI CTCAE 
Grade 3 and 4) 
28. Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
interleukin-2 [IL-2]) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to 
randomization   
29. Treatment with systemic corticosteroids or other immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents)  
o 
Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after 
discussion with and approval by the Medical Monitor. 
o 
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. 
o 
Patients with history of allergic reaction to IV contrast requiring steroid pre-treatment 
should have baseline and subsequent tumor assessments done by MRI. 
30. Patients not willing to stop treatment with traditional herbal medicines 


 
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Exclusion Criteria Related to Chemotherapy 
31. Known sensitivity and contraindications to the 2 comparative chemotherapy agents, i.e., 
vinorelbine (oral or intravenous) and gemcitabine (intravenous) 
END OF STUDY AND LENGTH OF STUDY 
This study is event-driven, with a recruitment period of approximately 24 months.  The required 
number of 380 events for the final analysis of the primary endpoint of OS is expected to occur 
approximately 42 months after the first patient has been enrolled.  A cut-off date for final 
analysis will be set at least 54 months after first patient in should 380 OS events not be 
reached. 
For patients randomized to the atezolizumab treatment arm, treatment may continue beyond 
disease progression per RECIST v1.1 until loss of clinical benefit, unacceptable toxicity, patient 
or physician decision to discontinue, or death.  For all patients, tumor response data collection 
will continue until disease progression, even if the patient stops study treatment prior to disease 
progression.  Patients randomized to receive atezolizumab who continue study treatment after 
disease progression continue to undergo tumor assessments until treatment discontinuation. 
Follow-up data capture, including subsequent anticancer therapies, will continue for each 
patient until death, withdrawal of consent, loss to follow-up, or study termination by Sponsor, 
whichever occurs first.  
The end of the study is when the required number of deaths has been observed. Additionally, 
the Sponsor may decide to terminate the study at any time. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Atezolizumab, at a dose of 1200 mg, will be administered by IV infusion every 21 days. 
COMPARATORS  
Single agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]) 
based on investigator’s choice will be administered per relevant local guidelines and SmPC 
management.  Doses and dose modifications for the selected single agent chemotherapy 
should be made per relevant local guidelines and SmPC management.    
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy analysis is the comparison of OS between the two treatment arms 
(atezolizumab arm and single agent chemotherapy arm).  
For OS, patients without a date of death will be censored on the date a patient was last known 
to be alive. If no post-baseline data are available, OS will be censored at the date of 
randomization plus 1 day. 
The null and alternative hypotheses for OS analysis can be phrased in terms of comparison of 
survival function S(t) for the two treatment arms:  
Ho: Schemo(t) =SAtezo(t) vs  
H1: Schemo(t) ≠SAtezo(t). 
The hazard ratio (HR) will be estimated using a stratified Cox regression model including 
95% confidence intervals (CIs).  The stratification factors will be: histologic subtype 
(non-squamous/squamous), PD-L1 IHC status (positive/negative/unknown) and brain 
metastases (yes/no). 
An unstratified analysis will also be performed.  
Kaplan-Meier methodology will be used to construct survival curves by treatment arms.  
The median OS and corresponding 95%CI will be provided for each treatment arm.   
If non proportionality of HR is detected, then further analyses and tests will be run. Further 
details on this scenario will be provided in the statistical Analysis Plan (SAP). 
DETERMINATION OF SAMPLE SIZE   
Assuming a 10% withdrawal rate and accrual duration of 24 months, approximately 441 patients 
will be randomized in a 2:1 ratio to atezolizumab (294 patients) or chemotherapy (147 patients). 
A total of 380 OS events will provide 90% power to detect a significant improvement in the 


 
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primary endpoint (median OS) for treatment with atezolizumab versus chemotherapy from 7 
months to 10 months (i.e., HR of 0.7) for a two-sided log-rank test at an alpha level of 5%. 
There is one planned interim analysis at 304 OS events. Operating characteristics (power and 
expected total number of events) for true underlying hazard ratio values of 0.7 are provided in 
the table below.   
Sample Size Calculation Parameters 
 
 
 
    Values 
Randomization ratio (Atezolizumab vs Chemotherapy) 
 
2:1 
Type 1 error (2-sided) 
 
 
 
 
 
 
 
 
5% 
Power 
 
 
 
 
 
 
 
 
 
 
 
90% 
Accrual duration 
 
 
 
 
 
 
 
 
 
24 months 
Duration until OS interim analysis  
 
 
 
 
 
30 months 
Duration until OS final analysis 
 
 
 
 
 
 
42 months 
Assumed drop-out rate  
 
 
 
 
 
 
 
10% 
Median control 
 
 
 
 
 
 
 
 
 
7 months 
Median atezolizumab 
 
 
 
 
 
 
 
 
10 months 
Hazard ratio  
 
 
 
 
 
 
 
 
 
0.7 
Number of events at interim analysis 
 
 
 
 
 
304 
Number of events at final analysis  
 
 
 
 
 
380 
Number of patients  
 
 
 
 
 
 
 
 
441 
 
Note:  This is assuming validity of proportional Hazards assumption.  
 
INTERIM ANALYSES  
An interim analysis of OS will be performed when approximately 304 events in the ITT 
population have been reached. A group sequential design (Lan-DeMets with O’Brien-Fleming 
stopping boundaries) will be used to control the overall type I error rate (Lan and DeMets 1983). 
 
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 planned interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP.  The iDMC charter will 
document potential recommendations the iDMC can make to the Sponsor as a result of the 
analysis and the iDMC charter will also be made available to relevant health authorities, if 
applicable. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-TNF 
anti-tumor necrosis factor 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibody 
AUC 
area under the curve 
BSA 
body surface area 
BSC 
best supportive care  
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CCOD 
clinical cutoff date 
CI  
confidence interval 
CL 
clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CNS 
central nervous system 
CRC 
colorectal carcinoma 
CRO 
clinical research organization 
CRP 
c-reactive protein 
CRS 
cytokine-release syndrome 
CT 
computed tomography 
CTC 
common toxicity criteria 
ctDNA 
circulating tumor DNA 
CTLA-4 
cytotoxic T lymphocyte−associated antigen 4 
Ctrough 
trough concentration 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 


 
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Abbreviation 
Definition 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
ePRO 
electronic PRO 
EQ-5D-5L 
EuroQol 5 dimensions, 5-level questionnaire 
ESMO 
European Society of Medical Oncology 
E.U. 
European Union 
FDA 
Food and Drug Administration 
FPPE 
formalin-fixed paraffin embedded 
5-FU 
5-fluorouracil 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
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 
HIV 
human immunodeficiency virus 
HLH 
hemophagocytic lymphohistiocytosis  
HR 
hazard ratio 
HRQoL 
health-related quality of life 
HUS 
hemolytic-uremic syndrome 
IC 
immune cell 
ICH 
International Conference on Harmonisation 
iDCC 
independent Data Coordinating Center  
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
imAE 
immune mediated adverse event 
imAR 
immune mediated adverse reaction 
IMP 
investigational medicinal product 
imRC 
immune-mediated response criteria 
IND 
Investigational New Drug application 
INR 
international normalized ratio 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 


 
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Abbreviation 
Definition 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IxRS 
interactive voice/web response system 
K-ras 
GTPase Kras 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LOQ 
lower limit of quantification 
LV 
leucovorin 
LVEF 
left ventricular ejection fraction 
MAS 
macrophage activation syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mUC 
metastatic urothelial carcinoma 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NCT 
National Clinical Trial 
NGS 
next-generation sequencing 
NHL 
Non-Hodgkin lymphoma 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
disease progression 
PD-1 
programmed death−1 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
Prescribing Information 
PK 
pharmacokinetic 
popPK 
population pharmacokinetic 


 
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Abbreviation 
Definition 
PRO 
patient-reported outcome 
PS 
performance status 
PUVA 
psoralen plus ultraviolet radiation 
q3w 
every 3 weeks 
QLQ-C30 
Quality-of-life Questionnaire Core 30 
QLQ-LC13 
Quality-of-Life Questionnaire Lung Cancer Module 
QoL 
quality of life 
qRT-PCR 
quantitative reverse transcriptase-polymerase chain 
reaction 
RBC 
red blood cell count 
RBR 
Research Biosample Repository 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
response rate 
SADR 
serious adverse drug reaction 
SAP 
statistical analysis plan 
SCLC 
squamous cell lung carcinoma 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
t1/2 
half live 
T3 
triiodothyronine 
T4 
thyroxine 
TC 
tumor cell 
TKI 
tyrosine kinase inhibitor 
TNBC 
triple-negative breast cancer 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid-stimulating hormone 
TTD 
time to deterioration 
TTF-1 
thyroid transcription factor−1 
TTP 
time-to-progression 
UBC 
urothelial bladder cancer 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
U.S. 
United States 
V1 
central compartment volume of distribution 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 


 
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Abbreviation 
Definition 
WGS 
whole genome sequencing 
 
 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON NON-SMALL CELL LUNG CANCER  
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most 
common cancer in both men and women and accounted for approximately 13% of all 
new cancers in 2008 (Jemal et al. 2011).  In 2016, it was estimated that there would be 
224,390 new cases of lung cancer and 158,080 lung cancer deaths in the United States 
(U.S.) alone (Siegel et al. 2016).  Similar data from Europe estimate that there were 
313,000 new cases of lung cancer and 268,000 deaths in 2012 (GLOBOCAN 2012). 
Non−small cell lung cancer (NSCLC) is the predominant subtype of lung cancer, 
accounting for approximately 85% of all cases (Molina et al. 2008; Howlader et al. 2014).  
NSCLC can be divided into two major histologic types: adenocarcinoma and squamous 
cell carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for more than 
half of all NSCLC, while squamous cell histology accounts for approximately 25% of 
NSCLC (Langer et al. 2010).  The remaining cases of NSCLC are represented by large 
cell carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly 
differentiated histology. 
Half of all newly diagnosed NSCLC patients present with advanced disease (stage IIIb 
and IV) (Davidoff et al. 2010) which directly contributes to poor survival prospects.   
The overall 5-year survival rate for advanced disease is 2%-4%, depending on 
geographic location (Cetin et al. 2011).  Poor prognostic factors for survival in patients 
with NSCLC include advanced stage of disease at the time of initial diagnosis, poor 
performance status (PS), and a history of unintentional weight loss.  More than half of 
the patients with NSCLC are diagnosed with distant disease. 
There are recognized differences in disease characteristics between adenocarcinoma 
and squamous NSCLC.  First, squamous tumors commonly present in the central 
airways and typically remain localized in the bronchial epithelium (Hirsch et al. 2008), 
whereas non-squamous tumors are more commonly located in the lung parenchyma 
distal to the central airways.  Evaluation of NSCLC tumor tissue will reveal cytological 
differences between the squamous cell type (keratinization, intracellular bridges, and 
central necrosis) and adenocarcinoma (glandular architecture).  In cases where the 
tumor sample is poorly differentiated or there is limited tissue available, 
immunohistochemical (IHC) markers may support the histologic diagnosis.  Thyroid 
transcription factor-1 (TTF-1) is infrequently expressed in squamous cells and strongly 
expressed in adenocarcinoma.  In contrast, p63, CK5/6, and 34βE12 are strongly 
expressed in squamous cell carcinoma and less frequently in adenocarcinoma 
(Travis et al. 2011). 
Genetic changes that have prognostic and/or predictive significance in NSCLC include 
mutations in the epidermal growth factor receptor (EGFR), the rearrangement in the 


 
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anaplastic lymphoma kinase (ALK) gene, and mutations in the GTPase Kras (K-ras) 
gene.  The rates of these mutations differ between squamous cell carcinoma and 
adenocarcinoma.  For example, EGFR kinase domain mutations have been reported in 
10%–40% of patients with adenocarcinoma NSCLC but are infrequently observed in 
squamous NSCLC (Herbst et al. 2008).  The ALK fusion oncogene, recognized as a 
driver of lung tumorigenesis, is very rare in the squamous histology but observed in 
approximately 7% of patients with adenocarcinoma (Herbst et al. 2008; Langer et 
al. 2010).  In addition, K-ras mutations are very rare in squamous NSCLC, while they 
can be observed in up to 30% of cases of adenocarcinoma NSCLC (Travis et al. 2011). 
1.2 
FIRST-LINE TREATMENT FOR NSCLC  
Patients with previously untreated NSCLC that does not harbor a driver mutation that 
confers sensitivity to a targeted agent are typically treated with chemotherapy.  The first 
evidence that chemotherapy produced a significant survival benefit in patients with 
advanced NSCLC came in 1995; a meta-analysis showed that platinum-based doublet 
chemotherapy conferred a 2-month improvement in median survival over best supportive 
care (BSC) (NSCLC Collaborative Group 1995).  More recently, the European Big Lung 
Trial demonstrated the potential benefits of chemotherapy.  In this trial, 725 patients with 
advanced NSCLC were randomly assigned to BSC plus cisplatin-based chemotherapy 
or BSC alone (Spiro et al. 2004).  Patients allocated to chemotherapy had a significantly 
longer median survival than did those managed with BSC (8 vs. 5.7 months; hazard ratio 
[HR] = 0.77, 95% confidence interval [CI]: 0.66, 0.89). 
The benefit conferred by platinum-based chemotherapy regimens appears to have 
reached a plateau in overall response rate (approximately 15%−22%) and median 
survival (7−10 months).  More recently, the addition of bevacizumab to carboplatin and 
paclitaxel resulted in an increase in response rate from 15% to 35% and an increase in 
median overall survival (OS) from 10 to 12 months (see Table 1).  
Despite the limited survival benefit conferred by cytotoxic chemotherapy, platinum-based 
regimens remain the standard first-line option for most patients with locally advanced 
and metastatic NSCLC not harboring an activating EGFR mutation or ALK gene 
rearrangement.  In particular, for newly diagnosed advanced stage non-squamous 
NSCLC, standard of care is a platinum doublet with either cisplatin or carboplatin and a 
taxane or pemetrexed, with or without bevacizumab.  However, well-designed clinical 
trials conducted over the last decade have clearly demonstrated that bevacizumab and 
pemetrexed are not appropriate agents for the treatment of patients with squamous cell 
carcinoma of the lung (Johnson et al. 2004; Scagliotti et al. 2008; Sandler et al. 2006).  
The combination of gemcitabine and a platinum analog (either carboplatin or cisplatin) 
has demonstrated efficacy as first-line treatment for NSCLC and, as a result, is often a 
reference arm in clinical trials evaluating new therapeutics (Schiller et al. 2002; Treat et 
al. 2010).  The median duration of progression-free survival (PFS) following treatment 


 
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with gemcitabine and a platinum analog in patients with treatment-naïve advanced 
NSCLC is approximately 4.2-4.7 months. 
In patients with metastatic non-squamous NSCLC who lack an actionable mutation, 
guidelines of the National Comprehensive Cancer Network (NCCN) recommend 
platinum-doublet chemotherapy with or without bevacizumab is recommended (Table 1) 
(Ettinger et al. 2016) 
Current guidelines for first, second and further treatment lines in advanced NSCLC have 
been published by the European Society for Medical Oncology (ESMO) (Novello et al. 
2016) and National Comprehensive Cancer Network (NCCN NSCLC v.3.2017). 
 


 
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Table 1 
Summary of Trials Assessing First- and Second-line Treatment of 
Metastatic Non-Squamous NSCLC Patients Lacking an 
Actionable Mutation 
Treatment Regimen 
Study 
Phase 
Response 
Rate (%) 
Median 
PFS 
(months) 
Median OS 
(months) 
First-line treatment 
Bevacizumab + paclitaxel/carboplatin 
(Sandler 2016, Patel 2013) 
III 
33–35 
5.6–6.2 
12.3–13.4 
Bevacizumab + 
pemetrexed/carboplatin (Patel 2013) 
III 
34.1 
6.0 
12.6 
Cetuximab a + cisplatin/vinorelbine, 
with cetuximab maintenance  
(Pirker 2009) 
III 
Not reported 
Not 
reported 
12.0 b 
Carboplatin/paclitaxel (Sandler 2006) 
III 
15 
4.5 
10.3 
Cisplatin/docetaxel (Fossella 2003) 
III 
31.6 
5.1ǁ 
11.3 
Cisplatin/vinorelbine (Fossella 2003) 
III 
24.5 
5.3ǁ 
10.1 
Cisplatin/paclitaxel (Smit 2003) c 
III 
31.8 
4.2 
8.1 
Cisplatin/gemcitabine (Smit 2003, 
Scagliotti 2008) c 
III 
36.6 
4.7 
8.9–10.4 
Cisplatin/pemetrexed (Scagliotti 
2008) 
III 
Not reported 
5.3 
11.8 
Second-line treatment 
Nivolumab (Borghaei 2015) 
III 
19 
2.3 
12.2 
Pembrolizumab (Herbst 2016) 
II/III 
18.0 d 
18.5 e 
3.9 d 
4.0 e 
10.4 d 
12.7 e 
Ramucirumab + docetaxel  
(Garon 2014) 
III 
23 
4.5 
10.5 
Docetaxel (Borghaei 2015, Garon 
2014, Hanna 2004) 
III 
8.8–14 
2.9–4.2 
7.9–9.4 
Pemetrexed (Hanna 2004, 
Karampeazis 2013) 
III 
9.1–11 
2.9 
8.3–10.1 
Erlotinib (Karampeazis 2013, 
Shepherd 2005, Ciuleanu 2012) 
III 
7.9–9 
2.2–3.6 
5.3–8.2 
Gemcitabine (Cho 2006) 
II 
18.5 
2.3 f 
8.8 f 
OS = overall survival; PFS = progression-free survival. 
a Cetuximab is listed in NCCN guidelines but is not FDA or EMA approved for NSCLC; 
b Patients with adenocarcinoma subtype;  
c Patients with non-squamous and squamous histology; 
d 2 mg/kg dose; 
e 10 mg/kg dose; 
f Estimated from original time in weeks. 
 


 
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In patients with metastatic squamous NSCLC who lack an actionable mutation, NCCN 
guidelines recommend chemotherapy and best standard of care are recommended 
(Ettinger et al. 2016). 
Table 2 
Summary of Trials Assessing First- and Second-line Treatment of 
Metastatic Squamous NSCLC Patients Lacking an Actionable 
Mutation 
Treatment 
Study 
Phase 
ORR  
(%) 
Median PFS 
(months) 
Median OS 
(months) 
First-line 
Gemcitabine/cisplatin  
(Scagliotti 2008) 
III 
Not reported 
5.5 
10.8 
First-line continuation maintenance therapy  
(combined squamous and non-squamous NSCLC population) 
Gemcitabine (Perol 2012) 
III 
Not reported 
3.8 
15.2 
First-line switch therapy  
(combined squamous and non-squamous NSCLC population) 
Docetaxel (Fidias 2009) 
III 
35.9 
5.7 
12.3 
Second-line  
(combined squamous and non-squamous NSCLC population unless noted otherwise) 
Docetaxel (Hanna 2004, Fossella 
2000, Shepherd 2000) 
III 
6.7–8.8 
2.0a–2.9 
5.7–7.9 
Gemcitabine (van Putten 2015) 
II 
13 
Not reported 
6* 
Nivolumab (Brahmer 2015, 
Reckamp 2015) b 
III 
20 
3.5 
7.2 
Pembrolizumab (Soria 2015) 
I 
18.7 
3.0 
11.3 
Ramucirumab + docetaxel (Garon 
2014) 
III 
23 
4.5 
10.5 
ORR = objective response rate; OS = overalls survival; PFS = progression-free survival 
a Estimated from original time in weeks;  
b Patients with squamous disease. 
 
1.2.1 
First-Line Therapy for NSCLC Patients with Poor Performance 
Status  
The majority of patients with newly diagnosed NSCLC present with locally advanced or 
metastatic disease (Carnio et al. 2014).  In addition, the average age at diagnosis of lung 
cancer in the U.S. is about 70 years (Avery et al. 2009, Gajra et al. 2014).  As a result, a 
significant proportion of patients with lung cancer have intercurrent illnesses or comorbid 
conditions that can potentially affect their ability to receive standard therapy for lung 
cancer.   


 
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Patients with lung cancer with a poor PS, irrespective of age, have an increased 
incidence of adverse effects with standard chemotherapy and have a poorer OS 
(Sweeney et al. 2001, Ruckdeschel et al. 1986).  An estimated 30% to 40% of patients 
diagnosed with NSCLC have a poor PS-defined as a score of 2 or higher on the Eastern 
Cooperative Oncology Group (ECOG) scale-because of their disease burden, 
comorbidities, or both (Govindan et al. 2004).   
Performance status is the most powerful independent prognostic factor in advanced 
NSCLC since it is a reliable measure of functional independence, ability to perform daily 
activities and work, and a strong predictor of survival and adverse events (Gebbia et al. 
2005). 
Survival is shorter in patients with advanced NSCLC and a PS of 2 than in those with a 
better PS of 0-1, regardless of therapy (Azzoli et al., 2010).  Patients with a PS of 2 do 
not tolerate chemotherapy as well, and treatment approaches should be different 
(Gridelli et al. 2006).   
Available chemotherapy regimens are associated with substantial toxicities (such as 
febrile neutropenia, myelosuppression, nausea, alopecia, nephropathy, and neuropathy) 
and are generally poorly tolerated by the majority of the elderly and poor-performance 
status NSCLC patients.  For this reason, fear of unacceptable toxicity is still one of the 
major concerns in treatment decisions for PS2 patients (Gridelli et al. 2004).   
There is a dearth of literature clearly defining the management of patients with stage IV 
NSCLC and a PS of 2, including issues such as treatment with single agent versus 
combination and choice of specific agents, such as biologics (Gajra et al. 2014).   
ESMO Guidelines 2016 (Novello et al. 2016) reference a recently published meta-
analysis of randomised trials comparing the efficacy and safety of platinum-based 
doublets versus single-agent regimens in the first-line therapy of PS2 patients, which 
revealed platinum-based regimens to be superior in terms of RR and survival 
(74% higher probability of being alive after 1 year) despite an increase in toxicities 
(mainly haematological).  In addition, the superiority of carboplatin-based combinations 
over monotherapy in PS2 patients has been identified in a subgroup analysis within 
large phase III trials, with an acceptable toxicity profile.  Moreover, combination 
chemotherapy with carboplatin significantly improved survival compared with 
monotherapy alone in patients with PS2.  Therefore, platinum-based (preferably 
carboplatin) doublets should be considered in eligible PS2 patients.   
Single-agent chemotherapy with gemcitabine, vinorelbine and docetaxel represents an 
alternative treatment option (Novello et al. 2016).  In this subgroup of patients, there are 
instances where poor PS is attributable to a high tumor burden, and improved PS may 
be expected in response to treatment.  In other cases, poor PS may be related to co-
morbidity, and a worsening PS may be expected during treatment. Therefore, clinicians 


 
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and patients should always discuss the risks and benefits of chemotherapy and should 
make a joint decision.  Poor PS (3-4) patients should be offered BSC in the absence of 
documented activating (sensitizing) EGFR mutations or ALK rearrangements.   
Recent studies that have examined single agents versus 2-drug combinations for 
patients with PS2 include 3 Phase III trials with planned subgroup analyses by PS, a 
phase II trial designed exclusively for patients with PS 2, a Phase II trial comparing 
traditional cytotoxic chemotherapy with erlotinib in patients with PS, and a recently 
published Phase III trial comparing carboplatin-based combination therapy to a single 
agent restricted to patients with PS2 (Novello et al. 2016).   
Taken together, the median PFS and median OS with platinum-based combination 
chemotherapy are numerically and, in some studies, statistically superior to those 
measures in patients with PS2 treated with monotherapy.  Notably, this improvement in 
survival comes with higher toxicity, including the risk of treatment-related death with 
combination therapy, ranging from 3.0% to 7.4% (Gajra et al. 2014). 
There is currently a highly unmet medical need for novel safe treatment options that 
deliver an improved therapeutic index in newly diagnosed advanced, recurrent or 
metastatic NSCLC deemed unsuitable for any platinum-doublet chemotherapy due to 
poor performance status and/or comorbidities. 
Targeted agents are widely believed to provide effective and less-toxic therapy while 
allowing patients to maintain their functional independence (Gonsalves and Ganti, 2011). 
As a result, great interest has been shown in using targeted agents in patients with poor 
PS.  Data from 2 trials suggest that erlotinib and gefitinib do not have a role in patients 
with poor PS without activated EGFR mutations (Lilenbaum et al. 2008, Goss et al. 
2009). 
Clinical data in the field of tumor immunotherapy have demonstrated that therapies 
focused on enhancing T-cell responses against cancer, such as atezolizumab, 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).  
Immune checkpoint inhibition such as targeting the programmed death-ligand 1 (PD-L1) 
pathway with atezolizumab may provide a safe, less toxic and similarly efficacious 
treatment alternative to single agent chemotherapy for newly diagnosed patients with 
advanced or metastatic NSCLC who are considered unsuitable for platinum-containing 
chemotherapy due to low performance status, substantial comorbidities or 
contraindications to chemotherapy.  Immune checkpoint inhibition treatment could 
increase the proportion of treatment naive advanced or metastatic NSCLC patients with 
low performance status who could be considered eligible for treatment (see also 
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1.2.2 
Platinum-Based Regimen for First-Line NSCLC  
Currently, the standard-of-care for newly diagnosed advanced stage NSCLC is a 
platinum doublet with either cisplatin or carboplatin and a taxane or pemetrexed, with or 
without bevacizumab.  In particular, the combination of platinum doublet with 
pemetrexed has been used more widely because of a better tolerability and safety profile 
(see also Section 1.2.3.1). 
Pemetrexed disodium for injection was approved in 2008 by the U.S. Food and Drug 
Administration (FDA) for use in combination with cisplatin therapy for the initial treatment 
of patients with locally advanced or metastatic NSCLC.  Pemetrexed is not indicated for 
treatment of patients with squamous cell lung carcinoma (SCLC). 
Several meta-analyses have compared the use of cisplatin and carboplatin as 
treatments for NSCLC.  In general, although the objective response rate (ORR) was 
higher in patients treated with cisplatin than in those treated with carboplatin, the 1-year 
and OS rates were comparable.  When given in combination with a third-generation 
chemotherapy, cisplatin may result in longer survival than carboplatin (overall response 
of 30% vs. 24% respectively; Hotta et al. 2004; Ardizzoni et al. 2007), but with quite 
marginal overall benefit.  Subgroup analyses including additional, more recent trials 
indicate that there may be no difference between the two agents (Azzoli et al. 2010; 
Jiang et al. 2007). 
As to safety, cisplatin-based chemotherapy has been associated with more severe 
nausea and vomiting and nephrotoxicity, while severe thrombocytopenia has been more 
frequent during carboplatin-based chemotherapy (Hotta et al. 2004; Ardizzoni et al. 
2007).  The risk of treatment-related deaths was greater in the cisplatin arm, but this 
increase was not statistically significant (Jiang et al. 2007). 
While randomized trials demonstrate that chemotherapy improves survival and quality of 
life in advanced NSCLC (Davidoff et al. 2010, Pfister et al. 2004) with two-drug platinum 
based regimens (platinum doublets) indicating a survival advantage compared with 
single agents (Sandler et al. 2000, Schiller at al. 2002, Kelly et al. 2001), the evidence of 
treatment efficacy for patients with diminished PS or with age older than 70 years is 
limited, as these patients are frequently excluded from clinical trials due to the potential 
for toxicity and an expectation of limited benefit (Gridelli et al. 2007).  Patients with 
ECOG PS ≥ 2 have been shown to experience inferior outcomes when included in 
clinical trials (Davidoff et al. 2010).   
Subset analyses of trials for patients with advanced NSCLC with eligibility ranging from 
PS 0 to 2 have historically shown that PS2 patients experience a much shorter survival, 
in the range of 3 to 4 months (Sweeney 2001, Soria et al. 2001, Quoix et al. 2011) 
highlighting the potential value of studying this population as a distinct clinical entity for 
which different treatment recommendations may be appropriate. 


 
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Current ESMO guidelines (Novello 2016) recommend to consider first-line chemotherapy 
with platinum doublets in all stage IV NSCLC patients with EGFR- and ALK-negative 
disease, without major comorbidities and PS 0-2.  
1.2.3 
Non-Platinum Based Chemotherapy for NSCLC PS2 Patients 
After 1995, some advantage of chemotherapy versus supportive care alone has been 
shown not only with platinum-based combination chemotherapy (Cullen et al. 1999, 
Billingham et al. 2001, Stephens et al. 2002) but also with many other cytotoxic agents 
such as gemcitabine (Anderson et al. 2000), vinorelbine (ELVIS group. 1999), paclitaxel 
(Anderson et al. 2000) and docetaxel (Roszkowski et al. 2000), administered as single 
agents.  These drugs are usually characterized by a good tolerability, with a low 
incidence of severe adverse events.  Most of the studies show some advantage of 
chemotherapy in terms of overall survival also in the sub-group of PS2 patients, although 
formal statistical comparisons are precluded by the low absolute number of patients 
(Gridelli et al. 2006). 
Fear of unacceptable toxicity is one of the major concerns in treatment decisions for PS2 
patients and, from this point of view, platinum-free combination chemotherapy deserves 
attention as it is potentially less toxic than platinum-based treatment (Gridelli et al. 2006).  
Several trials comparing platinum free combinations containing new cytotoxic agents 
versus platinum-based treatment, enrolling patients with PS between 0 and 2, have been 
performed (Georgoulias et al. 2001, Kosmidis et al. 2002, Giaccone et al. 2002, Alberola 
et al. 2003, Gridelli et al. 2003).  These trials are characterized by a remarkable 
heterogeneity among the drugs and schedules studied.  As expected, platinum-based 
treatment is often associated with a higher occurrence of toxicity (Georgoulias et al. 
2001, Gridelli et al. 2003). 
Although a trend of slightly lower efficacy of combination chemotherapy without platinum 
is reported in some trials (Giaccone et al. 2002, Gridelli et al. 2003), none of the trials 
show a statistically significant advantage for platinum-containing schedules.  No 
significant interaction between treatment and PS in terms of overall survival is described, 
and platinum-free combination chemotherapy could represent a reasonable, less toxic 
option for PS2 patients (Gridelli et al. 2006).   
However, there is no consistent evidence that combination chemotherapy without 
platinum is better than third generation drugs given as single agents.  An Italian 
randomised trial compared the combination of gemcitabine and vinorelbine to the two 
single drugs in patients > 70 years of age (Gridelli et al. 2003).  PS2 patients 
represented 18-19% in each of the 3 arms of the study.  The primary analysis of the 
study showed that the combination was more toxic, but it did not show advantage over 
monochemotherapy in terms of overall survival.  Also, in the sub-group of PS2 patients 
(130 patients), there was no advantage for combination chemotherapy over single 
agents. 


 
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The results of a European Experts Panel on the topic, indicate that single-agent 
chemotherapy could be the preferred option in the treatment of PS2 patients, with 
carboplatin-based or low-dose cisplatin-based doublets representing alternative options 
(Gridelli et al. 2004). 
Gemcitabine is one of the most widely used drugs for the treatment of NSCLC (Gridelli 
et al. 2006).  The taxanes (paclitaxel and docetaxel) have demonstrated both activity 
and tolerability in the treatment of advanced NSCLC (Gridelli et al. 2006).  Among the 
third-generation chemotherapy drugs, the vinca alkaloid vinorelbine showed better than 
supportive care controls on many quality of life (QoL) subscales in elderly NSCLC 
patients (Gridelli et al. 2006).  Single-agent therapy with pemetrexed is an option for PS2 
chemonaïve patients with excessive comorbidities and those who cannot tolerate 
combination therapy (Zinner et al. 2016).   
A systematic database review, performed in 2014, on patients who are considered not 
suitable candidates for platinum treatment found low-quality evidence suggesting that 
non-platinum combination and single-agent therapy regimens have similar effects on 
survival (Santos et al. 2015).    
A comparison of 4 studies assessing OS in PS2 patients treated with gemcitabine, 
docetaxel, pemetrexed and vinorelbine or gemcitabine respectively, is shown in Table 3.  
Table 3 
Overall Survival in PS2 Patients Treated with Gemcitabine, 
Docetaxel, Pemetrexed and Vinorelbine or Gemcitabine, 
respectively 
Publication 
Number of 
Patients 
Performance 
Status 
Chemo-
therapy 
Median OS 
estimate 
(months) 
95% CI 
(months) 
Morère 2010 
42  
PS2  
Gemcitabine 
2.4 
(1.6-4.4) 
Morère 2010 
42  
PS2  
Docetaxel 
3.5  
(1.8-6.6) 
Zukin 2013 
102 
PS2 
Pemetrexed 
5.3 
(4.1-6.5) 
Lilenbaum 
2009 
190 
PS2 
Vinorelbine 
or 
Gemcitabine 
6.6 
(5.8-7.3) 
CI = confidence interval; OS = overall survival 
 
1.2.3.1 
Pemetrexed Monotherapy 
Pemetrexed disodium (Alimta®) a third-generation multi-targeted antifolate (Shih et al. 
1998), is currently approved in the U.S. and European Union (E.U.) for use in locally 
advanced or metastatic NSCLC in initial first-line treatment in combination with cisplatin, 
as a single agent in maintenance treatment for patients whose disease has not 


 
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progressed after 4 cycles of platinum-based first-line chemotherapy, and as second-line 
treatment after prior therapy (Zinner et al. 2016 and references therein).   
The pemetrexed first-line and maintenance NSCLC registration trials enrolled patients 
with a PS of 0-1 (Zinner et al. 2016), whereas the second line registration trial enrolled 
patients with a PS of 0-2 (Hanna et al. 2004).  
A multi-center, randomized, double-blind, placebo-controlled Phase III study (JMEN), 
compared the efficacy and safety of maintenance treatment with pemetrexed plus BSC 
(N = 441) with that of placebo plus BSC (N = 222) in patients with locally advanced 
(Stage IIIB) or metastatic (Stage IV) NSCLC who did not progress after 4 cycles of first-
line doublet therapy containing cisplatin or carboplatin in combination with gemcitabine, 
paclitaxel, or docetaxel.  First-line doublet therapy containing pemetrexed was not 
included.  All patients included in this study had an ECOG PS of 0 or 1.  Patients 
received maintenance treatment until disease progression.  Efficacy and safety were 
measured from the time of randomization after completion of first-line (induction) 
therapy.  Patients received a median of 5 cycles of maintenance treatment with 
pemetrexed and 3.5 cycles of placebo.  A total of 213 patients (48.3%) completed ≥ 6 
cycles and a total of 103 patients (23.4%) completed ≥ 10 cycles of treatment with 
pemetrexed.   
The JMEN study met its primary endpoint and showed a statistically significant 
improvement in PFS in the pemetrexed arm over the placebo arm (N=581, 
independently reviewed population; median of 4.0 months and 2.0 months, respectively) 
(HR=0.60, 95% CI=0.49-0.73, p<0.00001).  The independent review of patient scans 
confirmed the findings of the investigator assessment of PFS.  The median OS for the 
overall population (N = 663) was 13.4 months for the pemetrexed arm and 10.6 months 
for the placebo arm, HR=0.79 (95% CI=0.65-0.95, p=0.01192).  For details refer to 
Alimta® prescribing information. 
A review of the literature on studies involving the use of pemetrexed in patients with 
advanced NSCLC and a PS of 2 concluded that single-agent therapy remains an option 
for PS2 chemonaïve patients with excessive comorbidities and those who cannot 
tolerate combination therapy (Zinner et al. 2016).  The authors concluded that supportive 
care with a focus on palliation of symptoms is important for all patients; and that quality 
of life should be a key determinant in selecting treatment. 
1.2.3.2 
Docetaxel Monotherapy 
Docetaxel (Taxotere®) is a member of the taxane family of antineoplastic agents and 
mediates its cytotoxic activity by inhibiting microtubule depolymerization. Docetaxel is 
administered intravenously (IV). 
Docetaxel monotherapy is indicated for the treatment of locally advanced or metastatic 
NSCLC after failure of prior platinum-based chemotherapy. Docetaxel is also indicated in 


 
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combination with cisplatin for the treatment of unresectable, locally advanced or 
metastatic NSCLC in patients who have not previously received chemotherapy. The 
recommended dosage is 75 mg/m² IV over 1 hour every three weeks (q3w).  
In NSCLC, docetaxel phase-III trials confirmed its effectiveness in pretreated and 
chemotherapy-naive patients. Single agent docetaxel showed significant improvement in 
both survival and quality of life when compared to either best supportive care or 
standard chemotherapy in previously treated patients. Therefore, it is considered 
standard for NSCLC second-line chemotherapy.  
1.2.3.3 
Gemcitabine Monotherapy 
Gemcitabine (Gemzar®) is a nucleoside metabolic inhibitor and is given in the 
management of solid tumors. Gemcitabine is indicated as first-line treatment of patients 
with locally advanced or metastatic NSCLC, in combination with cisplatin. Gemcitabine 
monotherapy can also be considered in elderly patients or those with PS2. 
Gemcitabine at 1250 mg/m2 is given intravenously on days 1 and 8 of each q3w cycle. 
In a randomised phase III study of 522 patients with inoperable, locally advanced or 
metastatic NSCLC, gemcitabine in combination with cisplatin showed a statistically 
significant higher response rate than cisplatin alone (31.0% and 12.0%, respectively, 
p<0.0001).  A statistically significant prolongation of the time to progression, from 3.7 to 
5.6 months (log-rank p<0.0012) and a statistically significant prolongation of median 
survival from 7.6 months to 9.1 months (log-rank p<0.004) was observed in patients 
treated with gemcitabine/cisplatin compared to patients treated with cisplatin.  In another 
randomised phase III study of 135 patients with stage IIIB or IV NSCLC, a combination 
of gemcitabine and cisplatin showed a statistically significant higher response rate than a 
combination of cisplatin and etoposide (40.6% and 21.2%, respectively, p=0.025).  A 
statistically significant prolongation of the time to progression, from 4.3 to 6.9 months 
(p=0.014) was observed in patients treated with gemcitabine/cisplatin compared to 
patients treated with etoposide/cisplatin.  In both studies it was found that tolerability was 
similar in the two treatment arms (see gemcitabine SmPC).  
ESMO Guidelines (Novello 2016) recommend gemcitabine single-agent chemotherapy 
as an alternative treatment option in patients with metastatic NSCLC and a PS of 2 and 
beyond. The NCCN Guidelines Version 3.2017 recommend gemcitabine as 
monotherapy after progression on doublet chemotherapy or bevacizumab plus 
chemotherapy in patients with PS 0-2, and as maintenance therapy in PS2 patients 
following response to chemotherapy or stable disease.  
1.2.3.4 
Vinorelbine Monotherapy (Intravenous and Oral) 
Vinorelbine tartrate (Navelbine®) is a semi-synthetic vinca alkaloid with antitumor activity. 
Vinorelbine is indicated as a single agent or in combination for first-line treatment of 
stage III or IV NSCLC.   


