A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Atezolizumab Plus Carboplatin and Etoposide With or Without Tiragolumab in Patients With Untreated Extensive-Stage Small Cell Lung Cancer
Phase: PHASE3
Conditions: Small Cell Lung Carcinoma
Sponsor: Hoffmann-La Roche

Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of 
Atezolizumab Plus Carboplatin and Etoposide With or Without 
Tiragolumab in Patients With Untreated Extensive-Stage Small Cell 
Lung Cancer (Skyscraper-02C) 
NCT Number: 
NCT04665856 
Document Date: 
Protocol Version 6: 14-Dec-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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol YO42373, Version 6 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB PLUS CARBOPLATIN AND 
ETOPOSIDE WITH OR WITHOUT TIRAGOLUMAB 
IN PATIENTS WITH UNTREATED  
EXTENSIVE-STAGE SMALL CELL LUNG CANCER 
(SKYSCRAPER-02C) 
PROTOCOL NUMBER: YO42373 
VERSION NUMBER: 
6 
TEST PRODUCTS: 
Tiragolumab (RO7092284) 
Atezolizumab (RO5541267) 
STUDY PHASE 
Phase III 
REGULATORY 
AGENCY 
IDENTIFIERS 
EudraCT Number:  Not applicable 
IND Number: 129258 
NCT Number:  NCT04665856 
SPONSOR'S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol YO42373, Version 6 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
6 
See electronic date stamp on the final 
page of this document. 
5 
13 December 2022 
4 
19 October 2021 
3 
7 December 2020 
2 
13 August 2020 
1 
7 May 2020 

 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol YO42373, Version 6 
PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
Protocol YO42373 (Version 6) has primarily been amended to update the risks and 
management guidelines for atezolizumab to align with the latest Atezolizumab 
Investigator's Brochure, Version 20, and to clarify assessments that are no longer 
required after the clinical cutoff date for primary analysis.  Changes to the protocol, along 
with a rationale for each change, are summarized below: 
 
The synopsis has been simplified as per internal Sponsor's guidelines. 
 
The list of approved indications for atezolizumab has been updated to include 
alveolar soft part sarcoma (Section 1.3). 
 
A section describing duration of participation has been added as per internal 
Sponsor's guidelines (Section 3.3). 
 
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). 
 
Text has been updated to indicate study sites will acknowledge receipt of 
investigational medicinal products supplied by the Sponsor by returning the 
appropriate documentation form to confirm the shipment condition and content 
instead of using the IxRS (Section 4.3.3). 
 
Text has been updated to clarify which procedures or assessments are no longer 
required after the clinical cutoff date for primary analysis.  After this, no further data 
collection and analysis relating to these assessments is required for this study 
(Sections 4.5.6, 4.5.9, 4.6.1, 4.6.2, and Appendices 1 and 2). 
 
Serum samples for assessment of anti-drug antibodies to atezolizumab has been 
removed because it has been tested in several studies in China and the Center for 
Drug Evaluation of National Products Administration has endorsed removing the 
testing (Section 4.5.7). 
 
Text has been updated to correct the reference to Appendix 14 regarding 
 
 
It has been made explicit that expedited safety reports are notified to EudraVigilance 
(Section 5.7). 
 
The adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator's Brochure, Version 20 (Appendix 14). 
 
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. 

 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol YO42373, Version 6 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND ............................................................................ 20 
1.1 
Background on Lung Cancer ................................................... 20 
1.2 
First-Line Treatment for Extensive-Stage Small Cell Lung 
Cancer ..................................................................................... 20 
1.3 
Background of Atezolizumab ................................................... 21 
1.4 
Background on Tiragolumab .................................................... 21 
1.4.1 
Background on Blockade of the TIGIT Pathway as a 
Potential Anti-Cancer Therapy ................................................. 22 
1.4.1.1 
Summary of Nonclinical Data for Blockade of the TIGIT 
Pathway ................................................................................... 23 
1.4.1.2 
Summary of Clinical Data for Inhibition of TIGIT ...................... 24 
1.4.1.3 
Summary of Clinical Data for Combined Inhibition of TIGIT 
and PD-L1/PD-1 Pathways ...................................................... 24 
1.5 
Study Rationale and BenefitRisk Assessment ....................... 27 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 31 
2.1 
Efficacy Objectives .................................................................. 31 
2.1.1 
Primary Efficacy Objective ....................................................... 31 
2.1.2 
Secondary Efficacy Objective .................................................. 31 
2.1.3 
Exploratory Efficacy Objective ................................................. 32 
2.2 
Safety Objectives ..................................................................... 32 
2.3 
Pharmacokinetic Objective ...................................................... 32 
2.4 
Immunogenicity Objectives ...................................................... 33 
2.5 
Exploratory Biomarker Objective ............................................. 33 
3. 
STUDY DESIGN ........................................................................... 33 
3.1 
Description of the Study ........................................................... 33 
3.1.1 
Overview of Study Design........................................................ 33 
3.1.2 
Treatment after Disease Progression ...................................... 37 
3.1.3 
Independent Data Monitoring Committee ................................ 37 
3.2 
End of Study and Length of Study ........................................... 38 

 
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3.3 
Duration of Participation ....................................................... 38 
3.4 
Rationale for Study Design ...................................................... 38 
3.4.1 
Rationale for Tiragolumab Dose and Schedule ....................... 38 
3.4.2 
Rationale for Control Arm ........................................................ 39 
3.4.3 
Rationale for Evaluation of Patients without Brain 
Metastases at Baseline (Primary Analysis Set for 
Statistical Analysis) .................................................................. 39 
3.4.4 
Rationale for Progression-Free Survival and Overall 
Survival as Co-Primary Endpoints ........................................... 40 
3.4.5 
Rationale for Tiragolumab and/or Atezolizumab Treatment 
beyond Initial Radiographic Disease Progression .................... 40 
3.4.6 
Rationale for Patient-Reported Outcome Assessments ........... 41 
3.4.7 
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens ............................................................................... 41 
4. 
MATERIALS AND METHODS ...................................................... 42 
4.1 
Patients .................................................................................... 42 
4.1.1 
Inclusion Criteria ...................................................................... 42 
4.1.2 
Exclusion Criteria ..................................................................... 45 
4.2 
Method of Treatment Assignment and Blinding ....................... 48 
4.2.1 
Treatment Assignment ............................................................. 48 
4.2.2 
Blinding .................................................................................... 49 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 50 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 50 
4.3.1.1 
Tiragolumab and Placebo ........................................................ 50 
4.3.1.2 
Atezolizumab ........................................................................... 50 
4.3.1.3 
Carboplatin and Etoposide....................................................... 50 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 51 
4.3.2.1 
Atezolizumab ........................................................................... 52 
4.3.2.2 
Tiragolumab/Placebo ............................................................... 52 
4.3.2.3 
Atezolizumab and Tiragolumab/Placebo ................................. 55 
4.3.2.4 
Carboplatin and Etoposide....................................................... 55 
4.3.3 
Investigational Medicinal Product Accountability ..................... 57 
4.3.4 
Continued Access to Tiragolumab and/or Atezolizumab ......... 58 

 
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4.4 
Concomitant Therapy .............................................................. 58 
4.4.1 
Permitted Therapy ................................................................... 58 
4.4.2 
Cautionary Therapy for Tiragolumab- and/or 
Atezolizumab-Treated Patients ................................................ 59 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors ......................................... 59 
4.4.2.2 
Herbal Therapies ..................................................................... 60 
4.4.3 
Prohibited Therapy .................................................................. 60 
4.5 
Study Assessments ................................................................. 60 
4.5.1 
Informed Consent Forms and Screening Log .......................... 61 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 61 
4.5.3 
Physical Examinations ............................................................. 62 
4.5.4 
Vital Signs ................................................................................ 62 
4.5.5 
Performance Status ................................................................. 62 
4.5.6 
Tumor and Response Evaluations ........................................... 63 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 65 
4.5.8 
Electrocardiograms .................................................................. 68 
4.5.9 
Clinical Outcome Assessments ............................................... 68 
4.5.9.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 68 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments ....... 70 
4.6 
Patient, Treatment, Study, and Site Discontinuation ................ 71 
4.6.1 
Study Treatment Discontinuation ............................................. 71 
4.6.2 
Patient Discontinuation from the Study .................................... 72 
4.6.3 
Study Discontinuation .............................................................. 73 
4.6.4 
Site Discontinuation ................................................................. 73 
5. 
ASSESSMENT OF SAFETY ......................................................... 73 
5.1 
Safety Plan .............................................................................. 73 
5.1.1 
Risks Associated with Tiragolumab ......................................... 74 
5.1.1.1 
Infusion-Related Reactions ...................................................... 74 
................................................... 75 
5.1.1.3 
Immune-Mediated Adverse Events .......................................... 75 
........................................................................ 75 

 
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5.1.1.5 
Embryofetal Toxicity ................................................................ 76 
5.1.2 
Risks Associated with Atezolizumab ........................................ 76 
5.1.3 
Risks Associated with Combination Use of Tiragolumab 
and Atezolizumab .................................................................... 76 
5.1.4 
Risks Associated with Etoposide ............................................. 77 
5.1.5 
Risks Associated with Carboplatin ........................................... 77 
5.1.6 
Management of Patients Who Experience Adverse Events ..... 77 
5.1.6.1 
Dose Modification .................................................................... 77 
5.1.6.2 
Tiragolumab and/or Atezolizumab Dose Modification, 
Treatment Interruption, or Treatment Discontinuation ............. 78 
5.1.6.3 
Management Guidelines for Adverse Events Associated 
with Tiragolumab, Placebo, and Atezolizumab ........................ 79 
5.1.6.4 
Chemotherapy Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events ........................................................................ 80 
5.1.7 
Potential Overlapping Toxicities ............................................... 80 
5.2 
Safety Parameters and Definitions .......................................... 81 
5.2.1 
Adverse Events ........................................................................ 81 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 82 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 82 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 83 
5.3.1 
Adverse Event Reporting Period .............................................. 84 
5.3.2 
Eliciting Adverse Event Information ......................................... 84 
5.3.3 
Assessment of Severity of Adverse Events ............................. 85 
5.3.4 
Assessment of Causality of Adverse Events............................ 87 
5.3.5 
Procedures for Recording Adverse Events .............................. 87 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release 
Syndrome ................................................................................ 88 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 88 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 89 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 89 
5.3.5.5 
Abnormal Laboratory Values ................................................... 89 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 90 

 
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5.3.5.7 
Abnormal Liver Function Tests ................................................ 91 
5.3.5.8 
Deaths ..................................................................................... 91 
5.3.5.9 
Preexisting Medical Conditions ................................................ 92 
5.3.5.10 
Lack of Efficacy or Worsening of SCLC ................................... 92 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 92 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ................. 93 
5.3.5.13 
Patient-Reported Outcome Data .............................................. 94 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 94 
5.4.1 
Medical Monitor and Emergency Medical Contact ................... 95 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 95 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 95 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 95 
5.4.3 
Reporting Requirements for Pregnancies ................................ 96 
5.4.3.1 
Pregnancies in Female Patients .............................................. 96 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 96 
5.4.3.3 
Abortions.................................................................................. 97 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 97 
5.5 
Follow-Up of Patients after Adverse Events............................. 97 
5.5.1 
Investigator Follow-Up ............................................................. 97 
5.5.2 
Sponsor Follow-Up .................................................................. 97 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 98 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 98 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 99 
6.1 
Determination of Sample Size ................................................. 99 
6.1.1 
Co-Primary Endpoint:  Progression-Free Survival in the 
Primary Analysis Set ................................................................ 99 
6.1.2 
Co-Primary Endpoint:  Overall Survival in the Primary 
Analysis Set ........................................................................... 100 
6.2 
Summaries of Conduct of Study ............................................ 101 
6.3 
Summaries of Treatment Group Comparability ...................... 101 