 
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Vinorelbine is available as concentrate for solution for infusion and as soft capsule for 
oral administration.  
Single-agent vinorelbine was studied in a North American, randomized clinical trial in 
which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky PS ≥ 70 
were treated with vinorelbine (30 mg/m2) weekly or 5-fluorouracil (5-FU) (425 mg/m2 IV 
bolus) plus leucovorin (LV) (20 mg/m2 IV bolus) daily for 5 days every 4 weeks.  A total 
of 211 patients were randomized at a 2:1 ratio to vinorelbine (143) or 5-FU/LV (68). 
Vinorelbine showed improved survival time compared to 5-FU/LV. In an intent-to-treat 
analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving 
vinorelbine versus 5-FU/LV, respectively (p=0.06). The 1-year survival rates were 24% 
(±4% SE) for vinorelbine and 16% (±5% SE) for the 5-FU/LV group, using the Kaplan-
Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or 
slightly better than that usually observed in untreated patients with advanced NSCLC, 
suggesting that the difference was not related to some unknown detrimental effect of 
5-FU/LV therapy. The response rates (all partial responses) for vinorelbine and 5-FU/LV 
were 12% and 3%, respectively. 
ESMO Guidelines 2016 (Novello 2016) recommend vinorelbine single-agent 
chemotherapy as an alternative treatment option in patients with metastatic NSCLC and 
a PS of 2 and beyond. The NCCN guidelines v. 3.2017 recommend vinorelbine single 
agent chemotherapy as second line treatment in patients who have experienced disease 
progression either during or after first-line therapy.  
1.3 
TARGETED THERAPY FOR NSCLC  
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC (mainly non-squamous histology) 
characterized by alterations of driver oncogenes, including sensitizing EGFR mutations 
and ALK rearrangements.  However, these mutations are more prevalent in 
adenocarcinoma NSCLC and are very rare in squamous NSCLC.   
Randomized Phase III trials of gefitinib (IPASS), erlotinib (EURTAC), and afatinib (Lux-
Lung 3) showed significant improvement of PFS and ORR compared with platinum 
doublet chemotherapy (Fukuoka et al. 2011; Rosell et al. 2012; Yang et al. 2012; 
respectively).  Similarly, the ALK inhibitor crizotinib has demonstrated efficacy in patients 
with NSCLC positive for ALK rearrangement as defined by fluorescence in situ 
hybridization (Crino et al. 2011; Camidge et al. 2012; Shaw et al. 2012; Shaw and 
Engelman 2014; Xalkori® U.S. Package Insert). 
A randomized open-label Phase III trial demonstrated superior PFS of alectinib to 
crizotinib in NSCLC patients positive for ALK rearrangement without prior ALK inhibitor 
treatment.  Treatment on both arms was continued until disease progression (PD) or 
unacceptable toxicity.  The PFS HR of the alectinib arm to crizotinib arm was 0.34 
(99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001).  Grade 3-4 adverse events (AEs) 


 
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occurred with greater frequency in the crizotinib arm (51%) compared to the alectinib 
arm (27%).  There were no treatment related deaths in either arm (Nokihara et al. 2016). 
Crizotinib (Xalkori) and ceritinib (Zykadia) are approved by the FDA for treatment of 
NSCLC.  Alectinib (Alecensa) was approved by the U.S. FDA in December 2015 to treat 
patients with advanced ALK-positive NSCLC whose disease worsened after, or who 
could not tolerate, treatment with crizotinib. These drugs have demonstrated robust 
clinical activity in patients who developed resistance to crizotinib, and they are now 
being investigated in the first-line setting (Katayama et al. 2015). Current ESMO 
guidelines recommend crizotinib as the preferred first-line treatment of patients with 
ALK-rearranged NSCLC (Novello et al 2016).  
Gainor et al. (2016) found that second-generation inhibitors are generally effective even 
in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition 
of ALK by crizotinib in many cases.  The authors found that each ALK inhibitor is 
associated with a distinct spectrum of ALK resistance mutations and that the frequency 
of one mutation, ALKG1202R, increases significantly after treatment with second-
generation agents.  The presence of ALK resistance mutations is highly predictive for 
sensitivity to the third-generation ALK inhibitor lorlatinib, whereas those cell lines without 
ALK mutations are resistant. 
Despite current progress in treatment of patients with EGFR mutations and ALK 
rearrangements, survival rates for advanced disease remain low and acquired 
resistance to targeted agents is a major clinical problem.  Therefore, alternative 
treatment options that yield durable responses and enhance OS remain an important 
focus of research.  Against this background, immunotherapeutic agents, such as cancer 
vaccines and antibodies that modulate immune cell activity, offer an alternative 
treatment approach that could potentially improve the prognosis of patients with this 
disease.  
1.4 
SECOND-LINE TREATMENT FOR NSCLC 
The large majority of NSCLC patients ultimately progress after first-line treatment 
(Bluthgen and Blesse 2015).  Many factors are taken into account when choosing further 
therapy, including performance status, previous treatment, histology and the presence of 
a driver mutation (Bluthgen and Blesse 2015).  However, only 50–70% of patients with 
advanced NSCLC patients will have second line treatment, while a substantial proportion 
of patients do not get further therapy due to side effects or low performance status 
(Chen et al. 2013). 
Several guidelines recommend erlotinib, pemetrexed, or docetaxel for second-line 
chemotherapy in patients with advanced NSCLC (Nishiyama et al. 2015, Carnio et al. 
2014).  There is growing evidence that cytotoxics are better than EGFR-tyrosine kinase 
inhibitors (TKIs) in EGFR wild-type patients. 


 
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Patients with a good performance status in second-line trials have a median survival 
duration of approximately 8 to 9 months and may receive two salvage therapies during 
the course of their treatment (Stinchcombe et al. 2008).   
A retrospective study performed in the U.S. (Pan et al. 2013) assessed actual 
second-line treatment patterns and outcomes in NSCLC patients with stage IIIB/IV at 
diagnosis and an ECOG PS < 3.  The most frequently used second-line therapies were 
pemetrexed (54.4%), erlotinib-containing regimens (17.6%), and docetaxel (10.0%).  
Median OS and PFS were 7.5 (95% CI: 6.6–8.4) and 4.1 (95% CI: 3.7-4.5) months, 
respectively.  Compared with other second-line treatment, erlotinib-containing regimens 
prolonged adjusted time-to-progression (TTP) (HR = 0.69; p=0.015). 
In NSCLC patients with ECOG PS ≥ 2, chemotherapy prolongs survival and possibly 
improves QoL (Gridelli et al. 2004), when compared with BSC.  Single-agent 
chemotherapy with gemcitabine, vinorelbine, and taxanes represents an option 
(Gridelli et al., 1999).  
A recent study (Maneechawakajorn et al. 2016) compared QoL achieved by carboplatin 
plus etoposide as third-line chemotherapy (27 cases) compared with BSC (20 cases) in 
NSCLC Stage IIIB/IV patients.  No statistically significant differences were found in 
baseline characteristics and QoL in the two groups.  The median PFS after two months 
was significantly higher (88.9% vs. 75.0%, p<0.001) in the chemotherapy group than in 
the best supportive care group, but there were no statistically significant differences 
between QoL of patients in the two groups. 
1.5 
IMMUNOTHERAPY IN METASTATIC NSCLC 
Immunotherapeutic targeting of PD-L1 or programmed cell death protein 1 (PD-1) is 
revolutionizing the treatment of metastatic NSCLC (see next section for mechanism).  
Currently, two anti-PD-1 therapeutic antibodies (pembrolizumab and nivolumab) 
(Keytruda PI, Opdivo PI) and one anti-PD-L1 antibody (atezolizumab) (Tecentriq PI) 
have been approved for treatment of NSCLC.  All three of these agents are 
recommended as second-line agents in advanced NSCLC after prior progression on 
platinum-containing chemotherapy. 
As the current clinical study focuses exclusively on atezolizumab, a detailed summary of 
the efficacy and safety profiles of atezolizumab is provided in subsequent sections.   
A brief summary of the activities of the two approved anti-PD-1 agents is provided in 
Table 4. 


 
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Table 4 
Nivolumab and Pembrolizumab Immunotherapy in Advanced 
NSCLC 
Trial 
Checkmate 017 
(Brahmer 2015, 
Reckamp 2015) 
Checkmate 057  
(Borghaei 2015) 
Keynote 010 
(Herbst 2016) 
Therapy 
2L nivo vs. doc 
2/3L nivo vs. doc 
≥2L pembro vs. 
doc 
n 
272 
582 
1033 
Histology 
Squamous 
Non-squamous 
All comers 
PD-L1 selected 
No 
No 
Yes (TPS ≥ 1) a 
Median OS (months) 
9.2 vs. 6.0 
12.2 vs. 9.4 
12.7 b vs. 8.5 
Median PFS 
(months) 
3.5 vs. 2.8 
2.3 vs. 4.2 
4.0 b vs. 4.0 
ORR (%) 
20% vs. 9% 
19% vs. 12% 
18% b vs. 9% 
Doc = docetaxel; L = line; nivo = nivolumab; ORR = objective response rate; OS = overall 
survival; PD-L1 = programmed death-ligand 1; pembro = pembrolizumab; PFS = progression-free 
survival; TPS = tumor proportion score. 
a Tumor proportion score (TPS) is the proportion of viable tumor cells showing partial or 
complete membrane PD-L1 expression. 
b 10 mg/kg q3w dose. 
 
Current ESMO Guidelines (Novello et al. 2016) state that PD-L1-positive tumor patients 
benefitted from the use of nivolumab (Opdivo), compared with docetaxel.  In PD-L1-
negative tumors, nivolumab and docetaxel showed similar results, with a more favorable 
toxicity profile for nivolumab.  Ramucirumab (Cyramza) combined with docetaxel is 
described as a treatment option in patients with NSCLC progressing after first-line 
chemotherapy with PS 0-2.  In patients unfit for chemotherapy, erlotinib (Tarceva) is 
described as a potential option in patients with unknown EGFR status, wild-type EGFR 
and unfit for chemotherapy (Novello et al. 2016).  
The NCCN Panel recommends immune checkpoint inhibitors nivolumab, 
pembrolizumab, and atezolizumab as preferred options for subsequent therapy for all 
histologic subtypes based on improved survival rates, longer duration of response, and 
fewer adverse events when compared with cytotoxic chemotherapy see NCCN 
Guidelines v.3 2017 NSCLC, page MS-55).  
1.6 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab (MPDL3280A) is a humanized IgG1 monoclonal antibody consisting of two 
heavy chains (448 amino acids) and two light chains (214 amino acids) and is produced 
in Chinese hamster ovary cells.  Atezolizumab was engineered to eliminate Fc-effector 
function via a single amino acid substitution at position 298 on the heavy chain, which 
results in a non-glycosylated antibody that has minimal binding to Fc receptors and 
prevents Fc-effector function at expected concentrations in humans. 


 
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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. 
On 18 Oct 2016, U.S. FDA approved atezolizumab for the treatment of patients with 
metastatic NSCLC whose disease progressed during or following platinum-containing 
chemotherapy.  Patients with EGFR or ALK genomic tumor aberrations should have 
disease progression on FDA-approved therapy for these aberrations prior to receiving 
atezolizumab. 
This approval was based on two international, randomized, open-label clinical trials 
(OAK and POPLAR) that demonstrated consistent results in efficacy and safety in a total 
of 1137 patients with NSCLC.  Compared with docetaxel, treatment with atezolizumab in 
the intended patient population in the two trials resulted in a 4.2 and a 2.9 month 
improvement in OS, respectively.   
The median OS in OAK was 13.8 months (95% CI 11.8,15.7) in the atezolizumab arm 
compared to 9.6 months (95% CI 8.6,11.2) in the docetaxel arm (HR=0.74 [95% CI 
0.63,0.87]; p=0.0004).  The median OS in POPLAR was 12.6 months (95% CI 9.7, 16.0) 
and 9.7 months (95% CI 8.6, 12.0) (HR=0.69 [95% CI 0.52, 0.92]) for the atezolizumab 
and docetaxel arms, respectively. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma. 
1.6.1 
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, PK, 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 


 
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proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical trials in patients. 
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies. 
1.7 
CLINICAL EXPERIENCE WITH ATEZOLIZUMAB 
Refer to the Atezolizumab Investigator’s Brochure for details on all clinical studies 
conducted to date. 
1.7.1 
Clinical Studies in NSCLC 
Atezolizumab clinical data are available from multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  Single-agent safety and 
efficacy studies that include patients with NSCLC include: 
 
Study PCD4989g is multicenter, first-in-human, open-label Phase Ia, dose-
escalation study evaluating the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of 
biologic activity of atezolizumab administered as a single agent by IV infusion q3w to 
patients with locally advanced or metastatic solid malignancies or hematologic 
malignancies. 
 
Study GO28625 (FIR) is an open-label, non-controlled, single-arm Phase II study of 
atezolizumab in PD-L1−positive patients with locally advanced or metastatic NSCLC, 
with the evaluation of ORR (modified Response Evaluation Criteria in Solid Tumors 
[modified RECIST] criteria) as the primary endpoint.  This study seeks to better 
understand whether the assessment of PD-L1 by IHC in fresh biopsy versus archival 
specimens is more predictive of response to atezolizumab. 
 
Study GO28753 (POPLAR) is an open-label, randomized, Phase II study of 
atezolizumab compared with docetaxel in patients with locally advanced or 
metastatic NSCLC following progression on a platinum-containing regimen.  Eligible 
patients were enrolled regardless of PD-L1 status and stratified by PD-L1 
expression.  The primary endpoint is OS.   
 
Study GO28915 (OAK) is an open-label, randomized, Phase III study of 
atezolizumab compared with docetaxel in patients with locally advanced or 
metastatic NSCLC after failure with platinum-containing chemotherapy.  
 
Study GO28754 (BIRCH) is an open-label, non-controlled, single-arm Phase II study 
of atezolizumab in PD-L1−positive patients with locally advanced or metastatic 
NSCLC. 


 
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 
Study GO29527 (IMpower010) is a randomized, open-label Phase III study of 
atezolizumab compared with best supportive care following adjuvant cisplatin-based 
chemotherapy in patients with completely resected Stage IB to IIIA NSCLC. 
 
Study GO29431 (IMpower110) is a randomized, open-label Phase III study of 
atezolizumab compared with cisplatin/carboplatin + pemetrexed or 
cisplatin/carboplatin + gemcitabine in PD-L1−selected chemotherapy-naïve patients 
with Stage IV non-squamous NSCLC.  
 
Study GO29436 (IMpower150) is an open-label Phase III study of atezolizumab + 
carboplatin + paclitaxel with or without bevacizumab compared with carboplatin + 
paclitaxel + bevacizumab in chemotherapy-naïve patients with Stage IV 
non-squamous NSCLC. 
 
Study GO29537 (IMpower130) is a randomized, open-label Phase III study of 
atezolizumab + carboplatin + nab-paclitaxel compared with carboplatin + 
nab-paclitaxel in chemotherapy-naïve patients with Stage IV non-squamous NSCLC. 
 
Study GO29437 (IMpower131) is a Phase III, open-label, multicenter, randomized 
study evaluating the efficacy and safety of atezolizumab in combination with 
Carboplatin+ Paclitaxel or atezolizumab in combination with carboplatin+nab-
paclitaxel versus carboplatin+nab-paclitaxel in chemotherapy-naive patients with 
stage IV NSCLC. 
 
GO29438 (IMpower132) is a phase III, open-label, randomized study of 
atezolizumab in combination with carboplatin or cisplatin + pemetrexed compared 
with carboplatin or cisplatin + pemetrexed in patients who are chemotherapy-naive 
and have stage IV NSCLC. 
1.7.2 
Clinical Safety 
1.7.2.1 
Single-Agent Clinical Safety in Patients with Non-Small Cell 
Lung Cancer in Study PCD4989g 
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.  It provides significant data (with 
629 safety-evaluable patients across all cancer types as of the data cutoff date of 
15 December 2015) for the safety profile of atezolizumab as monotherapy. 
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined. 


 
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The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications, including small cell lung cancer, NSCLC, urothelial carcinoma (UC), 
renal cell carcinoma (RCC), melanoma, gastric cancer, colorectal cancer, head and neck 
cancer, breast cancer, and sarcoma.   
Of the 629 patients across all cancer types in Study PCD4989g, 619 patients (98.4%) 
experienced at least one adverse event, including 444 patients (70.6%) who 
experienced one treatment-related adverse event.  Commonly reported events (reported 
in ≥ 10% of all patients) included fatigue, nausea, decreased appetite, diarrhea, 
constipation, dyspnea, pyrexia, and cough (see Table 5). 
A total of 89 safety-evaluable patients with NSCLC received atezolizumab in Study 
PCD4989g.  A total of 88 patients (98.9%) experienced at least one adverse event, 
including 67 patients (75.3%) with treatment-related adverse events, 35 (39.3%) patients 
with Grade 3-4 adverse events, 36 patients (40.4%) with serious adverse events, 
5 patients (5.6%) who discontinued study drug due to an adverse event, and 1 death 
(1.1%). 
The safety profile of the NSCLC cohort was consistent with the overall safety profile of 
all safety evaluable patients in Study PCD4989g, as well as with the safety evaluable 
patients with NSCLC who received atezolizumab monotherapy in other studies. 


 
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Table 5 
Adverse Events Reported in ≥ 10% of Patients in Study 
PCD4989g 
Preferred Term 
 
Any AE ≥ 10% incidence 
592 (94.1%) 
Fatigue 
248 (39.4%) 
Nausea 
175 (27.8%) 
Decreased appetite 
166 (26.4%) 
Diarrhea 
141 (22.4%) 
Constipation 
136 (21.6%) 
Dyspnea 
135 (21.5%) 
Pyrexia 
134 (21.3%) 
Cough 
127 (20.2%) 
Vomiting 
124 (19.7%) 
Anemia 
121 (19.2%) 
Back pain 
111 (17.6%) 
Headache 
104 (16.5%) 
Asthenia 
101 (16.1%) 
Arthralgia 
95 (15.1%) 
Pruritus 
89 (14.1%) 
Rash 
82 (13.0%) 
Abdominal pain 
77 (12.2%) 
Edema peripheral 
72 (11.4%) 
Urinary tract infection 
67 (10.7%) 
Insomnia 
66 (10.5%) 
Dizziness 
63 (10.0%) 
 
1.7.2.2 
Single-Agent Clinical Safety in Patients with Non-Small Cell 
Lung Cancer in Study GO28753 (POPLAR) 
As of the 1 December 2015 data cutoff date, 142 patients with NSCLC were treated with 
atezolizumab as a fixed dose of 1200 mg IV every 3 weeks and 135 patients were 
treated with docetaxel 75 mg/m2 IV q21d in Study GO28753.  The frequency of patients 
with any reported adverse event regardless of attribution was 96% in both arms.  Fewer 
patients in the atezolizumab arm (41%) experienced Grade 34 adverse events 
compared with the docetaxel arm (53%).  For Grade 34 adverse events that were 
assessed as treatment-related, the difference was greater between the two arms 
(12% vs. 39%, respectively).  The most common atezolizumab-related Grade 3 adverse 
events were pneumonia (2%) and increased aspartate aminotransferase (2%).  No 
atezolizumab-related Grade 4 events have been reported.  Treatment-related adverse 
events reported in at least 10% of patients in either treatment arm are listed in Table 6. 


 
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Table 6 
Treatment-Related Adverse Events Reported in at Least 10% of 
Patients in Either Treatment Arm in Study GO28753 (POPLAR) 
MedDRA Preferred Term 
Atezolizumab 
(n  142) 
No. (%) 
Docetaxel 
(n  135) 
No. (%) 
Fatigue 
55 (38.7%)  
54 (40.0 %) 
Decreased appetite 
49 (34.5%)  
28 (20.7%) 
Nausea 
32 (22.5%)  
45 (33.3%) 
Cough 
40 (28.2%) 
33 (24.4%) 
Dyspnoea 
39 (27.5%) 
27 (20.0%) 
Constipation 
31 (21.8%) 
32 (23.7%) 
Diarrhoea 
25 (17.6%)  
38 (28.1%) 
Alopecia 
3 (2.1%)  
52 (38.5%) 
Anaemia 
25 (17.6%) 
27 (20.0%) 
Pyrexia 
24 (16.9%) 
16 (11.9%) 
Vomiting 
20 (14.1%) 
18 (13.3%) 
Asthenia 
15 (10.6%) 
22 (16.3%) 
Arthralgia 
22 (15.5%) 
12 (8.9%) 
Insomnia 
22 (15.5%) 
11 (8.1%) 
Rash 
16 (11.3%) 
16 (11.9%) 
Back pain 
16 (11.3%) 
11 (8.1%) 
Myalgia 
9 (6.3%) 
18 (13.3%) 
Musculoskeletal pain 
19 (13.4%) 
7 (5.2%) 
Weight decreased 
16 (11.3%) 
9 (6.7%) 
Haemoptysis 
15 (10.6%) 
8 (5.9%) 
Pneumonia 
17 (12.0%) 
4 (3.0%) 
Neuropathy peripheral 
3 (2.1%)  
16 (11.9%) 
Neutropenia 
2 (1.4%)  
17 (12.6%) 
 
1.7.2.3 
Single-Agent Clinical Safety in Patients with Non-Small Cell 
Lung Cancer in Study GO28754 (BIRCH) 
As of the 1 December 2015 data cutoff date, 659 patients with NSCLC have been 
treated with atezolizumab as a fixed dose of 1200 mg IV q21d.  In Study GO28754, 
93.8% of patients experienced at least one adverse event, 65% of patients experienced 
one treatment-related adverse event, and 12% of patients experienced a 
Grade ≥ 3 treatment-related adverse event. 
For additional information, refer to the Atezolizumab Investigator’s Brochure. 


 
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1.7.2.4 
Atezolizumab as a Combination Agent
To date, there are no additional SADRs considered “expected” for regulatory reporting 
purposes specific to the combination of atezolizumab when given with another 
therapeutic agent beyond those presented in Section 1.7.2.1.  The SADRs of other 
therapeutic agents used in combination with atezolizumab can be found in their 
respective Investigators’ Brochure or Prescribing Information.
1.7.3 
Clinical Activity
Both the preliminary and more mature efficacy data available suggest that treatment with 
atezolizumab as a single agent or in combination with other therapeutic agents results in 
anti-tumor activity across a range of tumor types and hematologic malignancies
(urothelial carcinoma [UC], NSCLC, RCC, triple-negative breast cancer [TNBC], 
melanoma, colorectal carcinoma [CRC], and Non-Hodgkin lymphoma [NHL]) and across 
lines of therapy.
As of July 2016, the Phase Ia Study PCD4989g (NSCLC Cohort) and the Phase II FIR, 
POPLAR, and BIRCH had enrolled approximately 1170 efficacy-evaluable patients with 
locally advanced or metastatic NSCLC across all lines of therapy and PD-L1 expression 
subgroups who received atezolizumab monotherapy.  Overall, the results of these 
studies demonstrated that 1) higher PD-L1 expression on tumor cells (TCs) or immune 
cells (ICs) was associated with higher ORRs, 2) responses were durable, and 3) 
single-agent treatment with atezolizumab resulted in clinically meaningful OS 
improvement compared to docetaxel in the intent-to-treat (ITT) population, as well as in
a positive risk-benefit across all PD-L1 expression subgroups.
An IHC assay has been used that measures specific PD-L1 signals in tumor-infiltrating 
ICs and TCs.  PD-L1 staining categories in ICs are defined as IC0, IC1, IC2, and IC3 
and are defined in TCs as TC0, TC1, TC2, and TC3 (see Appendix 12).
Refer to the Atezolizumab Investigator’s Brochure for criteria for PD-L1 expression 
assessment in atezolizumab studies and for updated details on clinical activity in 
patients with NSCLC treated to date.
1.7.3.1 
Single-Agent Clinical Activity in Patients with NSCLC in Study
PCD4989g
Patients with multiple tumor types are included in Study PCD4989g, with the largest
cohorts consisting of patients with NSCLC, RCC, and urothelial bladder cancer (UBC).
As of the clinical cut-off date of 02 Dec 2014, there were 88 efficacy-evaluable patients 
with locally advanced or metastatic NSCLC from all lines of therapy in the single-arm 
Phase Ia Study PCD4989g.  The 88 patients received the following atezolizumab dosing: 
1 mg/kg q3w = 1, 10 mg/kg q3w = 11, 15 mg/kg q3w = 26, and 20 mg/kg q3w = 50.  The 
primary efficacy endpoint for the NSCLC Cohort in Study PCD4989g was investigator-
assessed ORR per RECIST v1.1.  Table 7 demonstrates that higher PD-L1 expression


 
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levels on TCs or ICs were associated with higher ORRs (50.0% in TC3 or IC3 vs. 33.3% 
in TC2/3 or IC2/3 vs. 22.7% in all patients).  
 
Table 7 
Study PCD4989g: Investigator-Assessed ORR and DOR per 
RECIST v1.1 in Efficacy-Evaluable Patients with NSCLC by PD-L1 
Expression Subgroup and All Patients 
Efficacy Endpoint 
TC3 or IC3 
TC2/3 or IC2/3 
All Patients a 
ORR 
Responders (%) 
95% CI 
Complete response 
Partial response 
n = 22 
11 (50.0) 
(28.2, 71.8) 
0 
11 
n = 48 
16 (33.3) 
(20.4, 48.4) 
0 
16 
n = 88 
20 (22.7) 
(14.5, 32.9) 
0 
20 
DOR 
Median DOR (months) 
95% CI 
Patients with event (%) 
n = 11 
14.6 
(8.7, 25.3) 
6 (66.7) 
n = 16 
17.3 
(14.2, NE) 
8 (50.0) 
n = 20 
17.3 
(14.2, 24.7) 
12 (60.0) 
CCOD = clinical cutoff date; CI = confidence interval, DOR = duration of response; IC = tumor-infiltrating 
immune cell; NE = not estimable; NSCLC = non−small cell lung cancer; ORR = objective response rate; 
RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, v1.1; TC = tumor cell. 
Notes: The CCOD for these data was 2 December 2014. These responses were confirmed responses. 
The primary efficacy analyses in NSCLC were performed using a combination of PD-L1 scores generated at 
the time of enrollment and available scores generated after enrollment (retrospectively) by pathologist 
consensus read. 
a The study population may be reflective of an enriched population, and may not reflect a natural 
distribution of IC scores. 
 
The median duration of survival follow-up at the time of the clinical cutoff date (CCOD) 
was 22.5 months. At that timepoint, the median duration of all responders was 
17.3 months, with 40% (8 of 20) of responders having an ongoing response. 
1.7.3.2 
Single-Agent Clinical Activity in Patients with NSCLC in Study 
GO28753 (POPLAR) 
For this Phase II study in advanced or metastatic NSCLC patients who failed prior 
platinum therapy, preliminary results at the cut-off date of 07 January 2015 (efficacy data 
available for 137 efficacy evaluable patients with locally advanced or metastatic NSCLC 
who had a minimum follow-up of 6 months) showed agreement between ORR per 
modified RECIST and RECIST v1.1.  Patients who were responders per modified 
RECIST but not RECIST v1.1 included a patient in Cohort 1 (first line treatment) who 
developed a new cerebellar metastasis that was irradiated; the patient went on to 
experience a complete remission of extra-cranial disease.  A patient in Cohort 2 
(≥ 2 lines of previous treatment, no brain metastases) who experienced an initial 
25% increase in the size of an adrenal lesion (progressive disease) and later achieved a 
durable response.  The majority of responding patients (per modified RECIST and 


 
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RECIST v1.1) continued to respond.  13 of 15 RECIST v1.1 responders in Cohort 2 
continued to respond, including 8 of 9 patients with TC3 or IC3 tumors.  TC3 and IC3 
were independently predictive for response in Cohort 2.  For patients with TC3 (any IC) 
tumors (n = 22) the ORR (95% CI) was 23% (8%-45%), and for patients with IC3 (any 
TC) tumors (n = 21), the ORR was 29% (11%-52%) (Spigel et al. 2015). 
At the time of primary analysis of OS (data cutoff: 08 May 2015), data was available for 
287 patients in the ITT population (144 and 143 patients in the atezolizumab and 
docetaxel treatment arms, respectively) with a minimum follow-up duration of 13 months.  
At this time, 173 deaths had occurred (60.3% event-patient rate; approximately 
13 months after the last patient was enrolled). The ITT population analysis showed a 
clinically meaningful and statistically significant improvement in OS for atezolizumab-
treated patients compared with docetaxel with a stratified HR of 0.73 (95% CI: 0.53, 
0.99; p=0.04).  The median OS was 12.6 months in the atezolizumab arm versus 9.7 
months in the docetaxel arm.  Improvement in OS in the atezolizumab arm relative to 
docetaxel increased with increasing PD-L1 expression.  TC3 or IC3 with unstratified HR 
of 0.49 (p = 0.068), TC2/3 or IC2/3 with unstratified HR of 0.54 (p=0.015), and TC1/2/3 
or IC1/2/3 with unstratified HR of 0.59 (p=0.0050).  In the TC0 or IC0 subgroup, median 
OS was 9.7 months in both, the atezolizumab and docetaxel arms, suggesting that 
atezolizumab-treated patients in this subgroup also derived clinical benefit.  
Relative to the primary analysis, an updated analysis of efficacy and safety with longer 
follow-up conducted with 200 events (70% event/patient ratio) and a minimum follow-up 
of 20 months (data cutoff: 01 Dec 2015) showed improvement in OS benefit in ITT (HR, 
0.69 vs 0.73) and PD-L1 subgroups, most notably, the TC0 and IC0 subgroup (HR, 0.88 
vs 1.04) (Smith et al. 2016). 
At the time of 173 OS events (data cutoff: 08 May 2015), in the ITT population, 
investigator-assessed ORR (confirmed responses) per RECIST v1.1 was similar in both 
treatment groups (14.6% in atezolizumab and 14.7% in docetaxel), with the 
atezolizumab arm having 1 confirmed response.  Objective response benefit was most 
pronounced in the atezolizumab arm relative to the docetaxel arm in the TC3 or IC3 
(37.5% vs. 13.0%) and TC2/3 or IC2/3 subgroups (22.0% vs. 14.5%).  The overall 
results suggested that higher PD-L1 expression levels on TCs or ICs correlated with 
higher ORRs. 
Among responders at the primary analysis on 8 May 2015, the median duration of 
response (DOR) in the atezolizumab arm of the ITT population was doubled that of the 
docetaxel arm: 14.3 months versus 7.2 months (unstratified HR of 0.41, 95% CI: 0.18, 
0.96).  Further, 12 of the 21 (57.1%) atezolizumab responders had ongoing responses 
compared with 5 of 21 (23.8%) docetaxel responders.  Across the PD-L1 expression 
subgroups, the atezolizumab arm generally had more patients with ongoing responses 
(range of 33% to 100% of patients without disease progression or death) than the 
docetaxel arm (range of 24% to 33% of patients without disease progression or death). 


 
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1.7.3.3 
First Phase III Study of Atezolizumab in Previously-treated 
NSCLC in Study GO28915 (OAK) 
OAK is a phase III study of atezolizumab monotherapy versus docetaxel in 1225 patients 
with locally-advanced or metastatic NSCLC.  Eligible patients had relapsed disease that 
was progressing after 1–2 prior lines of chemotherapy (including at least 1 platinum-
based regimen) and were allowed to have any PD-L1 expression status.  OAK has two 
co-primary endpoints: OS in the ITT population; and OS in the TC1/2/3 or IC1/2/3 
subgroup (≥ 1% PD-L1 expression).  A pre-specified analysis of the first 850 patients, 
which provided sufficient power to test both co-primary endpoints, was presented at the 
2016 meeting of the European Society for Medical Oncology (Barlesi 2016). 
At baseline, the atezolizumab (n=425) and the docetaxel (n=425) treatment groups had 
similar histology distributions, performance statuses, prior therapy rate, tobacco use, 
central nervous system (CNS) metastasis rates, and EGFR statuses.   
In all patients (ITT population), the median OS was 13.8 months (95% CI, 11.8–15.7 
months) in the atezolizumab group versus 9.6 months (95% CI, 8.6–11.2 months) in the 
docetaxel group, indicating a significant treatment effect in favor of atezolizumab 
(HR, 0.73; p=0.0003).  One-year survival rates were 55% and 41% in the atezolizumab 
and docetaxel groups of the ITT population, respectively, whereas the 18-month survival 
rates were 40% and 27% in the two treatment groups.   
In the TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression), which comprised 55% of 
enrolled patients, the median OS was 15.7 months (95% CI, 12.6–18.0 months) in the 
atezolizumab group versus 10.3 months (95% CI, 8.8–12.0 months) in the docetaxel 
group, again indicating a significant treatment effect in favor of atezolizumab (HR, 0.74; 
p=0.0102).  Median OS positively correlated with PD-L1 expression status.  Thus, 16% 
of patients were classified as TC3 or IC3; 31% were classified as TC2/3 or IC2/3; 55% 
were classified as TC1/2/3 or IC1/2/3; and 45% were classified as TC0 and IC0.  Median 
OS in these subgroups were 20.5 months, 16.3 months, 15.7 months, and 12.6 months, 
respectively.   
In other analyses, patients with nonsquamous histology, squamous histology, CNS 
metastases, and no CNS metastases all had significantly longer median survival rates in 
the atezolizumab group, while patients in the TC3 or IC3 subgroup and in the TC2/3 or 
IC2/3 subgroup had also longer PFS times in the atezolizumab group.  The ORR rates in 
the ITT population in the atezolizumab and docetaxel groups were 16.3% and 6.2%, 
respectively. 
1.7.3.4 
Single-Agent Clinical Activity in Patients with NSCLC in Study 
GO28625 (FIR) 
The single-arm Phase II FIR evaluated atezolizumab monotherapy (1200 mg IV q3w) in 
patients with PD-L1−selected (defined as TC2/3 or IC2/3) NSCLC.  Patients were 
enrolled in the following cohorts: Cohort 1 (1L), Cohort 2 (2L +) and Cohort 3 (2L + with 


 
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previously treated brain metastases).  At the primary analysis on 7 January 2015, there 
were 137 efficacy-evaluable patients with at least 6 months of follow-up across all 
3 cohorts. 
The primary efficacy endpoint was investigator-assessed ORR (confirmed responses) 
per modified RECIST.  For each cohort, the confirmed ORR for each PD-L1 expression 
subgroup was similar using either modified RECIST or RECIST v1.1 criteria.  At the time 
of the CCOD, median DOR per RECIST v1.1 was not reached in any cohort or PD-L1 
expression subgroup (see Table 8). 


 
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Table 8 
Study GO28625 (FIR): Investigator-Assessed ORR per RECIST v1.1 and Immune-Modified RECIST 
 
Immune-Modified RECIST 
RECIST v1.1 
 
Cohort 1 (1L) 
Cohort 2 (2L +) 
Cohort 3 (2L + 
with brain mets) 
Cohort 1 (1L) 
Cohort 2 (2L +) 
Cohort 3 (2L + 
with brain mets) 
ORR 
 
 
 
 
 
 
TC3 or IC3 
ORR n (%) 
(95% CI) 
CR 
PR 
n = 7 
2 (28.6) 
3.7, 71.0 
0 
2 
n = 38 
10 (26.3) 
13.4, 43.1 
1 
9 
n = 8 
2 (25.0) 
3.2, 65.1 
0 
2 
n = 7 
2 (28.6) 
3.7, 71.0 
0 
2 
n = 38 
9 (23.7) 
11.4, 40.2) 
1 
8 
n = 8 
2 (25.0) 
3.2, 65.1) 
0 
2 
TC2/3 or IC2/3 
ORR n (%) 
(95% CI) 
CR 
PR 
n = 31 
9 (29.0) 
14.2, 48.0 
1 
8 
n = 93 
16 (17.2) 
10.2, 26.4 
2 
14 
n = 13 
3 (23.1) 
5.0, 53.8 
0 
3 
n = 31 
8 (25.8) 
11.9, 44.6 
0 
8 
n = 93 
15 (16.1) 
9.3, 25.2 
2 
13 
n = 13 
3 (23.1) 
5.0, 53.8 
0 
3 
DOR 
 
 
 
 
 
 
TC3 or IC3 
Median DOR (months) 
(95% CI) 
Pts w. event (%) 
TC2/3 or IC2/3 
Median DOR (months) 
(95% CI) 
Pts w. event (%) 
n = 2 
NE 
(2.9, NE) 
1 (50.0) 
n = 9 
9.0 
(NE) 
3 (33.3) 
n = 10 
NE 
(10.4, NE) 
1 (10.0) 
n = 16 
NE 
(10.4, NE) 
2 (12.5) 
n = 2 
NE 
(NE) 
0 
n = 3 
NE 
(NE) 
0 
n = 2 
NE 
(2.9, NE) 
1 (50.0) 
n = 8 
NE 
(2.9, NE) 
2 (25.0%) 
n = 9 
NE 
(10.4, NE) 
1 (11.1) 
n = 15 
NE 
(10.4, NE) 
2 (13.3) 
n = 2 
NE 
(NE) 
0 
n = 3 
NE 
(4.2, NE) 
1 (33.3) 
1L = first line; 2L + = second line and beyond; CCOD = clinical cutoff date; CI = confidence interval; CR = complete response; DOR = duration of 
response; IC = tumor-infiltrating immune cell; L = line;  mets = metastases; NE = not estimable; ORR = objective response rate; PR = partial 
response; PTs = patients; RECIST = Response Evaluation Criteria in Solid Tumors; TC = tumor cell. 
Notes: The CCOD for these data was 7 January 2015. These responses were confirmed responses.