 
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6.4 
Efficacy Analyses ................................................................... 101 
6.4.1 
Co-Primary Efficacy Endpoints .............................................. 101 
6.4.2 
Secondary Efficacy Endpoints ............................................... 102 
6.4.2.1 
Progression-Free Survival and Overall Survival in the Full 
Analysis Set ........................................................................... 102 
6.4.2.2 
Objective Response Rate ...................................................... 102 
6.4.2.3 
Duration of Response ............................................................ 103 
6.4.2.4 
Patient-Reported Outcomes .................................................. 103 
6.5 
Safety Analyses ..................................................................... 104 
6.6 
Pharmacokinetic Analyses ..................................................... 104 
6.7 
Immunogenicity Analyses ...................................................... 105 
6.8 
Biomarker Analyses ............................................................... 105 
6.9 
Exploratory Analyses ............................................................. 105 
...................... 105 
...................... 105 
6.9.1.2 
Safety Monitoring ................................................................... 105 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 106 
7.1 
Data Quality Assurance ......................................................... 106 
7.2 
Electronic Case Report Forms ............................................... 106 
7.3 
Source Data Documentation .................................................. 106 
7.4 
Use of Computerized Systems .............................................. 107 
7.5 
Retention of Records ............................................................. 107 
8. 
ETHICAL CONSIDERATIONS .................................................... 108 
8.1 
Compliance with Laws and Regulations ................................ 108 
8.2 
Informed Consent .................................................................. 108 
8.3 
Institutional Review Board or Ethics Committee .................... 109 
8.4 
Confidentiality ........................................................................ 109 
8.5 
Financial Disclosure ............................................................... 110 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 110 
9.1 
Study Documentation ............................................................ 110 
9.2 
Protocol Deviations ................................................................ 111 
9.3 
Management of Study Quality ................................................ 111 

 
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9.4 
Site Inspections ..................................................................... 111 
9.5 
Administrative Structure ......................................................... 111 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 112 
9.7 
Protocol Amendments ........................................................... 113 
10. 
REFERENCES............................................................................ 114 
 
 
LIST OF TABLES 
Table 1 
Study YO42373 Treatment Arms ................................................ 35 
Table 2 
Administration of First and Subsequent Atezolizumab and 
Tiragolumab/Placebo Infusions ................................................... 53 
Table 3 
Treatment Regimen for Carboplatin and Etoposide .................... 55 
Table 4 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 85 
Table 5 
ASTCT CRS Consensus Grading ............................................... 86 
Table 6 
Causal Attribution Guidance ....................................................... 87 
. 100 
. 100 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 34 
 

 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 119 
... 125 
Appendix 3 
Veterans Administration Lung Study Group (VALG) Staging 
System for SCLC ...................................................................... 126 
Appendix 4 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) ........................................................................... 127 
Appendix 5 
Modified RECIST v1.1 for Immune-Based Therapeutics 
(iRECIST)
............................................................... 136 
............................................................... 140 
............................................................... 142 
............................................................... 143 
Appendix 9 
EuroQol EQ-5D-5L .................................................................... 145 
Appendix 10 
Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 148 
Appendix 11 
Anaphylaxis Precautions ........................................................... 149 
Appendix 12 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 150 
Appendix 13 
Overall Guidelines for Management of Patients Who 
Experience Adverse Events ...................................................... 151 
Appendix 14 
Risks Associated with Tiragolumab or Atezolizumab and 
Guidelines for Management of Adverse Events Associated 
with Tiragolumab or Atezolizumab ............................................ 155 
 

 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol YO42373, Version 6 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF 
ATEZOLIZUMAB PLUS CARBOPLATIN AND 
ETOPOSIDE WITH OR WITHOUT TIRAGOLUMAB 
IN PATIENTS WITH UNTREATED  
EXTENSIVE-STAGE SMALL CELL LUNG CANCER 
(SKYSCRAPER-02C) 
PROTOCOL NUMBER: YO42373 
VERSION NUMBER: 
6 
TEST PRODUCTS: 
Tiragolumab (RO7092284) 
Atezolizumab (RO5541267) 
SPONSOR NAME: 
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 of 
the signed form to the Sponsor or their designee. 
 

 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol YO42373, Version 6 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB PLUS 
CARBOPLATIN AND ETOPOSIDE WITH OR WITHOUT 
TIRAGOLUMAB IN PATIENTS WITH UNTREATED 
EXTENSIVE-STAGE SMALL CELL LUNG CANCER 
(SKYSCRAPER-02C) 
REGULATORY 
AGENCY 
IDENTIFIERS 
EudraCT Number:  Not applicable 
IND Number: 129258 
NCT Number:  NCT04665856 
 
STUDY RATIONALE 
The purpose of this study is to evaluate whether the anti-tumor effect of standard of care 
combination of atezolizumab plus carboplatin and etoposide (CE) can be enhanced by adding 
tiragolumab in patients with untreated extensive-stage small cell lung cancer (ES-SCLC).  
Patients with SCLC frequently present with symptoms of widespread metastatic disease and 
may experience fast clinical deterioration; therefore, there is a need for rapid treatment 
initiation for these patients. 
OBJECTIVES AND ENDPOINTS 
 
Primary Efficacy Objective 
Corresponding Endpoints  
 Evaluate the efficacy of tiragolumab 
plus atezolizumab and CE compared 
with placebo plus atezolizumab and 
CE in patients with untreated 
ES-SCLC 
 PFS defined as the time from randomization to the 
first occurrence of disease progression, as 
determined by the investigator according to 
RECIST v1.1, or death from any cause 
(whichever occurs first), in randomized patients 
without presence or history of brain metastases at 
baseline (PAS) 
 OS, defined as the time from randomization to 
death from any cause in the PAS 
CE = carboplatin and etoposide; ES-SCLC = extensive-stage small cell lung cancer; OS  = overall 
survival; PAS = primary analysis set; PFS = progression-free survival; RECIST v1.1  = Response 
Evaluation Criteria in Solid Tumors, Version 1.1. 

 
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Secondary Objective 
Corresponding Endpoints 
 Evaluate the efficacy of tiragolumab 
plus atezolizumab and CE compared 
with placebo plus atezolizumab 
and CE 
 PFS in the FAS 
 OS in the FAS 
 Confirmed ORR, defined as the proportion of 
patients with a complete response or partial 
response on two consecutive occasions  4 weeks 
apart, as determined by the investigator according 
to RECIST v1.1 in the PAS and the FAS who have 
measurable disease at baseline 
 DOR for patients with confirmed objective 
response, defined as the time from the first 
occurrence of a documented objective response to 
disease progression as determined by the 
investigator according to RECIST v1.1 or death 
from any cause, whichever occurs first, in the PAS 
and the FAS 
 PFS rates at 6 months and at 12 months, defined as 
the proportion of patients who have not experienced 
disease progression as determined by the 
investigator according to RECIST v1.1 or death 
from any cause at 6 and 12 months in the PAS and 
the FAS 
 OS rates at 12 months and 24 months, defined as 
the proportion of patients who have not experienced 
death from any cause at 12 and 24 months in the 
PAS and the FAS 
 TTCD in patient reported physical functioning and 
global health status, as measured by the respective 
scales of the EORTC QLQ-C30 in the PAS and 
the FAS 
Safety Objective 
Corresponding Endpoint 
 Evaluate the safety of tiragolumab 
plus atezolizumab and CE compared 
with placebo plus atezolizumab 
and CE 
 Incidence and severity of adverse events, with 
severity determined according to NCI CTCAE v5.0 
o 
Severity for cytokine-release syndrome will 
also be determined according to the American 
Society for Transplantation and Cellular 
Therapy consensus grading scale 
CE = carboplatin and etoposide; DOR  = duration of response; EORTC QLQ-C30 = European 
Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire Core; 
FAS = full analysis set; NCI CTCAE v5.0  = National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0; OS  = overall survival; ORR = objective response rate; 
PAS = primary analysis set; PFS = progression-free survival; RECIST v1.1  = Response 
Evaluation Criteria in Solid Tumors, Version 1.1; TTCD = time to confirmed deterioration. 

 
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Pharmacokinetic Objective 
Corresponding Endpoint 
 Characterize the pharmacokinetics of 
tiragolumab and atezolizumab 
 Serum concentration of tiragolumab and 
atezolizumab at specified timepoints 
Immunogenicity Objective 
Corresponding Endpoint 
 Evaluate the immune response to 
tiragolumab 
 Prevalence of ADAs to tiragolumab at baseline and 
incidence of ADAs to tiragolumab during the study 
ADAs = anti-drug antibodies. 
 
OVERALL DESIGN AND STUDY POPULATION 
This is a Phase III, randomized, double-blind, placebo-controlled multicenter study in China 
designed to evaluate the safety and efficacy of tiragolumab plus atezolizumab and CE 
compared with placebo plus atezolizumab and CE in patients with chemotherapy-naive 
ES-SCLC. 
Several key aspects of the study design and study population are summarized below.  
Phase: 
Phase III 
Population Type: 
Adult patients 
Control Method: 
Placebo 
Population Diagnosis 
or Condition: 
Extensive-stage small 
cell lung cancer 
Interventional 
Model: 
Parallel group 
Population Age: 
 18 years 
Test Products: 
Tiragolumab 
Atezolizumab 
Site Distribution: 
Multi-site 
Active Comparator: Not applicable 
Study Treatment 
Assignment Method: 
Randomization and 
stratification 
Number of Arms: 
2 
Number of 
Participants to Be 
Enrolled: 
Approximately 128 
 
STUDY TREATMENT 
On Day 1 of each 21-day cycle, all eligible patients will be administered infusion of study 
treatments in the following order: 
 
Induction (Cycles 1–4):  
Arm A:  atezolizumab  tiragolumab  carboplatin  etoposide 
Arm B:  atezolizumab  placebo  carboplatin  etoposide 
 
Maintenance (Cycles 5  +): 
Arm A:  atezolizumab  tiragolumab 
Arm B:  atezolizumab  placebo 
 
For Cycle 1, premedication administered for atezolizumab, or tiragolumab/placebo is not 
permitted.  Patients should receive anti emetics and IV hydration for carboplatin and 
etoposide according to the local standard of care and manufacturer’s instruction.  However, 
because of the immunomodulatory effects of corticosteroids, premedication with 
corticosteroids should be minimized to the extent that is clinically feasible. 

 
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During the induction phase, study treatment should be administered in the following manner 
on Day 1: 
1. 
Atezolizumab 1200 mg administered intravenously over 60 (± 15) minutes (for the first 
infusion and shortening to 30 [± 10] minutes for subsequent infusions), followed by 
2. 
Tiragolumab/placebo 600 mg administered intravenously over 60 (± 15) minutes (for the 
first infusion and shortening to 30 [± 10] minutes for subsequent infusions), followed by 
3. 
Carboplatin administered intravenously over 30-60 minutes to achieve an initial target 
area under the concentration-time curve of 5 mg/mL/min (Calvert formula dosing), 
followed by 
4. 
Etoposide (100 mg/m2) administered intravenously over 60 minutes 
 
During the induction phase, etoposide (100 mg/m2) will be also administered intravenously 
over 60 minutes on Days 2 and 3. 
Cycles in which no chemotherapy is given do not count toward the total number of induction 
chemotherapy cycles. 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to range from 1 day 
to more than 18 months. 
COMMITTEES 
Independent Committees: Independent Data Monitoring Committee 
Other Committees: 
Not applicable 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
1L 
first-line 
ADA 
anti-drug antibody 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ASTCT 
American Society for Transplantation and Cellular Therapy  
AUC 
area under the concentrationtime curve 
CCOD 
clinical cutoff date 
CE 
carboplatin and etoposide 
CHO 
Chinese hamster ovary 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CrCl 
creatinine clearance 
CRS 
cytokine-release syndrome  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EAE 
experimental autoimmune encephalitis 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EQ-5D-5L 
EuroQol 5-Dimension, 5-Level Questionnaire 
ES-SCLC 
extensive-stage small cell lung cancer 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GHS 
global health status 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HGRAC 
Human Genetic Resources Administration of China 
HCV 
hepatitis C virus 

 
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Abbreviation 
Definition 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IFN 
interferon 
IHC 
immunohistochemistry 
IL 
interleukin 
IL46 
Item List 46 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
iRECIST 
Modified RECIST v1.1 for Immune-Based Therapeutics 
IxRS 
interactive voice or web-based response system 
MAb 
monoclonal antibody 
MAS 
macrophage activation syndrome 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute  
NK 
natural killer 
NPT 
nonprotocol-specified anti-cancer therapy 
NSCLC 
nonsmall cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PCI 
prophylactic cranial irradiation 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PE 
polyethylene  
PFS 
progression-free survival 
PK 
pharmacokinetic 
PAS 
primary analysis set 
PR 
partial response 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events 
PVR 
poliovirus receptor 
Q3W 
every 3 weeks 
QLQ-C30 
Quality-of-Life Questionnaire Core 30 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 