 
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1.7.3.5 
Clinical Pharmacokinetics  
Atezolizumab PK and other data have been analyzed from the following atezolizumab 
monotherapy studies: PCD4989g, JO28944, IMvigor 210, BIRCH, POPLAR, and FIR.  
The key PK findings from the above-listed atezolizumab monotherapy clinical studies are 
summarized below: 
 
The PK of atezolizumab monotherapy has been characterized in patients in Study 
PCD4989g at doses 0.01 mg/kg to 20 mg/kg q3w, including the fixed dose 1200 mg 
(equivalent to 15 mg/kg).  Exposure to atezolizumab increased dose proportionally 
over the dose range of 1 mg/kg to 20 mg/kg.  While a subset of ATA-positive patients 
in Study PCD4989g receiving 0.3 to 3 mg/kg atezolizumab q3w experienced a 
reduction of atezolizumab minimum observed plasma concentration (Cmin) to below 
the PK assay lower limit of quantification (LOQ), patients receiving 10 to 20 mg/ kg 
atezolizumab, including the fixed 1200 mg dose, maintained geometric mean Cmin 
that was in excess of both the LOQ and the target serum concentration of 6 µg/mL.  
 
A Phase I population pharmacokinetic (popPK) analysis that included 472 patients 
from Studies PCD4989g and JO28944 described atezolizumab pharmacokinetics for 
the dose range 1−20 mg/kg with a linear two-compartment disposition model with 
first-order elimination.  The popPK analysis indicated that central compartment 
volume of distribution (V1) was 3.28 L and the volume of distribution at steady state 
(Vss) was 6.91 L in the typical patient.  Further, the clearance (CL) of atezolizumab 
was 0.20 L/day and the half live (t1/2) was 27 days.  Steady state was obtained after 
6 to 9 weeks (2 to 3 cycles) of repeated dosing.  The systemic accumulation in area 
under the curve (AUC), maximum observed plasma concentration (Cmax) and Cmin 
was 1.91, 1.46, and 2.75-fold, respectively. 
 
Based on an analysis of exposure, safety, and efficacy data, the following factors 
had no clinically relevant effect: age (21−89 years), body weight, gender, positive 
ATA status, albumin levels, tumor burden, region or ethnicity, renal impairment, mild 
hepatic impairment, level of PD-L1 expression, or ECOG status. 
 
The effect of moderate or severe hepatic impairment (bilirubin > upper limit of normal 
(ULN) and aspartate aminotransferase (AST) > ULN or bilirubin ≥ 1.0 to 1.5 × ULN 
and any AST) on the pharmacokinetics of atezolizumab is unknown. 
 
No formal PK drug-drug interaction studies have been conducted with atezolizumab. 
The drug interaction potential of atezolizumab is unknown. 
Refer to the Atezolizumab Investigator’s Brochure for details regarding atezolizumab 
pharmacokinetics. 


 
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1.7.3.6 
Immunogenicity 
Immunogenicity data are available for the following single-agent atezolizumab studies: 
PCD4989g, IMvigor 210, POPLAR, BIRCH, and FIR.  ATAs to atezolizumab have been 
observed at all dosing levels.  ATA positivity had no major effect on atezolizumab 
concentrations and pharmacokinetics although there was a trend for lower Cmin values in 
the ATA-positive subgroup.  For doses ≥ 10 mg/kg, average Cmin remained well in 
excess of the target serum concentration of 6 µg/mL in the ATA-positive patients. 
The presence of ATAs did not appear to have a clinically significant impact on 
pharmacokinetics, safety, or efficacy. Samples that could be evaluated for neutralizing 
antibodies in these studies were too few in number (approximately 6%) to draw any 
conclusions. 
Refer to the Atezolizumab Investigator’s Brochure for updated details regarding 
atezolizumab immunogenicity. 
1.8 
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 tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumor-specific T-cell immunity.   
PD-L1 expression is prevalent in many human tumors, and elevated PD-L1 expression 
is associated with a poor prognosis in patients with NSCLC (Mu et al. 2011).  Targeting 
the PD-L1 pathway with atezolizumab has demonstrated activity in patients with 
advanced malignancies and who have failed standard-of-care therapies.  In Study 
PCD4989g, a Phase I dose-escalation and expansion study, objective responses with 


 
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atezolizumab monotherapy were observed in a broad range of malignancies, including 
NSCLC, RCC, melanoma, UBC, CRC, head and neck cancer, gastric cancer, breast 
cancer, and sarcoma.   
Patients newly diagnosed with advanced or metastatic NSCLC and a poor PS, 
irrespective of age, have an increased incidence of adverse effects with standard 
chemotherapy and have a poorer OS (Gajra et al. 2014, Sweeney et al. 2001).  
Therefore, novel treatments are needed that provide comparable efficacy to the existing 
treatment options but ensure a higher tolerability of treatment.  
OS benefit with atezolizumab vs docetaxel has been seen in both unselected patients 
(ITT population) and PD-L1-expression subgroups in study GO28753 (POPLAR) 
(Vansteenkiste et al. 2015, Fehrenbacher et al. 2016, also Section 1.7.3.2) and OAK 
(see Section 1.7.3.3).   
In study GO28625 (FIR), which enrolled PD-L1-selected first-line or greater NSCLC 
patients, at the primary analysis on 137 efficacy-evaluable patients, confirmed ORR 
(RECIST v1.1) after the first-line treatment with atezolizumab was 28.6% 
(95% CI: 3.7-71.0) in IHC TC3 or IC3 patients and 25.8% (95% CI: 11.9-44.6) in IHC 
TC2/3 or IC2/3 patients (see Section 1.7.3.4).  
Study GO28754 (BIRCH) enrolled PD-L1-selected first-line or greater NSCLC patients 
with locally advanced or metastatic NSCLC.  At the time of the primary analysis on 
28 May 2015, 659 efficacy-evaluable patients had completed at least 6 months of 
follow-up.  The highest level of PD-L1 IHC expression (TC3 or IC3) showed the highest 
ORRs across all lines of therapy: 27.0% in third line and beyond, 25.3% in second line 
and beyond, 23.8% in second line, and 26.2% in first line.  The median OS was not 
reached for all subgroups with the exception of TC2/3 or IC2/3 in Cohort 1 (first line), 
where the median was 14.0 months (95% CI: 14.0, NE).  Overall, however, the OS data 
across all subgroups were not mature, with ≥ 60.5% of patient still alive (range of 60.5% 
to 74.1%).  The landmark 12-month event-free OS rate in the 2L + TC2/3 or IC2/3 
subgroup was 55.3%. 
Atezolizumab has been generally well tolerated (see Section 1.7).  Across all studies 
and tumor types, the most commonly reported adverse events with single-agent 
atezolizumab include fatigue, nausea, decreased appetite, diarrhea, constipation, and 
cough.  To date, these events have been manageable with treatment.  The tolerability 
profile of atezolizumab encourages atezolizumab treatment beyond disease progression 
(RECIST v.1.1) and until loss of clinical benefit in newly diagnosed NSCLC patients with 
advanced or metastatic disease who present with a poor performance status (≥ PS2). 
On the basis of these observations, Study MO29872 is designed to evaluate whether the 
anti-tumor effect seen in atezolizumab-treated patients would translate into prolonged 
OS compared with single agent chemotherapy in patients with in patients with 


 
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treatment-naïve locally advanced or metastatic NSCLC who are deemed unsuitable for 
any platinum-doublet chemotherapy due to an ECOG performance status of ≥ 2 or 
substantial comorbidities and/or contraindication(s) for platinum-based antineoplastic 
drugs.  
Given the unique toxicities (i.e., alopecia, neutropenia, febrile neutropenia) associated 
with the single agent chemotherapy agents used to treat patients with Stage IV NSCLC 
who are deemed unsuitable for any platinum-doublet chemotherapy, this study assumes 
about equal efficacy of atezolizumab treatment in prolonging OS compared to single 
agent chemotherapy while providing a significantly better tolerability profile. 
This study will enroll patients with NSCLC.  Given the relatively poor prognosis and 
limited treatment options for these patients, this population is considered appropriate for 
trials of novel therapeutic candidates.  The benefitrisk ratio for atezolizumab is 
expected to be acceptable in this setting. 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or 
how systemic cancer therapies such as chemotherapy, targeted therapy, or 
immunotherapy impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine-release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon- (Merad and Martin 2020).  While it is not known, there may be a potential for 
an increased risk of an enhanced inflammatory response if a patient develops acute 
SARS-CoV-2 infection while receiving atezolizumab.  At this time, there is insufficient 
evidence for causal association between atezolizumab and an increased risk of severe 
outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2 infectionrelated interstitial pneumonia.  Thus, investigators 


 
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should use their clinical judgment when evaluating and managing patients with 
pulmonary symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination 
(Society for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in 
such patients (NCCN 2021).  Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of COVID-19 
vaccination in patients who are receiving cancer immunotherapy (SITC 2020).  For 
patients enrolling in this study and receiving atezolizumab treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.   
SITC and NCCN recommendations along with institutional guidelines should be used 
by the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1.1). 
2. 
OBJECTIVES  
2.1 
EFFICACY OBJECTIVES  
2.1.1 
Primary Efficacy Objective  
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
compared with single agent chemotherapy in patients with treatment-naïve locally 
advanced or metastatic NSCLC who are deemed unsuitable for any platinum-doublet 
chemotherapy, as measured by OS. 
 
 


 
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2.1.2 
Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are:
 
To evaluate the efficacy of atezolizumab compared with single agent 
chemotherapy as measured by OS rates at 6, 12, 18 and 24 months 
 
To evaluate the efficacy of atezolizumab compared with single agent
chemotherapy with respect to antitumor effects as measured by 
investigator-assessed ORR using RECIST v1.1 (Appendix 3)
 
To evaluate the efficacy of atezolizumab compared with single agent
chemotherapy with respect to antitumor effects as measured by 
investigator-assessed PFS using RECIST v1.1
 
To evaluate the efficacy of atezolizumab compared with single agent 
chemotherapy with respect to antitumor effects as measured by
investigator-assessed DOR using RECIST v1.1.
 
To evaluate the efficacy (OS and investigator-assessed PFS using RECIST
v1.1) of atezolizumab compared with single agent chemotherapy in patients 
with PD-L1 expression defined by the PD-L1 SP263 IHC assay
2.2 
SAFETY OBJECTIVES
The safety objective of this study is:
 
To evaluate the safety and tolerability of atezolizumab compared with single
agent chemotherapy
2.3 
PATIENT-REPORTED OUTCOME OBJECTIVE
The patient-reported outcome (PRO) objective for this study is:
 
To evaluate and compare PROs of lung cancer symptoms, patient functioning,
and health-related quality of life (HRQoL) between treatment arms as measured 
by the European Organisation for Research and treatment of Cancer (EORTC) 
Quality-of-life Questionnaire Core 30 (QLQ-C30) (Appendix 6) and its Lung 
Cancer Module (QLQ-LC13) (Appendix 7)


 
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2.4 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are:
 
To evaluate the efficacy of atezolizumab compared with single agent 
chemotherapy with respect to antitumor effects as measured by
investigator-assessed ORR, PFS and DOR according to modified RECIST 
(immune-mediated response criteria; imRC) (Appendix 4)
 
To evaluate and compare investigator-assessed disease control rates (DCR)
between the two treatment arms using RECIST v1.1
 
To evaluate the relationship between the main efficacy endpoints and tumor
tissue PD-L1 expression
 
To evaluate the relationship between the main efficacy endpoints and
exploratory biomarkers in tumor tissue and plasma
 
To evaluate the relationship between the main efficacy endpoints and the
expression of immune markers in peripheral blood mononuclear cells (PBMCs)
 
To generate utility scores for use in economic models for reimbursement by
collecting patient’s health status data using the EuroQoL-5 Dimensions 5-level 
(EQ-5D-5L) questionnaire (Appendix 8)
3. 
STUDY DESIGN
3.1 
DESCRIPTION OF THE STUDY
This is a Phase III, global, multicenter, open-label, randomized, controlled study 
designed to evaluate the efficacy and safety of atezolizumab compared with a single 
agent chemotherapy regimen by investigator choice (vinorelbine or gemcitabine) in 
treatment-naïve patients with locally advanced or metastatic NSCLC who are deemed 
unsuitable for any platinum doublet chemotherapy due to poor performance status 
(ECOG PS of 2-3).
However, patients ≥ 70 years of age who have an ECOG PS of 0 or 1 may be included if 
they are deemed unsuitable for any platinum-doublet chemotherapy by the investigator 
due to:
a) substantial comorbidities
b) contraindication(s) for platinum-doublet chemotherapy.
Eligible patients will be stratified by (a) histologic subtype (non-squamous/squamous),
(b) PD-L1 IHC status (positive/negative/unknown) and (c) brain metastases (yes/no) and 
then randomized at a 2:1 ratio to receive either atezolizumab or single agent 
chemotherapy.
Eligible patients must therefore provide a tumor tissue specimen for central assessment 
of PD-L1 expression by IHC at a central laboratory.  The study will enroll all patients 
whose tissue is evaluable for PD-L1 analysis, regardless of PD-L1 expression status.


 
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Given the unique toxicities associated with chemotherapy (i.e., alopecia, neutropenia, 
febrile neutropenia) and the pre-medications required (i.e., steroid, anti-emetics, and 
potentially growth factor support), this will be an open-label study. 
No crossover will be allowed between treatment arms. 
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of 
each 21-day cycle.  
Patients randomized to receive single agent chemotherapy approved in their country 
(vinorelbine [oral or intravenous] or gemcitabine [intravenous]), based on investigator’s 
choice will receive chemotherapy per relevant local guidelines and SmPC management.  
Doses and dose modifications for the selected single agent chemotherapy should be 
made per relevant local guidelines and SmPC management.   
At any time-point after RECIST v1.1 criteria for progressive disease are met, patients in 
the experimental arm with atezolizumab who show evidence of clinical benefit, will be 
permitted to continue treatment with atezolizumab until loss of clinical benefit, 
unacceptable toxicity, patient or physician decision to discontinue, or death, if they meet 
all of the following criteria: 
 
Evidence of clinical benefit (i.e., in the absence of symptomatic deterioration 
attributed to disease progression as determined by the investigator after an 
integrated assessment of radiographic data, biopsy results [if available], clinical 
status, and of laboratory values)  
 
Absence of unacceptable toxicity   
 
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 for whom approved therapies exist must provide written consent to 
acknowledge deferring these treatment options in favor of continuing study 
treatment at the time of initial progression.  
Tumor assessments will be performed at baseline, every 6 weeks (± 5 days) following 
randomization for 48 weeks, and every 9 weeks (± 5 days) thereafter, with additional 
scans as clinically indicated. Assessments will continue until disease progression per 
RECIST v1.1. Patients randomized to atezolizumab who continue to receive 
atezolizumab following disease progression will undergo tumor assessments until 
treatment discontinuation. Tumor assessments should continue regardless of whether 
patients discontinue study treatment or start new anti-cancer therapy in the absence of 
disease progression unless they withdraw consent. 


 
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In all patients, response will be assessed by the investigator using RECIST v1.1 (see 
Appendix 3) until disease progression.  Patients randomized to receive atezolizumab 
will additionally be assessed by modified RECIST criteria (see Appendix 4) until 
treatment discontinuation.
Follow-up data capture, including subsequent anticancer therapies, will continue for
each patient until death, withdrawal of consent, loss to follow-up, or study termination by 
Sponsor, whichever occurs first.
In addition to PD-L1 analysis, exploratory research will be performed on histological 
tumor tissue samples pre-treatment.
Patients will undergo blood sample collection for exploratory biomarker analyses using 
plasma and PBMCs as per schedule of assessments.
Tissue and plasma samples will be analyzed for example by methods like IHC, 
quantitative reverse transcriptase PCR (qRT-PCR), next-generation sequencing (NGS) 
and/or other methods to study tumor biomarkers and changes thereof on DNA, RNA 
and/or protein (or other analytes).
These exploratory biomarker evaluations will not be used for any treatment-related 
decisions.  Exploratory analyses aim to study tumor-associated alterations to further 
understand disease pathobiology (including but not limited to mechanisms of disease 
progression, pseudo-progression, acquired resistance), to evaluate surrogate
biomarkers and to potentially allow for the development of blood-based and tissue-based 
diagnostic tests to help predict which patients may benefit from atezolizumab.
Primary imaging data used for tumor assessment may be collected by the Sponsor to 
enable centralized, independent review of response endpoints, if needed.
Safety assessments will include the incidence, nature, and severity of adverse events 
and laboratory abnormalities graded per the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 and assessed by immune-
mediated adverse event (imAE) and immune-mediated adverse reaction (imAR) 
methods.  Laboratory safety assessments will include the regular monitoring of 
hematology and blood chemistry.  An external independent Data Monitoring Committee 
(iDMC) will be assembled and will be responsible for monitoring the safety of patients in 
the study in accordance with a pre-specified iDMC charter.
During the study, assessments will be performed according to the Schedule of 
Assessments (Appendix 1).
3.1.1 
Overview of Study Design
An overview of the study design is provided in Figure 1.


 
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Figure 1 Study Schema 
 
 
 
IHC = immunohistochemistry; NSCLC = non-small cell lung cancer; PD = disease progression; 
PD-L1 = programmed cell death-ligand 1; q3w = every 3 weeks. 
a Patients in the experimental arm with atezolizumab who show evidence of clinical benefit, may 
continue atezolizumab treatment after disease progression (RECIST v 1.1) if they meet criteria 
specified in Section 3.1. 
b Single agent chemotherapy (vinorelbine, oral or intravenous, or gemcitabine, intravenous) 
based on investigator’s choice will be administered per relevant local guidelines and SmPC 
management. Chemotherapy cycles may be 3-weekly or 4-weekly. 
c 
Follow-up information, including subsequent anticancer therapies and any treatment related 
adverse events, will be collected via telephone calls and/or clinic visits every 2 months 
(± 5 days) until death, withdrawal of consent, loss to follow-up, study termination by the 
Sponsor, or protocol-defined end of study, whichever comes first. 


 
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3.1.2 
Independent Data Monitoring Committee 
An iDMC will be used to evaluate safety data during the study on a periodic basis, 
approximately every 6 months from the time when the first patient is enrolled.  Members 
of the iDMC will be external to the Sponsor and will follow a predefined Charter that 
outlines their roles and responsibilities. 
All summaries and analyses by treatment arm for the iDMC review will be prepared by 
an unblinded independent statistician (independent Data Coordinating Center [iDCC]) 
external to the Sponsor.  The safety data will include demographic data, adverse events, 
serious adverse events, and relevant laboratory data. 
Following the data review, the iDMC will provide a recommendation to the Sponsor 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. 
The iDMC will also be responsible for evaluating efficacy data at the pre-specified OS 
interim analysis.  The interim analysis of efficacy data will be conducted in accordance 
with the methods that are specified in the Statistical Analysis Plan (SAP).  The iDMC 
recommendations to stop the study because of substantial evidence of efficacy of the 
study drug or to continue to the final analysis shall be based on the specified interim 
analysis stopping guidelines as specified in the iDMC charter and SAP. 
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) and to the study sites. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
This study is event-driven, with a recruitment period of approximately 24 months.  The 
required number of 380 events for the final analysis of the primary endpoint of OS is 
expected to occur approximately 42 months after the first patient has been enrolled.  A 
cut-off date for final analysis will be set at least 54 months after first patient in should 
380 OS events not be reached. 
For patients randomized to the atezolizumab treatment arm, treatment may continue 
beyond disease progression per RECIST v1.1 until loss of clinical benefit, unacceptable 
toxicity, patient or physician decision to discontinue, or death.  For all patients, tumor 
response data collection will continue until disease progression, even if the patient stops 
study treatment prior to disease progression.  Patients randomized to receive 
atezolizumab who continue study treatment after disease progression continue to 
undergo tumor assessments until atezolizumab discontinuation.  


 
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Follow-up data capture, including subsequent anticancer therapies, will continue for 
each patient until death, withdrawal of consent, loss to follow-up, or study termination by 
Sponsor, whichever occurs first.  
The end of the study is when the required number of deaths have been observed. 
Additionally, the Sponsor may decide to terminate the study at any time. 
3.3 
RATIONALE FOR STUDY DESIGN 
This Phase III study design is based on the assumption that in patients with treatment-
naïve advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or 
metastatic (Stage IV) NSCLC, who are deemed unsuitable for any platinum-doublet 
chemotherapy, treatment with atezolizumab has the potential to demonstrate superior 
efficacy by prolonging OS with possibly favorable safety profile compared to single agent 
chemotherapy. 
This first Phase III trial of a PD-L1-directed drug in NSCLC, study GO28915 (OAK), 
demonstrated that atezolizumab treatment results in a statistically significant and 
clinically relevant improvement in OS versus docetaxel in second line/third line NSCLC, 
regardless of PD-L1 expression and histology.  Atezolizumab was well tolerated with a 
favorable safety profile versus docetaxel (Barlesi, Park et al. 2016).   
 
3.3.1 
Rationale for Patient Population 
Most of patients with newly diagnosed NSCLC present with locally advanced or 
metastatic disease (Carnio et al. 2014).  In addition, it is estimated that 30% to 40% of 
patients with NSCLC have a poor PS, defined as a score of 2 or higher on the ECOG 
scale, because of their disease burden, comorbidities, or both.  Survival is shorter in 
these patients than in those with a better PS, and they do not tolerate chemotherapy as 
well (Govindan, 2004). 
Efficient therapies for patients unsuitable for chemotherapy who have poor ECOG PS2 
are not available to date, which shows the need for a safe and tolerable treatment option 
in this patient population.  The safety profile of atezolizumab as well as the benefit seen 
in good performing patients across PD-L1 strata give rationale to include all patients 
irrespective of PD-L1 status into the study. 
Responses to atezolizumab have been observed in patients with high PD-L1 expression 
(TC2/3 or IC2/3) as well as patients in the TC0 or IC0 subgroups, suggesting that PD-L1 
negative patients also derive clinical benefit (see Section 1.7.3.2 and Section 1.7.3.3).  
The inclusion of patients irrespective of PD-L1 expression level will allow (a) a robust 
assessment of the hypothesis that PD-L1-positive status is predictive of increased 
efficacy with atezolizumab treatment relative to PD-L1-negative status, but also (b) allow 
for the evaluation of OS benefit in the overall population relative to single agent 
chemotherapy treatment irrespective of PD-L1 status.  In addition, because of the 


 
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assumed higher tolerability of atezolizumab compared to chemotherapy and also 
assumed higher efficacy, this immunotherapeutic agent should not be withheld from 
patients who have a low, negative or unknown PD-L1 status, given there is a chance of 
treatment benefit.  
The OAK phase III randomized trial assessed atezolizumab versus docetaxel alone in 
patients with metastatic NSCLC who had progressed during or after systemic therapy 
survival was improved with atezolizumab regardless of PD-L1 expression levels, 
including in patients with no PD-L1 expression (TC0 and IC0; HR=0.75) (Barlesi, Park et 
al. 2016).   
This study includes NSCLC patients with squamous and non-squamous histology, as 
OS benefit to atezolizumab has been observed in both groups (see OAK study, 
Section 1.7.3.3).  
3.3.2 
Rationale for Control Arm 
This study aims to compare response to atezolizumab treatment with standard of care 
treatment in patients with locally advanced or metastatic NSCLC who are deemed 
unsuitable for any platinum-doublet chemotherapy.   
The two chemotherapeutic agents permitted in this study, vinorelbine (oral capsules and 
for intravenous infusion) or gemcitabine (for intravenous infusion), are internationally 
recognized and recommended treatment options in locally advanced stage III and 
metastatic non-small-cell lung cancer) (Eberhardt et al. 2015, Reck et al. 2014).   
Current ESMO guidelines recommend single-agent chemotherapy with gemcitabine, 
vinorelbine (oral and intravenous) and docetaxel as an alternative treatment option for 
NSCLC patients with a PS of 2 and beyond who do not tolerated platinum-based 
chemotherapy (Novello 2016).   
However, docetaxel is not included in this trial because of the assumption that docetaxel 
has a markedly worse safety profile compared to vinorelbine (oral and intravenous) and 
gemcitabine in the study population of patients with a PS of 2-3.  Immunotherapy is 
generally better tolerated than chemotherapy. Considering further the lower safety profile 
of docetaxel compared with atezolizumab observed in the POPLAR study (Table 9), the 
use of docetaxel as a comparator in this study seems unjustified.  


 
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Table 9 
Safety Profile of Atezolizumab versus Docetaxel in Study 
GO28753 (POPLAR) 
Parameter 
Docetaxel 
(n=135) 
Atezolizumab 
(n=142) 
Any AE 
130 (96.3%) 
136 (95.8%) 
Related AE 
119 (88.1%) 
95 (66.9%) 
Grade 3-4 
71 (52.6%) 
58 (40.8%) 
Related Grade 3-4 
52 (38.5%) 
17 (12.0%) 
Grade 5 
5 (3.7%) 
7 (4.9%) 
Related Grade 5 
3 (2.2%) 
1 (0.7%) 
SAE 
46 (34.1%) 
51 (35.9%) 
Any AE leading to 
withdrawal of study drug 
30 (22.2%) 
12 (8.5%) 
AE = adverse event; SAE = serious adverse event.  
a The CCOD for POPLAR was 1 December 2015, corresponding to an updated safety analysis. 
 
3.3.3 
Rationale for Atezolizumab Dosing 
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 µg/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.  
Currently, no maximum tolerated dose, no dose-limiting toxicities, and no clear dose-
related trends in the incidence of adverse events have been determined, and no DLTs 
have been observed.  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 µg/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 
pharmacokinetics evaluation. 
Refer to the Atezolizumab Investigator’s Brochure for updated details regarding 
nonclinical and clinical pharmacology of atezolizumab. 
3.3.4 
Rationale for Open-Label Study 
An open-label study design was chosen for this study for the following reasons: Given 
the known toxicities associated with single agent chemotherapy and due to different 
dosing schedules, patients assigned to chemotherapy, as well as physicians, may be 
capable of identifying treatment assignment in a blinded study.  In addition, a blinded 
study would require prolonged administration of placebo, which would pose a significant 
burden to patients. 
Adequate steps have been taken to ensure the validity of data in an open-label study 
design.  This includes performing efficacy assessments at the same frequency in both 
arms, adhering to protocol-defined schedules, and determining the strategy for the final 
analysis of the primary endpoint prior to study start, including predefined methods for 
handling missing data and censoring rules.  Efficacy analyses will only be performed at 
the prespecified analysis timepoints in the protocol (primary analysis once the number of 
OS events presented in Section 6.1 have occurred in the ITT population). 
3.3.5 
Rationale for Primary and Secondary Endpoints 
Improvement in OS is generally accepted as the best measure of clinical benefit for 
patients with advanced/unresectable or metastatic NSCLC.  The assumption that 
treatment with atezolizumab will prolong OS compared with treatment with single-agent 
chemotherapy is based on the durable response rates observed in Phase I trials with 
atezolizumab, as well as other PD-L1/PD-1 blocking agents.  Given the poor prognosis 
with an assumed median duration of OS in the control arm in this study population of 
7 months, a surrogate primary endpoint (e.g., PFS, response rate [RR]) would be 
unjustifiable.  
In Study GO28915 (OAK), OS was improved regardless of PD-L1 expression levels, 
including in pts with no PD-L1 expression (TC0 and IC0).  OS was 59% greater among 
patients in the highest tertile of PD-L1 expression (TC3 or IC3) (p<0.0001).  However 
even in patients with no PD-L1 expression, there was still a significant 25% improvement 
in OS with atezolizumab compared to those treated with docetaxel. The improvements in 
overall survival were similar in patients with squamous and non-squamous histology.   
The secondary efficacy endpoints of OS rates at 6, 12, 18 and 24 months, ORR, PFS 
and DOR will allow the evaluation of differences in response and progression patterns 


 
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between the two treatment groups.  The secondary efficacy endpoint of OS and PFS in 
patients with PD-L1 expression defined by the PD-L1 SP263 IHC assay will help to 
identify subsets of patients who benefit most from atezolizumab monotherapy when 
tested with the Ventana PD-L1 SP263 IHC assay.  Patients will be evaluated for disease 
progression at predefined, standard intervals to minimize evaluation-time biases and will 
be followed off-treatment for continued safety monitoring and date of death.  Safety and 
tolerability of study treatments will be assessed.  The evaluation of efficacy data across 
the PD-L1 IHC category strata will be defined by IHC-subpopulations and analyzed by 
subgroups defined by the different PD-L1 IHC categories used for patient stratification. 
PRO data will allow further evaluation of the relative tolerability of treatment and the 
impact of therapy on disease symptoms between the two treatment groups.
3.3.6 
Rationale for Allowing Patients to Continue Atezolizumab
Treatment until Loss of Clinical Benefit 
Conventional response criteria may not adequately assess the activity of
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure.  Because of the potential for 
pseudoprogression/tumor-immune infiltration, this study will allow patients randomized to 
the atezolizumab treatment arms to remain on atezolizumab after apparent radiographic 
progression, provided the benefit-risk ratio is judged to be favorable.  Patients should be 
discontinued for unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as determined by the investigator after an integrated assessment of 
radiographic data and clinical status (see also Section 3.1).
In addition, while the secondary endpoint measures of efficacy (OS rates, ORR, PFS, 
DOR) comparing the atezolizumab and single agent chemotherapy arms will be using 
RECIST v1.1 criteria, noncomparative analyses of these measures using modified
RECIST criteria (see Appendix 3) will only be performed for patients randomized to 
receive atezolizumab.  Modified RECIST criteria allow the incorporation of new lesions 
into the calculation of total tumor burden after baseline.  Similar to the imRC (Wolchok et
al. 2009), it is recommended that radiological progression be confirmed at a subsequent 
tumor assessment to take into account the potential for pseudoprogression/tumor 
immune infiltration.  Additionally, it is highly recommended that evidence of progressive 
disease in responding patients be confirmed by a biopsy of the growing or new lesion 
when feasible.
3.3.7 
Rationale for Patient-Reported Outcome Assessments
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on HRQoL (Hyde and 
Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).  This is especially true for 
studies in patients with a low performance status, where it is important to better 
understand in what regard the delay in disease progression is meaningful to patients.


 
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Chest pain, dyspnea, and cough have been regarded as the most frequent and clinically 
relevant disease-related symptoms experienced by patients with NSCLC.  The BR.21 
study (erlotinib vs. best supportive care in second- or third-line NSCLC) demonstrated 
that longer time to deterioration (TTD) in the pain, dyspnea, and cough scales of the 
EORTC QLQ-C30 and QLQ-LC13 was consistent with superior PFS, OS, and 
quality-of-life benefits in the erlotinib arm compared with the placebo arm (Aaronson et 
al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  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 and symptom severity.
The EQ-5D-5L instrument is included in the study to generate utility scores for potential 
use in economic models for reimbursement.
3.3.8 
Rationale for Assessment of Response using Modified
(Immune-Mediated) RECIST Criteria
Immunotherapeutic agents produce antitumor effects by inducing cancer-specific
immune responses or by modifying native immune processes.  Resulting clinical
response patterns extend beyond those of cytotoxic agents and can manifest after an 
initial increase in tumor burden or the appearance of new lesions (progressive disease). 
RECIST or WHO criteria, designed to detect early effects of cytotoxic agents, may not 
provide a complete assessment of immunotherapeutic agents.  Novel criteria for the 
evaluation of antitumor responses with immunotherapeutic agents use designated imRC, 
which can better capture the response patterns observed with some immunotherapeutic 
agents.  Use of the imRC may allow more comprehensive evaluation of 
immunotherapeutic agents in clinical trials and, potentially, may offer guidance in clinical 
care (Wolchok et al. 2009).
In the phase II GO28625 (FIR) study, which assessed atezolizumab in patients with 
PD-L1 positive locally advanced or metastatic NSCLC, efficacy data by 
investigator-assessed modified RECIST and RECIST v1.1, showed an overall 
agreement between ORR per modified RECIST and RECIST v1.1, however 2 patients 
were responders per modified RECIST but not RECIST v1.1.
While the primary endpoint in this study measures efficacy (OS) by using RECIST v1.1 
criteria, exploratory analyses of ORR, PFS, DCR and DOR will be using modified 
RECIST criteria (see Section 2.4) for patients randomized to receive atezolizumab. 
Modified RECIST criteria (Appendix 4) allow for the incorporation of new lesions into 
the calculation of total tumor burden after baseline.


 
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3.3.9 
Rationale for Biomarker Assessments 
3.3.9.1 
Tumor Tissue Specimens for Patient Stratification According 
to PD-L1 IHC Status and Exploratory Biomarker Analyses 
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to anti-PD-1 therapy (Topalian et al. 2012). This correlation is also observed 
with atezolizumab in preliminary data from Study PCD4989g.   
In this study, tumor specimens obtained pre-therapy (archival or during screening) from 
patients will be prospectively tested for PD-L1 expression by a central laboratory during 
the screening period.  PD-L1 positivity will be assessed for tumor and immune cells and 
patients will be stratified according to the percentage of positive cells within the tumor. In 
order to stratify based on PD-L1 IHC status, formalin-fixed paraffin-embedded (FPPE) 
tissue (block or slides) are mandated.  Refer to Section 4.2 for definition of PD-L1 status 
for stratification. 
Exploratory markers will be assessed with the objective to further study prognostic or 
predictive biomarkers related to the response to atezolizumab, tumor immunobiology or 
mechanisms of resistance.  Biomarker assessments include the analysis of e.g., protein, 
DNA or RNA (or other analytes) to study gene expression signatures related to response 
to atezolizumab and tumor mutational burden. 
3.3.9.2 
Blood Sample 
An exploratory objective of this study is to evaluate surrogate biomarkers (that may 
include circulating tumor DNA [ctDNA]) in blood samples.  Evaluation of blood 
biomarkers may provide evidence for biologic activity of atezolizumab in patients with 
NSCLC and may allow for the development of blood-based biomarkers to help predict 
which patients may benefit from atezolizumab. 
In addition, potential correlations of these biomarkers with the safety and activity of 
atezolizumab will be explored.   
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study is the following: 
 
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 the following: 
 
OS rates at 6, 12, 18 and 24 months 
 
ORR, defined as overall response (partial response plus complete response), 
as determined by the investigator using RECIST v1.1  


 
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 
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
 
DOR, defined as the time from the first occurrence of a documented objective 
response to the time of disease progression, as determined by the investigator
using RECIST v1.1, or death from any cause, whichever occurs first 
3.4.2 
Safety Outcome Measures
The safety outcome measures for this study are the following:
 
Incidence, nature, and severity of adverse events graded according to the NCI
CTCAE v4.0
 
Changes in vital signs, physical findings, and clinical laboratory results during
and following study drug administration
3.4.3 
Patient-Reported Outcome Measures
The patient-reported outcome measures for this study are the following:
 
Change from baseline in PROs of lung cancer symptoms, patient functioning,
HRQoL as assessed by EORTC QLQ-C30 and its supplementary Lung Cancer 
module (LC13)
 
TTD in patient-reported lung cancer symptoms of cough, dyspnea (single-item 
and multi-item subscales), chest pain, arm/shoulder pain, or fatigue using
EORTC QLQ-C30 and QLQ-LC13
3.4.4 
Exploratory Outcome Measures
The exploratory outcome measures for this study are the following:
 
ORR, PFS and DOR as determined according to modified RECIST v1.1
(Appendix 4)
 
DCR defined as the rate of patients with complete response or partial response
as best response or stable disease as determined by the investigator per 
RECIST v1.1
 
Tumor tissue PD-L1 expression
 
Exploratory biomarkers in tumor tissue and plasma
 
Expression of immune markers in PBMCs
 
Utility scores of the EQ-5D-5L questionnaire
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 120 sites globally will participate in the study, and approximately 
441 treatment-naïve patients with locally advanced or metastatic NSCLC who are 
deemed unsuitable for any platinum-doublet chemotherapy will be enrolled in this study. 


 
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4.1.1 
Inclusion Criteria
Patients must meet the following criteria for study entry:
1. 
Signed Informed Consent Form
2. 
Male or female, age  ≥ 18 years
3. 
Able to comply with the study protocol, in the investigator’s judgment
4. 
Histologically or cytologically confirmed diagnosis of advanced or recurrent
(Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) 
NSCLC as per the American Joint Committee on Cancer (AJCC) 7th edition (see 
Appendix 2)
5. 
No sensitizing EGFR mutation (L858R or exon 19 deletions) or ALK fusion
oncogene detected
6. 
No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for
multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th 
edition (see Appendix 2)
7. 
Life expectancy ≥ 8 weeks
8. 
Deemed unsuitable by the investigator for any platinum-doublet chemotherapy due
to poor performance status (ECOG PS of 2-3)
However, patients ≥ 70 years of age who have an ECOG PS of 0 or 1 may be 
included due to:
a)  substantial comorbidities
b)  contraindication(s) for any platinum-doublet chemotherapy.
9. 
Representative FPPE tumor tissue block obtained during course of disease (archival
tissue) or at screening (tumor blocks are highly preferred for central analysis of 
PD-L1 expression and exploratory biomarkers [see Section 4.5.7 for details on 
tissue requirements])
10. Patients with treated, asymptomatic CNS metastases are eligible, provided they
meet all of the following criteria:
a) Measurable disease outside CNS
b) Only supratentorial and cerebellar metastases allowed (i.e., no metastases
to midbrain, pons, medulla or spinal cord)
c) 
No ongoing requirement for corticosteroids as therapy for CNS disease;
anticonvulsants at a stable dose allowed
d) No stereotactic radiation within 7 days or whole-brain radiation within
14 days prior to randomization
e) No evidence of interim progression between the completion of
CNS-directed therapy and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening scan
must receive radiation therapy and/or surgery for CNS metastases.  Following 
treatment, these patients may then be eligible without the need for an additional


 
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brain scan prior to randomization, if all other criteria are met, including clinical 
confirmation of no evidence of interim disease progression  
11. Measurable disease (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. 
12. Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to randomization: 
a) Absolute neutrophil count (ANC)  1500 cells/µL without granulocyte 
colony-stimulating factor support  
b) White blood cell (WBC) counts > 2500/µL 
c) 
Lymphocyte count  500/µL 
d) Serum albumin  2.5 g/dL 
e) Platelet count  100,000/µL without transfusion (without transfusion within 
2 weeks of laboratory test used to determine eligibility) 
f) 
Hemoglobin  9.0 g/dL, patients may be transfused or receive 
erythropoietic treatment to meet this criterion 
g) International normalized ratio (INR) or activated partial thromboplastin time 
(aPTT) ≤ 1.5 × ULN.  This applies only to patients who are not receiving 
therapeutic anticoagulation; patients receiving therapeutic anticoagulation 
must have an INR or aPTT within therapeutic limits for at least 1 week prior 
to randomization. 
h) AST, alanine aminotransferase (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 
i) 
Serum bilirubin ≤ 1.5 × ULN.  Patients with known Gilbert’s syndrome who 
have serum bilirubin level ≤ 3 × ULN may be enrolled 
j) 
Serum creatinine ≤ 1.5 × ULN. 
13. For female patients of childbearing potential randomized to the atezolizumab 
treatment arm: agreement (by patient and/or partner) to remain abstinent (refrain 
from heterosexual intercourse) or to use highly effective form(s) of contraceptive 
methods that result in a failure rate of < 1% per year when used consistently and 
correctly during the treatment period and for at least 5 months after the last dose of 
atezolizumab. 
 