 
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Abbreviation 
Definition 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCLC 
small cell lung cancer 
SITC 
Society for Immunotherapy for Cancer 
TC 
tumor cell 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
TNF 
tumor necrosis factor 
TPS 
tumor proportion score 
TSH 
thyroid-stimulating hormone 
TTCD 
time to confirmed deterioration 
ULN 
upper limit of normal 
VALG 
Veterans Administration Lung Study Group 
VCA 
viral capsid antigen 
 
 
 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON LUNG CANCER 
Lung cancer remains the leading cause of cancer deaths worldwide.  It is the most 
common form of cancer in both men and women with an estimated diagnosis of 
2.1 million new case and 1.8 million deaths in 2018 (Bray et al. 2018).  In China, there 
were an estimated 509,300 new cases of lung cancer and 432,400 lung cancer deaths 
in 2015 (Chen et al. 2015). 
Nonsmall cell lung cancer (NSCLC) comprises approximately 85% of all cases of lung 
cancer (Molina et al. 2008; Howlader et al. 2014).  Small cell lung cancer (SCLC) 
accounts for approximately 15% of all cases and is distinguished from NSCLC by its 
rapid growth rate and early development of metastatic disease (Govindan et al. 2006).  
Nearly all cases of SCLC are attributable to cigarette smoking (Pesch et al. 2012).  
Poor prognostic factors for survival in patients with SCLC include extensive-stage 
disease, poor performance status, weight loss, and markers associated with excessive 
bulk of disease, such as LDH (Yip et al. 2000; Foster et al. 2009).  
1.2 
FIRST-LINE TREATMENT FOR EXTENSIVE-STAGE SMALL 
CELL LUNG CANCER 
Patients with limited-stage SCLC can be treated with chemotherapy and radiation with 
the potential for long-term survival (Stinchcombe and Gore 2010), though a majority will 
relapse.  Approximately 70% of patients with SCLC are diagnosed with extensive-stage 
disease (ES-SCLC), which has poor survival prospects with chemotherapy (median 
overall survival [OS] approximately 10 months) (Socinski et al. 2009).  Most recently, 
immune checkpoint inhibitors have demonstrated clinical activity in ES-SCLC in several 
different studies, particularly in the first-line (1L) setting, which have advanced the OS to 
more than one year for patients with ES-SCLC (Horn et al. 2018; Paz-Ares, et al. 2019). 
The current standard 1L treatment for patients with ES-SCLC consists of an immune 
checkpoint inhibitor, including PD-L1 blocking antibodies, with platinum-based 
chemotherapy consisting of carboplatin and etoposide (CE) as induction therapy for 
4 cycles, followed by atezolizumab maintenance therapy (National Comprehensive 
Cancer Network [NCCN] 2019).  In the randomized Phase III Study GO30081 
(IMpower133) of 403 enrolled patients, OS and progression-free survival (PFS) were 
improved with atezolizumab plus CE compared to placebo plus CE in patients with 
untreated ES-SCLC.  The hazard ratio (HR) for death was 0.70 (95% CI: 0.54, 0.91; 
p  0.007) with a median OS of 12.3 months in the atezolizumab plus CE group 
compared to 10.3 months in the placebo plus CE group.  The HR for PFS was 0.77 
(95% CI: 0.62, 0.96; p  0.02) with a median PFS of 5.2 months and 4.3 months for 
atezolizumab plus CE and placebo plus CE, respectively.  The safety profile of 
atezolizumab plus CE was consistent with the previously reported safety profile of the 
individual agents, with no new findings observed (Horn et al. 2018). 

 
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Similar to Study GO30081 (IMpower133), the Phase III CASPIAN trial evaluated 
durvalumab, a human checkpoint inhibitor antibody that inhibits PD-L1.  Durvalumab in 
combination with etoposide-platinum chemotherapy met its primary endpoint with an 
improved median OS of 13.0 months (95% CI: 11.5, 14.8) compared to 10.3 months 
(95% CI: 9.3, 11.2) with chemotherapy alone, translating to a 27% reduction in the risk of 
death with a HR of 0.73 (95% CI: 0.591, 0.909; p  0.0047) (Paz-Ares et al, 2019). 
Despite these advances, the majority of patients with ES-SCLC progress on currently 
available treatment options, and upon relapse, they ultimately succumb to the disease.  
Therefore, high unmet medical need persists for novel strategies to deliver better 
long-term survival.  The addition of complementary immunomodulatory agents to the 
current treatment backbone is an appealing strategy to further improve the prognosis of 
patients with advanced SCLC. 
1.3 
BACKGROUND OF ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients, 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab has been approved by some health authorities for the treatment of 
urothelial carcinoma, NSCLC, SCLC, triple-negative breast cancer, hepatocellular 
carcinoma, melanoma, and alveolar soft part sarcoma.  
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies for atezolizumab. 
1.4 
BACKGROUND ON TIRAGOLUMAB 
Tiragolumab is a fully human IgG1/kappa monoclonal antibody (MAb) that binds TIGIT 
(T-cell Immunoreceptor with Immunoglobulin [Ig] and Immunoreceptor Tyrosine-Based 
Inhibition Motif [ITIM] domains) and prevents its interaction with poliovirus receptor 
(PVR).  The recombinant antibody is produced in Chinese hamster ovary (CHO) cells 
and consists of two heavy chains (456 amino acid residues each) and two light chains 
(220 amino acid residues each).  There are two N-linked glycosylation sites (Asn306) in 

 
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the Fc domain.  The predicted molecular weight of tiragolumab is 148,409 Da 
(peptide chains only, without heavy chain C-terminal lysine residue). 
Therapeutic blockade of TIGIT by tiragolumab represents an attractive strategy for 
cancer therapy and is expected to enhance the magnitude and quality of the 
tumor-specific T-cell responses, which may result in improved meaningful anti-tumor 
activity when tiragolumab is used as a single agent or in combination with other cancer 
immunotherapies.  The available nonclinical and clinical data provide a strong rationale 
for evaluating the potential clinical benefit of tiragolumab in cancer patients. 
Please refer to the Tiragolumab Investigator's Brochure for additional details on the 
nonclinical and clinical studies for tiragolumab. 
1.4.1 
Background on Blockade of the TIGIT Pathway as a Potential 
Anti-Cancer Therapy 
The inhibitory immunoreceptor TIGIT has been shown to limit the effector function of 
tumor-associated lymphocytes.  TIGIT is an immunoglobulin super family member 
expressed on subsets of activated T cells and natural killer (NK) cells, and found highly 
expressed in tumor tissue and in immune cells in many human cancers.  In multiple 
tumor types, TIGIT is coordinately expressed with PD-1 (Yu et al. 2009; Johnston et al. 
2014; Manieri et al. 2017).  Genetic ablation or antibody blockade of TIGIT has been 
shown to enhance NK-cell killing, CD4  and CD8 T-cell activation, and effector function 
in vitro and in vivo in nonclinical models (Stanietsky et al. 2009; Yu et al. 2009; Joller 
et al. 2011; Johnston et al. 2014).  In the nonclinical tumor models, TIGIT interacted with 
high affinity to CD155 (also known as PVR), which also has an activating 
counter-receptor CD226.  Activation of TIGIT on T cells and NK cells limits proliferation, 
effector cytokine production, and killing of target tumor cells (TC) (Stanietsky et al. 2009; 
Yu et al. 2009; Johnston et al. 2014; Wang et al. 2015; Manieri et al. 2017).  These 
studies identify TIGIT as an important immune checkpoint inhibitor that functionally limits 
chronically activated CD8  T cells and tumor-infiltrating lymphocytes. 
Similarly, TIGIT and PD-1 are expressed on CD8   tumor-infiltrating lymphocytes in 
SCLC (Xu et al. 2019).  The TIGIT ligand PVR is broadly expressed in SCLC cell lines 
and tumor samples (Yu et al. 2018a, 2018b; Xu et al. 2019).  PVR is predominantly 
present on the membrane of TCs, and 79% of SCLC patients express PVR with a tumor 
positivity score  50% (Yu et al. 2018a). 
Therefore, TIGIT may be a promising target for therapeutic intervention aimed at 
restoring the immune response against the tumor.  Therapeutic blockade of TIGIT may 
relieve an important source of tumor-associated immune suppression and may enhance 
the activity of other immune-based therapies, such as atezolizumab.  Early nonclinical 
results using genetically deficient mice and blocking antibodies reveal a key role for 
TIGIT in regulating T-cell responses.  Together, these data support the hypothesis that 

 
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anti-TIGIT treatment in combination with antiPD-L1 treatment may reactivate anti-tumor 
immunity in SCLC, which may lead to clinical benefit for patients. 
1.4.1.1 
Summary of Nonclinical Data for Blockade of the TIGIT 
Pathway 
The nonclinical strategy for tiragolumab was to demonstrate in vitro and in vivo 
pharmacology, to evaluate the pharmacokinetic (PK) profile, to demonstrate an 
acceptable safety profile, and to identify a Phase Ia and Phase Ib starting dose for 
tiragolumab.  Comprehensive pharmacology, PK, and toxicology evaluations were thus 
undertaken with tiragolumab. 
The completed nonclinical pharmacology studies demonstrate that tiragolumab binds 
TIGIT and prevents TIGIT/PVR interactions.  Tiragolumab is a human IgG1 MAb and 
therefore binds to Fc receptors and is capable of mediating antibody-dependent 
cell-mediated cytotoxicity (ADCC).  However, neither complement-dependent cytotoxicity 
nor increased cytokine release was detected in the nonclinical models following 
tiragolumab treatment when compared with the control-treated models.  In the CT26 
syngeneic colon tumor model, co-inhibition of the TIGIT/PVR and PD-L1/PD-1 pathways 
improves anti-tumor activity when compared with inhibition of only one pathway with 
either monotherapy in the absence of body weight loss or any other observable adverse 
responses.  Taken together, these data provide a rationale for evaluating the 
combination of anti-TIGIT with antiPD-L1 in clinical studies (Johnston et al. 2014). 
Because tiragolumab does not cross-react with rodent TIGIT, the pharmacokinetics and 
toxicokinetics of tiragolumab were investigated in cynomolgus monkeys.  Overall, the 
nonclinical PK behavior observed for tiragolumab is consistent with that expected for 
a receptor-targeting human IgG1 MAb.  The pivotal repeat-dose toxicity study 
demonstrated that weekly IV administration of tiragolumab at dose levels up to 
100 mg/kg for 1 month (for a total of 5 doses) was well tolerated in cynomolgus 
monkeys, and no findings were directly attributed to tiragolumab administration.  On the 
basis of the proposed mechanism of action of tiragolumab, possible safety risks to 
patients following TIGIT/PVR pathway inhibition include heightened immune responses 
and the potential to increase the frequency and/or the severity of immune-associated 
inflammatory lesions.  These potential effects are considered to be monitorable and are 
expected to be manageable (see Section 5.1 for the safety plan). 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for tiragolumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical studies. 
Please refer to the Tiragolumab Investigator's Brochure for additional details on 
nonclinical studies. 

 
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1.4.1.2 
Summary of Clinical Data for Inhibition of TIGIT 
Phase Ia Study GO30103  
In the Phase Ia/Ib, dose-escalation and dose-expansion study (GO30103) tiragolumab 
was administered alone and in combination with atezolizumab to patients with locally 
advanced, recurrent, or metastatic incurable tumors to evaluate the safety, tolerability, 
immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and preliminary 
evidence of biologic activity. 
Preliminary clinical efficacy data from the Phase I Study GO30103 is available as of 
2 December 2019.  In the Phase Ia portion of Study GO30103, there were no complete 
or partial responses (PRs) per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. RECIST best overall response of stable disease was observed in 8 of 
42 patients with post-baseline tumor assessments at tiragolumab dose levels of 8 mg 
(n  1/4 enrolled), 100 mg (n  2/4), 400 mg (n  4/14), and 1200 mg (n  1/9). 
As of 2 December 2019, 41 of 42 patients (97.6%) in the Phase Ia portion of 
Study GO30103 had reported at least one adverse event regardless of attribution to 
study drug.  A total of 43 adverse events reported in 23 patients (54.8%) were assessed 
by the investigator to be related to tiragolumab in the Phase Ia portion of the study.  
The most common related adverse events reported in  5% of patients include 
fatigue, infusion-related reaction (IRR), pruritus (5 patients each; 11.9%), and rash 
(4 patients; 9.5%). 
Please refer to the Tiragolumab Investigator's Brochure for additional details on best 
overall response of stable disease, PK analysis, and the adverse events observed in 
patients treated with single-agent tiragolumab. 
1.4.1.3 
Summary of Clinical Data for Combined Inhibition of TIGIT and 
PD-L1/PD-1 Pathways 
The combined inhibition of the TIGIT and PD-L1/PD-1 pathways by tiragolumab and 
atezolizumab, respectively, has demonstrated promising clinical activity in the Phase Ib 
portion of Study GO30103 and the Phase II Study CITYSCAPE (GO40290). 
Phase Ib Study GO30103  
In the Phase Ib portion of Study GO30103, complete response was observed in 4 of 
171 patients at tiragolumab dose levels of 400 mg (n  3/48) and 600 mg (n  1/79) in 
combination with 1200 mg atezolizumab.  Partial response was observed in 23 of 
171 patients at tiragolumab dose levels of 30 mg (n  2/13), 400 mg (n  6/48), and 
600 mg (n  15/79) in combination with 1200 mg atezolizumab, including two patients 
who crossed over from the Phase Ia portion at the 600 mg dose level.  Stable disease 
was observed in 39 of 171 patients at tiragolumab dose levels of 2 mg (n  1/8), 8 mg 
(n  3/12), 30 mg (n  2/13), 100 mg (n  3/8), 400 mg (n  12/48), 600 mg (n  17/79), and 
1200 mg (n  1/3) in combination with 1200 mg atezolizumab, including 8 patients who 

 
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crossed over from the Phase Ia portion (2 at 8 mg, 1 at 30 mg, 2 at 100 mg, and 
3 at 400 mg). 
As of 2 December 2019, 163 of 170 patients (95.9%) in the Phase Ib portion of 
Study GO30103 had reported at least one adverse event regardless of attribution to 
study drug.  A total of 364 adverse events reported in 110 patients (64.7%) were 
assessed by the investigator to be related to the study drug(s) (tiragolumab and/or 
atezolizumab) in the Phase Ib portion of the study.  The most common related adverse 
events reported in  5% of patients include pruritus (28 patients; 16.5%), rash 
(23 patients; 13.5%), hypothyroidism (14 patients; 8.2%), asthenia and pyrexia 
(12 patients each; 7.1%), IRR (11 patients; 6.5%), myalgia (10 patients; 5.9%), and 
fatigue, lymphocyte count decrease, and arthralgia (9 patients each; 5.3%). 
As of 2 December 2019, no dose-limiting toxicity (DLTs), as defined in the study 
protocol, have been reported for patients enrolled in either the Phase Ia or Phase Ib 
portions of Study GO30103. 
As of 2 December 2019, a preliminary PK analysis was conducted based on 
available data from Study GO30103 (2 to 1200 mg every 3 weeks [Q3W] tiragolumab 
administered as a single-agent [Phase Ia] and in combination with 1200 mg Q3W 
atezolizumab [Phase Ib]) using standard non-compartmental PK methods.  Tiragolumab 
exposures increased in an approximately dose-proportional manner both as a 
single-agent and in combination with atezolizumab.  In addition, the PK of tiragolumab in 
combination with atezolizumab appeared to be consistent with the PK of tiragolumab 
administered as a single-agent. 
Preliminary population-PK analyses show that tiragolumab exposures increased 
approximately dose-proportionally following IV administration at doses ranging from 
100 to 1200 mg Q3W as monotherapy or in combination with 1200 mg Q3W 
atezolizumab. 
Preliminary population-PK analysis estimated tiragolumab clearance at 0.28 L/day with 
a linear drug elimination half-life of approximately 15 days. 
Please refer to the Tiragolumab Investigator's Brochure for additional details on best 
overall response of stable disease, PK analysis using standard non-compartmental 
PK methods, and the adverse events observed in patients treated with single-agent 
tiragolumab and tiragolumab plus atezolizumab. 
Please refer to the Atezolizumab Investigator's Brochure for details on the clinical 
pharmacokinetics of atezolizumab. 

 
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Phase II Study CITYSCAPE (GO40290) 
The combination of tiragolumab plus atezolizumab is being investigated further in 
Study GO40290 (CITYSCAPE), an ongoing Phase II, global, multicenter, randomized, 
blinded, placebo-controlled trial.  This study was designed to evaluate the safety and 
efficacy of tiragolumab plus atezolizumab compared with placebo plus atezolizumab in 
patients with previously untreated, locally advanced, unresectable or metastatic 
PD-L1selected (tumor proportion score [TPS]  1%) NSCLC without a sensitizing 
epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) 
rearrangement.   
Patients were eligible if they were  18 years old with an Eastern Cooperative Oncology 
Group (ECOG) Performance Status of 0 or 1 and PD-L1selected NSCLC.  Patients 
were stratified by the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay result 
(TPS 1%49% vs. TPS  50%), tumor histology (non-squamous vs. squamous), and 
patient's history of tobacco use (yes vs. no). 
As of the primary clinical cutoff date (CCOD) of 30 June 2019, a total of 135 patients 
with a PD-L1 TPS  1% (22C3) by local analysis were included in the intent-to-treat (ITT) 
population and were randomly assigned to tiragolumab plus atezolizumab (n  67) or 
placebo plus atezolizumab (n  68).  The three stratification factors were well balanced 
between treatment groups.  Of the enrolled patients, 43% had a TPS  50% versus 57% 
of patients with a TPS 1%49%; 59.3% had non-squamous histology versus 40.7% of 
patients who had squamous histology; and 10.4% were never-smokers versus 89.6% of 
patients who had smoked. 
Demographics were generally well balanced between treatment groups as well, with 
a median age of 68 years in both the tiragolumab plus atezolizumab and placebo plus 
atezolizumab groups.  There were more females (41.8% vs. 29.4%) and more White 
patients (62.7% vs. 58.8%) in the tiragolumab plus atezolizumab group compared with 
the placebo plus atezolizumab group. 
As of the primary CCOD of 30 June 2019, the confirmed objective response rate (ORR) 
in the ITT population was higher in the tiragolumab plus atezolizumab arm (31.3%) than 
in the placebo plus atezolizumab arm (16.2%).  Investigator-assessed PFS was also 
improved with a stratified HR of 0.57 (95% CI: 0.37, 0.90) with a median PFS not 
estimable and 3.9 months in the tiragolumab plus atezolizumab arm compared to the 
placebo plus atezolizumab arm, respectively.  Responses to tiragolumab plus 
atezolizumab arm were observed in patients with both squamous and non-squamous 
histology.  In the ITT population, 47.8% of patients in the tiragolumab plus atezolizumab 
group versus 27.9% of patients in the placebo plus atezolizumab group were still 
receiving study treatment.  In the TPS  50% population, 65.5% of patients in the 
tiragolumab plus atezolizumab group versus 24.1% of patients in the placebo plus 
atezolizumab group were still receiving study treatment. 

 
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The safety profile assessed as of the CCOD of 30 June 2019 was comparable 
between the tiragolumab plus atezolizumab arm and the placebo plus atezolizumab 
arm for all grades of adverse events (98.5% vs. 95.6%), Grade  3 adverse events 
(41.8% vs. 44.1%), Grade 5 adverse events (3.0% vs. 7.4%), serious adverse events 
(34.3% vs. 35.3%), and adverse events leading to study treatment withdrawal 
(7.5% vs. 10.3%).  Study treatment-related adverse events occurred at a higher 
frequency in the tiragolumab plus atezolizumab arm (80.6%) compared to the placebo 
plus atezolizumab arm (72.1%). 
The Grade 5 adverse events that occurred in the tiragolumab plus atezolizumab arm 
were Epstein-Barr virus (EBV), infection, and pyrexia (reported for 1 patient each), and 
the Grade 5 adverse events in the placebo plus atezolizumab arm were 
cardiorespiratory arrest, cerebrovascular accident, multiple-organ dysfunction syndrome, 
pneumonia, and pulmonary embolism (1 patient each). 
Using a comprehensive medical concepts strategy, immune-mediated adverse events 
were reported with a higher frequency in the tiragolumab plus atezolizumab arm (65.7%) 
compared to the placebo plus atezolizumab arm (47.1%).  The difference ( 10% 
difference between arms) was predominately attributed to events of immune-mediated 
rash (preferred terms of rash, maculopapular rash, dermatitis, pruritic rash, eczema, 
erythema, and folliculitis) (38.8% vs. 14.7%) and infusion-related reactions (IRR, 
preferred term) (28.4% vs. 10.3%). 
Please refer to the Tiragolumab Investigator's Brochure for additional details on best 
overall response of stable disease, PK analysis using standard non-compartmental 
PK methods, and combination safety and preliminary efficacy data observed in patients 
treated with tiragolumab plus atezolizumab. 
Collectively, these data from Phase Ib GO30103 and Phase II CITYSCAPE studies have 
led to the hypothesis that anti-TIGIT treatment (tiragolumab) in combination with 
antiPD-L1/PD-1 treatment (atezolizumab) plus chemotherapy may result in enhanced 
and more durable responses.  This combination is currently under evaluation in an 
expansion cohort of Study GO30103 and in the Phase III Study SKYSCRAPER-02 
(GO41767) in patients with untreated ES-SCLC and provides the framework for 
this study. 
1.5 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
Encouraging clinical data 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 metastatic cancer, including SCLC.  
PD-L1/PD-1 inhibitors in combination with chemotherapy have demonstrated significant 
improvement in survival compared with standard chemotherapy, which has led to the 
recent approvals by the U.S. Food and Drug Administration (FDA) of atezolizumab plus 

 
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chemotherapy in metastatic SCLC in the 1L setting and validate the inhibition of the 
PD-L1/PD-1 pathway for achieving clinical benefit in these patients. 
Despite the robust activity observed with atezolizumab plus chemotherapy, durable 
clinical benefit appears limited to a minority of treated patients.  It is hypothesized that 
many of these patients with metastatic SCLC may have intrinsic or acquired resistance 
to checkpoint inhibition.  Thus, another strategy to increase the response to checkpoint 
inhibitors among patients has focused on treatment with novel immunotherapy 
combinations that may overcome such intrinsic or acquired resistance to PD-L1/PD-1 
antibodies. 
TIGIT is an inhibitory immunoreceptor that can limit the effector function of 
tumor-associated lymphocytes.  Unlike other inhibitory co-receptors, TIGIT is often 
coordinately expressed with PD-1 on tumor-infiltrating T cells in multiple tumors, 
including SCLC.  In nonclinical models, combined blockade of the TIGIT and 
PD-L1/PD-1 pathways has shown superior efficacy compared with blockade of each 
pathway alone (Johnston et al. 2014).  Thus, the combined inhibition of the TIGIT and 
PD-L1/PD-1 pathways is a unique and attractive strategy to potentiate the activity of 
a PD-L1 antibody such as atezolizumab, due to the complementary mechanisms of 
action of anti-TIGIT and antiPD-L1. 
In the Phase Ib Study GO30103 of tiragolumab with atezolizumab, (PRs) occurred in 
patients with metastatic cancers, including NSCLC, with varying degrees of PD-L1 
and/or TIGIT expression.  The combination of tiragolumab with atezolizumab was well 
tolerated in Phase Ib, and the addition of tiragolumab did not alter the safety profile of 
atezolizumab.  In preliminary data from the interim analysis of the Phase II Study 
CITYSCAPE (GO40290), the ORR (confirmed and unconfirmed responses) was higher 
in the tiragolumab plus atezolizumab group than in the placebo plus atezolizumab group 
in both the ITT and TPS  50% populations.  Consistent with the Phase Ib study, the 
combination of tiragolumab with atezolizumab was well tolerated in the Phase II study.  
In addition, safety data derived from both the Phase Ib (GO30103) and Phase II 
(GO40290) studies indicate that the combination of tiragolumab plus atezolizumab is 
well tolerated.  Adverse events with potentially immune-mediated causes have been 
observed, but do not suggest such events are increased beyond what one would expect 
with atezolizumab alone.  To date, such events have been manageable with standard 
treatment in the Phase Ib and Phase II studies.   
In light of these observations, this study is designed to evaluate whether the anti-tumor 
effect of standard of care combination of atezolizumab plus CE (IMpower133 regimen) 
can be enhanced by adding tiragolumab.  This study will enroll patients with ES-SCLC 
with no prior systemic treatment and all patients will receive standard atezolizumab 
plus CE.  Those randomized to the experimental arm will receive tiragolumab in addition 
to the standard atezolizumab plus CE.   