A woman is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state 


 
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(≥ 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, and 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 
adequate methods of contraception. 
14. Female patients of childbearing potential and male patients with partners of 
childbearing potential treated in the comparative single agent chemotherapy arm 
should continue contraception use for at least 6 months after the last dose of study 
treatment.  Such methods include: combined (estrogen and progestogen containing) 
hormonal contraception, progestogen-only hormonal contraception associated with 
inhibition of ovulation together with another additional barrier method always 
containing a spermicide, intrauterine device (IUD): intrauterine hormone-releasing 
system (IUS), bilateral tubal occlusion, vasectomized partner (on the understanding 
that this is the only one partner during the whole study duration), and sexual 
abstinence. Male patients should not donate sperm during this study and for at least 
6 months after the last dose of comparative single agent chemotherapy treatment. 
 
Oral contraception should always be combined with an additional 
contraceptive method because of a potential interaction with the study 
drug.  The same rules are valid for male patients involved in this 
clinical study if they have a partner of childbirth potential. Male patients 
must always use a condom. 
15. Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug. 
4.1.2 
Exclusion Criteria 
4.1.2.1 
Cancer-Specific Exclusion Criteria 
1. 
Patients younger than 70 years who have an ECOG PS of 0 or 1. 
2. 
Active or untreated CNS metastases as determined by CT or magnetic resonance 
imaging (MRI) evaluation of the brain during screening and prior radiographic 
assessments (see Section 4.1.1 for definition of treated and asymptomatic CNS 
metastases) 
a) Spinal cord compression not definitively treated with surgery and/or 
radiation or previously diagnosed and treated spinal cord compression 
without evidence that disease has been clinically stable for > 2 weeks prior 
to randomization 
b) Leptomeningeal disease 


 
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c) 
History of CNS metastases intracranial haemorrhage 
3. Uncontrolled tumor-related pain 
a) Patients requiring pain medication must be on a stable regimen at study 
entry. 
b) Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated 
prior to enrollment.  Patients should have recovered from the effects of 
radiation. There is no required minimum recovery period. 
c) 
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment. 
4. 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. 
5. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L or 
calcium > 12 mg/dL or corrected serum calcium > ULN)  
6. History of other malignancy within 5 years prior to screening, 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 with curative intent, breast ductal carcinoma in situ treated surgically with 
curative intent)  
7. NCI CTCAE (v4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., 
radiotherapy) (excluding alopecia), which have not shown improvement and are 
strictly considered to interfere with current study medication. 
8. Patients who have received prior neo-adjuvant, adjuvant chemotherapy, 
radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease 
must have experienced a treatment-free interval of at least 6 months from 
randomization since the last chemotherapy, radiotherapy, or chemoradiotherapy.  
4.1.2.2 
General Medical Exclusion Criteria  
1. 
Women who are pregnant or lactating or intending to become pregnant during the 
study.  Women of childbearing potential including women who have had a tubal 
ligation, must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug. 
2. 
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, granulomatosis with polyangiitis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 11 for 
a more comprehensive list of autoimmune diseases) 


 
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 
Patients with a history of autoimmune-mediated hypothyroidism on a stable 
dose of thyroid-replacement hormone may be eligible for this study 
 
Patients with controlled Type I diabetes mellitus on a stable dose of insulin 
regimen are eligible for this study 
3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
a) Rash must cover less than 10% of body surface area (BSA) 
b) Disease is well controlled at baseline and only requiring low potency topical 
steroids 
c) 
No acute exacerbations of underlying condition within the last 12 months 
requiring treatment with either psoralen plus ultraviolet radiation (PUVA), 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or high 
potency or oral steroids 
4. History of idiopathic pulmonary fibrosis (IPF), 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. 
5. Known positivity for human immunodeficiency virus (HIV)  
 
Testing is not required in the absence of clinical symptoms and signs 
suggestive of HIV infection. 
 
Patients with a past history of/or symptoms of HIV are eligible only if 
serological tests are negative. 
6. Known active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or known active hepatitis C   
 
Patients with past hepatitis B virus (HBV) infection or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [HBcAb] and 
absence of HBsAg) are eligible. HBV DNA test must be performed in these 
patients prior to randomization.  Patients positive for hepatitis C virus 
(HCV) antibody are eligible only if polymerase chain reaction is negative for 
HCV RNA. 
7. Active tuberculosis 
8. Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
9. Significant cardiovascular disease, such as New York Heart Association (NYHA) 
cardiac disease (Class II or greater), myocardial infarction 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 
(LVEF) < 50% must be on a stable medical regimen that is optimized 


 
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in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate. 
10. Major surgical procedure other than for diagnosis within 4 weeks prior to 
randomization or anticipation of need for a major surgical procedure during the 
course of the study 
11. Prior allogeneic bone marrow transplantation or solid organ transplant 
12. Any serious medical condition (including metabolic dysfunction, physical examination 
finding) or abnormality in clinical laboratory tests that, in the investigator’s judgment, 
precludes the patient’s safe participation in and completion of the study or that may 
affect the interpretation of the results or render the patient at high risk for treatment 
complications 
13. Patients with an illness or condition that may interfere with capacity or compliance 
with the study protocol, as per investigator's judgment  
14. Treatment with any other investigational agent or participation in another clinical 
study with therapeutic intent within 28 days prior to randomization 
4.1.2.3 
Exclusion Criteria Related to Atezolizumab   
1. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies or fusion proteins 
2. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
3. Oral or IV antibiotic treatment.  Patients will thus need to have recovered from any 
infection requiring antibiotics.  Patients receiving prophylactic antibiotics (e.g., for 
prevention of a urinary tract infection or to prevent chronic obstructive pulmonary 
disease exacerbation) are eligible. 
4. 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 
 
Influenza vaccination is allowed but should be given during influenza 
season.  However, patients must not receive live, attenuated influenza 
vaccine (e.g., FluMist®) within 4 weeks prior to randomization, at any time 
during the study or within 5 months after the last atezolizumab dose. 
5. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
anti−PD-1, and anti−PD-L1 therapeutic antibodies.  Patients who have had prior 
anti−cytotoxic T lymphocyte−associated antigen 4 (CTLA-4) treatment may be 
enrolled, provided the following requirements are met: 
a) Minimum of 6 weeks from the last dose of anti-CTLA-4 
b) No history of severe immune-mediated adverse effects from anti-CTLA-4 
(NCI CTCAE Grade 3 and 4) 
6. Treatment with systemic immunostimulatory agents (including but not limited to 
interferons, interleukin-2 [IL-2]) within 4 weeks or 5 half-lives of the drug, whichever 
is shorter, prior to randomization   


 
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7. Treatment with systemic corticosteroids or other immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] 
agents)  
 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled in the study after discussion with and approval by 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. 
 
Patients with history of allergic reaction to IV contrast requiring steroid pre-
treatment should have baseline and subsequent tumor assessments done 
by MRI. 
8. Patients not willing to stop treatment with traditional herbal medicines 
4.1.2.4 
Exclusion Criteria Related to Chemotherapy 
1. 
Known sensitivity and contraindications to the 2 comparative chemotherapy agents 
(i.e., vinorelbine, oral or intravenous, and gemcitabine, intravenous)  
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an open-label study. 
After written informed consent has been obtained and eligibility has been established, 
the study site will enter demographic and baseline characteristics in the interactive 
voice/web response system (IxRS).  For patients who are eligible for enrollment, the 
study site will obtain the patient’s randomization number and treatment assignment from 
the IxRS. 
Randomization to one of the two treatment arms will occur at a 2:1 ratio.  
Permuted-block randomization will be applied to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified by the following criteria: 
 
Histologic subtype (non-squamous/squamous)  
 
PDL-1 IHC status (positive/negative/unknown)  
 
Brain metastases (yes/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 
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PD-L1 IHC status for treatment assignment is assessed by IHC and defined as: 
PD-L1 IHC Positive: 
Presence of discernible PD-L1 staining of any intensity in tumor-
infiltrating immune cells covering ≥10% of tumor area occupied by 
tumor cells, associated intratumoral, and contiguous peri-tumoral 
desmoplastic stroma (IC3) 
OR 
Presence of discernible PD-L1 staining of any intensity in ≥ 50% 
tumor cells (TC3) 
PD-L1 IHC 
Negative: 
Presence of discernible PD-L1 staining of any intensity in tumor-
infiltrating immune cells covering <10% of tumor area occupied by 
tumor cells, associated intratumoral, and contiguous peri-tumoral 
desmoplastic stroma 
AND 
Presence of discernible PD-L1 staining of any intensity in <50% 
tumor cells 
PD-L1 IHC Status 
unknown: 
PD-L1 IHC status could not be determined (e.g. not enough tumor) 
 
4.3 
STUDY TREATMENT  
The investigational medicinal products (IMPs) for this study are atezolizumab, 
vinorelbine (oral or intravenous) and gemcitabine (intravenous), and will be provided by 
the Sponsor (see Section 4.3.3). 
4.3.1 
Formulation, Packaging, and Handling  
4.3.1.1 
Atezolizumab 
The atezolizumab Drug Product is provided by Roche or its designee in a single-use, 
20-mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, 
preservative-free clear liquid solution intended for IV administration.  The vial is designed 
to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than the 
stated volume to enable delivery of the entire 20 mL volume.  The atezolizumab Drug 
Product is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM 
sucrose, 0.04% polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C-8°C (36°F-46°F) upon receipt until use. 
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer.  No preservative is used in the atezolizumab Drug Product or the diluent; 
therefore, each vial is intended for single use only.  Discard any unused portion of drug 
remaining in a vial.  Vial contents should not be frozen or shaken and should be 
protected from light. 
For further details on the storage and preparation of atezolizumab, see the Pharmacy 
Manual and Atezolizumab Investigator’s Brochure. 
Atezolizumab will be supplied by the Sponsor. 


 
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4.3.1.2 
Vinorelbine, Gemcitabine  
Vinorelbine, oral and intravenous, and gemcitabine, intravenous will be provided as 
study medication by Roche or its designee in compliance with local drug management 
regulations. 
For information on the formulation, packaging, and handling of, vinorelbine (oral and 
intravenous) and gemcitabine (intravenous), see the local Prescribing Information for 
each drug and formulation (vinorelbine). 
4.3.2 
Dosage, Administration, and Compliance  
4.3.2.1 
Atezolizumab  
Patients randomized to atezolizumab will receive 1200 mg of atezolizumab administered 
by IV infusion every 21 days in a monitored setting where there is immediate access to 
trained personnel and adequate equipment/medicine to manage potentially serious 
reactions. 
Atezolizumab infusions will be administered per the instructions outlined in Table 10. 
Table 10 Administration of First and Subsequent Infusions 
of Atezolizumab 
First Atezolizumab Infusion 
Subsequent Infusions 
 No premedication administered for 
atezolizumab specifically is permitted 
 Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 min before starting 
infusion. 
 Infuse atezolizumab (1200 mg in a 250 mL 
0.9% NaCl IV infusion bag) over 60 min 
(± 15 min). 
 If clinically indicated: record patient’s vital 
signs (heart rate, respiratory rate, blood 
pressure, and temperature) during the 
infusion at 15 min, 30 min, 45 min, and 
60 min (± 5 min windows are allowed for all 
timepoints). 
 If clinically indicated: record patient’s vital 
signs (heart rate, respiratory rate, blood 
pressure, and temperature) at 30 min 
(± 10 min) after the infusion. 
 Patients will be informed about the possibility 
of delayed post-infusion symptoms and 
instructed to contact their study physician if 
they develop such symptoms. 
 If patient experienced infusion-related 
reaction during any previous infusion, 
premedication with antihistamines may be 
administered for Cycles ≥ 2 at the 
discretion of the treating physician. 
 Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 min before starting 
infusion. 
 If the patient tolerated the first infusion 
well without infusion-associated adverse 
events, the second infusion may be 
delivered over 30 min (± 10 min).  
 If no reaction occurs, subsequent 
infusions may be delivered over 30 min 
(± 10 min) minutes. 
Continue to record vital signs within 
60 minutes before starting infusion and 
during and after the infusion, if clinically 
indicated. 
 If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be delivered 
over 60 min (± 15 min). 


 
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First Atezolizumab Infusion 
Subsequent Infusions 
 Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) every 15 min (± 5 min) 
during the infusion if clinically indicated or 
patient experienced symptoms during the 
previous infusion. 
 Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) 30 min (± 10 min) after the 
infusion if clinically indicated or patient 
experienced symptoms during previous 
infusion. 
 
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are 
provided in Sections 5.1.3.2 and 5.1.3.3. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  Section 5.3.5.12 summarizes available safety data related 
to overdosing of atezolizumab. 
4.3.2.2 
Vinorelbine 
Vinorelbine is indicated as a single agent or in combination for the first line treatment of 
stage III or IV NSCLC.  Vinorelbine will be administered (orally or intravenously) per 
relevant local guidelines and SmPC management.  Reliable dose correspondence has 
been confirmed between vinorelbine 80 mg/m2 oral and 30 mg/m2 IV (Bourgeois et al. 
2007). 
Vinorelbine for infusion may be administered at 25-30 mg/m2 d1/8 q21d or d1/8/15 q28d. 
Vinorelbine for oral administration may be administered at 60-80 mg/m2 d1/8 q21d or 
d1/8/15 q28d, with weekly dosing recommended in some labels. 
All patients receiving vinorelbine should be monitored for myelosuppression both during 
and after therapy.  Granulocytopenia is dose-limiting, with granulocyte nadirs occurring 
between 7 and 10 days after dosing and granulocyte count recovery usually within the 
following 7 to 14 days.  Vinorelbine should not be administered to patients with 
granulocyte counts < 1,000 cells/mm3.   
Risks and adverse reactions following vinorelbine administration are summarized in 
Section 5.1.1.2. Dose modifications should be performed according to Section 5.1.3.4.  
For further details, see the local Prescribing Information for vinorelbine. 


 
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4.3.2.3 
Gemcitabine 
Gemcitabine, in combination with cisplatin, is indicated as first-line treatment of patients 
with locally advanced or metastatic NSCLC.  Gemcitabine monotherapy can be 
considered in elderly patients or those with PS2. 
Gemcitabine will be administered per relevant local guidelines and SmPC management.   
Gemcitabine may be administered intravenously at 1000-1250 mg/m2 d1/8 q21d or 
d1/8/15 q28d. 
Myelosuppression is the principal dose-limiting toxicity with gemcitabine.  Risks and 
adverse reactions following gemcitabine administration are summarized in 
Section 5.1.1.3. Dose modifications should be performed according to Section 5.1.3.5.  
For further details, see the local Prescribing information for gemcitabine. 
4.3.3 
Additional Required Medication 
Any premedication doses administered should be in compliance with the respective 
Summary of Product Characteristics (SmPC).  
For further details, see the respective local Prescribing Information for chemotherapy 
agents. 
4.3.3.1 
Atezolizumab 
No premedication is indicated for the administration of atezolizumab in Cycle 1.  Patients 
who experience an infusion-related reaction with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions (see Section 4.4.1.1). 
4.3.3.1.1 
Infusion Related Reactions 
Guidelines for medical management of infusion-related reactions during Cycle 1 are 
provided in Table 11.  For subsequent cycles, infusion-related reactions should be 
managed according to institutional guidelines. 
Table 11 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. 


 
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Event 
Management 
 
Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 
After symptoms have resolved to baseline, resume infusion at half the 
rate being given at the time of event onset. 
 
For subsequent infusions, administer oral premedication with 
antihistamine and anti-pyretic and monitor closely for IRRs. 
IRR, Grade 3 or 4 
 
Stop infusion. 
 
Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 
Permanently discontinue atezolizumab and contact the Medical 
Monitor.a 
IRR = infusion-related reaction; IV = intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
 
4.3.3.2 
Vinorelbine 
No pre- and additional medications are required for vinorelbine.  
For further details, see the local Prescribing Information for vinorelbine.   
4.3.3.3 
Gemcitabine 
No pre- and additional medications are required for gemcitabine.  
For further details, see the local Prescribing Information for gemcitabine.   
4.3.4 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(atezolizumab, vinorelbine and gemcitabine) will be provided by the Sponsor where 
required by local health authority regulations.  The study site is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by each 
patient, and disposition or return of unused IMP, thus enabling reconciliation of all IMP 
received, and for ensuring that patients are provided with doses specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of the IMPs using IxRS to confirm shipment condition 
and content.  Any damaged shipments will be replaced.  The investigator or designee 
must confirm that appropriate temperature conditions have been maintained during 
transit, either by time monitoring (shipment arrival date and time) or temperature 
monitoring, for all IMPs received and that any discrepancies have been reported and 
resolved before use of the IMPs.  All IMPs must be stored in a secure, environmentally 


 
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controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions, with access limited to the investigator and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
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. 
Refer to the pharmacy manual and/or the atezolizumab Investigator's Brochure or 
vinorelbine and gemcitabine local prescribing information for information on IMP 
handling, including preparation and storage, and accountability.  
4.3.5 
Continued Access to Atezolizumab 
The Sponsor will offer continued access to Roche IMP (atezolizumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive Roche IMP (atezolizumab) after completing the study 
if all of the following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being 
 
There are no appropriate alternative treatments available to the patient 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive Roche IMP (atezolizumab) after completing the 
study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for NSCLC 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
NSCLC 
 
Provision of the Roche IMP for is not permitted under the laws and regulations of 
the patient's country 


 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening until death, withdrawal of consent, loss to follow up, or study 
termination by Sponsor, whichever occurs first.  All such medications should be reported 
to the investigator, and must be recorded on the appropriate Concomitant Medications 
eCRF. 
4.4.1 
Atezolizumab Concomitant Therapy 
4.4.1.1 
Permitted Therapy with Atezolizumab  
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions. 
Guidelines for medical management of infusion-related reactions during Cycle 1 are 
provided in Section 4.3.3.1.1.  For subsequent cycles, infusion-related reactions should 
be managed according to institutional guidelines. 
The following therapies should continue while patients are in the study: 
 
Oral contraceptives 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level) 
 
Palliative radiotherapy (e.g., treatment of known bony metastases) provided it does 
not interfere with the assessment of tumor target lesions (e.g., the lesion being 
irradiated is not the only site of disease, as that would render the patient not 
evaluable for response by tumor assessments according to RECIST v1.1).  
 
It is not a requirement to withhold atezolizumab during palliative radiotherapy. 
 
Vaccinations (such as influenza, COVID-19). Live attenuated vaccines are not 
permitted (see Section 4.4.1.3). 
 
Megastrol 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 


 
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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.  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 β2-adrenergic agonists; see Appendix 10).
The concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However, their use for patients in the study is allowed at the discretion of the 
investigator provided that there are no known interactions with any study treatment. As 
noted below, herbal therapies intended for the treatment of cancer are prohibited.
4.4.1.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor 
alpha (TNF-α) inhibitors may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab.  Therefore, in situations where systemic corticosteroids, 
immunosuppressive medications, or TNF-α inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF-α 
inhibitors may be administered at the discretion of the treating physician.
Systemic corticosteroids or immunosuppressive medications are recommended, with 
caution at the discretion of the treating physician, for the treatment of specific adverse 
events when associated with atezolizumab therapy.  Guidelines for the management of 
immune-mediated adverse events are described in Section 5.1.3.3 and in the 
Investigator’s Brochure.
4.4.1.3 
Prohibited Therapy with Atezolizumab
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited for various time periods prior to starting 
study treatment, depending on the anti-cancer agent (see Section 4.1.2), and during 
study treatment until disease progression is documented and patient has discontinued 
study treatment.  This includes, but is not limited to, chemotherapy, hormonal therapy, 
immunotherapy, radiotherapy, investigational agents, or herbal therapy (unless
otherwise noted).
The following medications are prohibited while in the study, unless otherwise noted:
 
Any live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to randomization,
during treatment, or within 5 months after the last atezolizumab dose (for patients 
randomized to atezolizumab).


 
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 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
 
4.4.2 
Chemotherapy Concomitant Therapy 
Interactions common to all cytotoxics: 
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation 
treatment is frequent.  The high intra-individual variability of the coagulation status during 
diseases and the possibility of interaction between oral anticoagulants and anti-cancer 
chemotherapy require increased frequency of INR monitoring, if it is decided to treat the 
patient with oral anticoagulants. 
4.4.2.1 
Vinorelbine Concomitant Therapy 
Vinorelbine should be used with extreme caution in patients whose bone marrow reserve 
may have been compromised by prior irradiation or chemotherapy, or whose marrow 
function is recovering from the effects of previous chemotherapy.  Administration of 
vinorelbine to patients with prior radiation therapy may result in radiation recall reactions. 
Patients with a prior history or pre-existing neuropathy, regardless of etiology, should be 
monitored for new or worsening signs and symptoms of neuropathy while receiving 
vinorelbine. 
Care must be taken to avoid contamination of the eye with concentrations of vinorelbine 
used clinically. Severe irritation of the eye has been reported with accidental exposure to 
another vinca alkaloid. If exposure occurs, the eye should immediately be thoroughly 
flushed with water. 
For further details, see the local Prescribing Information for vinorelbine.   
4.4.2.2 
Gemcitabine Concomitant Therapy 
Drug-induced liver injury, including liver failure and death, has been reported in patients 
receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs.  
Administration of gemcitabine in patients with concurrent liver metastases or a 
pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to 
exacerbation of the underlying hepatic insufficiency.  Assess hepatic function prior to 
initiation of gemcitabine and periodically during treatment.  Discontinue gemcitabine in 
patients that develop severe liver injury. 
Gemcitabine is not indicated for use in combination with radiation therapy. 
For further details, see the local Prescribing Information for gemcitabine.   


 
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4.5 
STUDY ASSESSMENTS
Please see Appendix 1 for the schedule of activities to be performed during the 
study.
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-related procedures.  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 enrollment.  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.
4.5.2 
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history
(including prior cancer therapies, procedures, and an assessment of tumor mutational 
status), 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.
Cancer history will include prior cancer therapies, procedures, and tumor mutational 
status (e.g., EGFR mutation status, ALK fusion status).
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3 
Physical Examinations
A complete physical examination should include the assessment of height and weight, 
respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is 
in a seated position, and temperature, an evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be


 
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recorded in patient notes. New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of temperature, pulse rate, respiratory rate, and 
systolic and diastolic blood pressures while the patient is in a seated position. 
Vital signs will be measured and recorded for all patients as described in Table 12. 
Table 12 Vital Signs Measurements at Cycle 1 and all Subsequent Cycles  
Cycle 1 and all Subsequent Cycles 
Treatment Arm 
Timepoints 
Atezolizumab  
 
Within 60 minutes prior to atezolizumab infusion  
 
During (every 15 [± 5] minutes) the infusion and within 30 (± 10) 
minutes after atezolizumab infusion, if clinically indicated 
Chemotherapy  
 
Within 60 minutes prior to chemotherapy administration 
 
Within 30 (± 10) minutes after chemotherapy administration 
Subsequent Cycles 
Treatment Arm 
Timepoints 
Atezolizumab  
 
Within 60 minutes prior to atezolizumab infusion  
 
During (every 15 [± 5] minutes) the infusion and within 30 (± 10) 
minutes after atezolizumab infusion, if clinically indicated or if 
symptoms occurred during prior infusion 
Chemotherapy  
 
Within 60 minutes prior to chemotherapy administration 
 
During infusion if clinically indicated or if symptoms occurred during 
the prior administrations 
 
Within 30 (± 10) minutes after chemotherapy infusion if clinically 
indicated or if symptoms occurred during the prior administration 
 
For patients in the atezolizumab arm, also refer to Section 4.3.2.1.
4.5.5 
Tumor and Response Evaluations
Measurable and non-measurable disease must be documented at screening and 
re-assessed at each subsequent tumor evaluation.  Tumor assessments are to be 
performed at the timepoints specified in Appendix 1, regardless of drug delays or 
interruptions.
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRIs of the chest and abdomen.  A CT scan of the pelvis is required 
at screening and as clinically indicated or as per local practice at subsequent response 
evaluations.  A spiral CT scan of the chest may be obtained but is not a requirement. 
MRIs of the chest, abdomen, and pelvis with a non-contrast CT scan of the chest may


 
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be used in patients for whom CT scans with contrast are contraindicated (i.e., patients 
with contrast allergy or impaired renal clearance).
A CT (with contrast unless contraindicated) or MRI scan of the head must be done at 
screening to evaluate brain metastasis in all patients.  In case of newly detected brain 
metastases, the patient must be treated and may then be included without the need for 
an additional brain scan prior to randomization, if all other criteria are met, including 
clinical confirmation of no evidence of interim disease progression.  Patients with active 
or untreated CNS metastases are not eligible for the study (see Section 4.1.2.1).
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan.
Bone scans and CT scans of the neck should also be performed if clinically indicated.  At 
the investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.
Tumor assessments performed as standard-of-care prior to obtaining informed consent 
and within 28 days of Cycle 1, Day 1 may be used rather than repeating tests.  It is 
recommended to have the screening/baseline tumor assessment done within 14 days 
before randomization, as close as possible to baseline.  All known sites of disease must 
be documented at screening and re-assessed 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).
Tumor assessments will be performed at baseline, every 6 weeks (± 5 days) following 
randomization for 48 weeks, and every 9 weeks (± 5 days) thereafter, with additional 
scans as clinically indicated. Assessments will continue until disease progression per 
RECIST v1.1. Patients randomized to atezolizumab who continue to receive 
atezolizumab following disease progression will undergo tumor assessments until 
treatment discontinuation. Tumor assessments should continue regardless of whether 
patients discontinue study treatment or start new anti-cancer therapy in the absence of 
disease progression unless they withdraw consent.
In all patients, response will be assessed by the investigator using RECIST v1.1 (see 
Appendix 3) until disease progression.  Patients randomized to receive atezolizumab 
will additionally be assessed by modified RECIST criteria (see Appendix 4) until 
treatment discontinuation.  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.


 
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4.5.6 
Determination of EGFR and ALK Status
Patients known to have a sensitizing mutation in the EGFR gene or an ALK fusion 
oncogene are excluded from the study.  Therefore, all patients with non-squamous 
NSCLC must have undergone EGFR and ALK analysis before study inclusion.  Testing 
is not required for patients who have squamous NSCLC, except for patients who are 
never-smokers or who have a mixed histology.
EGFR and ALK may be assessed locally or at a central lab.  Central testing for EGFR 
and ALK requires submission of tumor tissue to the central laboratory (1 FFPE tissue 
block or at least 7 slides cut from a tumor tissue block).
4.5.7 
Tumor Tissue Requirements for Central PD-L1 Analysis
(Stratification)
In order to perform prospective stratification by PD-L1 IC/TC status, patients must
provide tumor tissue meeting the following requirements.
Tumor tissue must meet the following requirements:
 
A representative FPPE tumor tissue block obtained during course of disease
(archival tissue) or screening (tumor blocks are highly preferred); ideally, 3 cores 
should be submitted in case smaller core biopsies are available in order to have 
sufficient tumor cells available.
 
In case the tumor block is not available, 10-15 unstained, consecutive slides not
older than 60 days will be accepted.  A minimum of five slides is mandated for 
PD-L1 analysis and patient stratification.
 
If archival tissue (most recent sample) is unavailable, a pretreatment tumor biopsy is
required.  Cytological or fine-needle aspiration samples are not acceptable.
 
Tumor tissue from bone metastases are not acceptable.
 
Tumor tissue should be of good quality based on total and viable tumor content (at
least 300 viable tumor cells across cores are needed for determination of TC/IC 
status at low cut-offs).
During screening, 5 slides will be cut from the tumor block for analysis of PD-L1.  Once 
the patient enters the study, additional 10 slides will be cut for exploratory analyses. 
Tissue blocks will be returned upon completion of exploratory biomarker analyses (as 
early as possible but no later than 5 years after blocks had been sent).  Slides will not be 
returned unless requested by the site for diagnostic purpose.
Samples will be sent to a central laboratory for PD-L1 IHC analysis.  Percent PD-L1 
positive tumor and immune cells will be assessed and categorized based on predefined 
criteria (see Appendix 12).
The study will enroll all patients whose tissue is evaluable for PD-L1 analysis, regardless 
of PD-L1 status.


 
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4.5.8 
Laboratory Assessments and Biomarker Samples  
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology (complete blood count [CBC], including red blood cell count [RBC] 
count, hemoglobin, hematocrit, white blood cell (WBC) count with differential 
[neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells], 
platelet count and coagulation parameters [aPTT or INR]). 
 
Serum chemistry (glucose, blood urea nitrogen [BUN] or urea, creatinine, sodium, 
potassium, chloride, bicarbonate or total carbon dioxide (if considered standard of 
care for the region), calcium, phosphorus, total and direct bilirubin, ALT, AST, 
alkaline phosphatase, uric acid, LDH, total protein, and albumin) 
 
Serum and urine pregnancy tests for women of childbearing potential, including 
women who have had a tubal ligation. On study pregnancy tests must be performed 
prior to each treatment cycle (21-day cycle for atezolizumab and per relevant local 
guidelines and SmPC management for chemotherapy) while receiving the IMP.  For 
female patients of childbearing potential, the pregnancy tests will be repeated during 
the Safety FU visit and then every 2 months during Follow-up for at least 5 months 
after the last dose of atezolizumab and for at least 6 months after the last dose of 
chemotherapy, respectively.  Results from a treating physician can be used. The 
pregnancy test can be conducted with serum or urine. If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being postmenopausal 
(≥ 12 months of amenorrhea). 
 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood); dipstick 
permitted 
 
Thyroid function testing (thyroid-stimulating hormone [TSH], free triiodothyronine 
[T3] (or total T3 for sites where free T3 is not performed), free thyroxine [also known 
as T4]) 
 
HIV testing: Testing is not required in the absence of clinical symptoms and signs 
suggestive of HIV infection or known HIV positivity.  Patients with a past history of/or 
symptoms of HIV are eligible only if serological tests are negative. 
 
HBV serology:  HBsAg, hepatitis B surface antibody, total HBcAb, and (if HBsAg 
test is negative and total HBcAb test is positive) HBV DNA 
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection. 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection. 


 
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Samples for the following laboratory tests are mandatory and will be sent to one or 
several central laboratories or to the Sponsor for analysis: 
 
FFPE tumor tissue (archival or obtained at screening) for patient stratification based 
on PD-L1 IHC results (see Section 4.5.7).  Residual samples will be used for 
exploratory research. 
 
Whole) blood (at baseline) for analysis of protein expression and gene expression of 
PBMCs  
 
Plasma (at baseline, Week 7 and at time of disease progression) for analysis of 
ctDNA using NGS (or other methods)  
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 13. 
See the laboratory manual for additional details on laboratory assessments and sample 
handling.  
 
 


 
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Table 13 Proposed Biomarkers for Exploratory Research 
Sample Type  
Timing  
Proposed Biomarkers 
FFPE Tissue Block  
(or 10-15 slides) 
Pre-treatment (archival 
tissue or screening) 
PD-L1 IHC (stratification) 
RNA expression (T-effector 
signature and/or analysis of 
cancer-related mutations (incl. 
mutational load) 
Whole blood (PBMC Whole 
Blood) for isolation of PBMCs 
and their derivatives 
Baseline 
RNA expression analysis 
(including but not limited to 
PD-L1, IFN 
 
Plasma for extraction of cell-
free DNA and/or RNA  
Baseline, Week 7 and at 
time of disease progression  
Cancer-related, disease 
specific mutations using NGS 
FFPE = formalin fixed paraffin embedded; IFN= interferon gamma; 
IHC = immunohistochemistry; NGS = next generation sequencing; NSCLC = non-small cell lung 
cancer; PBMC = peripheral blood mononuclear cell; PD-L1 = programmed death-ligand 1. 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
FFPE tissue blocks from screen failed patients will be returned within 6 weeks 
(unstained slides will not be returned but destroyed at the central lab).  
 
FFPE tissue blocks from eligible patients will be returned as early as possible but no 
later than 5 years after blocks had been sent.  Leftover slides will be destroyed 
within 2 years after the date of final closure of the clinical database and will not be 
returned.   
 
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.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.9 
Electrocardiograms
A twelve-lead electrocardiogram (ECG) is required at screening and as clinically 
indicated at other time points, as indicated in the Schedule of Activities (Appendix 1). 
ECGs for each patient should be obtained from the same machine wherever possible. 
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.


 
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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 questionnaires to document the treatment benefit and 
treatment safety.  The PRO questionnaires will be completed with each tumor 
assessment until disease progression per RECIST v1.1, even if patients discontinue 
study treatment for any reason other than progressive disease or loss of clinical benefit.
The questionnaires, translated into the local language as required, will be completed in 
their entirety at specified timepoints during the study.  To ensure instrument validity and 
that data standards meet health authority requirements, each questionnaire will be 
self-administered or interviewer-administered (as appropriate) before the patient or 
clinician receives any information on disease status, prior to the performance of 
non-PRO assessments, and prior to the administration of study treatment, unless 
otherwise specified.
PRO data will be collected via the EORTC QLQ-C30, the EORTC QLQ-LC13, and 
EQ-5D-5L to more fully characterize the clinical profile of atezolizumab.
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),
3 symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and
6 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.
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.
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 will be utilized in this study for economic modeling.
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported as outlined in Section 5.3.5.13.


 
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4.5.11 
Samples for Research Biosample Repository (RBR) 
4.5.11.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) 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, 
storage, and analysis of RBR 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 RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR 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 RBR is contingent upon the 
review and approval of the exploratory research and the RBR 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 RBR 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 will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to NSCLC: 
 
Remaining or unused fluids (plasma, PBMCs, blood cell derivatives) after study-
related tests have been performed 
 
Remaining or unused FFPE tissue slides and/or derivatives thereof obtained during 
screening (with the exception of archival FFPE blocks, which will be returned to 
sites) after study-related tests have been performed 
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations, somatic mutations via whole genome sequencing 
(WGS), or other genomic analysis methods.   
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 


 
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data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.11.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR 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. 
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.11.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 


 
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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.11.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient. However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  
If a patient wishes to withdraw consent to the testing of his or her samples during the 
study, the investigator must inform the Medical Monitor in writing of the patient's wishes 
through use of the appropriate RBR Subject Withdrawal Form and must enter the date of 
withdrawal on the RBR Research Sample Withdrawal of Informed Consent eCRF.  If a 
patient wishes to withdraw consent to the testing of his or her RBR 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: global.rcr-withdrawal@roche.com.  The 
patient will be provided with instructions on how to withdraw consent after the trial is 
closed.   
A patient's withdrawal from Study MO29872 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study MO29872. 
4.5.11.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with Good Clinical Practice 
(GCP) 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.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  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 RBR samples. 
4.5.12 
Timing of Assessments 
4.5.12.1 
Screening/Baseline Assessments 
Screening tests and evaluations will be performed within 28 days prior to Cycle 1, Day 1.  
Screening laboratory test results must be obtained within 14 days prior to initiation of 
study treatment.  Results of standard-of-care tests or examinations performed prior to 


 
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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.
4.5.12.2 
Assessments During Study Treatment
All visits must occur ± 5 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 administration 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 per original schedule.  If treatment was postponed for 
fewer than 3 days, the patient can resume the original schedule.
After completion of single agent chemotherapy treatment (for patients in the 
chemotherapy arm) or after five cycles (for patients in the atezolizumab arm), one of
3 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 atezolizumab cycle must be delivered 21 days from the 
previous dose administration.  Two consecutive 28-day atezolizumab cycles are not 
permitted.
If a dose modification is required due to toxicity, refer to Section 5.1.
Tumor assessments will be done at baseline, every 6 weeks (± 5 days) following 
randomization for 48 weeks, and every 9 weeks (± 5 days) thereafter, with additional 
scans as clinically indicated. Assessments will continue until disease progression per 
RECIST v1.1. Patients randomized to atezolizumab who continue to receive 
atezolizumab following disease progression will undergo tumor assessments until 
treatment discontinuation. Tumor assessments should continue regardless of whether 
patients discontinue study treatment or start new anti-cancer therapy in the absence of 
disease progression unless they withdraw consent. In all patients, response will be 
assessed by the investigator using RECIST v1 until disease progression.  Patients 
randomized to receive atezolizumab will additionally be assessed by modified RECIST 
criteria until treatment discontinuation.
The following assessments should be performed ≤ 96 hours before Day 1 of each cycle 
(for the Cycle 1, Day 1 treatment administration, the following Day 1 procedures should 
occur after randomization but before study treatment is administered):
 
ECOG performance status


 
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 
Limited physical examination
 
Local laboratory tests
See Appendix 1 for the schedule of assessments during treatment.
4.5.12.3 
Assessments at Treatment Discontinuation Visit
Patients who discontinue study treatment will return to the clinic for a treatment 
discontinuation visit within 30 days after the last dose of study treatment, regardless of 
the reason for treatment discontinuation.
See Appendix 1 for assessments to be performed at the treatment discontinuation visit. 
4.5.12.4 
Assessments After Treatment Discontinuation Until Disease
Progression
For all patients who discontinue study treatment for any reason other than progressive
disease per RECIST v1.1, tumor assessments and PRO assessments will continue at 
the same frequency until progressive disease per RECIST v1.1.
See Appendix 1 for assessments to be performed for patients who discontinue study 
treatment for reasons other than progressive disease.
4.5.12.5 
Follow-Up Assessments
After the Treatment Discontinuation Visit, adverse events should be followed as outlined 
in Section 5.3.
Follow-up data collection will include ongoing or new serious adverse events, adverse 
events of special interest or adverse events thought to be related to study treatment, 
which will be followed until the event has resolved to the baseline grade, the event is 
assessed by the investigator as stable, new anti-tumor treatment is initiated, the patient 
is lost to follow-up, the patient withdraws consent, or it has been determined that the 
study treatment or participation is not the cause of the adverse events.
Follow-up information, including subsequent anticancer therapies and adverse events 
(see Section 5.3.1 for adverse event reporting period), will be collected via telephone 
calls and/or clinic visits every 2 months (± 5 days) until death, withdrawal of consent, 
loss to follow-up, or study termination by the Sponsor, or protocol-defined end of study, 
whichever comes first.  If the patient withdraws from study, the study staff may use a 
public information source (e.g., county records) when permissible, to obtain information 
about survival status and date only.
See Appendix 1 for assessments to be performed during Follow-up.


 
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4.5.12.6 
Assessments at Unscheduled Visits 
Assessments for unscheduled visits related to a patient’s underlying NSCLC, study 
treatment, or adverse events should be performed as clinically indicated and entered 
into Unscheduled Visit eCRFs. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
 
Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status. 
 
Intolerable toxicity related to atezolizumab treatment, 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 chemotherapy treatment 
 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment 
 
Use of another non-protocol anti-cancer therapy (see Section 4.4.1.3) 
 
Pregnancy 


 
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Patients randomized to the atezolizumab treatment arm may continue study treatment 
beyond disease progression per RECIST v1.1 until loss of clinical benefit, unacceptable 
toxicity, withdrawal of consent, death, study termination by the Sponsor, or 
protocol-defined end of study, whichever occurs first, if they meet all of the following 
criteria: 
 
Evidence of clinical benefit as assessed by the investigator (i.e., in the absence of 
symptomatic deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic data, biopsy results [if 
available], clinical status, and of laboratory values)  
 
Absence of unacceptable toxicity   
 
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 for whom approved therapies exist must provide written consent to 
acknowledge deferring these treatment options in favor of continuing study 
treatment at the time of initial progression.  
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
After termination of study treatment, all patients can be treated with locally approved 
chemotherapy or other treatments.  All patients will remain in this study until withdrawal 
of consent, death, loss to follow-up, study termination by the Sponsor, or 
protocol-defined end of study, whichever occurs first. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 


 
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 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
Atezolizumab was approved by the U.S. FDA in May 2016 for the treatment of patients 
with locally advanced or mUC who 1) have disease progression during or following 
platinum-containing chemotherapy or 2) have disease progression within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 
On October 18, 2016, the FDA approved atezolizumab (Tecentriq®) also for the 
treatment of patients with metastatic NSCLC whose disease progressed during or 
following platinum-containing chemotherapy.  Patients with EGFR or ALK genomic tumor 
aberrations should have disease progression on FDA-approved therapy for these 
aberrations prior to receiving atezolizumab. 
The following information is based on results from nonclinical and clinical studies and 
published data on similar molecules. 
5.1 
SAFETY PLAN 
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Section 4.1.1 and Section 4.1.2) 
and close monitoring (as indicated below and in Section 4.5).  See Section 5.3 (Methods 
and Timing for Capturing and Assessing Safety Parameters) for complete details 
regarding safety reporting for this study. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.  All serious adverse events and adverse events of special 
interest will be recorded during the trial and for up to 90 days after the last dose of study 
treatment or initiation of new anti-cancer therapy, whichever occurs first.  All other 
adverse events will be recorded during the trial and for up to 30 days after the last dose 
of study treatment or until the initiation of another anti-cancer therapy, whichever occurs 
first. 
Investigators are instructed to report all serious adverse events and adverse events of 
special interest considered related to study treatment regardless of time after study.  The 
potential safety issues anticipated in this trial, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections. 
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 


 
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guidelines or guidelines of applicable professional societies (e.g., American 
Society of Clinical Oncology or European Society for Medical Oncology). 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines. 
5.1.1 
Risks Associated with Investigational Medicinal Products 
5.1.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and immune-mediated 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, facial paresis, myelitis, meningoencephalitis, myocarditis, pericardial 
disorders, nephritis, myositis, and severe cutaneous adverse reactions.  In addition, immune-
mediated reactions may involve any organ system and lead to hemophagocytic 
lymphohistiocytosis (HLH).  Refer to Appendix 13 of the protocol and Section 6 of the 
Atezolizumab Investigator's Brochure for a detailed description of anticipated safety risks 
for atezolizumab.   
Guidelines for managing patients who experience anticipated adverse events are 
provided in Appendix 13.  To date, there are no additional identified risks/ADRs specific 
to the combination of atezolizumab when given with another therapeutic agent.  The 
identified risks/ADRs of other therapeutic agents used in combination with atezolizumab 
can be found in their respective Investigator’s Brochures or local Prescribing Information.  
5.1.1.2 
Risks Associated with Vinorelbine 
Vinorelbine (soft capsule for oral administration, concentrate for intravenous 
administration) should be used with extreme caution in patients whose bone marrow 
reserve may have been compromised by prior irradiation or chemotherapy, or whose 
marrow function is recovering from the effects of previous chemotherapy.  Vinorelbine 
should not be administered to patients with granulocyte counts < 1,000 cells/mm3.  
Patients developing severe granulocytopenia should be monitored carefully for evidence 
of infection and/or fever. 
In case of oral administration of the soft capsules, caution must be taken not to damage 
the capsule. If the patient chews or sucks the capsule by error, the liquid is an irritant. 
Please refer to the Navelbine® 30 mg soft capsule SmPC for further information.  
Patients treated with vinorelbine should be frequently monitored for myelosuppression 
both during and after therapy.  Granulocytopenia is dose-limiting. Granulocyte nadirs 


 
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occur between 7 and 10 days after dosing with granulocyte count recovery usually within 
the following 7 to 14 days.  Complete blood counts with differentials should be performed 
and results reviewed prior to administering each dose of vinorelbine.   
Patients with a prior history or pre-existing neuropathy, regardless of etiology, should be 
monitored for new or worsening signs and symptoms of neuropathy while receiving 
vinorelbine.  Care must be taken to avoid contamination of the eye with concentrations 
of vinorelbine used clinically. Severe irritation of the eye has been reported with 
accidental exposure to another vinca alkaloid.  If exposure occurs, the eye should 
immediately be thoroughly flushed with water. 
Adverse reactions reported as more than isolated cases following intravenous 
vinorelbine administration as single agent are listed in Table 14.  Adverse reactions 
reported as more than isolated cases following oral vinorelbine administration as single 
agent are listed in Table 15.  Additional adverse reactions from post marketing 
experience have been added according to the MedDRA classification with the frequency 
Not known. 
 
Table 14 Adverse Reactions for Vinorelbine as Single Agent 
(Intravenous) 
Adverse Reactions for intravenous Vinorelbine as single agent 
by System Organ Class and by the MedDRA Frequency  
Infections and infestations 
Common 
 
Infection bacterial, viral or fungal at different sites mild to moderate and 
usually reversible with an appropriate treatment 
Uncommon 
 
Severe sepsis sometimes with other organ failure 
 
Septicaemia  
Very rare 
 
Complicated septicaemia and sometimes fatal 
Not known 
 
Neutropenic sepsis 
 
Neutropenic infection G3-4 
Blood and lymphatic system disorders 
Very common 
 
Bone marrow depression resulting mainly in neutropenia (G3: 24.3%; 
G4: 27.8%) reversible within 5 to 7 days and noncumulative over time.  
 
Anaemia (G3-4: 7.4%) 
Common 
 
Thrombocytopenia (G3-4: 2.5%) may occur but are seldom severe 
Not known 
 
Febrile neutropenia 
 
Pancytopenia 
 
Leucopenia.G1-4 
Immune system disorders 
Not known 
 
Systemic allergic reactions as anaphylaxis, anaphylactic shock or 
anaphylactoïd type reaction. 


 
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Table 14 Adverse Reactions for Vinorelbine as Single Agent 
(Intravenous) 
Adverse Reactions for intravenous Vinorelbine as single agent 
by System Organ Class and by the MedDRA Frequency  
Endocrine disorders 
Not known 
 
Inappropriate antidiuretic hormone secretion (SIADH). 
Metabolism and nutrition disorders 
Rare 
 
Severe hyponatremia 
Not known 
 
Anorexia 
Nervous system disorders 
Very common 
 
Neurologic disorders (G 3-4: 2.7%) including loss of deep tendon 
reflexes.  
 
Weakness of the lower extremities has been reported after a prolonged 
chemotherapy.  
Uncommon 
 
Severe paresthesias with sensory and motor symptoms are infrequent, 
generally reversible. 
Not known 
 
Headache 
 
Dizziness 
 
Ataxia 
Cardiac disorders 
Rare 
 
Ischemic heart disease: angina pectoris, myocardial infarction 
(sometimes fatal).  
Very rare 
 
Tachycardia, palpitation and heart rhythm disorders 
Not known 
 
Heart failure 
Vascular disorders 
Uncommon 
 
Arterial hypotension, arterial hypertension, flushing and peripheral 
coldness.  
Rare 
 
Severe hypotension, collapse. 
Respiratory system, thoracic and mediastinal disorders 
Uncommon 
 
Dyspnoea and bronchospasm may occur in association with vinorelbine 
treatment as with other vinca alkaloids.  
Rare 
 
Interstitial pneumonopathy sometimes fatal has been reported. 
Not known 
 
Cough G1-2 
Gastrointestinal disorders 
Very Common 
 
Stomatitis (G1-4: 15%, with vinorelbine as single agent).  
 
Nausea and vomiting (G 1-2: 30.4% and G 3-4: 2.2%). Anti-emetic 
therapy may reduce their occurrence.  
 
Constipation is the main symptom (G 3-4: 2.7%) which rarely 
progresses. to paralytic ileus with vinorelbine as single agent and (G3-4: 
4.1%), with the combination of vinorelbine and other chemotherapeutic 
agents  
Common 
 
Diarrhoea usually mild to moderate may occur.  


 
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Table 14 Adverse Reactions for Vinorelbine as Single Agent 
(Intravenous) 
Adverse Reactions for intravenous Vinorelbine as single agent 
by System Organ Class and by the MedDRA Frequency  
Rare 
 
Paralytic ileus, treatment may be resumed after recovery of normal 
bowel mobility.  
 
Pancreatitis has been reported.  
Not known 
 
Gastrointestinal bleeding 
 
Severe diarrhoea 
 
Abdominal pain 
Hepatobiliary disorders 
Very common 
 
Transient elevations of liver function tests (G1-2) without clinical 
symptoms were reported (SGOT in 27.6% and SGPT in 29.3%). 
Not known 
 
Hepatic disorder 
Skin and subcutaneous tissue disorders 
Very common 
 
Alopecia, usually mild in nature, may occur (G3-4: 4.1% with vinorelbine 
as single chemotherapeutic agent).  
Rare 
 
Generalized cutaneous reactions have been reported with vinorelbine.  
Not known  
 
Erythema on hands and feet (Palmer-plantar erythrodysesthesia 
syndrome). 
Musculoskeletal and connective tissue disorders 
Common 
 
Arthralgia including jaw pain and myalgia. 
General disorders and administration site conditions 
Very common 
 
Reactions at the injection site may include erythema, burning pain, vein 
discoloration and local phlebitis (G 3-4: 3.7% with vinorelbine as single 
chemotherapeutic agent).  
Common 
 
Asthenia, fatigue, fever, pain at different sites including chest pain and 
pain at the tumor site.  
Rare 
 
Local necrosis has been observed. Proper positioning of the cannula in 
the vein before starting to infuse vinorelbine followed by liberal flushing of the 
vein can limit these effects.  
Not known 
 
Chills G1-2 
Investigations 
Not known 
 
Weight loss 
Frequencies are defined as: Very common: ≥ 1/10; Common: ≥ 1/100 to < 1/10; 
Uncommon: ≥ 1/1000 to < 1/100; Rare: ≥ 1/10,000 to < 1/1000; Very rare: < 1/10,000, including 
isolated reports; Not known: Post marketing reports.   
Source: Navelbine® Summary of Product Characteristics [27 Jul 2020], Available from: 
https://www.medicines.org.uk/emc/medicine/16029#CONTRAINDICATIONS. 
 
 
 


 
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Table 15 Adverse Reactions for Vinorelbine as Single Agent (Soft 
Capsule) 
Adverse Reactions for oral Vinorelbine as single agent 
by System Organ Class and by the MedDRA Frequency  
Infections and infestations 
Very common 
 
Bacterial, viral or fungal infections without neutropenia at different sites: 
G1-4: 12.7%; G3-4: 4.4% 
Common 
 
Bacterial, viral or fungal infections resulting from bone marrow 
depression and/or immune system compromise (neutropenic infections) are 
usually reversible with an appropriate treatment 
 
Neutropenic infection: G3-4: 3.5% 
Not known 
 
Neutropenic sepsis 
 
Complicated septicaemia and sometimes fatal 
 
Severe sepsis sometimes with other organ failure 
 
Septicaemia 
Blood and lymphatic system disorders 
Very common 
 
Bone marrow depression resulting mainly in neutropenia G1-4: 71.5%; 
G3: 21.8%; G4: 25.9%, is reversible and is the dose limiting toxicity.  
 
Leucopenia: G1-4: 70.6%; G3: 24.7%; G4: 6% 
 
Anaemia: G1-4: 67.4%; G3-4: 3.8% 
 
Thrombocytopenia: G1-2: 10.8% 
Common 
 
G4 Neutropenia associated with fever over 38°C including febrile 
neutropenia 2.8%. 
Not known 
 
Thrombocytopenia G3-4 
 
Pancytopenia 
Metabolism and nutrition disorders 
Very common 
 
Anorexia: G1-2: 34.5%, G3-4: 4.1% 
Not known 
 
Severe hyponatraemia 
Psychiatric disorders 
Common 
 
Insominia: G1-2: 2.8% 
Nervous system disorders 
Very common 
 
Neurosensory disorders: G1-2: 11.1%, generally limited to loss of tendon 
reflexes and infrequently severe 
Common 
 
Neuromotor disorders: G1-4: 9.2%; G3-4:1.3%.  
 
Headache: G1-4: 4.1%, G3-4: 0.6%.  
 
Dizziness: G1-4: 6%; G3-4: 0.6%.  
 
Taste disorders: G1-2:3.8% 
Uncommon 
 
Ataxia grade 3: 0.3% 
Eye disorders 
Common 
 
Visual impairment: G1-2: 1.3%.  
Cardiac disorders 
Uncommon 
 
Heart failure and cardiac dysrhythmia 


 
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Table 15 Adverse Reactions for Vinorelbine as Single Agent (Soft 
Capsule) 
Adverse Reactions for oral Vinorelbine as single agent 
by System Organ Class and by the MedDRA Frequency  
Not known 
 
Myocardial infarction in patients with cardiac medical history or cardiac 
risk factors.  
Vascular disorders 
Common 
 
Arterial hypertension: G1-4: 2.5%; G3-4: 0.3%.  
 
Arterial hypotension: G1-4: 2.2%; G3-4: 0.6%.  
Respiratory system, thoracic and mediastinal disorders 
Common 
 
Dyspnoea: G1-4: 2.8%; G3-4: 0.3%.  
 
Cough: G1-2: 2.8%.  
Gastrointestinal disorders 
Very common 
 
Nausea: G1-4: 74.7% ; G3-4: 7.3%  
 
Vomiting: G1-4: 54.7%; G 3-4: 6.3%, Supportive treatment such as 
5HT3 antagonists (ondansetron) may reduce the occurrence of nausea and 
vomiting  
 
Diarrhoea: G1-4: 49.7%; G3-4: 5.7%  
 
Stomatitis: G1-4:10.4%; G3-4: 0.9%  
 
Abdominal pain: G1-4: 14.2%  
 
Constipation: G1-4: 19%; G3-4: 0.9%, Prescription of laxatives may be 
appropriate in patients with prior history of constipation and/or who receive 
concomitant treatment with opioid analgesics  
 
Gastric disorders: G1-4: 11.7%  
Common 
 
Oesophagitis: G1-3: 3.8%; G3: 0.3%  
 
Dysphagia: G1-2: 2.3%.  
Uncommon 
 
Paralytic ileus: G3-4: 0.9% [rarely fatal], treatment may be resumed after 
recovery of normal bowel mobility. 
Not known 
 
Gastro-intestinal bleeding.  
Hepatobiliary disorders 
Common 
 
Hepatic disorders: G1-2: 1.3%. 
No known 
 
Transient elevations of liver function tests G1-2 
Skin and subcutaneous tissue disorders 
Very common 
 
Alopecia usually mild in nature G1-2: 29.4%, may occur.  
Common 
 
Skin reactions: G1-2: 5.7%.  
Musculoskeletal and connective tissue disorders 
Common 
 
Arthralgia including jaw pain 
 
Myalgia: G1-4: 7 %, G3-4: 0.3%. 
Renal and urinary disorders 
Common 
 
Dysuria: G1-2: 1.6%. 
 
Other genitourinary disorders: G1-2: 1.9% 
General disorders and administration site conditions 


 
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Table 15 Adverse Reactions for Vinorelbine as Single Agent (Soft 
Capsule) 
Adverse Reactions for oral Vinorelbine as single agent 
by System Organ Class and by the MedDRA Frequency  
Very common 
 
Fatigue/malaise: G1-4: 36.7%; G3-4: 8.5%.  
 
Fever: G1-4: 13.0%, G3-4: 12.1%).  
Common 
 
Pain including pain at the tumour site: G1-4: 3.8%, G3-4: 0.6%.  
 
Chills: G1-2: 3.8%.  
Investigations 
Very common 
 
Weight loss: G1-4: 25%, G3-4: 0.3%.  
Common 
 
Weight gain: G1-2: 1.3%.  
Frequencies are defined as: Very common: ≥ 1/10; Common: ≥ 1/100 to < 1/10; 
Uncommon: ≥ 1/1000 to < 1/100; Rare: ≥ 1/10,000 to < 1/1000; Very rare: < 1/10,000, including 
isolated reports; Not known: Post marketing reports.   
Source: Navelbine 30 mg soft capsule Summary of Product Characteristics, Last Updated on 
eMC 27 May 2020 (Available from: https://www.medicines.org.uk/emc/medicine/1604). 
 
Information on vinorelbine dose modification and the management of specific adverse 
events is provided in Section 5.1.3.4.  For more details regarding the safety profile of 
vinorelbine, see the respective Navelbine® Prescribing Information (intravenous or oral 
administration).   
5.1.1.3 
Risks Associated with Gemcitabine 
Infusion times of gemcitabine longer than 60 minutes and more frequent than weekly 
dosing have been shown to increase toxicity. 
Pulmonary toxicity has been reported with the use of gemcitabine.  In cases of severe 
lung toxicity, gemcitabine therapy should be discontinued immediately and appropriate 
supportive care measures instituted. 
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia has been 
reported with gemcitabine as a single agent or in combination with other cytotoxic drugs.  
Monitoring for myelosuppression should occur prior to each cycle. 
Hemolytic-uremic syndrome (HUS) and/or renal failure have been reported following one 
or more doses of gemcitabine.  Renal failure leading to death or requiring dialysis, 
despite discontinuation of therapy, has been rarely reported.  The majority of the cases 
of renal failure leading to death were due to HUS. 
Serious hepatotoxicity, including liver failure and death, has been reported very rarely in 
patients receiving gemcitabine alone or in combination with other potentially hepatotoxic 
drugs. 


 
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Use caution in patients with pre-existing renal impairment or hepatic insufficiency. 
Undesirable effects following gemcitabine administration and their frequencies based on 
data from clinical trials are presented in  Table 16.  
Table 16 Adverse Reactions for Gemcitabine Observed in Clinical Trials 
Adverse Reactions in NSCLC for Gemcitabine in Clinical Trials 
System Organ Class and Frequency Grouping 
Blood and lymphatic system disorders 
Very common 
 
Leucopenia (Neutropenia Grade 3 = 19.3 %; Grade 4 = 6 %).  
Bone-marrow suppression is usually mild to moderate and mostly affects the 
granulocyte count  
 
Thrombocytopenia  
 
Anaemia 
Common 
 
Febrile neutropenia 
Very rare 
 
Thrombocytosis 
 
Thrombotic microangiopathy 
Immune system disorders 
Very rare 
 
Anaphylactoid reaction 
Metabolism and nutrition disorders 
Common 
 
Anorexia 
Nervous system disorders 
Common 
 
Headache  
 
Insomnia  
 
Somnolence 
Uncommon 
 
Cerebrovascular accident 
Very rare 
 
Posterior reversible encephalopathy syndrome 
Cardiac disorders 
Uncommon 
 
Arrhythmias, predominantly supraventricular in nature  
 
Heart failure 
Rare 
 
Myocardial infarct 
Vascular disorders 
Rare 
 
Clinical signs of peripheral vasculitis and gangrene  
 
Hypotension 
Very rare 
 
Capillary leak syndrome 
Respiratory, thoracic and mediastinal disorders 
Very common 
 
Dyspnoea -usually mild and passes rapidly without treatment 
Common 
 
Cough  
 
Rhinitis 
Uncommon 
 
Interstitial pneumonitis  


 
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Table 16 Adverse Reactions for Gemcitabine Observed in Clinical Trials 
Adverse Reactions in NSCLC for Gemcitabine in Clinical Trials 
System Organ Class and Frequency Grouping 
 
Bronchospasm -usually mild and transient but may require parenteral 
treatment 
Rare 
 
Pulmonary oedema  
 
Adult respiratory distress syndrome 
Not known 
 
Pulmonary eosinophilia  
Gastrointestinal disorders 
Very common 
 
Vomiting 
 
Nausea 
Common 
 
Diarrhoea 
 
Stomatitis and ulceration of the mouth  
 
Constipation 
Very rare 
 
Ischaemic colitis 
Hepatobiliary disorders 
Very common 
 
Elevation of liver transaminases (AST and ALT) and alkaline 
phosphatase 
Common 
 
Increased bilirubin 
Uncommon 
 
Serious hepatotoxicity, including liver failure and death 
Rare 
 
Increased gamma-glutamyl transferase (GGT) 
Skin and subcutaneous tissue disorders 
Very common 
 
Allergic skin rash frequently associated with pruritus  
 
Alopecia 
Common 
 
Itching  
 
Sweating 
Rare 
 
Severe skin reactions, including desquamation and bullous skin 
eruptions  
 
Ulceration  
 
Vesicle and sore formation  
 
Scaling 
Very rare 
 
Toxic epidermal necrolysis  
 
Stevens-Johnson Syndrome 
Not known 
 
Pseudocellulitis 
Musculoskeletal and connective tissue disorders 
Common 
 
Back pain  
 
Myalgia 
Renal and urinary disorders 
Very common 
 
Haematuria  
 
Mild proteinuria 
Uncommon 
 
Renal failure  
 
Haemolytic uraemic syndrome 


 
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Table 16 Adverse Reactions for Gemcitabine Observed in Clinical Trials 
Adverse Reactions in NSCLC for Gemcitabine in Clinical Trials 
System Organ Class and Frequency Grouping 
General disorders and administration site conditions 
Very common 
 
Influenza-like symptoms - the most common symptoms are fever, 
headache, chills, myalgia, asthenia and anorexia. Cough, rhinitis, malaise, 
perspiration and sleeping difficulties have also been reported.  
 
Oedema/peripheral oedema-including facial oedema. Oedema is usually 
reversible after stopping treatment 
Common 
 
Fever  
 
Asthenia  
 
Chills 
Rare 
 
Injection site reactions - mainly mild in nature 
Injury, poisoning, and procedural complications 
Rare 
 
Radiation toxicity  
 
Radiation recall 
Infections and infestations 
Common 
 
Infections 
Not known 
 
Sepsis 
Frequencies are defined as: Very common: > 1/10; Common: > 1/100 to < 1/10; 
Uncommon: > 1/1000, < 1/100; Rare: ≥ 1/10,000, < 1/1000; Very rare: < 1/10,000, including 
isolated reports; Not known: Post marketing experience.   
Source: Gemzar® Summary of Product Characteristics [July 2019]. Available from: 
https://www.medicines.org.uk/emc/product/4483/smpc 
 
Information on gemcitabine dose modification and the management of specific adverse 
events is provided in Section 5.1.3.5.  For more details regarding the safety profile of 
vinorelbine, see the Gemzar® Prescribing Information.
5.1.2 
General Plan to Manage Safety Concerns
5.1.2.1 
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 study drug 
administration.
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.


 
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All serious adverse events and protocol-defined events of special interest (see 
Section 5.2.2 and Section 5.2.3) will be reported in an expedited fashion. In addition, the 
iDMC and Medical Monitor will review and evaluate observed adverse events on a 
regular basis. 
Patients will be followed for serious adverse events and adverse events of special 
interest for 90 days after their last dose of study drug or initiation of new anti-cancer 
therapy, whichever occurs first. For all other adverse events, patients will be followed for 
30 days after their last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first. Investigators are instructed to report all serious adverse events 
and adverse events of special interest considered related to study treatment regardless 
of time after study. 
Patients who have an ongoing study treatment-related adverse event upon study 
completion or at discontinuation from the study will be followed until the event has 
resolved to baseline grade, the event is assessed by the investigator as stable, new 
anti-cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws 
consent, or it has been determined that study treatment or participation is not the cause 
of the adverse event. 
5.1.3 
Dose Modifications and Management of Special Adverse 
Events 
5.1.3.1 
General Notes Regarding Dose Modification 
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  The 
severity of adverse events will be graded according to the NCI CTCAE v4.0 grading 
system. 
 
For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator 
feels it is appropriate.  For example, if a patient has Grade 1 asthenia at baseline 
that increases to Grade 2 during treatment, this will be considered a shift of one 
grade and treated as Grade 1 toxicity for dose-modification purposes. 
 
When several toxicities with different grades of severity occur at the same time, the 
dose modifications should be according to the highest grade observed.  
The investigator may use discretion in modifying or accelerating the dose modification 
guidelines described below depending on the severity of toxicity and an assessment of 
the risk versus benefit for the patient, with the goal of maximizing patient compliance and 
access to supportive care. 
5.1.3.2 
Atezolizumab Dose Modification 
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 12 weeks after event onset if they experience an 
adverse event that requires a dose to be withheld.  If atezolizumab is withheld because 


 
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of adverse events for > 12 weeks after event onset, then the patient will be discontinued 
from atezolizumab treatment and will be followed for safety and efficacy as specified in 
Section 5.2.1. 
If a patient must be tapered off steroids used to treat adverse events, atezolizumab may 
be withheld for additional time > 12 weeks after event onset 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 toxicity, such as surgical procedures, may be 
allowed with Medical Monitor approval.  The acceptable length of interruption will depend 
on agreement between the investigator and the Medical Monitor.  
Management of atezolizumab-specific adverse events is present in Section 5.1.3.3. 
5.1.3.3 
Management of Atezolizumab-Specific Adverse Events 
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 determine a possible immunogenic etiology.  
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect and, in severe cases, immune-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, mycophenolate, or TNF-α inhibitors. 
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 event can be 
rechallenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.. 
For the management of other adverse events associated with atezolizumab, refer to the 
Atezolizumab Investigator’s Brochure.   
For the management of infusion-related reactions, see Section 4.3.3.1. 
5.1.3.4 
Vinorelbine Dose Modification and Management of Specific 
Adverse Events 
5.1.3.4.1 
Intravenous Vinorelbine  
The usual initial dose of single-agent vinorelbine is 30 mg/m2 administered weekly.  


 
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If administered intravenously, intravenous injection is done over 6 to 10 minutes. In 
controlled trials, single-agent vinorelbine was given weekly until progression or 
dose-limiting toxicity.  
Most drug-related adverse events of vinorelbine are reversible.  If severe adverse events 
occur, vinorelbine should be reduced in dosage or discontinued and appropriate 
corrective measures taken.  Reinstitution of therapy with vinorelbine should be carried 
out with caution and alertness as to possible recurrence of toxicity. 
The dosage should be adjusted according to hematologic toxicity or hepatic 
insufficiency, whichever results in the lower dose for the corresponding starting dose of 
vinorelbine, as shown in Section 5.1.3.4.2 and Section 5.1.3.4.3.  If 
Grade ≥ 2 neurotoxicity develops, vinorelbine should be discontinued. 
For more details regarding the dose modifications and the management of specific 
adverse events, see the Navelbine® Prescribing Information. 
5.1.3.4.2 
Hematologic Toxicity – Intravenous Vinorelbine 
Granulocyte count should be ≥ 1,000 cells/mm3 prior to the administration of vinorelbine.  
Adjustments in the dosage of vinorelbine should be based on granulocyte counts 
obtained on the day of treatment according to Table 17. 
Table 17 Intravenous Vinorelbine Dose Adjustments Based on 
Granulocyte Counts  
Granulocytes on Day of Treatment 
(cells/mm3) 
Percentage of Starting Dose  
of Vinorelbine 
≥ 1,500 
100% 
1,000 to 1,499 
50% 
< 1,000 
Do not administer.  Repeat granulocyte count in 
1 week.  If 3 consecutive weekly doses are held 
because granulocyte count is < 1,000 cells/mm3, 
discontinue vinorelbine. 
Note: For patients who, during treatment with vinorelbine, experienced fever and/or sepsis while 
granulocytopenic or had 2 consecutive weekly doses held due to granulocytopenia, subsequent 
doses of vinorelbine should be: 
≥1,500 
75% 
1,000 to 1,499 
37.5% 
<1,000 
See above 
 
5.1.3.4.3 
Hepatic Insufficiency - Intravenous Vinorelbine 
Vinorelbine should be administered with caution to patients with hepatic insufficiency. In 
patients who develop hyperbilirubinemia during treatment with vinorelbine, the dose 
should be adjusted for total bilirubin according to Table 18. 


 
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Table 18 Intravenous Vinorelbine Dose Adjustments for Hepatic 
Insufficiency  
Total Bilirubin 
(mg/dL) 
Percentage of Starting Dose  
of  Vinorelbine 
≤ 2.0 
100% 
2.1 to 3.0 
50% 
> 3.0 
25% 
 
5.1.3.4.4 
Oral Vinorelbine  
If administered orally, vinorelbine is administered once weekly at 60mg/m² of body 
surface area for the first three administrations. Beyond the third administration, it is 
recommended to increase the dose of vinorelbine to 80 mg/m² once weekly except in 
those patients for whom the neutrophil count dropped once below 500/mm3 or more than 
once between 500 and 1000/mm3 during the first three administrations at 60 mg/m². 
Table 19 Oral Vinorelbine Dose Adjustments during First Three Weeks 
Based on Neutrophils 
Neutrophil count 
during the first 
3 administrations of 
60 mg/m2/week  
Neutrophils 
> 1000 
Neutrophils 
≥ 500 and 
< 1000 
(1 episode) 
Neutrophils 
≥ 500 and 
< 1000 
(2 episodes) 
Neutrophils 
< 500 
Recommended dose 
starting with the 
4th administration 
80  
80 
60 
60 
 
For any administration planned to be given at 80 mg/m², if the neutrophil count is below 
500/mm3 or more than once between 500 and 1000/mm3 the administration should be 
delayed until recovery and the dose reduced from 80 to 60 mg/m2 per week during the 
3 following administrations.  
If the neutrophil count is below 1500/mm3 and/or the platelet count below 100000/mm3, 
then the treatment should be delayed until recovery. 
Table 20 Oral Vinorelbine Dose Adjustments beyond Fourth Week Based 
on Neutrophils 
Neutrophil count 
beyond the 4th 
administration of 
80 mg/m2/week 
Neutrophils 
> 1000 
Neutrophils 
≥ 500 and 
< 1000 
(1 episode) 
Neutrophils 
≥ 500 and 
< 1000 
(2 episodes) 
Neutrophils 
< 500 
Recommended dose 
starting with the next 
administration 
80 
60 


 
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It is possible to re-escalate the dose from 60 to 80 mg/m2 per week if the neutrophil 
count did not drop below 500/mm3 or more than once between 500 and 1000/mm3 
during 3 administrations given at 60 mg/m2 according to the rules previously defined for 
the first 3 administrations. 
5.1.3.4.5 
Special Warnings - Oral Vinorelbine  
If the patient chews or sucks the capsule by error, the liquid is an irritant. Proceed to 
mouth rinses with water or preferably a normal saline solution.  
In the event of the capsule being cut or damaged, the liquid content is an irritant, and so 
may cause damage if in contact with skin, mucosa or eyes.  Damaged capsules should 
not be swallowed and should be returned to the pharmacy or to the doctor in order to be 
properly destroyed. If any contact occurs, immediate thorough washing with water or 
preferably with normal saline solution should be undertaken. 
In the case of vomiting within a few hours after drug intake, do not re-administer. 
Supportive treatment such as metoclopramide or 5HT3 antagonists (e.g., ondansetron, 
granisetron) may reduce the occurrence of this. Vinorelbine soft capsules are associated 
with a higher incidence of nausea/vomiting than the intravenous formulation. Primary 
prophylaxis with antiemetics and administration of the capsules with some food is 
recommended as this has also been shown to reduce the incidence of nausea and 
vomiting. 
Patients receiving concomitant morphine or opioid analgesics: laxatives and careful 
monitoring of bowel mobility are recommended. Prescription of laxatives may be 
appropriate in patients with prior history of constipation.  
For further information see the Navelbine® soft capsule SmPC.  
5.1.3.5 
Gemcitabine Dose Modification and Management of Specific 
Adverse Events 
Dose modification guidelines for gemcitabine are described in Table 21, Table 22, and 
Table 23.  Additionally, manufacturer’s instructions as well as local hospital or clinical 
practice will also be followed. 
5.1.3.5.1 
Hematologic Toxicity 
Dose adjustments for hematologic toxicity may be required for gemcitabine.  
Gemcitabine dosage adjustments for hematologic toxicity are based on the granulocyte 
and platelet counts taken on Days 1 and Week 3 of therapy.  Patient receiving 
gemcitabine should be monitored prior to each dose with a CBC, including differential 
and platelet counts.  If bone marrow suppression is detected, therapy should be modified 
or suspended according to the guidelines in Table 21 and Table 22. 


 
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Table 21 Dose Modification Guidelines for Hematological Toxicities on 
Day 1 of Gemcitabine  
Absolute Granulocyte 
Count (x 106/L) 
 
Platelet Count   
(x 106/L) 
Gemcitabine  
% of full dose 
≥ 1,500 
and 
≥ 100,000 
100% 
< 1,500 
or 
< 100,000 
withhold 
 
Table 22 Dose Modification Guidelines for Hematological Toxicities at 
Week 3 of Gemcitabine  
Absolute Granulocyte 
Count (x 106/L) 
 
Platelet Count 
(x 106/L) 
Gemcitabine  
% of full dose 
≥ 1000 
and 
≥ 100,000 
100% 
500-999 
or 
50,000−99,999 
75% 
< 500 
or 
< 50,000 
Withhold 
 
5.1.3.5.2 
Dose Modifications Guidelines of Non-Hematologic Toxicity 
In general, for severe (Grade 3 or 4) non-hematological toxicity, and nausea/vomiting, 
therapy with gemcitabine should be held or dose reduced by 50% depending on the 
judgment of the investigator. 
 
Permanently discontinue gemcitabine for any of the following: 
 
Unexplained dyspnea or other evidence of severe pulmonary toxicity 
 
Severe hepatic toxicity 
 
Hemolytic-uremic syndrome 
 
Capillary-leak syndrome 
 
Posterior reversible encephalopathy syndrome 
Table 23 summarizes dose modifications guidelines for non-hematologic toxicities based 
on grade and severity. 
 
 


 
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Table 23 Gemcitabine Dose Modification Guidelines for 
Non-Hematological Toxicities  
Toxicity 
Grade 2 
Grade 3 
Grade 4 
Non 
hematological 
toxicity,  
first appearance 
Interrupt treatment 
until resolved to 
Grade 0-1 then 
continue at same dose 
with prophylaxis where 
possible 
Interrupt treatment 
until resolved to 
Grade 0-1, then 
continue at 75% of 
original dose with 
prophylaxis where 
possible 
Discontinue treatment 
unless investigator considers 
it to be in the best interest of 
the patient to continue at 
50% of original dose, once 
toxicity has resolved to 
Grade 0-1 (after approval by 
the Sponsor) 
Second 
appearance of 
same toxicity 
Interrupt treatment 
until resolved to 
Grade 0-1, then 
continue at 75% of 
original dose 
Interrupt treatment 
until resolved to 
Grade 0-1, then 
continue at 50% of 
original dose 
 
Third appearance 
of same toxicity 
Interrupt treatment 
until resolved to 
Grade 0-1, then 
continue at 50% of 
original dose 
Discontinue 
treatment 
permanently 
 
Fourth 
appearance of 
same toxicity 
Discontinue treatment 
permanently 
 
 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events, non-serious adverse events and adverse events of special 
interest, performing protocol-specified safety laboratory assessments, measuring 
protocol-specified vital signs, and conducting other protocol-specified tests that are 
deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Sections 5.3.5.9 and 5.3.5.10 


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


 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include: 
 
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 treatment, 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 study treatment is suspected. 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hypothyroidism, hypophysitis, and hyperthyroidism 
 
Hepatitis, including AST or ALT > 10 x ULN 
 
Systemic lupus erythematosus 
 
Neurologic disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS  
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myositis 
 
Myopathies including rhabdomyolysis 
 
Grade  2 cardiac disorders  
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
 
Myelitis 
 
Facial paresis 


 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 to 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  
All other adverse events, regardless of relationship to study drug, will be reported until 
30 days after the last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first.  After this period, investigators should report any deaths, serious 
adverse events, or other adverse events of concern that are believed to be related to 
prior treatment with study drug, regardless of time after study (see Section 5.6). 
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 trial-related 
procedures until a final outcome can be reported. 
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?"  
 