 
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Patients with SCLC frequently present with symptoms of widespread metastatic disease 
and may experience fast clinical deterioration; therefore, there is a need for rapid 
treatment initiation for these patients.  In addition, tissue sample collection for 
investigational biomarker testing may be difficult in this patient population because the 
amount of tissue available in many cases is limited.  Because the benefit of 
atezolizumab plus chemotherapy was observed in all-comer patients in IMpower133, 
this study will enroll patients with ES-SCLC whose disease is unselected for PD-L1 
expression.  Pre-treatment tumor tissue samples will be collected (unless tissue sample 
collection is not permitted by Human Genetic Resources Administration of China 
[HGRAC]) to allow for the analysis of biomarkers including but not limited to PD-L1 
expression and patient outcomes.  
Therefore, the current study is designed to evaluate whether the anti-tumor effects of 
atezolizumab plus chemotherapy, as measured by OS, PFS, ORR, and duration of 
response (DOR), can be improved with the addition of the anti-TIGIT antibody 
tiragolumab to atezolizumab and CE in patients with ES-SCLC.  This study design will 
allow for the evaluation of efficacy of tiragolumab plus atezolizumab plus CE in the 
primary analysis set (PAS) and the full analysis set (FAS) and for the evaluation of 
exploratory biomarkers and their association with patient outcomes. 
In summary, the combination of tiragolumab with atezolizumab plus CE in this study may 
benefit patients beyond treatment with atezolizumab plus chemotherapy.  As the 
toxicities of atezolizumab alone and in combination with tiragolumab appear to be 
similar, and generally mild, transient, and manageable in nature, patients are not 
expected to have significantly increased toxicity with the combination of tiragolumab and 
atezolizumab.  The toxicities of the combination of tiragolumab and atezolizumab plus 
chemotherapy are also expected to be comparable with the standard of care of 
atezolizumab plus chemotherapy.  Therefore, the overall benefitrisk ratio is considered 
to be appropriate for the study population and the experimental arm can represent 
a potential valuable treatment option for patients with ES-SCLC. 
Neutropenia and 
 associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab and/or tiragolumab in 
combination with chemotherapy. 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with lung cancer, are considered a more vulnerable 
population, with the potential for more severe clinical outcomes from COVID-19.  
However, it is unclear whether or how systemic cancer therapies such as chemotherapy, 
targeted therapy, or immunotherapy impact the incidence or severity of COVID-19. 
A possible consequence of immune checkpoint inhibition 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 

 
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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; Wykes and Lewin 2018; Schorer et al. 2020).  However, 
there are insufficient and inconsistent clinical data to assess if outcome from COVID-19 
is altered by cancer immunotherapy. 
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-gamma 
(IFN-) (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 severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while receiving 
atezolizumab and/or tiragolumab.  At this time, there is insufficient evidence for causal 
association between atezolizumab or tiragolumab and an increased risk of severe 
outcomes from COVID-19. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with immune checkpoint inhibitors and clinical and 
radiologic features for COVID-19related interstitial pneumonia.  Thus, investigators 
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 for Cancer [SITC] 2020). 
Per recommendations of the 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 tiragolumab and/or 
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 tiragolumab and/or 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.   

 
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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). 
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of tiragolumab 
plus atezolizumab and CE compared with placebo plus atezolizumab and CE in patients 
with untreated ES-SCLC on the basis of the following co-primary endpoints: 
 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by the investigator according to RECIST v1.1, or death 
from any cause (whichever occurs first), in randomized patients without presence or 
history of brain metastases at baseline (PAS) 
 
OS, defined as the time from randomization to death from any cause in the PAS 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of tiragolumab 
plus atezolizumab and CE compared with placebo plus atezolizumab and CE on the 
basis of the following endpoints: 
 
PFS in the FAS 
 
OS in the FAS 
 
Confirmed ORR, defined as the proportion of patients with a CR or PR on two 
consecutive occasions  4 weeks apart, as determined by the investigator according 
to RECIST v1.1 in the PAS and the FAS who have measurable disease at baseline 
 
DOR for patients with confirmed objective response, defined as the time from the 
first occurrence of a documented objective response to disease progression as 
determined by the investigator according to RECIST v1.1 or death from any cause, 
whichever occurs first, in the PAS and the FAS 
 
PFS rates at 6 months and at 12 months, defined as the proportion of patients who 
have not experienced disease progression as determined by the investigator 
according to RECIST v1.1 or death from any cause at 6 and 12 months in the PAS 
and the FAS 
 
OS rates at 12 months and 24 months, defined as the proportion of patients who 
have not experienced death from any cause at 12 and 24 months in the PAS and 
the FAS 

 
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 
Time to confirmed deterioration (TTCD) in patient-reported physical functioning and 
global health status (GHS), as measured by the respective scales of the European 
Organisation for the Research and Treatment of Cancer (EORTC) Quality-of-Life 
Questionnaire Core (QLQ-C30) in the PAS and the FAS 
 
2.1.3 
Exploratory Efficacy Objective 
 
 
 
 
 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of tiragolumab plus 
atezolizumab and CE compared with placebo plus atezolizumab and CE on the basis of 
the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
Version 5.0 (CTCAE v5.0) 
Severity for CRS will also be determined according to the American Society for 
Transplantation and Cellular Therapy (ASTCT) consensus grading scale. 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the pharmacokinetics of tiragolumab 
and atezolizumab on the basis of the following endpoint: 
 
Serum concentration of tiragolumab and atezolizumab at specified timepoints 
 

 
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2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
tiragolumab on the basis of the following endpoints: 
 
Prevalence of anti-drug antibodies (ADAs) to tiragolumab at baseline and incidence 
of ADAs to tiragolumab during the study 
 
 
 
 
 
 
2.5 
EXPLORATORY BIOMARKER OBJECTIVE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase III, randomized, double-blind, placebo-controlled multicenter study in 
China designed to evaluate the safety and efficacy of tiragolumab plus atezolizumab 
and CE compared with placebo plus atezolizumab and CE in patients with 
chemotherapy-naive ES-SCLC. 
Figure 1 illustrates the study design.  The Schedule of Activities is provided in 
Appendix 1. 

 
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Figure 1 Study Schema 
 
1L  first-line; CE  carboplatin and etoposide; ECOG PS  Eastern Cooperative Oncology Group 
Performance Status; ES-SCLC  extensive-stage small cell lung cancer; FAS  full analysis set; 
LDH  lactase dehydrogenase; PAS  primary analysis set; RECIST  Response Evaluation Criteria 
in Solid Tumors; ULN  upper limit normal. 
 

 
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After providing informed consent, patients will undergo screening procedures as outlined 
in the Schedule of Activities (Appendix 1).  Patients who do not initially meet all eligibility 
criteria for participation in this study may qualify for one re-screening opportunity 
(for a total of two screenings per patient) at the investigator's discretion.  Patients are not 
required to re-sign the Consent Form if they are re-screened within 60 days after 
previously signing the Consent Form.  For patients who are rescreened, all eligibility 
criteria must be re-evaluated and screening assessments should be repeated as 
applicable to meet the eligibility criteria outlined in Section 4.1.  The investigator will 
record reasons for screening failure in the screening log (see Section 4.5.1). 
Eligible patients will be randomized 1:1 to receive one of the following treatment 
regimens as shown in Table 1. 
Table 1 
Study YO42373 Treatment Arms 
Treatment Arm 
Induction 
(Four 21-Day Cycles) 
Maintenance 
(21-Day Cycles) 
A 
Tiragolumab  Atezolizumab  CE 
Tiragolumab  Atezolizumab  
B 
Placebo  Atezolizumab  CE 
Placebo  Atezolizumab   
CE  carboplatin and etoposide. 
  
The randomization scheme is designed to ensure that an approximately equal number of 
patients will be enrolled in each treatment arm within the baseline characteristics of the 
following stratification factors: 
 
ECOG Performance Status (0 vs. 1) 
 
LDH ( upper limit of normal [ULN] vs.  ULN)  
 
Induction treatment with tiragolumab plus atezolizumab and CE (Arm A) or placebo plus 
atezolizumab and CE (Arm B) will be administered on a 21-day cycle for 4 cycles.  
Following the induction phase, patients will continue maintenance therapy with either 
tiragolumab plus atezolizumab (Arm A) or placebo plus atezolizumab (Arm B).  
During the maintenance phase, prophylactic cranial irradiation (PCI) is permitted 
(though not mandated) per local standard of care and will be reported on the 
Prophylactic Cranial Irradiation Electronic Case Report Form (eCRF).  Consolidative 
thoracic radiation with curative intent or the intent to eliminate residual disease is not 
permitted.  Palliative radiation for symptomatic management is allowed (please refer to 
Section 4.4.1 for further details). 
Treatment will be continued until radiographic disease progression according to 
RECIST v1.1, or as long as patients are experiencing clinical benefit, as assessed by the 
investigator, in the absence of unacceptable toxicity or symptomatic deterioration 
attributed to disease progression after an integrated assessment of radiographic data, 
biopsy results (if available), and clinical status.  Patients who meet the criteria for 

 
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disease progression per RECIST v1.1 will be permitted to continue study treatment 
(tiragolumab plus atezolizumab or placebo plus atezolizumab) if they meet all of the 
criteria specified in Section 3.1.2 and provide written consent. 
A safety review of unblinded data will be performed by an independent Data Monitoring 
Committee (iDMC; see Section 3.1.3) after approximately 6 months from the time of 
randomization of the first patient until the study data are unblinded or the study is 
terminated by the Sponsor.  
Patients will undergo tumor assessments at baseline and every 6 weeks ( 7 days) for 
48 weeks following Cycle 1, Day 1, regardless of treatment dose delays.  
After completion of the Week 48 tumor assessment, tumor assessments will be required 
every 9 weeks ( 7 days) thereafter, regardless of treatment dose delays.  Patients will 
undergo tumor assessments until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs 
first.  Patients who are treated beyond disease progression per RECIST v1.1 
(see Section 3.1.2) will undergo tumor assessments at the frequency described above 
until study treatment is discontinued.  Patients who discontinue treatment for reasons 
other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, 
symptomatic deterioration) will continue scheduled tumor assessments at the same 
frequency as would have been followed if the patient had remained on study treatment 
(i.e., every 6 weeks [ 7 days] for 48 weeks following Cycle 1, Day 1 and then every 
9 weeks [ 7 days] thereafter, until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by the Sponsor, or death, whichever occurs 
first), regardless of whether the patient starts a new anti-cancer therapy. 
The investigator's assessment of overall tumor response at all timepoints should only be 
based on RECIST v1.1.  Assessments should be performed by the same evaluator, 
if possible, to ensure internal consistency across visits.  The Sponsor will derive the 
overall tumor assessment as per Modified RECIST v1.1 for Immune-Based Therapeutics 
(iRECIST; see Appendix 5) based on entries for all target lesions, non-target lesions, 
and new lesions. 
In order not to confound the OS endpoint, crossover will not be allowed from the 
control arm (placebo plus atezolizumab plus CE) to the experimental arm (tiragolumab 
plus atezolizumab plus CE). 
During the study, patients will be asked to complete PRO questionnaires at the 
beginning of the study, during study treatment, at treatment discontinuation, and during 
survival follow-up (see Section 4.5.9 and Appendix 1 for details on the surveys and 
schedule). 