 
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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 24 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 24 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE    National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of 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 


 
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 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions  
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction). 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 


 
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 
If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity 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  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 


 
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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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it 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 only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
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 


 
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injury (as defined by Hy's law).  Therefore, investigators must report as an adverse event 
the occurrence of either of the following: 
 
Treatment-emergent ALT or AST >  3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which    35% is direct bilirubin) 
 
Treatment-emergent ALT or AST >  3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded on the Death Attributed 
to Progressive Disease eCRF.  All other on-study deaths, regardless of relationship to 
study drug, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.4.2).  The iDMC will monitor the frequency of deaths from all 
causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
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"). 


 
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5.3.5.10 
Lack of Efficacy or Worsening of Non-Small Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 criteria.  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient 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 insertion of access device for study drug administration) 
 
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 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as ‘special situations’) are defined as follows:  
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 


 
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 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
Special situations are not themselves adverse events, but may result in adverse events.  
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria 
or qualifies as an adverse event of special interest, 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). For atezolizumab, vinorelbine, or gemcitabine, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Overdose" and 
"Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Overdose" box.  If 
drug abuse is suspected, check the "Abuse" box.  If drug abuse is not suspected, 
check the "Misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Overdose" and "Abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Overdose" and "Misuse" boxes. 
 
In addition, all special situations associated with atezolizumab, vinorelbine, or 
gemcitabine, regardless of whether they result in an adverse event, should be recorded 
on the Adverse Event eCRF as described below: 


 
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 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Overdose" box.  If drug abuse is suspected, check the "Abuse" 
box.  If drug abuse is not suspected, check the "Misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Overdose" and "Medication error" boxes.  
Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Overdose" and "Abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Overdose" and "Misuse" boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Misuse" box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Overdose" and "Medication error" boxes would need 
to be checked for both entries. 
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.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 


 
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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 Sections 5.2.2 and 5.4.2 for further details) 
 
Adverse events of special interest (see Sections 5.2.3 and 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 
5.4.1.1 
Medical Monitor Contact Information for All Sites 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. An Emergency 
Medical Call Center will be available 24 hours a day, 7 days per week. The Emergency 
Medical Call Center will connect the investigator with an Emergency Medical Contact, 
provide medical translation service if necessary, and track all calls.  Contact 
information, including toll-free numbers for the Emergency Medical Call Center, will 
be distributed to investigators. 
  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Clinical Trial Adverse Event/Special Situation Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 


 
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5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment or initiation of 
new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of 
relationship to study treatment, will be reported until 30 days after the last dose of study 
drug or initiation of new anti-cancer therapy, whichever occurs first.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Clinical Trial Adverse 
Event/Special Situation Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events 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 through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the last dose of atezolizumab or within 6 months after the last dose 
of single agent chemotherapy.  A Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the last dose of atezolizumab or within 6 months after the last dose of 


 
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single agent chemotherapy.  The investigator should report the pregnancy on the paper 
Clinical Trial Pregnancy Reporting Form and submit the form to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).    
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 


 
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serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
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 
Investigators are instructed to report all serious adverse events, and all adverse events 
of special interest that occur after the end of the adverse event reporting period (defined 
as 90 days after the last dose of study drug for serious adverse events and adverse 
events of special interest, and 30 days after the last dose of study drug for all other 
adverse events or initiation of new anti-cancer therapy, whichever occurs first), if the 
event is believed to be related to prior study drug treatment. 
In addition, if the investigator becomes aware of a serious adverse event 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 Roche or its designee, either by faxing 
or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form with use of the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following documents as a reference: 


 
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 
Atezolizumab Investigator's Brochure 
 
Vinorelbine SmPC 
 
Gemcitabine SmPC 
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 the 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 
Primary and secondary analyses (OS, PFS) will be performed on all randomized patients 
(i.e., ITT) irrespective of whether the assigned treatment was actually received.  ORR 
and DCR analyses will be performed on all randomized patients who have measurable 
disease at baseline.  DOR analyses will be performed on the subset of patients who 
achieve an objective response.  For all efficacy analyses, patients will be grouped 
according to the treatment assigned at randomization. 
The safety population will include all randomized patients who received any amount of 
study treatment.  Patients who are randomized into the study but did not receive any 
amount of study drug will not be included in the safety population.  For safety analyses, 
patients will be grouped according to whether any amount of atezolizumab was received, 
including the case when atezolizumab was received in error. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This is a randomized, Phase III, global, multicenter, open-label study designed to 
evaluate the safety and efficacy of atezolizumab on duration of OS relative to the current 
treatment practice.  Point and interval estimates of the true underlying hazard ratio will 
be obtained.  Assuming a 10% withdrawal rate and accrual duration of 24 months, 
approximately 441 patients will be randomized in a 2:1 ratio to atezolizumab (294 
patients) or chemotherapy (147 patients).  A total of 380 OS events will provide 90% 
power to detect a significant improvement in the primary endpoint (median OS) for 
treatment with atezolizumab versus chemotherapy from 7 months to 10 months (i.e., 
hazard ratio [HR] of 0.7) for a two-sided log-rank test at an alpha level of 5%.  One 
interim analysis for OS in the ITT population will be conducted when approximately 304 
events have been reached.  Operating characteristics are provided in Table 25.   


 
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Table 25 Operating Characteristics for Proposed Study Design  
Sample Size Calculation  
Parameters 
Values 
Randomization ratio (atezolizumab vs 
chemotherapy)  
2:1 
Type 1 error (2-sided) 
5% 
Power 
90% 
Accrual duration  
24 months 
Duration until OS interim analysis 
30 months 
Duration until OS final analysis  
42 months 
Assumed drop-out rate 
10% 
Median control  
7 months 
Median atezolizumab 
10 months 
Hazard ratio 
0.7 
Number of events at interim analysis 
304 
Number of events at final analysis 
380 
Number of patients 
441 
Note:  This is assuming validity of proportional Hazards assumption.  
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study drug administration, and discontinuation from the study will be 
summarized by treatment arm.  The incidence of study drug discontinuation for reasons 
other than disease progression will be tabulated.  Protocol deviations, including major 
deviations of inclusion/exclusion criteria, will be summarized. 
 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables such as age, sex, race/ethnicity, stratification factors (histologic 
subtype, PD-L1 status, brain metastases), baseline and disease characteristics (e.g., 
PD-L1 status, cancer histology, ECOG performance status) will be summarized by 
treatment arm for the ITT population.  Continuous variables will be summarized using 
means, standard deviations, medians, and ranges.  Categorical variables will be 
summarized by proportions.  
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment, unless otherwise noted. 
6.4 
EFFICACY ANALYSES 
Primary and secondary efficacy analyses will be based on the assigned treatment at 
randomization and will include all randomized patients (the ITT population).   


 
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6.4.1 
Primary Efficacy Endpoint 
The primary efficacy analysis is the comparison of OS between the two treatment arms 
(atezolizumab arm and single agent chemotherapy arm).  
For OS, patients without a date of death will be censored on the date a patient was last 
known to be alive.  If no post-baseline data are available, OS will be censored at the 
date of randomization plus 1 day. 
The null and alternative hypotheses for OS analysis can be phrased in terms of 
comparison of survival function S(t) for the two treatment arms:  
Ho: Schemo(t) =SAtezo(t) vs  
H1: Schemo(t) ≠SAtezo(t). 
The HR will be estimated using a stratified Cox regression model including 95% CIs.  
The stratification factors will be: histologic subtype (non-squamous/squamous), PD-L1 
IHC status (positive/negative/unknown) and brain metastases (yes/no). 
An unstratified analysis will also be performed.   
Kaplan-Meier methodology will be used to construct survival curves by treatments arms.  
The median OS and corresponding 95% CI will be provided for each treatment arm.   
If non proportionality of Hazard Ratio is detected, then further analyses and tests will be 
run.  Further details on this scenario will be provided in the SAP. 
A group sequential design will be used for testing OS at the interim analysis.  Details on 
the timing of the interim analysis and stopping boundaries are provided in Section 6.8.  
Details on the hypothesis testing will be provided in the SAP. 
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1
 Six
-
month, 12
-
month, 18
-
month and 24
-
month Landmark OS
 
The rates of OS at various timepoints (i.e., every 6 months after randomization until 
24 months) will be estimated by the Kaplan-Meier methodology for each arm and the 
95% CI will be calculated using Greenwood’s formula.  The 95% CIs for the difference in 
OS rates between the two arms will be estimated using the normal approximation 
method. 
6.4.2.2 
Objective Response Rate 
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 arms will be determined using the normal approximation to the binomial 
distribution.   


 
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The ORR will be compared between the two arms using z-statistics and the normal 
approximation. 
6.4.2.3 
Progression-Free Survival 
PFS is defined as the time (in months) between the date of randomization and the date 
of first documented disease progression or death, whichever occurs first.  Disease 
progression will be determined based on investigator assessment using RECIST v1.1.  
Patients who have not experienced disease progression or death at the time of analysis 
will be censored at the time of last tumor assessment.  Patients with no postbaseline 
tumor assessment will be censored at the randomization date plus 1 day. 
6.4.2.4 
Duration of Response 
DOR is defined as the time from initial response to disease progression or death among 
patients who have experienced a complete or partial response during the study.  
Patients who have not progressed 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 complete or partial response, DOR will be censored at the 
date of the first occurrence of a complete or partial response plus 1 day. 
DOR is based on a nonrandomized subset of patients (specifically, patients who achieve 
an objective response); therefore, formal hypothesis testing will not be performed for this 
endpoint.  
6.4.2.5 
OS and Investigator-assessed PFS in Patients with PD-L1 
Positive Status 
OS and investigator-assessed PFS according to RECIST v1.1 will be assessed in 
patients whose tumors express PD-L1 protein as measured by PD-L1 SP263 IHC assay 
(Ventana Medical Systems, Tucson, USA). 
6.5 
SAFETY ANALYSES 
Safety analyses will include all randomized patients who receive at least one dose of 
study drug (the safety population), with patients allocated to the treatment arm 
associated with the regimen actually 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 MedDRA 
thesaurus terms and graded according to NCI CTCAE v4.0.  All adverse events 
occurring during or after the first study drug dose will be summarized by treatment arm 
and NCI CTCAE grade.  In addition, serious adverse events, severe adverse events 
(Grade ≥ 3), adverse events of special interest, and adverse events leading to study 
drug discontinuation or interruption will be summarized accordingly.  Multiple 
occurrences of the same event will be counted once at the maximum severity. 


 
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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 and grade.
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion/discontinuation will be summarized by 
treatment arm.
Additionally, safety data from the re-treatment period, which will include patients who 
qualified for re-treatment with atezolizumab and who received at least one dose, will be 
summarized and/or listed.
6.6 
PATIENT-REPORTED OUTCOME ANALYSES
PROs of lung cancer-related symptoms (i.e., cough, dyspnea, fatigue, pain in chest; pain 
in arm/shoulder), patient functioning, and HRQoL will be assessed using the EORTC 
QLQ-C30 (Aaronson et al. 1993) and the QLQ-LC13 (Bergman et al. 1994).
Summary statistics (mean, standard deviation, median, and range) of linear transformed 
scores will be reported for all the items and subscales of the EORTC QLQ-C30 
questionnaire and the QLQ-LC13 according to the EORTC scoring manual guidelines. 
The mean change of the linear transformed scores from baseline (and 95% CI using the 
normal approximation) will also be assessed.  Line charts depicting the mean changes 
(and standard errors) over time from the baseline assessment of items and subscales 
will be provided for each treatment arm.  The proportion of patients showing clinically 
meaningful change in selected items and subscales at each assessment timepoint will
be calculated, with clinically meaningful defined as a change in symptoms/functioning 
(i.e., reduction or increase) from baseline to the threshold of 10 points or more
(Osoba et al. 1998).
Completion rates will be summarized at each timepoint by treatment arm.  Only patients 
with a baseline assessment and at least one post-treatment assessment will be included 
in the analyses.  Summaries will be performed for the ITT population only.
6.7 
EXPLORATORY ANALYSES
Analyses using modified RECIST criteria (atezolizumab arm only with no comparison to 
the chemotherapy arm): ORR, PFS and DOR will also be evaluated using definitions of 
response per modified RECIST criteria (see Appendix 4).  The investigator-assessed 
ORR is defined as the proportion of patients whose confirmed best overall response is 
either a partial response or complete response per modified RECIST.
DCR is defined as the rate of patients with complete or partial response as best
response or stable disease per RECIST v1.1.  The analysis methods for DCR will be the 
same as those for the analysis of ORR.


 
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Exploratory biomarker analyses will be performed in order to understand the association 
of these markers with study drug response, including efficacy and/or adverse events.   
The exploratory biomarker analyses will include patients with biomarker assessment at 
baseline as well as analyses comparing pre- and post-dose samples to explore changes 
in biomarker expression over time, with patients grouped according to the treatment 
actually received.  Tissue and blood samples will be analyzed by e.g., IHC, qRT-PCR, 
NGS and/or other methods to study tumor biomarkers and changes thereof on DNA, 
RNA and/or protein (or other analytes) derived from blood and tumor tissue samples to 
address exploratory objective.  
EQ-5D-5L health status data will be used for obtaining utility measures for economic 
modeling.  Patients without postbaseline assessments will be excluded from this 
analysis. 
6.8 
INTERIM AND FINAL ANALYSES 
There will be one interim analysis of OS conducted when approximately 304 deaths 
have occurred in the ITT population.  The final OS analysis will be conducted when 
380 events have occurred in the ITT population or when the follow-up time reaches at 
least 54 months after first patient in, whichever occurs first.  
A group sequential design (Lan-DeMets with O’Brien-Fleming stopping boundaries) will 
be used to control the overall type I error rate (Lan and DeMets 1983).  The information 
fraction at the time of each analysis will be re-calculated using the actual number of 
events included in the analysis, and the nominal alpha level re-calculated accordingly.  
The stopping boundaries for the planned interim and final analyses are shown in 
Table 26. 
 
 
Table 26 Analysis Timing and Stopping Boundaries for Interim and Final 
Analysis for Overall Survival 
Analysis Timing 
Time from First 
Patient In (months) 
Information Fraction 
(number of events) 
Stopping Boundary 
HR (p-valuea) 
Interim Analysis 
30 
80% (304) 
0.76 (p ≤ 0.0244) 
Final Analysis 
42b 
100% (380) 
0.8 (p ≤ 0.0428) 
HR = hazard ratio 
a Two-sided p-value 
b A cut-off date for final analysis will be set at least 54 months after first patient in should 380 OS 
events not be reached 


 
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The interim analysis will be conducted by an external statistical group and reviewed by 
the iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified 
in the iDMC charter.  The decision to conduct the planned interim analysis, along with 
the rationale, timing, and statistical details for the analysis, will be documented in the 
SAP.  The iDMC charter will document potential recommendations the iDMC can make 
to the Sponsor as a result of the analysis and the iDMC charter will also be made 
available to relevant health authorities, if applicable. 
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 contract research organization (CRO) will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system. 
The CRO will produce eCRF Specifications for the study based on Sponsor’s templates 
including 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 at the CRO 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 CRO. 
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 may be collected electronically through use of electronic devices 
provided by an electronic PRO (ePRO) vendor.  The electronic device is designed for 
entry of data in a way that is attributable, secure, and accurate, in compliance with U.S. 
FDA regulations for electronic records (21 Code of Federal Regulations, Part 11).  


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


 
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trial-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, name of the 
person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for at least 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 U.S. or under a U.S. Investigational 
New Drug (IND) application will comply with U.S. FDA regulations and applicable local, 
state, and federal laws.  Studies conducted in the E.U. or European Economic Area will 
comply with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, regional, 
and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Mobile Nursing Informed Consent Form, if applicable) will be provided 


 
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to each site.  It will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
The Informed Consent Form will contain separate sections for any optional procedures.  
The investigator or authorized designee will explain to each patient the objectives, 
methods, and potential risks associated with each optional procedure.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
for any reason.  A separate, specific signature will be required to document a patient's 
agreement to participate in optional procedures.  Patients who decline to participate will 
not provide a separate signature. 
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 U.S., each Consent Form may also include patient authorization to allow 
use and disclosure of personal health information in compliance with the U.S. Health 
Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 


 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written investigational 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. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 


 
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Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted clinical study reports 
and other summary reports will be provided upon request. 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor 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. 


 
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9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ 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 120 sites globally will participate in the study and approximately 
631 patients will be screened in order to randomize the required 441 patients. 
Randomization will occur through an IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests).  Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be collected.  
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or other summaries of clinical study results may 
be available in health authority databases for public access, as required by local 
regulation, and will be made available upon request.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 


 
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In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
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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Appendix 1  
Schedule of Activities 
 
Screening 
Period a 
Treatment Period w 
Treatment 
Discontinuation b 
Follow-Up 
Period c 
Assessment Window (Days) 
Day –28 to 
Day –1 
Baseline  
(Cycle 1 Day 1) 
Cycles ≥ 2  
(Day 1 ± 5 days) 
≤ 30 Days after  
Last Dose 
- 
Signed Informed Consent Form(s) a 
x 
 
 
 
 
Tumor Tissue for ALK/EGFR 
analysis, central PD-L1 IHC 
(stratification) and exploratory 
biomarkers d 
x 
 
 
 
 
Review of eligibility criteria 
x 
 
 
 
 
Medical, surgical, and cancer 
histories, including demographic 
information, EGFR, and ALK 
mutational status e 
x 
 
 
 
 
HIV, HBV, HCV serology f 
x y 
 
 
 
 
TSH, free T3 (or total T3), free T4 g 
x y 
x 
Cycles 5, 9, 13 etc. 
x 
 
Concomitant medications h 
x 
x 
x 
x 
 
Tumor response assessments i, x 
x i   
  
x 
Patient-reported outcomes j 
x 
 
With tumor response assessments z 
Complete physical examination k 
x 
 
 
x 
 
Limited physical examination k 
 
x 
x 
  
 
ECOG performance status l 
x 
x 
x m 
x 
 
Vital signs n 
x 
x 
x 
x 
 
12-lead electrocardiogram o 
x 
x 
x 
x 
 
Hematology p 
x y 
x 
x 
x 
 
Serum chemistry q 
x y 
x 
x 
x 
 


APPENDIX 1 
 
SCHEDULE OF ACTIVITIES (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
169/Protocol MO29872, Version 8  
 
Screening 
Period a 
Treatment Period w 
Treatment 
Discontinuation b 
Follow-Up 
Period c 
Assessment Window (Days) 
Day –28 to 
Day –1 
Baseline  
(Cycle 1 Day 1) 
Cycles ≥ 2  
(Day 1 ± 5 days) 
≤ 30 Days after  
Last Dose 
- 
Urinalysis r 
x y 
x 
x 
x 
 
Pregnancy test s 
x y 
Prior to each treatment cycle 
x 
x s 
Coagulation (INR, aPTT)  
x y 
 
 
x 
 
Whole blood for PBMC (exploratory 
biomarker) t 
 
x 
 
 
 
Plasma for exploratory biomarkers u 
 
x 
Week 7 and at PD  
 
 
Adverse events / adverse events of 
special interest v 
 
x 
x 
x 
x v 
Study drug administration w 
 
x 
x 
 
 
Survival and anticancer therapy 
follow-up c 
 
 
 
 
x 
ALK = anaplastic lymphoma kinase; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus, IHC = immunohistochemistry; PBMC = peripheral blood mononuclear cell; 
PD = disease progression; PD-L1 = programmed cell death-ligand 1; q3w = every 3 weeks; TSH = thyroid-stimulating hormone; T3 = free triiodothyronine; T4 = free 
thyroxine. 
Note:  All assessments should be performed within ± 5 days of the scheduled visit, unless otherwise specified. 
a Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur outside the 28-day 
screening period.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to study entry 
(except where otherwise specified) may be used for screening assessments rather than repeating such tests. 
b Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit ≤ 30 days after the last dose of study drug.  The visit at which the 
decision is made to discontinue treatment (e.g., disease progression is determined or confirmed) may be used as the treatment discontinuation visit.  After study 
drug discontinuation, patients will be treated at the discretion of the investigator according to local practice.  The decision to continue treatment with 
atezolizumab (experimental arm only) beyond disease progression (RECIST v.1.1) is at the investigator’s discretion for patients who can continue to benefit from 
the treatment (for criteria see Section 3.1). 
c Required follow-up information, including subsequent anticancer therapies and any treatment related AEs, will be collected via telephone calls and/or clinic visits 
every 2 months (± 5 days) until death, withdrawal of consent, loss to follow-up, study termination by the Sponsor, or protocol-defined end of study, whichever 
comes first.  In case of serious side effects during the study, follow-up examinations at the study site may be required.  


APPENDIX 1 
 
SCHEDULE OF ACTIVITIES (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol MO29872, Version 8  
d Screening: A representative formalin-fixed paraffin-embedded (FPPE) tumor tissue block obtained during course of disease (archival tissue) or screening (tumor 
blocks are highly preferred; ideally, 3 cores should be submitted in case smaller core biopsies are available in order to have sufficient tumor cells available.  In 
case the tumor block is not available, 10-15 unstained, consecutive slides not older than 60 days will be accepted.  A minimum of five slides is mandated for 
PD-L1 analysis and patient stratification.  If archival tissue (most recent sample) is unavailable, a pretreatment tumor biopsy is required.  Cytological or 
fine-needle aspiration samples are not acceptable.  Tumor tissue from bone metastases or are not acceptable.  Tumor tissue should be of good quality based on 
total and viable tumor content (at least 300 viable tumor cells across cores are needed for determination of TC/IC status at low cut-offs).   
e Cancer history includes stage, date of diagnosis, results of EGFR mutation and ALK rearrangement testing (if available), and prior antitumor treatment.  
Demographic information includes sex, age, and self-reported race/ethnicity.  Patients with non-squamous NSCLC and unknown EGFR or ALK status will be 
required to be tested at pre-screening/screening.  Patients with squamous NSCLC and unknown EGFR or ALK status will not be required to be tested at 
pre-screening/ screening, except for patients who are never smokers or have mixed histology.  EGFR and/or ALK may be assessed locally or at a central lab.  
Additional tissue will be required for central testing of EGFR and/or ALK.  An FFPE tumor tissue block (or at least 7 slides) will be required for testing. 
f 
Patients with a history of, or signs of active HIV or hepatitis B/C disease must be tested for seropositivity prior to the inclusion into the study.  HIV-positive 
patients will be excluded from the clinical study.  Patients with a positive hepatitis B surface antigen [HBsAg] test at screening will be excluded from this clinical 
study.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.   
g TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening, on Day 1 of Cycle 1 and every four cycles 
thereafter (i.e., Cycles 5, 9, 13, etc.). 
h Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening until the treatment discontinuation visit.  All such medications should be reported to the investigator and must be recorded on the 
appropriate Concomitant Medications eCRF.  
i 
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.  It is recommended to have the screening/baseline tumor assessment done within 14 days before randomization, as close as possible to baseline.  All 
measurable and evaluable lesions should be assessed and documented at the screening visit.  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).  Results must be reviewed by the investigator before dosing at 
the next cycle.  All patients should undergo a brain scan at Screening.  Patients with CNS metastases newly detected at the screening scan should have 
received 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, including clinical confirmation of no evidence of interim disease progression.   
j 
PRO assessments (EORTC QLQ-C30, QLQ-LC13, and EQ-5D-5L) will be completed before the patient receives any information on disease status and prior to 
the performance of non-PRO assessments and the administration of study treatment.  Study personnel should review all questionnaires for completeness before 
the patient leaves the investigational site.  
k Complete and limited physical examinations are defined in Section 4.5.3. 
l 
ECOG performance status, limited physical examination, local laboratory assessments may be obtained ≤ 96 hours before Day 1 of each cycle. 
m ECOG PS is mandatory at all timepoints.  
n Includes height, weight, respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature, an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 


APPENDIX 1 
 
SCHEDULE OF ACTIVITIES (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
171/Protocol MO29872, Version 8  
neurological systems.  Record abnormalities observed at baseline 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 AE eCRF. 
o ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  ECG recordings will be obtained as described in Section 4.5.9. 
p Hematology includes complete blood count [CBC], including red blood cell count [RBC] count, hemoglobin, hematocrit, white blood cell (WBC) count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells], and platelet count  
q Serum chemistry panel (serum or plasma) includes glucose, blood urea nitrogen [BUN] or urea, creatinine, sodium, potassium, chloride, bicarbonate or total 
carbon dioxide (if considered standard of care for the region), calcium, phosphorus, total and direct bilirubin, ALT, AST, alkaline phosphatase, uric acid, LDH, 
total protein, and albumin. 
r Dipstick permitted: pH, specific gravity, glucose, protein, ketones, blood. 
s A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
within 14 days prior to Day 1.  On study pregnancy tests must be performed prior to each treatment cycle (21-day cycle for atezolizumab and per relevant local 
guidelines and SmPC management for chemotherapy) while receiving the IMP.  For female patients of childbearing potential, the pregnancy tests will be 
repeated during the treatment discontinuation visit and then every 2 months during follow-up for at least 5 months after the last dose of atezolizumab and for at 
least 6 months after the last dose of chemotherapy, respectively.  Pregnancy tests during follow-up do not require on-site visits; results from a treating physician 
can be used.  The pregnancy test can be conducted with serum or urine.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
t 18 mL whole blood (ACD tubes) should be obtained pre-dose and shipped to the central laboratory for PBMC preparation, RNA isolation and gene expression 
analysis.  Details are specified in a separate laboratory manual.  If consented, residual material will be transferred to RBR. 
u 20 mL whole blood (K3 EDTA tubes) for preparation of plasma should be obtained pre-dose.  Plasma samples will be shipped to the central laboratory for 
exploratory biomarker analyses.  If consented, residual material (including extracted RNA or DNA or other) will be transferred to RBR. 
v After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention (e.g., 
invasive procedures such as biopsies, discontinuation of medications) should be reported (see Section 5.4.2 for instructions for reporting serious adverse 
events).  After initiation of study drug, all serious adverse events, and adverse events of special interest, regardless of relationship to study drug, will be reported 
until 90 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of relationship 
to study drug, will be reported until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After these respective 
periods, investigators should report any deaths, serious adverse events, or other adverse events of concern that are believed to be related to prior treatment with 
study drug, regardless of time after study (see Section 5.6).  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 trial-related procedures until a final outcome can be reported. 
w Atezolizumab at a fixed dose of 1200 mg will be administered intravenously at the study site on Day 1 of each 21-day cycle.  Single agent chemotherapy 
(vinorelbine, oral or intravenous, or gemcitabine) will be administered per relevant local guidelines and SmPC management.  Chemotherapy cycles may be 
3-weekly or 4-weekly.  A 28-day assessment schedule will be followed for patients receiving 4-weekly chemotherapy cycles.  
x Tumor assessments will be performed at baseline, every 6 weeks (± 5 days) following randomization for 48 weeks, and every 9 weeks (± 5 days) thereafter, 
regardless of dose delays, with additional scans as clinically indicated, until radiographic disease progression per RECIST v1.1 or (for patients who continue 


APPENDIX 1 
 
SCHEDULE OF ACTIVITIES (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
172/Protocol MO29872, Version 8  
atezolizumab after radiographic disease progression), loss of clinical benefit as determined by the investigator (see Section 3.1 and 4.5.5 for details).  Thus, 
tumor assessments are to continue according to schedule in patients who discontinue study treatment for reasons other than disease progression or loss of 
clinical benefit, even if patients start new anti-cancer therapy.  In all patients, response will be assessed by the investigator using RECIST v1.1 until disease 
progression.  Patients randomized to receive atezolizumab will additionally be assessed by modified RECIST criteria until treatment discontinuation.  Follow-up 
tumor assessments are not required after discontinuation of atezolizumab for patients continuing atezolizumab beyond PD. 
y Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment. 
z The EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L questionnaires will be completed by the patients with each tumor assessment until disease 
progression per RECIST v1.1, even if patients discontinue study treatment for any reason other than progressive disease or loss of clinical benefit. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
173/Protocol MO29872, Version 8 
Appendix 2  
American Joint Committee on Cancer Non−Small Cell Lung 
Cancer Staging, 7th Edition 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 
 
 


 
APPENDIX 2 
 
AMERICAN JOINT COMMITTEE ON CANCER NON−SMALL CELL LUNG 
CANCER STAGING, 7TH EDITION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
174/Protocol MO29872, Version 8  
 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
175/Protocol MO29872, Version 8  
Appendix 3  
Response Evaluation Criteria in Solid Tumors:   
Modified Excerpt from Original Publication 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
176/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
177/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
178/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
179/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
180/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
181/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
182/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
183/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
184/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
185/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 3 
 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS:   
MODIFIED EXCERPT FROM ORIGINAL PUBLICATION (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
186/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
187/Protocol MO29872, Version 8  
Appendix 4  
Modified Response Evaluation Criteria in Solid Tumors 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 4 
 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
188/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 4 
 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
189/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 4 
 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
190/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 4 
 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
191/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 4 
 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
192/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 4 
 
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
193/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
194/Protocol MO29872, Version 8  
Appendix 5  
Anti-PD-L1 Immunohistochemistry 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
195/Protocol MO29872, Version 8 
Appendix 6  
EORTC QLQ-C30 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 6 
 
EORTC QLQ-C30 (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
196/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
197/Protocol MO29872, Version 8  
Appendix 7  
EORTC QLQ-LC13 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
198/Protocol MO29872, Version 8  
Appendix 8  
EuroQoL 5 Dimension, 5 Level Questionnaire 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 


APPENDIX 8 
 
EUROQOL 5 DIMENSION, 5 LEVEL QUESTIONNAIRE (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
199/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


APPENDIX 8 
 
EUROQOL 5 DIMENSION, 5 LEVEL QUESTIONNAIRE (CONT.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
200/Protocol MO29872, Version 8 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
201/Protocol MO29872, Version 8 
Appendix 9  
Eastern Cooperative Oncology Group Performance Status Scale 
Do not reproduce or distribute. The Sponsor will provide sites with all instruments 
to be completed in the study. 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
202/Protocol MO29872, Version 8 
Appendix 10  
Anaphylaxis Precautions 
EQUIPMENT NEEDED 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice  
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
1. 
Stop the study drug infusion. 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible. 
5. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 
 
 


 
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Appendix 11  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously expereinced a servere or life-threatening 
skin adverse reaction or pericardial disorder while receiving another immunostimulatory 
anti-cancer agent. The Medical Monitor is available to advise on any uncertainty over 
autoimmune exclusions. 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Anti-phospholipid antibody 
syndrome 
 Aplastic anemia 
 Autoimmune hemolytic 
anemia 
 Autoimmune hepatitis 
 Autoimmune 
hypoparathyroidism 
 Autoimmune hypophysitis 
 Autoimmune myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease  
 Dermatomyositis 
 Diabetes mellitus type 1 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme disease, chronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anemia 
 Polyarteritis nodosa 
 Polyarthritis 
 Polyglandular autoimmune 
syndrome 
 Primary biliary cholangitis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 
 Granulomatosis with 
polyangiitis 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
204/Protocol MO29872 Version 8  
Appendix 12  
PD-L1 IHC Scoring Criteria 
 
Tumor area is defined as tumor cells, associated intratumoral, and contiguous peri-
tumoral desmoplastic stroma. 
 
Immune Cell (IC) Score includes the assessment of PD-L1 positive tumor-infiltrating 
immune cells relative to the tumor area. 
 
Tumor Cell (TC) score is the assessment of PD-L1 positive tumor cells relative to 
the total number of tumor cells. 
 
PD-L1 Immune Cell (IC) Positivity 
IC0 
Absence of any discernible PD-L1 staining  
OR 
presence of discernible PD-L1 staining of any intensity in tumor-infiltrating 
immune cells covering < 1% of tumor area occupied by tumor cells, 
associated intratumoral, and contiguous peri-tumoral desmoplastic stroma 
IC1 
Presence of discernible PD-L1 staining of any intensity in tumor-filtrating 
immune cells covering between ≥ 1% and < 5% of tumor area occupied by 
tumor cells, associated intratumoral, and contiguous peri-tumoral 
desmoplastic stroma 
IC2 
Presence of discernible PD-L1 staining of any intensity in tumor-infiltrating 
immune cells covering between ≥ 5% and < 10% of tumor area occupied by 
tumor cells, associated intratumoral, and contiguous peri-tumoral 
desmoplastic stroma 
IC3 
Presence of discernible PD-L1 staining of any intensity in tumor-infiltrating 
immune cells covering ≥ 10% of tumor area occupied by tumor cells, 
associated intratumoral, and contiguous peri-tumoral desmoplastic stroma 
 
PD-L1 Tumor Cell (TC) Positivity 
TC0 
Absence of any discernible PD-L1 staining OR 
presence of discernible PD-L1 staining of any intensity in < 1% tumor cells 
TC1 
Presence of discernible PD-L1 staining of any intensity in ≥ 1% and < 5% 
tumor cells 
TC2 
Presence of discernible PD-L1 staining of any intensity in ≥ 5% and < 50% 
tumor cells 
TC3 
Presence of discernible PD-L1 staining of any intensity in ≥ 50% tumor cells 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
205/Protocol MO29872 Version 8  
Appendix 13  
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents.  
The following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections.  
 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment and survival follow-up.  There should be a high level of suspicion that 
new symptoms are treatment related. 
 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
 
Consider holding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids 
(initial dose of 0.5
1 mg/kg/day of prednisone or equivalent) may be administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1
2 mg/kg/day prednisone or equivalent).  Corticosteroids should 
be tapered over 1 month to 10 mg/day oral prednisone or equivalent, before 
atezolizumab can be resumed.  If symptoms do not improve within 48 to 72 hours 
of high-dose corticosteroid use, other immunosuppressants may be offered for some 
toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by 
hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance for a given patient prior 
to further administration of atezolizumab.  Resumption of atezolizumab may be 
considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event.  The decision to re-challenge patients with atezolizumab 
should be based on the investigator’s assessment of the benefits and risks and 


 
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documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
DOSE MODIFICATIONS  
There will be no dose modifications for atezolizumab in this study. 
TREATMENT INTERRUPTION 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to the equivalent of  10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for  12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for  12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s benefit-
risk assessment and documented by the investigator. The Medical Monitor is available to 
advise as needed.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator. The 
Medical Monitor is available to advise as needed. 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  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.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in Table 1
 
. 


 
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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. 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
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 with or without transbronchial 
biopsy. 
 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 
the Medical Monitor.  c 
 For recurrent events or events with no improvement after 48-72 
hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor.  c, d 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methyprednisolone. 
 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 based on the investigator’s benefit-risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator. 
The Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 


 
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HEPATIC EVENTS 
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 the Medical Monitor.  c 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the 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. 


 
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Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
LFT  liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefit-risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit-risk 
assessment and documented by the investigator.  The Medical Monitor is available 
to advise as needed.   
 
GASTROINTESTINAL EVENTS 
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.  
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. 
 If strong clinical suspicion for immune-mediated colitis, start 
empiric IV steroids while waiting for definitive diagnosis. 
 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 
the 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 


 
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea 
or Colitis) 
Event 
Management 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
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 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 the 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
 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 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 based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed.   
 
ENDOCRINE EVENTS 
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 


 
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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. 
Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 Consider withholding atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled, and 
thyroid function is improving. 
 
 


 
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Table 4     Management Guidelines for Endocrine Events
Event 
 Management
Grade 3 and 4 
hypothyroidism
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
 Resume atezolizumab when symptoms are controlled, and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hypothyroidism. c 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism. 
 Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
 Consider withholding 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. 
Grade 3 and 4 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drugs such as 
methimazole or carbimazole as needed. 
 Refer to endocrinologist. 
 Resume atezolizumab when symptoms are controlled, and 
thyroid function is improving. 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism. c 
  
 
 
 


 
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Table 4  
Management Guidelines for Endocrine Events 
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 the 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. 
 Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
 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 based on in the investigator’s benefit-risk assessment and in alignment with 
the protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 


 
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Table 4 
Management Guidelines for Endocrine Events  
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 the Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab and contact the 
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 based on the investigator’s benefit-risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
 
 


 
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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 
the Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the 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 based on the investigator’s benefit-risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator. 
The Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 6. 


 
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IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-
type matriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis or associated with pericarditis (see section on 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6 . 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, and 
should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 


 
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according to the guidelines in Table 6.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2-
4 
 
Immune-mediated 
pericardial disorders, 
Grades 2-4 
 Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD or 
pericardiocentesis 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. 
 
 
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines, 
antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs 
because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 


 
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with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs and CRS are provided in Table 7.   
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
COVID-19, which should be confirmed or refuted through assessment of exposure 
history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator's judgement.  If a diagnosis of COVID-19 is confirmed, the disease should 
be managed as per local or institutional guidelines. 
Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms  
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
 For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretics medications, and/or analgesics, and 
monitor closely for IRRs and/or CRS. 


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


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


 
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Table 7 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
Event 
Management 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive 
airway pressure; CAR  chimeric antigen receptor; CPAP  continuous positive airway 
pressure; CRS  cytokine-release syndrome; CTCAE  Common Terminology Criteria for 
Adverse Events; eCRF  electronic Case Report Form; HLH  hemophagocytic 
lymphohistiocytosis; ICU  intensive care unit; IRR  infusion-related reaction; 
MAS  macrophage activation syndrome; NCCN  National Cancer Comprehensive Network; 
NCI  National Cancer Institute. 
Note:  These management guidelines have been adapted from the NCCN guidelines for the 
management of CAR T-cellrelated toxicities (Version 2.2019). 
a Grading system for these management guidelines is based on ASTCT consensus grading 
for CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities associated 
with CRS should not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at  6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator. The Medical Monitor is available to advise as needed.  For 
subsequent infusions, administer oral premedication with antihistamines, antipyretic 
medications, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication 
with corticosteroids and extending the infusion time may also be considered after 
assessing the benefitrisk ratio. 
 
f Refer to Riegler et al. (2019). 
 