 
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Safety assessments will include the incidence, nature, and severity of adverse events, 
protocol-mandated vital signs, laboratory abnormalities, and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study. 
During the study, serum samples will be collected to monitor tiragolumab and 
atezolizumab pharmacokinetics and to detect the presence of antibodies to tiragolumab 
and atezolizumab.  Patient samples, including archival and fresh tumor tissue, will also 
be collected for exploratory biomarker assessments. 
3.1.2 
Treatment after Disease Progression 
During the study, patients who meet criteria for disease progression per RECIST v1.1 
and show evidence of clinical benefit may continue treatment at the investigator's 
discretion, provided that the patients meet all of the following criteria: 
 
Evidence of clinical benefit, as assessed by the investigator 
 
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease 
 
No decline in ECOG Performance Status that can be attributed to disease 
progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
The patient has been informed that continuing study treatment may result in further 
progression and delay treatment with subsequent therapies for which they are 
eligible and has signed the Optional Treatment Beyond Initial Radiographic 
Progression Informed Consent Form 
 
Investigator assessment of overall tumor response at all timepoints will be based only on 
RECIST v1.1.  Objective response per iRECIST will be calculated programmatically by 
the Sponsor on the basis of investigator assessments of individual lesions at each 
specified timepoint. 
3.1.3 
Independent Data Monitoring Committee 
An iDMC will be used to evaluate safety during the study.  The safety review of 
unblinded data by the iDMC will occur approximately every 6 months.  The safety data 
will include disposition, demographic data, adverse events, serious adverse events, and 
relevant laboratory data. 
The Sponsor will remain blinded to the efficacy results until the primary PFS analysis.  
All summaries and analyses by treatment arm for the iDMC reviews will be prepared by 
an external independent Data Coordinating Center (iDCC).  Following the data review, 
the iDMC will provide a recommendation as to whether the study may continue, whether 
amendment(s) to the protocol should be implemented, or whether the study should be 

 
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stopped.  The final decision will rest with the Sponsor, taking into consideration the 
iDMC's recommendation. 
Members of the iDMC will be external to the Sponsor and will follow a separate 
iDMC Charter that outlines their roles and responsibilities, as well as a detailed 
monitoring plan. 
Any outcomes of these safety reviews that affect study conduct will be communicated in 
a timely manner to the investigators for notification of the sites' Institutional Review 
Boards/Ethics Committees (IRBs/ECs). 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of study will occur when both of the following criteria have been met: 
 
The last patient, last visit has occurred. 
 
Approximately 
 deaths have been observed in the PAS. 
 
Additionally, the Sponsor may decide to terminate the study at any time.  If the Sponsor 
decides to terminate the study, patients who are still receiving study treatment or 
undergoing survival follow-up may be enrolled in an extension study. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 49 months. 
3.3 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual is expected to range from 
1 day to more than 18 months. 
3.4 
RATIONALE FOR STUDY DESIGN 
3.4.1 
Rationale for Tiragolumab Dose and Schedule 
 
 
 
 

 
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3.4.2 
Rationale for Control Arm 
The current standard of care in the 1L treatment for ES-SCLC is atezolizumab plus CE 
(NCCN 2019).  In this study, patients in the control arm will receive 4 cycles of placebo 
plus atezolizumab and CE followed by placebo plus atezolizumab until disease 
progression per RECIST v1.1.  During the maintenance phase, PCI is permitted per local 
standard of care.  This control arm treatment is recognized as the recommended 
standard of care for the 1L treatment of ES-SCLC (see Section 1.2). 
3.4.3 
Rationale for Evaluation of Patients without Brain Metastases 
at Baseline (Primary Analysis Set for Statistical Analysis)  
The brain is a common site of metastases for ES-SCLC patients with some studies 
showing as high as 18% of patients having brain metastases at diagnosis, and up to 
80% are expected to have brain disease involvement during the first 2 years following 
diagnosis (Seute et al. 2004; Pacheco and Bunn 2019).  In general, benefits from the 
immunotherapy and chemotherapy combination have been shown in patients with 
ES-SCLC.  However, this benefit may be attenuated in those with brain metastasis at 
baseline as seen in the IMpower133 trial where this patient subgroup had a hazard ratio 
(HR) of 1.07 compared to a HR of 0.68 for patients without brain metastases 
(Horn et al. 2018). 
KEYNOTE-604 is another phase 3 trial that suggests that ES-SCLC patients with brain 
metastasis at diagnosis may achieve less or no overall survival benefit to first-line 
immunotherapy plus chemotherapy in comparison to those without.  In fact, patients with 
brain metastases had an OS HR of 1.32 versus 0.75 for patients without brain 
metastases (Rudin et al. 2020).  The CASPIAN study initially reported an OS HR of 0.69 
in patients with brain metastasis, however, in the updated analysis the HR became 0.79.  
The OS HR in those without brain metastasis in initial and updated reports was 0.74 and 
0.76, respectively (Paz-Ares et al. 2018, 2020). 
It is critical to understand the benefit of the study regimen in both of the patient 
subgroups, thus, the statistical analyses will be implemented in the PAS first, and then 
subsequently the FAS. 

 
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3.4.4 
Rationale for Progression-Free Survival and Overall Survival 
as Co-Primary Endpoints 
Investigator-assessed PFS and OS are the co-primary endpoints for this study. 
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; additionally, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents 
a direct clinical benefit or a surrogate for clinical benefit depends upon the magnitude of 
the effect and the benefitrisk of the new treatment compared with available therapies 
(FDA 2007; European Medicines Agency [EMA] 2012). 
To ensure the validity of investigator-assessed PFS as the primary endpoint, a number 
of measures have been implemented:  a substantial target magnitude of benefit and 
study assessments that will allow a robust evaluation of benefitrisk (conventional 
RECIST v1.1 criteria to define radiographic disease progression with fixed assessment 
intervals that are identical in both treatment arms, and a robust definition of PFS and 
prospectively-defined methods to assess, quantify, and analyze PFS, including 
sensitivity analyses). 
OS is a co-primary endpoint in this study.  Improvement in OS is generally accepted as 
the best measure of clinical benefit for patients with advanced/unresectable or 
metastatic lung cancer.  In the randomized Phase III study in patients with advanced 
SCLC (IMpower133), an OS benefit in the atezolizumab plus chemotherapy arm was 
observed compared with the placebo plus chemotherapy arm (Horn et al. 2018). 
3.4.5 
Rationale for Tiragolumab and/or Atezolizumab Treatment 
beyond Initial Radiographic Disease Progression 
Patients with ES-SCLC experience rapid tumor growth and fast clinical deterioration and 
have an overall poor prognosis.  First-line therapy with atezolizumab plus CE has 
demonstrated high response rates and significant clinical benefit.  However, after 
disease progression, treatment options are limited, and such options have shown limited 
efficacy and significant toxicity (see Section 1.2).  Given that the greatest opportunity to 
achieve a clinically significant benefit from therapy is in the front-line setting and given 
the poor efficacy and high toxicity profile of second-line therapies, patients may be 
considered for treatment beyond radiographic disease progression per RECIST v1.1 at 
the discretion of the investigator and after appropriate discussion with the patient, only if 
they meet all of the criteria described in Section 3.1.2. 
In addition, conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure.  Because of the potential for 
pseudoprogression/tumor-immune infiltration, this study will allow patients to remain on 
treatment after apparent radiographic disease progression per RECIST v1.1, provided all 
criteria in Section 3.1.2 are met.  Treatment should be discontinued if clinical 

 
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deterioration due to disease progression occurs at any time or if persistent disease 
growth is confirmed in a follow-up scan.  In addition, patients should be discontinued for 
unacceptable toxicity or for any other signs or symptoms of deterioration attributed to 
disease progression as determined by the investigator after an integrated assessment of 
radiographic data and clinical status (see Section 4.6.1). 
3.4.6 
Rationale for Patient-Reported Outcome Assessments 
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on health-related quality 
of life (HRQoL) (Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).  
This is especially true for studies that have PFS as a primary endpoint, to inform how 
delays in radiographic progression might be associated with delays in clinical 
progression of symptoms and their interference on functioning, including maintenance of 
low disease burden. 
In addition, many of the most frequent adverse events attributed to tiragolumab and 
atezolizumab (e.g., fatigue, rash, nausea) are symptoms directly reportable by patients; 
therefore, patients' reporting of their experience with these symptoms will complement 
the evaluation of treatment tolerability (King-Kallimanis et al. 2019). 
This study includes use of validated patient-reported measures of symptom severity 
and symptom impact on functioning including HRQoL:  the EORTC QLQ-C30 
(see Appendix 6), the single-item EORTC IL46 (see Appendix 7), and select items from 
the PRO-CTCAE (see Appendix 8).  Data generated from these instruments will inform 
patients' experience with disease burden and treatment tolerability as part of the totality 
of evidence generated to inform the riskbenefit profile of tiragolumab and atezolizumab. 
The EuroQol 5-Dimension, 5-Level Questionnaire ([EQ-5D-5L]; see Appendix 9) is also 
included in this study to generate utility scores for use in economic models for 
reimbursement. 
3.4.7 
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens 
This study will allow for the evaluation of the efficacy of tiragolumab plus atezolizumab in 
the PAS and the FAS, 
 
 
 
 

 
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4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Patients with chemotherapy-naive ES-SCLC will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria to be eligible for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
ECOG Performance Status of 0 or 1 (see Appendix 10) 
 
Histologically or cytologically confirmed ES-SCLC (per the modified Veterans 
Administration Lung Study Group (VALG) staging system (Micke et al. 2002; 
see Appendix 3) 
 
No prior systemic treatment for ES-SCLC 
 
For patients who have received prior chemoradiotherapy for limited-stage SCLC:  
must have had treatment with curative intent and a treatment-free interval of at least 
6 months between the last dose/cycle of chemotherapy, thoracic radiotherapy, 
or chemoradiotherapy and the diagnosis of ES-SCLC 
 
Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can only be considered as measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation therapy, and the previously irradiated lesion is not the only site of 
measurable disease. 
 
Submission of a pre-treatment tumor tissue sample (see Section 4.5.7 for 
information on tumor specimens) 
Any available tumor tissue sample can be submitted. 
The tissue sample should be submitted within 4 weeks after randomization 
unless tissue sample collection is not permitted by HGRAC.  However, patients 
may be enrolled in the study before the pre-treatment tumor tissue sample is 
submitted. 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to randomization: 
– 
ANC  1.5  109/L (1500/L) without granulocyte colony-stimulating factor 
support 
– 
Lymphocyte count  0.5  109/L (500/L) 
– 
Platelet count  100  109/L (100,000/L) without transfusion 

 
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– 
Hemoglobin  90 g/L ( 9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
– 
– 
– 
– 
 
For patients not receiving therapeutic anticoagulation:  INR and aPTT  1.5  ULN 
 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
 
Negative HIV test at screening 
 
Negative hepatitis B surface antigen (HBsAg) test at screening 
 
Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb 
at screening accompanied by either of the following:  
– 
Negative total hepatitis B core antibody (HBcAb) 
– 
Positive total HBcAb test followed by a negative (per local laboratory definition) 
hepatitis B virus (HBV) DNA test 
 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
 
Negative Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgM test or negative 
EBV polymerase chain reaction (PCR) test at screening  
Patients with a positive IgM test or EBV PCR test are excluded. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from 
donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period, and for 90 days after the final 
dose of tiragolumab or placebo, 5 months after the final dose of atezolizumab, 
and for 6 months after the final dose of carboplatin and etoposide.  
Women must refrain from donating eggs during this same period. 

 
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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 is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, 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.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods, and agreement to refrain from donating sperm, as 
defined below: 
With a female partner of childbearing potential who is not pregnant, men who 
are not surgically sterile must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of  1% per 
year during the treatment period and for 90 days after the final dose of 
tiragolumab or placebo, and for 6 months after the final dose of carboplatin and 
etoposide.  Men must refrain from donating sperm during this same period. 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period, for 90 days after the final dose of tiragolumab or 
placebo, and for 6 months after the final dose of carboplatin and etoposide to 
avoid exposing the embryo. 
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 preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 

 
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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Symptomatic or actively progressing CNS metastases  
Note:  Asymptomatic patients with treated (i.e., local CNS-directed therapy) or 
untreated CNS lesions are eligible, provided that all of the following criteria are met: 
– 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
– 
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage from CNS disease.  
– 
Metastases are limited to the cerebellum or the supratentorial region 
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord). 
– 
The patient has no symptoms caused by CNS disease (i.e., no headache, 
nausea, vomiting, convulsion, paralysis, etc.). 
– 
The patient has no ongoing requirement for anticonvulsants for CNS disease. 
– 
The patient has no ongoing requirement for dexamethasone/corticosteroids for 
CNS disease (previously untreated patients must also not have any history of 
requiring or receiving dexamethasone/corticosteroids for CNS disease). 
– 
For patients with previously treated CNS metastases, there is no evidence of 
interim CNS progression between the completion of CNS-directed therapy and 
randomization.  
– 
For previously untreated patients, there is no evidence of brain edema related 
to CNS disease (e.g., vasogenic edema). 
– 
For previously untreated patients, a brain magnetic resonance imaging (MRI) 
scan with contrast is required at screening and is the preferred modality for all 
subsequent scheduled follow-up tumor assessments. 
Note:  Computed tomography (CT) scan with contrast may be 
acceptable for all subsequent scheduled follow-up tumor assessments 
if the following criteria are met. 
– 
Both brain MRI and CT scan with contrast must be performed at 
screening to assess untreated CNS disease.  
– 
The CT scan with contrast can be used to reliably evaluate lesions 
identified on the screening MRI with contrast. 
If CT scan with contrast cannot be used to reliably evaluate lesions 
identified on the screening MRI with contrast, then MRI scan with 
contrast must be used at all subsequent scheduled follow-up tumor 
assessments. 
The same modality must be used at every tumor assessment. 
 
Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for  1 week prior to randomization 

 
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 
Leptomeningeal disease 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed regardless of 
drainage frequency. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, total 
serum calcium  12 mg/dL, or corrected calcium  ULN) 
 
Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse 
 
Malignancies other than SCLC within 5 years prior to randomization, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 
5-year OS  90%) treated with expected curative outcome (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized 
prostate cancer treated surgically with curative intent, ductal breast carcinoma in 
situ treated surgically with curative intent) 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, 
Guillain-Barré syndrome, or multiple sclerosis (see Appendix 12 for a more 
comprehensive list of autoimmune diseases and immune deficiencies), with the 
following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone therapy are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of the following conditions 
are met:  
– 
Rash must cover  10% of body surface area. 
– 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
– 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months. 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 

 
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 
Known active tuberculosis 
 
Current treatment with anti-viral therapy for HBV or HCV 
 
Severe chronic or active infection within 4 weeks prior to initiation of study 
treatment, including, but not limited to, hospitalization for complications of infection, 
bacteremia, or severe pneumonia, or any active infection that, in the opinion of the 
investigator, could impact patient safety 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease [COPD] exacerbation) are 
eligible for the study. 
 
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction, or cerebrovascular accident 
within 3 months prior to randomization, unstable arrhythmias, or unstable angina 
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or left ventricular ejection fraction  50% must be on 
a stable medical regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist if appropriate. 
 
Major surgical procedure other than for diagnosis within 28 days prior to 
randomization or anticipation of need for a major surgical procedure during the 
course of the study 
 
Prior allogeneic bone marrow transplantation or solid organ transplant 
 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk for treatment 
complications 
 
Patients with illnesses or conditions that interfere with their capacity to understand, 
follow, and/or comply with study procedures 
 
Treatment with any other investigational agent with therapeutic intent within 28 days 
prior to randomization 
 
Administration of a live, attenuated vaccine within 4 weeks before randomization or 
anticipation that such a live attenuated vaccine will be required during the study 
Patients must not receive live, attenuated influenza vaccines (e.g., FluMist®) 
within 4 weeks prior to randomization, during treatment, and for 5 months 
following the last dose of study treatment 
 
Prior treatment with CD137 agonists, T-cell co-stimulating, or immune checkpoint 
blockade therapies, including antiCTLA-4, anti-TIGIT, antiPD-1, and antiPD-L1 
therapeutic antibodies 

 
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 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2) within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to randomization 
 
Treatment with systemic immunosuppressive medications (including, but not limited 
to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [TNF]- agents) within 1 week prior to randomization or 
anticipation of need for systemic immunosuppressive medication during study 
treatment, with the following exceptions: 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study. 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for COPD or asthma, or low-dose mineralocorticoids for orthostatic hypotension 
or low-dose mineralocorticoids and corticosteroids for adrenal insufficiency are 
eligible for the study. 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to CHO cell products or to any component of the 
tiragolumab or atezolizumab formulations 
 
History of allergic reactions to carboplatin or etoposide 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during study 
treatment or within 5 months after the final dose of atezolizumab or within 90 days 
after the final dose of tiragolumab or for 6 months after the final dose of carboplatin 
or etoposide 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to randomization. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1 
Treatment Assignment 
This is a Phase III, randomized, double-blind, placebo-controlled multicenter study.  
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient's identification number and treatment assignment 
from the interactive voice or web-based response system (IxRS). 
Patients will be randomized to one of two treatment arms:  
 
Arm A:  tiragolumab  atezolizumab  CE 
 
Arm B:  placebo  atezolizumab  CE 
 

 
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Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method to ensure that an approximately equal number of patients will 
be enrolled in each treatment arm within the baseline characteristics of the following 
stratification factors: 
 
ECOG Performance Status (0 vs. 1) 
 
LDH ( ULN vs.  ULN) 
 
Patients should receive their first dose of study drug on the day of randomization if 
possible.  If this is not possible, the first dose should occur within 5 days after 
randomization. 
4.2.2 
Blinding 
Study site personnel (with the exception of the unblinded pharmacist) and patients will 
be blinded to treatment assignment during the study.  The Sponsor and its agents will 
also be blinded to treatment assignment, with the exception of individuals who require 
access to patient treatment assignments to fulfill their job roles during a clinical 
trial.  These roles include the unblinding group responsible, clinical supply chain 
managers, sample handling staff, operational assay group personnel, IxRS service 
provider, and iDMC members. 
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm (Arm B) to maintain the blinding of treatment assignment, PK and ADA 
assay results for tiragolumab in these patients are generally not needed for the safe 
conduct or proper interpretation of the study data.  Laboratories responsible for 
performing tiragolumab PK and ADA assays will be unblinded to patient treatment 
assignments to identify appropriate samples for analysis.  PK samples from patients 
assigned to the comparator arm will not be analyzed for tiragolumab PK concentration 
except by request (e.g., to evaluate a possible error in dosing).  Baseline (Cycle 1, Day 1 
pre-infusion) immunogenicity samples will be analyzed for all patients.  Post-baseline 
immunogenicity samples from patients assigned to the comparator arm will not be 
analyzed for ADAs to tiragolumab except by request. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  Unblinding 
may be permitted if an investigator is deciding whether a patient should withdraw from 
the study and initiate subsequent treatment with a proven therapy.  However, unblinding 

 
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will not be permitted if an investigator is deciding whether a patient should initiate 
subsequent treatment with an unproven therapy.  The investigator should document and 
provide an explanation for any non-emergency unblinding. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
tiragolumab/placebo.  The patient may continue to receive treatment, and the 
investigator, patient, and Sponsor personnel, with the exception of the Drug Safety 
representative and personnel who must have access to patient treatment assignments to 
fulfill their roles (as defined above), will remain blinded to treatment assignment. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are tiragolumab, placebo, 
and atezolizumab.  Carboplatin and etoposide are considered non-investigational 
medicinal products. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Tiragolumab and Placebo 
Tiragolumab and placebo will be supplied by the Sponsor as a sterile liquid in 
a single-use, 15-mL glass vial.  The vial contains approximately 10 mL (600 mg) of 
tiragolumab or placebo solution.  For information on the formulation and handling of 
tiragolumab and placebo, see the pharmacy manual and the Tiragolumab Investigator's 
Brochure.  
4.3.1.2 
Atezolizumab 
The atezolizumab will be supplied by the Sponsor as a sterile liquid in a single-use, 
20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab 
solution.  Atezolizumab formulation will be prepared by an unblinded pharmacist and is 
compatible with infusion bags constructed with product contacting materials of 
polyvinyl chloride, polyethylene (PE), or polyolefin composed of PE and polypropylene.  
For detailed instructions on the preparation of the following atezolizumab formulation, 
see the pharmacy manual. 
 
20 mL (1200 mg) atezolizumab 
 
180 mL of 0.9% Sodium Chloride Injection, USP 
 
4.3.1.3 
Carboplatin and Etoposide 
Carboplatin and etoposide will be used in the commercially available formulation.  
For information on the formulation, packaging, and handling of carboplatin and 
etoposide, refer to the local prescribing information for each drug. 

 
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4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1, Table 1. 
On Day 1 of each 21-day cycle, all eligible patients will be administered infusion of study 
treatments in the following order: 
 
Induction (Cycles 1–4):  
Arm A:  atezolizumab  tiragolumab  carboplatin  etoposide 
Arm B:  atezolizumab  placebo  carboplatin  etoposide 
 
Maintenance (Cycles 5 ):  
Arm A:  atezolizumab  tiragolumab  
Arm B:  atezolizumab  placebo  
 
For Cycle 1, premedication administered for atezolizumab, or tiragolumab/placebo is not 
permitted.  Patients should receive anti-emetics and IV hydration for carboplatin and 
etoposide according to the local standard of care and manufacturer's instruction.  
However, because of the immunomodulatory effects of corticosteroids, premedication 
with corticosteroids should be minimized to the extent that is clinically feasible 
(see Section 4.4.2).  All medications must be recorded on the appropriate Concomitant 
Medications eCRF. 
During the induction phase, study treatment should be administered in the following 
manner on Day 1: 
1. 
Atezolizumab 1200 mg administered intravenously over 60 ( 15) minutes (for the 
first infusion and shortening to 30 [ 10] minutes for subsequent infusions) 
(see Table 2), followed by 
2. 
Tiragolumab/placebo 600 mg administered intravenously over 60 ( 15) minutes 
(for the first infusion and shortening to 30 [ 10] minutes for subsequent infusions) 
(see Table 2), followed by 
3. 
Carboplatin administered intravenously over 3060 minutes to achieve an initial 
target area under the concentrationtime curve (AUC) of 5 mg/mL/min (Calvert 
formula dosing), followed by 
4. 
Etoposide (100 mg/m2) administered intravenously over 60 minutes  
 
During the induction phase, etoposide (100 mg/m2) will be also administered 
intravenously over 60 minutes on Days 2 and 3. 
Cycles in which no chemotherapy is given do not count toward the total number of 
induction chemotherapy cycles. 
The suggested infusion times for CE may be adapted in accordance with local standard 
of care. 

 
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Any dose modification should be noted on the Study Drug Administration eCRF.  
Cases of accidental overdose or medication error, along with any associated adverse 
events, should be reported as described in Section 5.3.5.12. 
Administration of atezolizumab and tiragolumab/placebo will be performed in a 
monitored setting where there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  For anaphylaxis 
precautions, see Appendix 11. 
Guidelines for dose modification and treatment interruption or discontinuation for 
carboplatin and etoposide are provided in Sections 5.1.6.1 and 5.1.6.4. 
4.3.2.1 
Atezolizumab 
All patients will receive fixed-dose 20 mL (1200 mg) atezolizumab administered by IV 
infusion on Day 1 of each 21-day cycle.  Atezolizumab infusions will be administered per 
the instructions outlined in Table 2. 
For Cycle 1, premedication for atezolizumab is not permitted. 
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation are provided in Appendix 13 and Appendix 14.  Guidance on study 
drug administration in the context of management of specific adverse events is provided 
in Section 5.1.6.3. 
For further details on dose preparation, storage, and administration instructions for 
atezolizumab, please refer to the pharmacy manual and/or the Atezolizumab 
Investigator's Brochure.  
4.3.2.2 
Tiragolumab/Placebo 
Following the administration of atezolizumab and an observation period (see Table 2), 
patients will receive fixed-dose 10 mL (600 mg) tiragolumab in Arm A or 10 mL placebo 
in Arm B administered by IV infusion on Day 1 of each 21-day cycle (see Section 3.4.1).  
Tiragolumab/placebo infusions will be administered per the instructions outlined 
in Table 2. 
For Cycle 1, premedication for tiragolumab/placebo is not permitted. 
No dose modification for tiragolumab/placebo is allowed.  Guidelines for treatment 
interruption or discontinuation are provided in Appendix 13 and Appendix 14.  Guidance 
on study drug administration in the context of management of specific adverse events is 
provided in Section 5.1.6.3. 
For further details on dose preparation, storage, and administration instructions for 
tiragolumab/placebo, please refer to the pharmacy manual and/or the Tiragolumab 
Investigator's Brochure. 