PANCREATIC EVENTS 
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 . 
 
 


 
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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 the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the 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 based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator. The Medical Monitor is 
available to advise as needed. 
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 event. The decision to re-challenge patients with atezolizumab 
should be based on the investigator’s benefit-risk assessment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 


 
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Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)  
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 
 Withhold atezolizumab for up to 12 weeks after event onset. 
a 
 Refer patient to GI specialist. 
 Initiate treatment with 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 the Medical Monitor. c 
 For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact the 
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 based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator. The Medical Monitor is 
available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented 
by the investigator. The Medical Monitor is available to advise as needed. 
 
 
 


 
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DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limited, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  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 for evaluation and, if indicated, 
biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if event 
does not improve. 
 If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day. 
Dermatologic 
event, Grade 3  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
 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 the 
Medical Monitor. c 
Dermatologic 
event, Grade 4 
 Permanently discontinue atezolizumab and contact the Medical Monitor. c 


 
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Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
 Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic 
epidermal necrolysis. 
 Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist or urologist as relevant) for evaluation and, if indicated, 
biopsy. 
 Follow the applicable treatment and management guidelines above. 
 If Stevens-Johnson syndrome or toxic epidermal necrolysis, permanently 
discontinue atezolizumab. 
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 based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator. The Medical Monitor is available to 
advise as needed. 
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 event.  The decision to re-challenge patients with atezolizumab 
should be based on the investigator’s benefit-risk assessment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
 
NEUROLOGIC DISORDERS 
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 , with specific guidelines for myelitis provided in Table 11. 


 
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Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
 Continue atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology and refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
– 
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 the Medical Monitor. c 
 For facial paresis: 
– 
If event resolves fully, resume atezolizumab b 
 If event does not resolve fully while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 
4 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. c  
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 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 based on the investigator’s benefit-risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator. The 
Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
 


 
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Table 11 Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 12 . 


 
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Table 12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 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. 
 
RENAL EVENTS 
Eligible patients must have adequate renal function. 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 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 13. 


 
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Table 13 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine and urine protein, 
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 the Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact the 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 based on the investigator’s benefit-risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed. 
 
IMMUNE-MEDIATED MYOSITIS 
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 possible myositis should be referred to a rheumatologist or neurologist and 
should be monitored for signs of myocarditis. 


 
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Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 
Table 14 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist.  
 Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact the 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 the Medical Monitor. c 
Immune-
mediated 
myositis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact the 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 the Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event. 


 
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Table 14 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, Grade 4 
 Permanently discontinue atezolizumab and contact the 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 based on the investigator’s benefit-risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
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 event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and 
documented by the investigator. The Medical Monitor is available to advise as 
needed. 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH). 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged. 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 


 
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 
Peripheral blood cytopenia consisting of at least two of the following: 
 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
 
Platelet count  100  109/L (100,000/L) 
 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble IL-2 receptor (soluble CD25) elevated  2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
 
Platelet count  181  109/L (181,000/L) 
 
AST  48 U/L 
 
Triglycerides  1.761 mmol/L (156 mg/dL) 
 
Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in  
Table 15 . 


 
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Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key 
role for monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 


 
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Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 
 


Signature Page for Protocol - MO29872 - TECENTRIQ - v8 - Published
System identifier: RIM-CLIN-485327
Approval Task
Company Signatory
09-May-2023 20:02:11 GMT+0000

SAP_001.pdf: 
Atezolizumab —F. Hoffmann-La Roche Ltd
Statistical Analysis Plan MO29872, Version 3.0
1
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III , OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY TO INVESTIGATE THE EFFICACY 
AND SAFETY OF ATEZOLIZUMAB COMPARED WITH
CHEMOTHERAPY IN PATIENTS WITH TREATMENT-NAÏVE
ADVANCED OR RECURRENT (STAGE IIIB NOT 
AMENABLE FOR MULTIMODALITY TREATMENT) OR
METASTATIC (STAGE IV) NON-SMALL CELL LUNG 
CANCER WHO ARE DEEMED UNSUITABLE FOR 
PLATINUM-CONTAINING THERAPY (IPSOS)
PROTOCOL NUMBER:
MO29872
STUDY DRUG:
Atezolizumab (RO5541267)
VERSION NUMBER:
3.0
IND NUMBER:
117296
EUDRACT NUMBER:
2015-004105-16
NCT NUMBER:
NCT03191786
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
 (Trial Statistician, Cytel, Inc), 
 (Study Lead Statistician, Roche)
DATE FINAL:
21 Aug 2020


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STATISTICAL ANALYSIS PLAN V3.0 AMENDMENT
RATIONALE
The Statistical Analysis Plan (SAP) for Study MO29872 (IPSOS) has been amended to 
reflect the following changes:

Analysis that handles the potential over-stratification is changed to be reported as 
sensitivity analysis (See Section 4.4.5.2)

Safety Population has been renamed to Safety-Evaluable Population

OS and Investigator assessed PFS according to RECIST v1.1 in patients with PD L1 
expression defined by the SP142 mmunohistochemistry (IHC) assay added as 
secondary endpoints (See section 4.4.2.5)

Addition of Unconfirmed ORR as sensitivity analysis (Section 4.4.5.8)

Clarification on analysis of Duration of Response (Section 4.4.2.4)

Clarification on the summary of ECG Abnormalities (Section 4.6.5)

Clarification on sensitivity analysis of primary endpoint in case of misstratification 
(Section 4.4.5.3)


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STATISTICAL ANALYSIS PLAN V2.0 AMENDMENT
RATIONALE
The Statistical Analysis Plan (SAP) for Study MO29872 (IPSOS) has been amended to 
reflect the following changes made in the Study:

The emerging data from other atezolizumab monotherapy studies in first-line NSCLC 
(IMpower110), as well as other studies in similar populations with anti-PD-1 treatment 
(PEPS2, CHECKMATE-817), suggest an earlier analysis can demonstrate overall 
survival benefit; therefore the Sponsor has added an efficacy interim analysis with 
adequate power for the primary efficacy endpoint (overall survival). The statistical 
details have been updated accordingly which may provide the community with evidence 
from a randomized, controlled study approximately 12 months earlier than planned.
(Sections 2.3, 2.4, 3.3 and 4.9)

OS and Investigator-assessed PFS according to RECIST v1.1 in patients with PD-L1 
expression defined by the SP263 immunohistochemistry (IHC) assay has been added 
as a secondary analysis. Both SP142 and SP263 assays have predictive value for PD-
L1 status and therefore help identify potential subsets of patients who benefit more from 
PD-L1 treatment (Section 2.2.2 and 4.4.2)

Protocol amendment version 3 introduced a change in the PRO visits. As some patients 
had already taken a PRO visit at week 3, this SAP defines that for those patients with 
the PRO visit to consider should be within a window of 30 days prior to the Tumor 
Assessment visit to address the issue of unequal timepoints in the longitudinal analysis 
of PRO data (Section 4.4.3). The schedule of assessments is updated accordingly.

Update of the protocol synopsis to be aligned with SAP V2.0 

Structural updates were made throughout the document to address the newest Sponsor 
SAP template; this includes:
o
ORR and BOR are described in the same section (Section 4.4.2.2)
o
Removal of any programming code, dataset specifications, computing 
environment, data conventions and list of outputs
o
Removal of appendixes that are readily referenced through external 
sources:

PD-L1 IHC Scoring Criteria; Vennapusa et al, 2017

EORTC QLQ-C30 and QLQ-LC13: Scoring Rules; 
Fayers et al, 2001
This amendment represents cumulative changes to the original analysis plan.  Additional 
minor changes and administrative changes have been made to improve clarity and 
consistency.


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE .............................2
1.
BACKGROUND.............................................................................................8
2.
STUDY DESIGN............................................................................................9
2.1
Protocol Synopsis...................................................................10
2.2
Endpoints ...............................................................................11
2.2.1
Primary Efficacy Endpoint ......................................................11
2.2.2
Secondary Efficacy Endpoints................................................11
2.2.3
Safety Endpoints ....................................................................11
2.2.4
Patient-Reported Outcome Endpoints....................................11
2.2.5
Pharmacokinetic Endpoints....................................................11
2.2.6
Exploratory Endpoints ............................................................11
2.3
Determination of Sample Size................................................12
2.4
Analysis Timing ......................................................................13
3.
STUDY CONDUCT......................................................................................13
3.1
Randomization Issues............................................................13
3.2
Independent Review Facility ..................................................14
3.3
Data Monitoring......................................................................14
4.
STATISTICAL METHODS ...........................................................................14
4.1
Analysis Populations ..............................................................14
4.1.1
Efficacy Analysis Population ..................................................14
4.1.2
Safety Population ...................................................................15
4.2
Analysis of Study Conduct .....................................................15
4.3
Analysis of Treatment Group Comparability...........................15
4.4
Efficacy Analysis ....................................................................15
4.4.1
Primary Efficacy Endpoint ......................................................15
4.4.2
Secondary Efficacy Endpoints................................................16
4.4.2.1
OS Rate at the 6, 12, 18, 24-Months Timepoints..................16
4.4.2.2
Objective Response Rate .....................................................16
4.4.2.3
Progression-Free Survival.....................................................16
4.4.2.4
Duration of Response ...........................................................17
4.4.2.5
Overall Survival and Investigator-Assessed 
Progression-Free Survival for SP263 PD-L1 Subpopulation...............17
4.4.3
Patient-Reported Outcomes...................................................17


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4.4.4
Exploratory Efficacy Endpoints...............................................18
4.4.4.1
ORR, PFS and DOR as Assessed by the 
Investigator Using Modified RECIST...................................................18
4.4.4.2
Disease Control Rate............................................................19
4.4.4.3
Utility scores of the EQ 5D 5L questionnaire.........................19
4.4.5
Sensitivity Analyses................................................................19
4.4.5.1
Unstratified Analysis .............................................................19
4.4.5.2
Mistratification.......................................................................19
4.4.5.3
Imbalance between Treatment Arms ....................................20
4.4.5.4
Non-Proportional Hazard ......................................................20
4.4.5.5
Non-Protocol-Specified Anti-Cancer Therapy .......................20
4.4.5.6
Missing Tumor Assessment..................................................20
4.4.6
Subgroup Analyses ................................................................21
4.5
Pharmacokinetic and Pharmacodynamic Analyses................21
4.6
Safety Analyses......................................................................21
4.6.1
Exposure of Study Medication................................................21
4.6.2
Adverse Events ......................................................................22
4.6.3
Laboratory Data......................................................................22
4.6.4
ECOG PS...............................................................................22
4.6.5
Electrocardiogram ..................................................................22
4.7
Biomarker Analysis.................................................................22
4.8
Missing Data...........................................................................23
4.9
Interim Analyses.....................................................................23
4.9.1
Planned Interim Analysis........................................................23
4.9.2
Safety Monitoring ...................................................................23
5.
REFERENCES ............................................................................................24
LIST OF TABLES
Table 1: Operating Characteristics......................................................................12
Table 2: Timing and Stopping Boundaries for Interim and Final Analyses for 
Overall Survival............................................................................13
Table 3: PD-L1 Status Assessed by SP142 Assay .............................................13
LIST OF APPENDICES
Appendix 1
Protocol Version 5 Synopsis.......................................................26
Appendix 2
Schedule of Assessments ..........................................................35


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List of Abbreviations
Abbreviation
Definition
AE
adverse events
AESI
adverse events of special interest
BOR
CI
best overall response
confidence interval
CR
complete response
CSR
clinical study report
ECG
electrocardiogram
ECOG
eCRF
EORTC
Eastern Cooperative Oncology Group
electronic Case Report Form
European Organization for the Research and
Treatment of Cancer
EQ-5D-5L
EuroQoL 5 Dimension questionnaire
FDA
HRQoL
Food and Drug Administration
Health-Related Quality of Life
ICH
International Conference on Harmonization
iDMC
IV
Independent Data Monitoring Committee
Intra-Venous
ITT
Intent-to-treat
KM
Kaplan Meier
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology
Criteria for Adverse Events
NE
not evaluable
NSCLC
Non-Small Cell Lung Cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression free survival
PK
pharmacokinetic
PR
partial response
PRO
patient reported outcome
PS
performance status
PT
preferred term
QLQ-C30
QLQ-LC13
Quality-of-life Questionnaire Core 30
Quality-of-Life Questionnaire Lung Cancer Module
RECIST
Response Evaluation Criteria in Solid Tumors
RMST
restricted mean survival time
RPFST
rank preserving structural failure time


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Abbreviation
Definition
SAP
statistical analysis plan
SD
stable disease
SI
System International
SOC
System Organ Class
TTD
time to deterioration


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1.
BACKGROUND
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most common 
cancer in both men and women and accounted for approximately 13% of all new cancers in 
2008 (Jemal et al. 2011). 
Non−small cell lung cancer (NSCLC) is the predominant subtype of lung cancer, accounting 
for approximately 85% of all cases (Molina et al. 2008, Howlader et al. 2014). Half of all newly 
diagnosed NSCLC patients present with advanced disease (stage IIIb and IV) (Davidoff et al. 
2010) which directly contributes to poor survival prospects. 
The overall 5-year survival rate for advanced disease is 2%-4%, depending on geographic 
location (Cetin et al. 2011). Poor prognostic factors for survival in patients with NSCLC include 
advanced stage of disease at the time of initial diagnosis, poor performance status (PS), and 
a history of unintentional weight loss. More than half of the patients with NSCLC are diagnosed 
with distant disease.
The majority of patients with newly diagnosed NSCLC present with locally advanced or 
metastatic disease (Carnio et al. 2014). In addition, the average age at diagnosis of lung 
cancer in the U.S. is about 70 years (Avery et al. 2009, Gajra et al. 2014)). As a result, a 
significant proportion of patients with lung cancer have intercurrent illnesses or comorbid 
conditions that can potentially affect their ability to receive standard therapy for lung cancer. 
Patients with lung cancer with a poor PS, irrespective of age, have an increased incidence of 
adverse effects with standard chemotherapy and have a poorer overall survival (OS)
(Sweeney et al. 2001, Ruckdeschel et al. 1986). An estimated 30% to 40% of patients 
diagnosed with NSCLC have a poor PS-defined as a score of 2 or higher on the Eastern 
Cooperative Oncology Group (ECOG) scale-because of their disease burden, comorbidities, 
or both (Govindan et al. 2004).
Survival is shorter in patients with advanced NSCLC and a PS of 2 than in those with a better 
PS of 0-1, regardless of therapy (Azzoli et al, 2010). Patients with a PS of 2 do not tolerate 
chemotherapy as well, and treatment approaches should be different (Gridelli et al. 2006).
There is currently a highly unmet medical need for novel safe treatment options that deliver 
an improved therapeutic index in newly diagnosed advanced, recurrent or metastatic NSCLC 
deemed unsuitable for platinum-containing therapy due to poor performance status and/or 
comorbidities.
Atezolizumab (MPDL3280A) is a humanized IgG1 monoclonal antibody consisting of two 
heavy chains (448 amino acids) and two light chains (214 amino acids) and is produced in 
Chinese hamster ovary cells. Atezolizumab 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. 
On 18 Oct 2016, U.S. FDA approved atezolizumab for the treatment of patients with metastatic 
NSCLC whose disease progressed during or following platinum-containing chemotherapy.
This Statistical Analysis Plan (SAP) specifies the planned analyses and statistical methods 
used for Study MO29872 (IPSOS) and supersedes those analyses specified in the protocol.


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2.
STUDY DESIGN
This randomized, Phase III, multicenter, open-label study is designated to evaluate the 
efficacy and safety of atezolizumab compared with a single agent chemotherapy regimen by 
investigator choice (vinorelbine or gemcitabine) in treatment-naïve patients with locally 
advanced or metastatic NSCLC
who are deemed unsuitable for platinum
doublet 
chemotherapy due to poor performance status (ECOG PS of 2-3).
However,  patients who are ineligible for platinum doublet chemotherapy but have ECOG 
performance status 0 or 1 may be enrolled if they are ≥70 years of age. They may be included 
if deemed unsuitable for platinum doublet chemotherapy by the investigator due to a) 
substantial comorbidities, b) contraindication(s) for platinum based antineoplastic drugs. 
Eligible patients will be stratified by (a) histologic subtype (non-squamous/squamous), 
(b) PD-L1 IHC status (positive/negative/unknown; see Section 3.1) and (c) brain metastases 
(yes/no) and then randomized at a 2:1 ratio to receive either atezolizumab or single agent 
chemotherapy. 
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 
21-day cycle.
Patients randomized to receive single agent chemotherapy approved in their country 
(vinorelbine or gemcitabine), based on investigator’s choice will receive chemotherapy 
according to the label. Doses and dose modifications for the selected single agent 
chemotherapy should be made according to the local guidelines and Summary of Product 
Characteristics (SmPC) management.
Given the unique toxicities associated with chemotherapy (i.e., alopecia, neutropenia, febrile 
neutropenia) and the pre-medications required (i.e., steroid, anti-emetics, and potentially 
growth factor support), this will be an open-label study. 
No crossover will be allowed between treatment arms. However, it is not possible to prevent 
use of other immunotherapies after discontinuing study drug.
At any time-point after RECIST v1.1 criteria for progressive disease are met, patients in the 
experimental arm who show evidence of clinical benefit, will be permitted to continue treatment 
with atezolizumab until loss of clinical benefit, unacceptable toxicity, patient or physician 
decision to discontinue, or death. 
Tumor assessments will be performed at baseline, every 6 weeks (± 5 days; approximately 
every two cycles) following randomization for 48 weeks, and every 9 weeks (± 5 days) 
thereafter, with additional scans as clinically indicated. Assessments will continue until disease 
progression per RECIST v1.1. Patients randomized to atezolizumab who continue to receive 
atezolizumab following disease progression will undergo assessments until treatment 
discontinuation. Tumor assessments should continue regardless of whether patients 
discontinue study treatment or start new anti-cancer therapy in the absence of disease 
progression unless they withdraw consent.  
In all patients, response will be assessed by the investigator using RECIST v1.1 until disease 
progression. Patients randomized to receive atezolizumab will additionally be assessed by 
modified RECIST criteria until treatment discontinuation.
Follow-up data capture, including subsequent anticancer therapies, will continue for each 
patient until death, withdrawal of consent, loss to follow-up, or study termination by Sponsor, 
whichever occurs first.


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Figure 1 Study Design
The primary efficacy endpoint is overall survival (OS). 
This study is event-driven, with a recruitment period of approximately 24 months. The required 
number of 380 events for the final analysis of the primary endpoint of OS is expected to occur 
approximately 42 months after the first patient has been enrolled.
One efficacy interim analysis of OS will be performed. 
An independent Data Monitoring Committee (iDMC) will be set up to evaluate safety data on 
an ongoing basis, as well as the efficacy interim analysis.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1. For additional details, see the schedule of 
assessments in Appendix 2.


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2.2
ENDPOINTS
2.2.1
Primary Efficacy Endpoint
The primary efficacy outcome measure for this study is OS, defined as the time from 
randomization to death from any cause. 
2.2.2
Secondary Efficacy Endpoints
The secondary efficacy outcome measures for this study are the following: 

OS rates at 6, 12, 18 and 24 months 

Objective Response Rate (ORR), defined as best overall response (partial response 
plus complete response, confirmation being required), as determined by the 
investigator using RECIST v1.1

Progression-Free Survival (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 

Duration of Response (DOR), defined as the time from the first occurrence of a 
documented objective response to the time of disease progression, as determined by 
the investigator using RECIST v1.1, or death from any cause, whichever occurs first 

OS and Investigator-assessed PFS according to RECIST v1.1 in patients with PD-L1 
expression defined by the SP142 and SP263 immunohistochemistry (IHC) assay
2.2.3
Safety Endpoints
The safety outcome measures for this study are the following:

Incidence, nature and severity of adverse events (AEs) based on 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 drug administration. 
2.2.4
Patient-Reported Outcome Endpoints
The patient-reported outcome (PRO) measures for this study are the following: 

Change from baseline in PROs of lung cancer symptoms, patient functioning, health-
related quality of life (HRQoL) as assessed by European Organisation for Research 
and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30)
and its supplementary Lung Cancer module (LC13) 

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 EORTC QLQ-C30 and QLQ-LC13 
2.2.5
Pharmacokinetic Endpoints
Not applicable.
2.2.6
Exploratory Endpoints
The exploratory endpoints will not be included in the CSR.
The exploratory outcome measures for this study are the following: 

ORR, PFS and DOR as determined according to modified RECIST v1.1 

Disease Control Rate (DCR) defined as the rate of patients with complete response or 
partial response as best response or stable disease as determined by the investigator 
per RECIST v1.1 




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2.4
ANALYSIS TIMING
There will be one interim OS analysis after approximatively 304 deaths have occurred, 
corresponding to 80% of the planned 380 events, expected to occur approximately 30 months 
after the first patient is randomized.
The final analysis of OS will occur when approximately 380 deaths have been observed,
expected to occur approximately 42 months after the first patient is randomized. For both 
interim and final OS analyses, the exact timing of the analysis will depend on the actual 
number and timing of OS events.
To control the Type 1 error for OS, a Lan-DeMets group sequential design with an O’Brien-
Fleming type boundary will be used (Table 2). The information fraction and stopping 
boundaries at the time of each analysis will be re-calculated using the actual number of events 
included in the analysis, and the nominal alpha level will be re-calculated accordingly so that 
the overall alpha level across both analyses is maintained at 5%.
Table 2: Timing and Stopping Boundaries for Interim and Final Analyses for 
Overall Survival
Interim and Final Analysis for OS
Analysis Timing
Time from First 
Patient in (months)
Information Fraction 
(No. of events)
Stopping Boundary 
HR (p-value¹)
Interim Analysis
30
80% (304)
0.76 (p ≤ 0.0244)
Final Analysis
42
100% (380)
0.80 (p ≤ 0.0428)
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Randomization to atezolizumab and chemotherapy arms will occur in a 2:1 ratio using 
permuted-block randomization method. Randomization will be stratified by the following 
factors: 

Histologic subtype (non-squamous vs. squamous) 

PD-L1 IHC status (positive vs. negative vs. unknown) as defined in Table 3.

Brain metastases (yes vs. no) 
Table 3: PD-L1 Status Assessed by SP142 Assay
PD-L1 IHC Positive: 
Presence of discernible PD-L1 staining of any intensity in 
tumor-infiltrating immune cells covering ≥10% of tumor 
area occupied by tumor cells, associated intratumoral, and 
contiguous peri-tumoral desmoplastic stroma (IC3) 
OR 
Presence of discernible PD-L1 staining of any intensity in 
≥ 50% tumor cells (TC3) 
PD-L1 IHC Negative: 
Presence of discernible PD-L1 staining of any intensity in 
tumor-infiltrating immune cells covering <10% of tumor 


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area occupied by tumor cells, associated intratumoral, and 
contiguous peri-tumoral desmoplastic stroma 
AND 
Presence of discernible PD-L1 staining of any intensity in 
<50% tumor cells 
PD-L1 IHC Status unknown: 
PD-L1 IHC status could not be determined (e.g. not 
enough tumor) 
3.2
INDEPENDENT REVIEW FACILITY
Not applicable.
3.3
DATA MONITORING
An iDMC will monitor study conduct and review aggregate safety data by treatment arm on a 
periodic basis. Members of the iDMC will be independent of the Sponsor and will follow a 
charter that outlines their roles and responsibilities. The iDMC will meet approximately every 
6 months from the point of first patient in (FPI) until study unblinding, to review study conduct 
and unblinded safety data prepared by an independent Data Coordinating Center (iDCC). 
Following each data review, the iDMC will provide recommendations to the Sponsor as to 
whether the study should continue as planned, or be amended, or whether the study should 
be stopped on safety grounds (i.e., evidence of harm). The Sponsor’s Data Review Board 
(DRB; a group consisting of employees of the Sponsor empowered to make critical decisions) 
will make a decision based on the iDMC’s recommendations. The final decision will rest with 
the Sponsor. 
Any outcomes of the iDMC safety reviews that affect the study conduct will be communicated 
in a timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees (IRBs/ECs). 
There is one interim analysis planned for the primary endpoint OS. The interim analysis will 
be carried out by the iDCC and provided to the iDMC. The iDMC will review these data and 
will recommend or not recommend to release the trial results and to unblind the study to the 
sponsor. The DRB of the sponsor will either accept or reject this recommendation. Details are 
specified in the iDMC charter.
4.
STATISTICAL METHODS
The analyses outlined in this SAP supersede those specified in the protocol.
4.1
ANALYSIS POPULATIONS
4.1.1
Efficacy Analysis Population
Intent-to-treat (ITT) Population: all randomized patients irrespective of whether the assigned 
treatment was actually received. For analyses on ITT, patients will be grouped according to 
the treatment assigned at randomization. The ITT population will be the population for the 
analysis of efficacy parameters.


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4.1.2
Safety-Evaluable Population
Safety-Evaluable Population: all randomized patients who received any amount of study 
treatment. For analyses on Safety-Evaluable Population, patients will be grouped according 
to whether any amount of atezolizumab was received, including the case when atezolizumab 
was received in error. The Safety-Evaluable Population will be the population for the analysis 
of safety parameters.
4.2
ANALYSIS OF STUDY CONDUCT
Study enrollment, patient disposition, reasons for discontinuation from the study treatment and 
reason for study termination will be summarized for all patients in the ITT population. 
Major protocol deviations, including violations of inclusion/exclusion criteria and deviations 
during study conduct will be reported and summarized in the ITT population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
The following analyses will be based on the ITT population.
Demographic variables such as age, sex, race/ethnicity, stratification variables and other
relevant baseline characteristics including disease history will be summarized using means, 
standard deviations (SDs), medians, ranges and inter-quartile ranges for continuous variables 
and frequencies and percentages for categorical variables, as appropriate. Summaries will be 
presented overall and by treatment arm.
The baseline value of any non-efficacy variable will be defined as the last available value 
recorded on or prior to the first administration of any study medication The baseline value of 
efficacy variable related to tumor assessment will be defined as the last available value 
recorded prior to randomization.
Previous and concurrent medical history will be summarized overall and by treatment arm.
Prior cancer therapy, prior cancer radiotherapy, prior cancer surgery, follow-up cancer therapy, 
follow-up cancer radiotherapy, on-study radiotherapy, on-study and follow-up cancer-related 
medical/surgical procedures will be summarized overall and by treatment arm. 
4.4
EFFICACY ANALYSIS
Efficacy analysis will be conducted on ITT population and presented by treatment arms
assigned at randomization, unless otherwise stated.
Hypothesis tests will be two-sided unless otherwise indicated. The overall type I error (α) for 
this study is 0.05 (two-sided). There will be no multiplicity adjustments for testing of 
secondary endpoints.  
4.4.1
Primary Efficacy Endpoint
The primary efficacy objective of this study is the comparison of OS between the two treatment 
arms (atezolizumab versus chemotherapy).
For OS, patients without a date of death will be censored on the date a patient was last known 
to be alive. If no post-baseline data are available, OS will be censored at the date of 
randomization plus 1 day.
The following analyses will be performed: 


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
Treatment comparisons will be based on the stratified log-rank test. The stratification 
factors will be the predefined randomization stratification factors: histologic subtype 
(non-squamous/squamous), PD-L1 IHC status (positive/negative/unknown) and brain 
metastases (yes/no) and will be obtained from the interactive Web/phone response 
system IxRS. 

The hazard ratio (HR) will be estimated using a stratified Cox regression model with 
the same stratification variables used for the stratified log-rank test, and the 95% CI 
for the HR will be provided. 

Kaplan-Meier methodology will be used to estimate median OS for each treatment arm 
and to construct survival curves for each treatment arm. The Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median OS for each treatment 
arm (Brookmeyer and Crowley 1982).
4.4.2
Secondary Efficacy Endpoints
4.4.2.1
OS Rate at the 6, 12, 18, 24-Months Timepoints
OS rate at 6, 12, 18 and 24 months will be estimated for each treatment arm using Kaplan-
Meier methodology, along with 95% CI calculated with the standard error derived from the 
Greenwood formula.
4.4.2.2
Objective Response Rate 
An objective response rate (ORR) is defined as a Best Overall Response (BOR) of either CR 
or PR, as determined by the investigator with use of RECIST v1.1.  Patients not meeting 
these criteria, including patients without any post-baseline tumor assessments, will be 
considered non-responders. A confirmation of response is also required.
A minimum interval of 6 weeks (42 days) will be considered for Stable Disease (SD) to be 
assigned as best overall response, i.e. in the case the single response is SD, PR or CR, this
single response must have been assessed no less than 6 weeks (at least 42 days) after start 
date of study treatment. Patients will be classified as missing or unevaluable if no post-
baseline response assessment is available or all post- baseline response baseline 
assessments are unevaluable.
An estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson method for 
each treatment arm. CIs for the difference in ORRs between the two arms will be determined 
using the normal approximation to the binomial distribution. 
The ORR will be compared between the two arms using a Chi-square test.
4.4.2.3
Progression-Free Survival
PFS is defined as the time from randomization to the first documented disease progression 
as determined by the investigator with the use of RECIST v1.1 or death from any cause, 
whichever occurs first. Data for patients who are alive and who have not experienced disease 
progression at the time of clinical cut-off date will be censored: i) at the date of the last tumor 
assessment, if post-baseline tumor assessment available, ii) at the date of randomization plus 
1 day, if no post-baseline tumor assessment available.
The same analysis as the primary analysis of OS will be repeated for PFS. 


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4.4.2.4
Duration of Response
DOR is defined as the time from the first tumor assessment that supports the patient’s 
objective response (CR or PR, whichever is first reported) to documented disease progression 
as determined by the investigator according to RECIST v1.1 or death from any cause, 
whichever occurs first, among patients who have a best overall response as CR or PR.
Patients who are alive and have not progressed at the time of clinical cut-off date 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 complete or partial response, DOR will be 
censored at the date of the first occurrence of a complete or partial response plus 1 day.
Because the determination of DOR is based on a non-randomized subset of patients, formal 
hypothesis testing will not be performed.  Comparisons between treatment arms will be made 
for descriptive purposes. The same methodologies detailed for the OS analysis will be used 
for the DOR analysis.
4.4.2.5
Overall Survival and Investigator-Assessed Progression-Free 
Survival for SP142 and SP263 PD-L1 Subpopulation
OS and investigator-assessed PFS in patients with PD L1 expression on tumor cells defined 
by the SP142 and SP263 IHC assay will be analyzed and included in the Clinical Study 
Report (CSR).  This will be analyzed through use of the same methods described for the OS 
and PFS analysis.
4.4.3
Patient-Reported Outcomes
Through the use of the EORTC QLQ-C30 and EORTC QLQ-LC13, lung cancer symptom data 
will be collected along symptoms commonly associated with cancer treatments, and disease 
and treatment impact on patients’ functioning and health-related quality of life.
The analysis of PRO measures will be conducted on ITT population, and will include all 
assessments until progressive disease as per RECIST 1.1. All assessments performed strictly 
after progressive disease as per RECIST 1.1 will only be listed. In addition, only the 
assessments within 30 days prior to the scheduled tumor assessment date will be analyzed. 
The EORTC QLQ-C30 and QLQ-LC13 data will be scored according to the EORTC scoring 
manual (Fayers 2001). Missing data will be assessed and reported by timepoint. In the event 
of incomplete data, for all questionnaire subscales, if >50% of the constituent items are 
completed, a pro-rated score will be computed consistent with the scoring manuals and 
published validation reports. For subscales with ≤50% of the items completed, the subscale 
will be considered as missing. PRO completion and compliance rates will be summarized at 
each timepoint by treatment arm on the ITT population. Summary statistics at each visit and 
change from baseline of linear-transformed scores will be reported for all the items and the 
subscales.
For analysis of functioning domains and Global Health Status/Health-related quality of life 
scale, a patient will be classified as improved if a 10-point or greater increase is observed in 
the average change from baseline scores at available timepoints for that patient. Similarly, a 
patient will be classified as worse if a decrement of 10 points or worse is observed in the 
average change from baseline scores at available timepoints for an individual patient. For 
analysis of symptom domains and single items, the classification into improved/worse 
categories is the reverse, such that a patient will be classified as improved if a decrement of 
10-point or worse is observed in the average change from baseline scores at available 
timepoints and will be classified as worse if a 10-point or greater increase is observed. For 


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analysis of symptom domains and single items, a positive change indicates worsening (i.e., 
greater symptom severity) and a negative change indicates symptom improvement. 
Improvement and worsening rates between treatments will be compared using the Chi-Square 
test. Bar Charts will be generated for both improvement and worsening separately for each 
PRO measure.  All scales for a specific PRO measure will be displayed on the same bar chart, 
as well as the two treatment arms. 
Time to Deterioration (TTD):
TTD with use of the EORTC is defined as the time from randomization to the first confirmed 
clinically meaningful deterioration in EORTC symptom scores. Confirmed clinically meaningful 
deterioration in lung cancer symptoms is defined as a ≥ 10-point increase above baseline in a 
symptom score that must be held for at least two consecutive assessments or an initial ≥ 10-
point increase above baseline followed by either (a) death within 6 weeks from the last
assessment through Week 48 or (b) death within 9 weeks from the last assessment from Week 
48 thereafter. A ≥ 10-point change in the EORTC scale score is perceived by patients as 
clinically significant (Osoba et al. 1998).
TTD will be documented for each of the following EORTC-based symptom scores: 

Cough (Question 31 on the EORTC QLQ-LC13) 

Chest pain (Question 40 on the QLQ-LC13) 

Dyspnea single item (Question 8 on the QLQ-C30) 

Dyspnea multi-item subscale (Questions 33-35 on the QLQ-LC13) 

Arm and/or shoulder pain (Question 41 on the QLQ-LC13) 

Fatigue (Questions 10, 12, 18 on the QLQ-C30) 

Composite of the 3 symptoms: cough, dyspnea (multi-item subscales QLQ-LC13) and 
chest pain
Patients who do not have an confirmed deterioration at the time of clinical data cut-off will be 
censored i) at the last non-missing assessment date if post-baseline assessment ii) on the 
date of randomization + 1 day if no post-baseline assessment.
TTD of the prespecified symptoms will be summarized using the KM method. Comparison of 
TTD using the EORTC QLQ-C30 and EORTC QLQ-LC13 measures between treatment arms 
will be performed using the stratified log-rank test; the stratified HRs and 95% CIs will also be 
reported. 
4.4.4
Exploratory Efficacy Endpoints
Results from exploratory analyses will not be included in the CSR .
4.4.4.1
ORR, PFS and DOR as Assessed by the Investigator Using 
Modified RECIST 
The endpoints assessed with modified RECIST will be limited to the atezolizumab arm. 
PFS by modified RECIST is defined as the time from randomization to disease progression 
as determined by the investigator per modified RECIST or death from any cause, whichever 
occurs first. A patient is considered to have disease progression by modified RECIST if either 
of the following conditions is met: 
a) Modified RECIST for progression is met at a tumor assessment and no subsequent 
tumor assessment is performed. 


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b) Modified RECIST for progression is met at a tumor assessment, and at the subsequent 
tumor assessment, the criteria for confirmed progression by modified RECIST are also 
met. 
For patients who meet criterion a), the date of progression is the date of the tumor assessment 
that met the criteria for progression per modified RECIST. For patients who meet criterion b), 
the date of progression is the date of the tumor assessment at which the modified RECIST for 
progression is first met. Patients who do not meet either of the above conditions are not 
considered to have disease progression by modified RECIST. 
ORR by modified RECIST is defined as the proportion of patients whose best overall response 
is either a PR or CR per modified RECIST.
DOR by modified RECIST is defined for patients who experienced an objective response (best 
overall response of CR or PR per modified RECIST) as assessed by the investigator 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 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 clinical cut-off date will be censored at the last available tumor assessment date.
Similar methodologies outlined for the primary and secondary efficacy endpoint analyses will 
be used for the analyses of PFS, ORR, and DOR as assessed by the investigator using 
modified RECIST in the experimental arm.
4.4.4.2
Disease Control Rate
Disease Control Rate (DCR) is defined as the proportion of patients with a best overall 
response, either CR or PR or SD, as determined by the investigator using RECIST v1.1
Patients not meeting this criterion, including those without any post-baseline assessment, will 
be considered non-responders. 
An estimate of DCR and its 95% CI will be calculated using the Clopper-Pearson method for 
each treatment arm. CIs for the difference in DCRs between the two arms will be determined 
using the normal approximation to the binomial distribution. The DCR will be compared 
between the two arms using a Chi-square test.
4.4.4.3
Utility scores of the EQ 5D 5L questionnaire
EQ-5D-3L data will be used to generate health status and utility scores for use in economic 
models.
4.4.5
Sensitivity Analyses
4.4.5.1
Unstratified Analysis
The primary analysis on OS, PFS, DOR and TTD will be repeated by using the unstratified 
Cox model and the unstratified log-rank test.  
4.4.5.2
Overstratification
Due to the potential risk of over-stratification (Akazawa et al. 1997), if at least 1 stratum has 
less than 10 OS events, the stratification factor which contains the level with the smallest 
number of patients will be removed from the stratified analyses and added to the next level.  


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The removal of stratification factors will continue until there is no stratum with less than 10 OS 
events in the analysis population. With the final set of stratification factors, stratified analyses 
of OS will be conducted using similar methods described in Section 4.4.1.  
4.4.5.3
Mistratification
The primary analysis on OS will be repeated by using  the stratification factors as per 
eCRF/Laboratory data. 
4.4.5.4
Imbalance between Treatment Arms
If strong baseline imbalances are observed between treatment arms, the stratified Cox 
regression analysis for OS endpoints including such prognostic factors as covariates in the 
model will be performed to investigate the potential impact of such imbalances on the 
treatment effect.
4.4.5.5
Non-Proportional Hazard 
The proportional hazards assumption will be tested with the Schoenfeld residuals. If there is 
evidence of non-proportionality, the following analysis could be conducted to assess a 
potential delayed clinical effect for atezolizumab. 
Restricted Mean Survival Time 
The restricted mean survival time (RMST) will be computed for OS using the area under the 
curve from baseline to several timepoints (defined a posteriori). RMST will be computed for 
each treatment arm and the difference with its 95% CI will be displayed (Uno 2014).
4.4.5.6
Non-Protocol-Specified Anti-Cancer Therapy
Following approval of atezolizumab in previously treated, locally advanced or metastatic 
NSCLC, and quickly evolving development of immunotherapies (IM) may lead to increased 
treatment options for patients in the NSCLC, either via trial participation or newly approved 
medicines in this class. Usage of such treatments by patients progressing on this first-line trial 
could result in biased estimate of the treatment effect on OS. To account for this possibility of 
bias the following sensitivity analyses might be conducted, if deemed appropriate:

Rank-preserving structural failure time (RPSFT) provides an estimate of the OS time 
for the control group had IM not occurred (Robins and Tsiatis 1991). It estimates OS 
measured from the time of IM by applying an estimate of the benefit of the IM. The 
total overall survival time (sum of time to IM and the estimated survival time after NPT 
started) will then be analyzed using the same methodology as for the primary analysis 
of OS. The key assumption is that all IM have the same effect, so if a patient from 
atezolizumab takes more IM the effect is assumed to be the same (not to change) from 
the one he is already carrying from atezolizumab. However, for a patient in the control 
arm, it is equivalent to a treatment switch.
4.4.5.7
Missing Tumor Assessment 
The impact of missing scheduled tumor assessments on PFS will be assessed by the following 
sensitivity analysis: 

Patients who missed two or more consecutive scheduled assessments immediately 
prior to the date of disease progression per RECIST v1.1 or death will be censored at 
the last available tumor assessment with response not ‘Not Evaluable’. Missing tumor 


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assessment will be assessment reported as ‘Not performed’ or with overall response 
as ‘Not evaluable’ on the ‘RECIST 1.1 Response Assessment’ eCRF page.
Statistical methodologies analogous to those used in the analysis of PFS as specified in 
Section 4.4.2 will be used for this sensitivity analysis.
4.4.5.8
Unconfirmed ORR
Due to possible rapid patient progression in pateints with poor performance status, Objective 
Response Rate not requiring the confirmation of response will also be analyzed. This will be 
analyzed through use of the same methods described for the ORR requiring confirmation of 
response.
4.4.6
Subgroup Analyses
The consistency of OS and PFS results in subgroups will be examined the following 
subgroups: 

PD-L1 expression by IHC (SP142 or SP263)

Demographics, including but not limited to: SLD (Median), Number of metastatic sites 
(<3 vs ≥3), age, sex and race 

Baseline disease characteristics: histologic subtype (squamous versus non-
squamous), ECOG performance status, brain metastases at baseline, liver metastases 
at baseline, smoking status 
Other subgroups might be added if deemed relevant.
Summaries of OS and PFS, including the unstratified HR estimated from a Cox proportional 
hazards model and KM estimates of median OS and PFS, will be produced separately for 
each level of the subgroup for the comparisons between both treatment arms and displayed 
in a forest plot.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Not applicable.
4.6
SAFETY ANALYSES
Safety summaries will be produced by treatment group on the Safety-Evaluable Population. 
4.6.1
Exposure of Study Medication
Given the variety of schedule assessments (various cycle length [3 versus 4 week cycles], day 
of administration etc…) and dosings for the chemotherapy, only the treatment duration will be 
summarized by treatment arm (atezolizumab versus chemotherapy). Treatment duration (as 
both continuous and categorical variables) will be summarized for each treatment arm with 
descriptive statistics. 
Number of doses received as well as number of doses missed will be summarized separately 
for each drug and each schedule. For vinorelbine, as patient might switch from one schedule 
to another during the study, the initial schedule will be used to classify a patient. For 
gemcitabine, no change of schedule is expected during the study. For vinorelbine, route at 
first administration, switch of route, switch of schedule will also be summarized.


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4.6.2
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0). Adverse events will 
be summarized by MedDRA term, appropriate MedDRA levels (system organ class [SOC] and 
preferred term [PT]), and when specified by NCI CTCAE grade. For each patient, if multiple
incidences of the same adverse events occur, the maximum severity reported will be used in 
the summaries. Only adverse events occurring on or after the first dose of any study treatment 
will be included in the summary tables of adverse events.
The following adverse events will be summarized:

AE

Common AEs (Occurring in ≥10% of patients)

AE related to study drug

AE with NCI CTCAE grade 3 and 4

AE with fatal outcome (Grade 5)

Serious AE 

Serious AE related to study drug

AE leading to discontinuation of study drug

AE leading to modification of study drug

AE of special interest (AESI)

AESI related to study drug
All deaths and causes of deaths will be summarized by treatment arm.
4.6.3
Laboratory Data
Laboratory data will be summarized descriptively over time including change from baseline by 
treatment arm. 
Laboratory data will be classified according to NCI CTCAE 4.0. Highest NCI CTCAE grade 
post-baseline will also be reported and shift tables from baseline to worst post-baseline will be 
presented by treatment arm. Values outside normal ranges will be summarized.
Potential Hy’s law patients will be listed. Potential Hy’s law cases are defined as elevated ALT 
or AST (3 ULN) with concomitant elevated total bilirubin (2 ULN)).
4.6.4
ECOG PS
ECOG PS will be summarized in a shift table of baseline versus worst post-baseline value.
4.6.5
Electrocardiogram
Electrocardiogram Abnormalities will be summarized for Screening and the worst assessment 
for the Post-Baseline visits. 
4.7
BIOMARKER ANALYSIS
Exploratory analyses for biomarker are not covered in this SAP.


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4.8
MISSING DATA
See Section Error! Reference source not found. and Section 4.4.2 for methods of handling 
missing data for the primary and secondary efficacy endpoints.    
4.9
INTERIM ANALYSES
4.9.1
Planned Interim Analysis
There will be one interim analysis of OS after 304 deaths (80% of information fraction) have 
occurred. The final analysis of OS will be conducted when 380 deaths have occurred in the 
ITT population. A group sequential design (Lan-DeMets with O’Brien-Fleming stopping 
boundaries) will be used to control the overall type I error rate (Lan and DeMets, 1983). Details 
of the timing and alpha spending function are included in Section 2.4. 
The information fraction at the time of each analysis will be re-calculated using the actual 
number of events included in the analysis, and the nominal alpha level re-calculated 
accordingly.
An iDMC will be used to evaluate interim safety data on a regular basis and interim efficacy 
data at a pre-specified timepoint. All summaries/analyses by treatment arm for the iDMC’s 
review will be prepared by an external iDCC. Members of the iDMC will be external to the 
Sponsor and will follow a charter that outlines their roles and responsibilities
4.9.2
Safety Monitoring
The iDMC will review the safety data periodically during the study. Full details are provided in 
the iDMC charter.


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5.
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Appendix 1
Protocol Version 5 Synopsis
TITLE:
A PHASE III, OPEN-LABEL, MULTICENTER, 
RANDOMIZED STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB 
COMPARED WITH CHEMOTHERAPY IN PATIENTS 
WITH TREATMENT-NAÏVE ADVANCED OR 
RECURRENT (STAGE IIIB NOT AMENABLE FOR 
MULTIMODALITY TREATMENT) OR METASTATIC 
(STAGE IV) NON-SMALL CELL LUNG CANCER WHO 
ARE DEEMED UNSUITABLE FOR PLATINUM-
CONTAINING THERAPY
PROTOCOL NUMBER:
MO29872
VERSION NUMBER:
5
EUDRACT NUMBER:
2015-004105-16
IND NUMBER:
NCT NUMBER:
Not applicable
NCT03191786
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
Phase III
INDICATION:
Non-small cell lung cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of atezolizumab compared with single agent 
chemotherapy with respect to antitumor effects in patients with treatment-naïve locally advanced or 
metastatic non-small cell lung cancer (NSCLC) who are deemed unsuitable for any platinum-doublet 
chemotherapy.  Specific objectives and corresponding endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab compared 
with single agent chemotherapy in patients with treatment-naïve locally advanced or metastatic 
NSCLC who are deemed unsuitable for any platinum-doublet chemotherapy, as measured by 
overall survival (OS).
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are: 

To evaluate the efficacy of atezolizumab compared with single agent chemotherapy as 
measured by OS rates at 6, 12, 18 and 24 months

To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with 
respect to antitumor effects as measured by investigator assessed ORR using RECIST v1.1 

To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with 
respect to antitumor effects as measured by investigator assessed progression-free survival 
(PFS) using RECIST v1.1 


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
To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with 
respect to antitumor effects as measured by investigator assessed duration of response 
(DOR) using RECIST v1.1

To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with 
respect to antitumor effects as measured by OS and Investigator-assessed PFS according 
to RECIST v1.1 in patients with PD-L1 expression defines by SP263 assay
SAFETY OBJECTIVE
The safety objective for this study is:

To evaluate the safety and tolerability of atezolizumab compared with single agent 
chemotherapy 
Patient-reported Outcome Objectives
The patient-reported outcome (PRO) objective for this study is 

To evaluate and compare PROs of lung cancer symptoms, patient functioning, and health-
related quality of life (HRQoL) between treatment arms as measured by the European 
Organisation for Research and treatment of Cancer (EORTC) Quality-of-life Questionnaire 
Core 30 (QLQ C30) and its Lung Cancer Module (QLQ LC13)  
Exploratory Objectives
The exploratory objectives for this study are:

To evaluate the efficacy of atezolizumab compared with single agent chemotherapy with 
respect to antitumor effects as measured by investigator-assessed ORR, PFS and DOR 
according to modified RECIST (immune--mediated response criteria; imRC)

To evaluate and compare investigator-assessed disease control rates (DCR) between the 
two treatment arms using RECIST v1.1

To generate utility scores for use in economic models for reimbursement by collecting 
patient’s health status data using the EuroQoL-5 Dimensions 5-level (EQ-5D-5L) 
questionnaire
Study Design
Description of Study
This is a Phase III, global, multicenter, open-label, randomized, controlled study designed to 
evaluate the efficacy and safety of atezolizumab compared with a single agent chemotherapy 
regimen by investigator choice (vinorelbine or gemcitabine) in treatment-naïve patients with locally 
advanced or metastatic NSCLC who are deemed unsuitable for any platinum-doublet chemotherapy 
due to poor performance status (Eastern Cooperative Oncology Group performance status [ECOG 
PS] of 2-3).
However, patients ≥70 years of age who have an ECOG PS of 0 or 1 may be included if they are 
deemed unsuitable for platinum doublet chemotherapy by the investigator due to:
a)
substantial comorbidities
b)
contraindication(s) for platinum-doublet chemotherapy. 
Eligible patients will be stratified by (a) histologic subtype (non-squamous vs squamous), (b) PD-L1 
immunohistochemistry (IHC) status (positive/negative/unknown) and (c) brain metastases (yes/no) 
and then randomized at a 2:1 ratio to receive either atezolizumab or single agent chemotherapy. 
Eligible patients must therefore provide a tumor tissue specimen for central assessment of PD-L1 
expression by IHC at a central laboratory.  The study will enroll all patients whose tissue is evaluable 
for PD-L1 analysis, regardless of PD-L1 expression status.  
Given the unique toxicities associated with chemotherapy (i.e., alopecia, neutropenia, febrile 
neutropenia) and the pre-medications required (i.e., steroid, anti-emetics, and potentially growth 
factor support), this will be an open-label study.
No crossover will be allowed between treatment arms.
Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-
day cycle. 
Patients randomized to receive single agent chemotherapy (vinorelbine [oral or intravenous] or 
gemcitabine [intravenous]), based on investigator’s choice will receive chemotherapy per relevant 
local guidelines and summary of product characteristics (SmPC) management.  Doses and dose 


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modifications for the selected single agent chemotherapy should be made per relevant local 
guidelines and SmPC management.  
At any time-point after RECIST v1.1 criteria for progressive disease are met, patients in the 
experimental arm who show evidence of clinical benefit, will be permitted to continue treatment with 
atezolizumab if they meet all of the following criteria:

Evidence of clinical benefit (i.e., in the absence of symptomatic deterioration attributed to 
disease progression as determined by the investigator after an integrated assessment of 
radiographic data, biopsy results [if available], clinical status, and of laboratory values) 

Absence of unacceptable toxicity  

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 for whom approved therapies exist must provide written consent to acknowledge 
deferring these treatment options in favor of continuing study treatment at the time of initial 
progression. 
Tumor assessments will be performed at baseline, every 6 weeks (± 5 days) following randomization 
for 48 weeks, and every 9 weeks (± 5 days) thereafter, with additional scans as clinically indicated. 
Assessments will continue until disease progression per RECIST v1.1. Patients randomized to 
atezolizumab who continue to receive atezolizumab following disease progression will undergo 
tumor assessments until treatment discontinuation. Tumor assessments should continue regardless 
of whether patients discontinue study treatment or start new anti-cancer therapy in the absence of 
disease progression unless they withdraw consent.
In all patients, response will be assessed by the investigator using RECIST v1 until disease 
progression.  Patients randomized to receive atezolizumab will additionally be assessed by modified 
RECIST criteria until treatment discontinuation.  
Follow-up data capture, including subsequent anticancer therapies, will continue for each patient 
until death, withdrawal of consent, loss to follow up, or study termination by Sponsor, whichever 
occurs first.
In addition to PD-L1 analysis, exploratory research will be performed on histological tumor tissue 
samples pre-treatment.  
Patients will undergo blood sample collection for exploratory biomarker analyses using plasma and 
PBMCs as per schedule of assessments. 
Tissue and plasma samples will be analyzed for example by methods like IHC, quantitative reverse 
transcriptase PCR (qRT-PCR), next-generation sequencing (NGS) and/or other methods to study  
tumor biomarkers and changes thereof on DNA, RNA and/or protein (or other analytes).  These 
exploratory biomarker evaluations will not be used for any treatment-related decisions.  Exploratory 
analyses aim to study tumor-associated alterations to further understand disease pathobiology 
(including but not limited to mechanisms of disease progression, pseudo-progression, acquired 
resistance), to evaluate surrogate biomarkers and to potentially allow for the development of
blood-based and tissue-based diagnostic tests to help predict which patients may benefit from 
atezolizumab.
Primary imaging data used for tumor assessment may be collected by the Sponsor to enable 
centralized, independent review of response endpoints, if needed.  
Safety assessments will include the incidence, nature, and severity of adverse events and laboratory 
abnormalities graded per the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v4.0 and assessed by immune mediated adverse events (imAEs) and immune 
mediated adverse reactions (imARs) methods.  Laboratory safety assessments will include the 
regular monitoring of hematology and blood chemistry. An external independent Data Monitoring 
Committee (iDMC) will be assembled and will be responsible for monitoring the safety of patients in 
the study in accordance with a pre specified iDMC charter.  
During the study, assessments will be performed according to the Schedule of Assessments.
Number of Patients
Approximately 120 sites globally will participate in the study, and 441 patients are expected to be 
randomized.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:


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1.
Signed Informed Consent Form
2.
Male or female, age  ≥18 years
3.
Able to comply with the study protocol, in the investigator’s judgment
4.
Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not 
amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American 
Joint Committee on Cancer (AJCC) 7th edition 
5.
No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 19 deletions) 
or anaplastic lymphoma kinase (ALK) fusion oncogene detected
6.
No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for 
multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th edition 
7.
Life expectancy ≥8 weeks
8.
Deemed unsuitable for any platinum-doublet chemotherapy by the investigator due to poor 
performance status (ECOG PS of 2-3)

However, patients ≥70 years of age who have an ECOG PS of 0 or 1 may be included due 
to:
a)
substantial comorbidities
b)
contraindication(s) for any platinum-doublet chemotherapy
9.
Representative formalin-fixed paraffin-embedded (FPPE) tumor tissue block obtained during 
course of disease (archival tissue) or at screening (tumor blocks are highly preferred for central 
analysis of PD-L1 expression and exploratory biomarkers) 
10. Patients with treated, asymptomatic central nervous system (CNS) metastases are eligible, 
provided they meet all of the following criteria:
a)
Measurable disease outside CNS
b)
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla or spinal cord)
c)
No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants 
at a stable dose allowed
d)
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
randomization
e)
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study

Patients with new asymptomatic CNS metastases detected at the screening scan 
must receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior to 
randomization, if all other criteria are met, including clinical confirmation of no evidence of 
interim disease progression.
11. Measurable disease (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.
12. Adequate hematologic and end organ function, defined by the following laboratory results
obtained within 14 days prior to randomization:
a)
Absolute neutrophil count (ANC) ≥1500 cells/µL without granulocyte colony-stimulating 
factor support 
b)
White blood cell (WBC) counts > 2500/µL
c)
Lymphocyte count ≥500/µL
d)
Serum albumin ≥2.5 g/dL
e)
Platelet count ≥100,000/µL without transfusion (without transfusion within 2 weeks of 
laboratory test used to determine eligibility)
f)
Hemoglobin ≥9.0 g/dL, patients may be transfused or receive erythropoietic treatment to 
meet this criterion


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g)
International normalized ratio (INR) or activated partial thromboplastin time (aPTT) 
≤1.5 × upper limit of normal (ULN).  This applies only to patients who are not receiving 
therapeutic anticoagulation; patients receiving therapeutic anticoagulation must have an INR 
or aPTT within therapeutic limits for at least 1 week prior to randomization
h)
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline 
phosphatase ≤2.5 × ULN with the following exceptions: 
o
Patients with documented liver metastases: AST and/or ALT ≤5 × ULN
o
Patients with documented liver or bone metastases: alkaline phosphatase 
≤5 × ULN
i)
Serum bilirubin ≤ 1.5 × ULN.  Patients with known Gilbert’s syndrome who have serum 
bilirubin level ≤ 3 × ULN may be enrolled 
j)
Serum creatinine ≤1.5 × ULN
13. For female patients of childbearing potential randomized to the atezolizumab treatment arm: 
agreement (by patient and/or partner) to remain abstinent (refrain from heterosexual 
intercourse) or to use highly effective form(s) of contraceptive methods that result in a failure 
rate of < 1% per year when used consistently and correctly during the treatment period and for 
at least 5 months after the last dose of atezolizumab.
o
A woman is considered to be of childbearing potential if she is postmenarchal, 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).
o
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, and established, proper use of hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
o
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 
adequate methods of contraception.
14. Female patients of childbearing potential and male patients with partners of childbearing 
potential treated in the comparative single agent chemotherapy arm should continue 
contraception use for at least 6 months after the last dose of study treatment.  Such methods 
include: combined (estrogen and progestogen containing) hormonal contraception, 
progestogen-only hormonal contraception associated with inhibition of ovulation together with 
another additional barrier method always containing a spermicide, intrauterine device (IUD): 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on 
the understanding that this is the only one partner during the whole study duration), and sexual 
abstinence. Male patients should not donate sperm during this study and for at least 6 months 
after the last dose of comparative single agent chemotherapy treatment. 
o
Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drug.  The same rules are valid for male 
patients involved in this clinical study if they have a partner of childbirth potential. Male 
patients must always use a condom. 
15. Women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Cancer-Specific Exclusion Criteria
1.
Patients younger than 70 years who have an ECOG PS of 0 or 1.
2.
Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic 
resonance imaging (MRI) evaluation of the brain during screening and prior radiographic 
assessments
a)
Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for > 2 weeks prior to randomization
b)
Leptomeningeal disease


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c)
History of CNS metastases intracranial haemorrhage 
3.
Uncontrolled tumor-related pain
a)
Patients requiring pain medication must be on a stable regimen at study entry.
b)
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment. Patients 
should have recovered from the effects of radiation. There is no required minimum recovery 
period.
c)
Asymptomatic metastatic lesions whose further growth would likely cause functional deficits 
or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord 
compression) should be considered for loco-regional therapy if appropriate prior to 
enrollment.
4.
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.
5.
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L or 
calcium > 12 mg/dL or corrected serum calcium > ULN) 
6.
History of other malignancy within 5 years prior to screening, 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 with curative intent, breast ductal 
carcinoma in situ treated surgically with curative intent) 
7.
NCI CTCAE (v4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) 
(excluding alopecia), which have not shown improvement and are strictly considered to interfere 
with current study medication
8.
Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or 
chemoradiotherapy with curative intent for non-metastatic disease must have experienced a 
treatment-free interval of at least 6 months from randomization since the last chemotherapy, 
radiotherapy, or chemoradiotherapy

General Medical Exclusion Criteria
9.
Women who are pregnant or lactating, or intending to become pregnant during the study.  
Women of childbearing potential including women who have had a tubal ligation, must have a 
negative serum pregnancy test result within 14 days prior to initiation of study drug
10. 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
o
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-
replacement hormone may be eligible for this study
o
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study
11. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions:
a)
Rash must cover less than 10% of body surface area (BSA)
b)
Disease is well controlled at baseline and only requiring low potency topical steroids
c)
No acute exacerbations of underlying condition within the last 12 months requiring treatment 
with either psoralen plus ultraviolet radiation (PUVA), methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors or high potency or oral steroids
12. History of idiopathic pulmonary fibrosis (IPF), 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
13. Known positivity for human immunodeficiency virus (HIV)


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o
Testing is not required in the absence of clinical symptoms and signs suggestive of HIV 
infection.
o
Patients with a past history of/or symptoms of HIV are eligible only if serological tests are 
negative.
14. Known active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) or known active hepatitis C  
o
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 test must be performed in these patients prior to randomization.  Patients positive for 
hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for 
HCV RNA
15. Active tuberculosis
16. Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia
17. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to randomization, 
unstable arrhythmias, or unstable angina  
o
Patients with known coronary artery disease, congestive heart failure not meeting the above 
criteria, or left ventricular ejection fraction (LVEF) < 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
18. Major surgical procedure other than for diagnosis within 4 weeks prior to randomization or 
anticipation of need for a major surgical procedure during the course of the study
19. Prior allogeneic bone marrow transplantation or solid organ transplant
20. Any serious medical condition (including metabolic dysfunction, physical examination finding) or 
abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the 
patient’s safe participation in and completion of the study or that may affect the interpretation of 
the results or render the patient at high risk for treatment complications
21. Patients with an illness or condition that may interfere with capacity or compliance  with the 
study protocol, as per investigator's judgment 
22. Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 28 days prior to randomization

Exclusion Criteria Related to Atezolizumab
23. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins
24. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any 
component of the atezolizumab formulation
25. Oral or IV antibiotic treatment.  Patients will thus need to have recovered from any infection 
requiring antibiotics.  Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary 
tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
26. 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
o
Influenza vaccination is allowed, but should be given during influenza season.  However, 
patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks 
prior to randomization, at any time during the study or within 5 months after the last 
atezolizumab dose
27. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
anti-programmed death−1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies.  Patients who 
have had prior anti-cytotoxic T lymphocyte−associated antigen 4 (CTLA-4) treatment may be 
enrolled, provided the following requirements are met:
a)
Minimum of 6 weeks from the last dose of anti−CTLA-4
b)
No history of severe immune mediated adverse effects from anti-CTLA-4 (NCI CTCAE 
Grade 3 and 4)


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28. Treatment with systemic immunostimulatory agents (including but not limited to interferons, 
interleukin-2 [IL-2]) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to 
randomization  
29. Treatment with systemic corticosteroids or other immunosuppressive medications (including but 
not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) 
o
Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after 
discussion with and approval by the Medical Monitor.
o
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.
o
Patients with history of allergic reaction to IV contrast requiring steroid pre-treatment should 
have baseline and subsequent tumor assessments done by MRI.
30. Patients not willing to stop treatment with traditional herbal medicines

Exclusion Criteria Related to Chemotherapy
31. Known sensitivity and contraindications to the 2 comparative chemotherapy agents, i.e. 
vinorelbine (oral or intravenous) and gemcitabine (intravenous)
End of Study and Length of Study
This study is event-driven, with a recruitment period of approximately 24 months.  The required 
number of 380 events for the final analysis of the primary endpoint of OS is expected to occur 
approximately 42 months after the first patient has been enrolled.
For patients randomized to the atezolizumab treatment arm, treatment may continue beyond 
disease progression per RECIST v1.1 until loss of clinical benefit, unacceptable toxicity, patient or 
physician decision to discontinue, or death.  For all patients, tumor response data collection will 
continue until disease progression, even if the patient stops study treatment prior to disease 
progression.  Patients randomized to receive atezolizumab who continue study treatment after 
disease progression continue to undergo tumor assessments until treatment discontinuation. Follow-
up data capture, including subsequent anticancer therapies, will continue for each patient until 
death, withdrawal of consent, loss to follow-up, or study termination by Sponsor, whichever occurs 
first. 
The end of the study is when the required number of deaths has been observed. Additionally, the 
Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
Test Product (Investigational Drug)
Atezolizumab, at a dose of 1200 mg, will be administered by IV infusion every 21 days.
Comparators
Single agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]) based on 
investigator’s choice will be administered per relevant local guidelines and SmPC management.  
Doses and dose modifications for the selected single agent chemotherapy should be made per 
relevant local guidelines and SmPC management.   
Statistical Methods
Primary Analysis
The primary efficacy analysis is the comparison of OS between the two treatment arms 
(atezolizumab arm and single agent chemotherapy arm). 
For OS, patients without a date of death will be censored on the date a patient was last known to be 
alive. If no post-baseline data are available, OS will be censored at the date of randomization plus 1 
day.
The null and alternative hypotheses for OS analysis can be phrased in terms of comparison of 
survival function S(t) for the two treatment arms: 
Ho: Schemo(t) =SAtezo(t) vs 
H1: Schemo(t) ≠SAtezo(t).
The hazard ratio (HR) will be estimated using a stratified Cox regression model including 
95% confidence intervals (CIs).  The stratification factors will be: histologic subtype 


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(non-squamous/squamous), PD-L1 IHC status (positive/negative/unknown) and brain metastases 
(yes/no).
An unstratified analysis will also be performed. 
Kaplan-Meier methodology will be used to construct survival curves by treatment arms.  The median 
OS and corresponding 95%CI will be provided for each treatment arm.  
If non proportionality of HR is detected, then further analyses and tests will be run. Further details on 
this scenario will be provided in the statistical Analysis Plan (SAP).
Determination of Sample Size  
.  Assuming a 10% withdrawal rate and accrual duration of 24 months, approximately 441 patients 
will be randomized in a 2:1 ratio to atezolizumab (294 patients) or chemotherapy (147 patients). A 
total of 380 OS events will provide 90% power to detect a significant improvement in the primary 
endpoint (median OS) for treatment with atezolizumab versus chemotherapy from 7 months to 10 
months (i.e. HR of 0.7) for a two-sided log-rank test at an alpha level of 5%.  There is one planned 
interim analysis at 304 OS events. Operating characteristics (power and expected total number of 
events) for true underlying hazard ratio values of 0.7 are provided in the table below.  
Sample Size Calculation Parameters
    Values
Randomization ratio (Atezolizumab vs Chemotherapy)
2:1
Type 1 error (2-sided)
5%
Power
90%
Accrual duration
24 months
Duration until OS interim analysis
30 months
Duration until OS final analysis
42 months
Drop-out rate
10%
Median Control
7 months
Median Atezolizumab
10 months
Hazard ratio
0.7
Number of events at interim analysis
304
Number of events at final analysis
380
Number of patients
441
Note:  This is assuming validity of proportional Hazards assumption. 
Interim Analyses
An interim analysis of OS will be performed when approximately 304 events in the ITT population 
have been reached. A group sequential design (Lan-DeMets with O’Brien-Fleming stopping 
boundaries) will be used to control the overall type I error rate (Lan and DeMets 1983).
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 planned interim analysis, along with the rationale, timing, and statistical 
details for the analysis, will be documented in the SAP.  The iDMC charter will document potential 
recommendations the iDMC can make to the Sponsor as a result of the analysis and the iDMC 
charter will also be made available to relevant health authorities, if applicable.


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Appendix 2
Schedule of Assessments
Screening 
Period a
Treatment Period w
Treatment 
Discontinuation b
Follow-Up 
Period c
Assessment Window (Days)
Day –28 to 
Day –1
Baseline 
(Cycle 1 Day 1)
Cycles ≥2 
(Day 1 ± 5 days)
≤ 30 Days after 
Last Dose
-
Signed Informed Consent Form(s) a
x
Tumor Tissue for ALK/EGFR 
analysis, central PD-L1 IHC 
(stratification) and exploratory 
biomarkers d
x
Review of eligibility criteria
x
Medical, surgical, and cancer 
histories, including demographic 
information, EGFR, and ALK 
mutational status e
x
HIV, HBV, HCV serology f
x y
TSH, free T3 (or total T3), free T4 g
x y
x
Cycles 5, 9, 13 etc.
x
Concomitant medications h
x
x
x
x
Tumor response assessments i
x i  
x x
Patient-reported outcomes j
x
With tumor response assessments z
Complete physical examination k
x
x
Limited physical examination k
x
x
ECOG performance status l
x
x
x m
x
Vital signs n
x
x
x
x
12-lead electrocardiogram o
x
x
x
x
Hematology p
x y
x
x
x
Serum chemistry q
x y
x
x
x
Urinalysis r
x y
x
x
x


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Screening 
Period a
Treatment Period w
Treatment 
Discontinuation b
Follow-Up 
Period c
Assessment Window (Days)
Day –28 to 
Day –1
Baseline 
(Cycle 1 Day 1)
Cycles ≥2 
(Day 1 ± 5 days)
≤ 30 Days after 
Last Dose
-
Pregnancy test s
x y
Prior to each treatment cycle
x
x s
Coagulation (INR, aPTT) 
x y
x
Whole blood for PBMC  (exploratory 
biomarker) t
x
Plasma for exploratory biomarkers u
x
Week 7 and at PD 
Adverse events / adverse events of 
special interest v
x
x
x
x v
Study drug administration w
x
x
Survival and anticancer therapy 
follow-up c
x
ALK = anaplastic lymphoma kinase; ECG = electrocardiogram; EGFR = epidermal growth factor receptor; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus, IHC = immunhistochemistry; PBMC = peripheral blood mononuclear cell; PD = disease progression; 
PD-L1 = programmed cell death-ligand 1; q3w = every 3 weeks; TSH = thyroid-stimulating hormone; T3 = free triiodothyronine; T4 = free thyroxine.
Note:  All assessments should be performed within ± 5 days of the scheduled visit, unless otherwise specified.
a
Written informed consent is required for performing any study-specific tests or procedures. Signing of the Informed Consent Form can occur outside the 28-day screening 
period. Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to study entry (except where otherwise 
specified) may be used for screening assessments rather than repeating such tests.
b
Patients who discontinue study drug will return to the clinic for a treatment discontinuation visit ≤30 days after the last dose of study drug.  The visit at which the decision is 
made to discontinue treatment (e.g., disease progression is determined or confirmed) may be used as the treatment discontinuation visit. After study drug discontinuation, 
patients will be treated at the discretion of the investigator according to local practice. The decision to continue treatment with atezolizumab (experimental arm only) beyond 
disease progression (RECIST v.1.1) is at the investigator’s discretion for patients who can continue to benefit from the treatment (for criteria see protocol Section 3.1).
c
Required follow-up information, including subsequent anticancer therapies and any treatment related AEs, will be collected via telephone calls and/or clinic visits every 
2 months (± 5 days) until death, withdrawal of consent, loss to follow-up, study termination by the Sponsor, or protocol-defined end of study, whichever comes first.  In case 
of serious side effects during the study, follow-up examinations at the study site may be required. 


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d
Screening: A representative formalin-fixed paraffin-embedded (FPPE) tumor tissue block obtained during course of disease (archival tissue) or screening (tumor blocks are 
highly preferred; ideally, 3 cores should be submitted in case smaller core biopsies are available in order to have sufficient tumor cells available.  In case the tumor block is 
not available, 10-15 unstained, consecutive slides not older than 60 days will be accepted.  A minimum of five slides is mandated for PD-L1 analysis and patient 
stratification.  If archival tissue (most recent sample) is unavailable, a pretreatment tumor biopsy is required.  Cytological or fine-needle aspiration samples are not 
acceptable.  Tumor tissue from bone metastases or are not acceptable.  Tumor tissue should be of good quality based on total and viable tumor content (at least 300 viable 
tumor cells across cores are needed for determination of TC/IC status at low cut-offs).  
e
Cancer history includes stage, date of diagnosis, results of EGFR mutation and ALK rearrangement testing (if available), and prior antitumor treatment. Demographic 
information includes sex, age, and self-reported race/ethnicity.  Patients with non-squamous NSCLC and unknown EGFR or ALK status will be required to be tested at 
pre-screening/screening.  Patients with squamous NSCLC and unknown EGFR or ALK status will not be required to be tested at pre-screening/ screening, except for 
patients who are never smokers or have mixed histology.  EGFR and/or ALK may be assessed locally or at a central lab.  Additional tissue will be required for central testing 
of EGFR and/or ALK.  An FFPE tumor tissue block (or at least 7 slides) will be required for testing.
f
Patients with a history of, or signs of active HIV or hepatitis B/C disease must be tested for seropositivity prior to the inclusion into the study. HIV-positive patients will be 
excluded from the clinical study. Patients with a positive hepatitis B surface antigen [HBsAg] test at screening will be excluded from this clinical study. Patients positive for 
hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.  
g
TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening, on Day 1 of Cycle 1 and every four cycles thereafter (i.e., 
Cycles 5, 9, 13, etc.).
h
Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 days prior to 
screening until the treatment discontinuation visit. All such medications should be reported to the investigator, and must be recorded on the appropriate Concomitant 
Medications eCRF. 
i
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.  It is 
recommended to have the screening/baseline tumor assessment done within 14 days before randomization, as close as possible to baseline.  All measurable and evaluable 
lesions should be assessed and documented at the screening visit. 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). Results must be reviewed by the investigator before dosing at the next cycle. All patients should undergo a brain 
scan at Screening. Patients with CNS metastases newly detected at the screening scan should have received 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, including clinical 
confirmation of no evidence of interim disease progression..  
j
PRO assessments (EORTC QLQ-C30, QLQ-LC13, and EQ-5D-5L) will be completed before the patient receives any information on disease status and prior to the 
performance of non-PRO assessments and the administration of study treatment.  Study personnel should review all questionnaires for completeness before the patient 
leaves the investigational site. 
k
Complete and limited physical examinations are defined in protocol Section 4.5.3.
l
ECOG performance status, limited physical examination, local laboratory assessments may be obtained ≤96 hours before Day 1 of each cycle.
m ECOG PS is mandatory at all timepoints. 
n
Includes height, weight, respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature, an evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, (or as clinically indicated), limited, symptom-


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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 AE eCRF.
o
ECG recordings will be obtained during screening and as clinically indicated at other timepoints. .ECG recordings will be obtained as described in protocol Section 4.5.9.
p
Hematology includes complete blood count [CBC], including red blood cell count [RBC] count, hemoglobin, hematocrit, white blood cell (WBC) count with differential 
[neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells], and platelet count 
q
Serum chemistry panel (serum or plasma) includes glucose, blood urea nitrogen [BUN] or urea, creatinine, sodium, potassium, chloride, bicarbonate or  total carbon dioxide 
(if considered standard of care for the region), calcium, phosphorus, total and direct bilirubin, ALT, AST, alkaline phosphatase, uric acid, LDH, total protein, and albumin.
r
Dipstick permitted: pH, specific gravity, glucose, protein, ketones, blood.
s
A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative within 14 
days prior to Day 1.  On study pregnancy tests must be performed prior to each treatment cycle (21 day cycle for atezolizumab and per relevant local guidelines and SmPC 
management for chemotherapy) while receiving the IMP.  For female patients of childbearing potential, the pregnancy tests will be repeated during the treatment 
discontinuation visit and then every 2 months during follow-up for at least 5 months after the last dose of atezolizumab and for at least 6 months after the last dose of 
chemotherapy, respectively.  Pregnancy tests during follow-up do not require on-site visits; results from a treating physician can be used. The pregnancy test can be 
conducted with serum or urine.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
t
18 mL whole blood (ACD tubes) should be obtained pre-dose and shipped to the central laboratory for PBMC preparation, RNA isolation and gene expression analysis. 
Details are specified in a separate laboratory manual. If consented, residual material will be transferred to RBR.
u
20 mL whole blood (K3 EDTA tubes) for preparation of plasma should be obtained pre-dose. Plasma samples will be shipped to the central laboratory for exploratory 
biomarker analyses. If consented, residual material (including extracted RNA or DNA or other) will be transferred to RBR.
v
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 protocol Section 5.4.2 for instructions for reporting serious adverse events).  After 
initiation of study drug, all serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days after the last 
dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of relationship to study drug, will be reported until 30 
days after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  After these respective periods, investigators should report any deaths, 
serious adverse events, or other adverse events of concern that are believed to be related to prior treatment with study drug, regardless of time after study (see protocol 
Section 5.6 ).  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 
trial-related procedures until a final outcome can be reported.
w Atezolizumab at a fixed dose of 1200 mg will be administered intravenously at the study site on Day 1 of each 21-day cycle. Single agent chemotherapy (vinorelbine, oral or 
intravenous, or gemcitabine) will be administered per relevant local guidelines and SmPC management.  Chemotherapy cycles may be 3-weekly or 4-weekly.  A 28-day 
assessment schedule will be followed for patients receiving 4-weekly chemotherapy cycles. 
x
Tumor assessments will be performed at baseline, every 6 weeks (± 5 days) following randomization for 48 weeks, and every 9 weeks (± 5 days) thereafter, regardless of 
dose delays, with additional scans as clinically indicated, until radiographic disease progression per RECIST v1.1 or (for patients who continue atezolizumab after 
radiographic disease progression), loss of clinical benefit as determined by the investigator (see protocol Section 3.1.1 for details).  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue study treatment for reasons other than disease progression or loss of clinical benefit, even if patients start new 
anti-cancer therapy.  In all patients, response will be assessed by the investigator using RECIST v1.1 until disease progression. Patients randomized to receive 


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atezolizumab will additionally be assessed by modified RECIST criteria until treatment discontinuation.  Follow-up tumor assessments are not required after discontinuation 
of atezolizumab for patients continuing atezolizumab beyond PD.
y
Screening laboratory test results must be obtained within 14 days prior to initiation of study treatment.
z
The EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L questionnaires will be completed by the patients with each tumor assessment until disease progression per 
RECIST v1.1, even if patients discontinue study treatment for any reason other than progressive disease or loss of clinical benefit.