 
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Table 2 
Administration of First and Subsequent Atezolizumab and 
Tiragolumab/Placebo Infusions 
Study Drug 
First Infusion 
Subsequent Infusions 
Atezolizumab 
infusion 
 No premedication is permitted 
prior to the first atezolizumab 
infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood 
pressure, and temperature) 
should be recorded within 
60 minutes prior to starting the 
infusion. 
 Atezolizumab should be 
infused over 60 ( 15) minutes. 
 If clinically indicated, vital signs 
should be measured every 
15 ( 5) minutes during the 
infusion.  
 If the patient experienced an IRR 
with any previous infusion of 
atezolizumab, premedication with 
an antihistamine and/or antipyretic 
may be administered for 
subsequent doses and beyond at 
the discretion of the treating 
physician. 
 Vital signs should be recorded 
within 60 minutes prior to the 
infusion.  
 Atezolizumab should be infused 
over 30 ( 10) minutes if the 
previous infusion was tolerated 
without an IRR or 
60 ( 15) minutes if the patient 
experienced an IRR with the 
previous infusion. 
 If the patient experienced an IRR 
with the previous infusion, or if 
clinically indicated, vital signs 
should be recorded during the 
infusion. 
Observation period 
after atezolizumab 
infusion 
 After the infusion of 
atezolizumab, the patient 
begins a 60-minute observation 
period. 
 Vital signs should be recorded 
at 30 ( 10) minutes after the 
infusion of atezolizumab. 
 Patients should be informed 
about the possibility of delayed 
post-infusion symptoms and 
instructed to contact their study 
physician if they develop such 
symptoms. 
 If the patient tolerated the 
previous atezolizumab infusion 
well without infusion-associated 
adverse events, the observation 
period after the next and following 
infusions may be reduced to 
30 minutes. 
 If the patient experienced 
infusion-associated adverse 
events in the previous infusion, 
the observation period should be 
60 minutes. 
 If clinically indicated, vital signs 
should be recorded at 
30 ( 10) minutes after the 
infusion of atezolizumab. 
IRR  infusion-related reaction. 
  

 
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Table 2 
Administration of First and Subsequent Atezolizumab and 
Tiragolumab/Placebo Infusions (cont.) 
 
First Infusion 
Subsequent Infusions 
Tiragolumab/ 
placebo infusion 
 No premedication is permitted 
prior to the first 
tiragolumab/placebo infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood pressure, 
and temperature) should be 
recorded within 60 minutes prior 
to the infusion. 
 Tiragolumab/placebo should be 
infused over 60 ( 15) minutes. 
 Vital signs should be recorded 
every 15 ( 5) minutes during 
the infusion. 
 If the patient experienced an IRR 
during any previous infusion of 
tiragolumab/placebo, 
premedication with an 
antihistamine and/or antipyretic 
may be administered for 
subsequent doses at the 
discretion of the treating 
physician. 
 Vital signs should be recorded 
within 60 minutes prior to the 
tiragolumab/placebo infusion. 
 Tiragolumab/placebo should be 
infused over 30 ( 10) minutes if 
the previous infusion was 
tolerated without an 
infusion-related reaction, or 
60 ( 15) minutes if the patient 
experienced an infusion-related 
reaction with the previous infusion. 
 Vital signs should be recorded 
during the infusion if clinically 
indicated. 
Observation period 
after tiragolumab/ 
placebo infusion 
 After the infusion of 
tiragolumab/placebo, the patient 
begins a 60-minute observation 
period. 
 Vital signs should be recorded 
at 30 ( 10) minutes after the 
infusion of tiragolumab/placebo. 
 Patients will be informed about 
the possibility of delayed 
post-infusion symptoms and will 
be instructed to contact their 
study physician if they develop 
such symptoms. 
 If the patient tolerated the 
previous infusion of 
tiragolumab/placebo well without 
infusion-associated adverse 
events, the observation period 
may be reduced to 30 minutes. 
 If the patient experienced an 
infusion-associated adverse event 
in the previous infusion, the 
observation period should be 
60 minutes.  
 If clinically indicated, vital signs 
should be recorded at 
30 ( 10) minutes after the infusion 
of tiragolumab/placebo. 
 Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and will be instructed to 
contact their study physician if 
they develop such symptoms. 
IRR  infusion-related reaction. 
  
Guidelines for medical management of IRRs are provided in Appendix 14. 

 
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4.3.2.3 
Atezolizumab and Tiragolumab/Placebo 
The following rules apply as long as neither atezolizumab nor tiragolumab/placebo has 
been permanently discontinued:  
 
Treatment cycles will normally begin with dosing of atezolizumab and 
tiragolumab/placebo on Day 1 of each 21-day cycle.  If either study drug 
(atezolizumab or tiragolumab/placebo) is delayed for related toxicity, it is 
recommended that the other study drug (atezolizumab or tiragolumab/placebo) is 
also delayed since the safety profiles for atezolizumab and tiragolumab are similar; 
however, a cycle may begin with the administration of the other study drug 
(atezolizumab or tiragolumab/placebo) if considered appropriate at the discretion of 
the investigator.   
 
In case of delays in dosing of one study drug (atezolizumab or tiragolumab/placebo) 
for drug-related toxicity while the other study drug (atezolizumab or 
tiragolumab/placebo) is given as planned, it is recommended that the study drug 
being delayed will be administered at the next scheduled infusion (i.e., at the next 
scheduled 21-day cycle). 
 
Carboplatin and/or etoposide may be administered as planned in the event that 
atezolizumab and/or tiragolumab/placebo dose(s) are delayed.  If carboplatin and/or 
etoposide doses must be delayed, atezolizumab and/or tiragolumab may be 
administered as planned. 
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6.1 
and 5.1.6. 
4.3.2.4 
Carboplatin and Etoposide 
Table 3 lists the doses and suggested infusion times for treatment administration for 
carboplatin and etoposide. 
Table 3 
Treatment Regimen for Carboplatin and Etoposide 
Study Drug 
Dose and Route 
Induction Period 
(Four Cycles) 
Maintenance 
(Until PD) 
Carboplatin 
AUC 5 IV 
Over approximately 
3060 minutes on 
Day 1 Q3W 
Not applicable 
Etoposide 
100 mg/m2 IV 
Over 60 minutes on Day 1, 2, 
and 3 of each 21-day cycle 
Not applicable 
AUC  area under the concentrationtime curve; IV  intravenous; PD  progressive disease; 
Q3W  every 3 weeks. 
  

 
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Carboplatin 
During the induction phase, carboplatin will be administered after completion of 
tiragolumab/placebo by IV infusion over 3060 minutes to achieve an initial target AUC 
of 5 mg/mL/min (Calvert formula dosing) with standard anti-emetics per local practice 
guidelines.  Because the effects of corticosteroids on T-cell proliferation have the 
potential to attenuate tiragolumab- and/or atezolizumab-mediated anti-tumor immune 
activity, premedication with corticosteroids should be minimized to the extent that is 
clinically feasible (see Section 4.4.2).  Carboplatin infusion times may be adapted in 
accordance with local standard of care. 
The carboplatin dose of AUC 5 will be calculated using the Calvert formula 
(Calvert et al. 1989): 
Calvert Formula 
Total dose (mg)  (target AUC)  (glomerular filtration rate [GFR]  25) 
NOTE:  The GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min. 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the CrCl.  
The CrCl is calculated by institutional guidelines or by the Cockcroft-Gault formula 
(Cockcroft and Gault 1976): 
CrCl   
(140  age)  (wt) 
( 0.85 if female) 
72  Scr 
 
Where: 
CrCl  creatinine clearance in mL/min 
  
age  patient's age in years  
  
wt  patient's weight in kg 
  
Scr  serum creatinine in mg/dL 
 
NOTE:  For patients with an abnormally low serum creatinine level, estimate the GFR 
through use of a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 
125 mL/min. 
If a patient's GFR is estimated based on serum creatinine measurements by the isotope 
dilution mass spectroscopy method, the FDA recommends that physicians consider 
capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity 
due to overdosing.  On the basis of the Calvert formula described in the carboplatin 
label, the maximum doses can be calculated as follows: 
Maximum carboplatin dose (mg)  target AUC (mg  min/mL)  (GFR  25 mL/min) 
 

 
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The maximum dose is based on a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function.  No higher estimated GFR values should be used. 
For a target AUC  5, the maximum dose is 5  (125  25)  5  150  750 mg. 
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6.1 
and 5.1.6. 
Etoposide 
During the induction phase, on Day 1 of each cycle, etoposide (100 mg/m2) will be 
administered by IV infusion over 60 minutes following carboplatin administration.  
On Days 2 and 3 of each cycle, etoposide (100 mg/m2) will be administered by IV 
infusion over 60 minutes.  Premedication should be administered according to local 
standard of care.  Because the effects of corticosteroids on T-cell proliferation have the 
potential to attenuate tiragolumab- and/or atezolizumab-mediated anti-tumor immune 
activity, premedication with corticosteroids should be minimized to the extent that is 
clinically feasible (see Section 4.4.2).  Etoposide infusion times may be adapted in 
accordance with local standard of care. 
Guidelines for treatment interruption or discontinuation are provided in Sections 4.6.1 
and 5.1.6. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) 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 IMPs supplied by the Sponsor by returning 
the appropriate documentation form to confirm the 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 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. 

 
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IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied 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 accountability log.  
Refer to the pharmacy manual, and/or the Tiragolumab Investigator's Brochure, 
Atezolizumab Investigator's Brochure, or local prescribing information for information on 
IMP handling, including preparation and storage, and accountability. 
4.3.4 
Continued Access to Tiragolumab and/or Atezolizumab  
Patients may be eligible to receive tiragolumab and/or atezolizumab as part of an 
extension study, as described in Section 3.2.  The Roche Global Policy on Continued 
Access to Investigational Medicinal Product is available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 7 days prior to initiation of study treatment to the 
treatment discontinuation visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy 
: 
 
 
 
 
 
 
 
 
 

 
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 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.4.2 
Cautionary Therapy for Tiragolumab- and/or 
Atezolizumab-Treated Patients 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with tiragolumab and/or 
atezolizumab.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF- 
inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with tiragolumab and/or atezolizumab therapy (refer to Appendix 14 for 
details). 

 
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4.4.2.2 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section 4.4.3) may be used during the study at the discretion of the investigator. 
4.4.3 
Prohibited Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5 
STUDY ASSESSMENTS 
The Schedule of Activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.   
Patients will be closely monitored for safety and tolerability throughout the study.  
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. 
Screening tests and evaluations will be performed within 28 days prior to Day 1 of 
Cycle 1.  Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Day 1 of Cycle 1 may be used; such tests 
do not need to be repeated for screening. 
All treatment visits must occur  3 days from the scheduled date unless otherwise noted 
(see Appendix 1).  All assessments will be performed on the day of the specified visit 
unless a time window is specified.  Assessments scheduled on the day of study 

 
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treatment administration (Day 1) of each cycle should be performed prior to study 
treatment infusion unless otherwise noted. 
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing continuing on a 21-day schedule.  If treatment was postponed 
for fewer than 3 days, the patient can resume the original schedule. 
The following assessments may be performed  96 hours before Day 1 of each cycle: 
 
ECOG Performance Status 
 
Limited physical examination 
 
Local laboratory tests 
 
Screening assessments performed  96 hours before Day 1 of Cycle 1 are not required 
to be repeated on Day 1 of Cycle 1. 
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 (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Written informed consent for continuation of study treatment beyond initial radiographic 
progression must be obtained prior to dosing of study treatment beyond the initial 
disease progression (see Section 4.3.4). 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, 
all concomitant medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 
7 days prior to initiation of study treatment will be recorded.  At the time of each 
follow-up physical examination, an interval medical history should be obtained and any 
changes in medications and allergies should be recorded. 

 
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SCLC cancer history will include the VALG staging system and staging by the American 
Joint Committee on Cancer, Eighth Edition. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
On study treatment days, vital signs will be measured within 60 minutes before the first 
study drug infusion of the day (see Table 2). 
For the first infusion of atezolizumab, measure vital signs every 15 ( 5) minutes during 
the infusion and within 30 ( 10) minutes after the infusion.  For the first infusion of 
tiragolumab/placebo, measure vital signs every 15 ( 5) minutes during the infusion and 
within 30 ( 10) minutes after the infusion.  For subsequent administration of 
atezolizumab and/or tiragolumab/placebo, measure vital signs during each infusion only 
as clinically indicated and within 30 ( 10) minutes after the end of each infusion.  
Additional vital signs should be measured during the infusion if clinically indicated or if 
symptoms occurred in the prior infusion. 
4.5.5 
Performance Status 
Performance status will be measured using ECOG Performance Status at baseline and 
will be assessed at regular intervals throughout the study (see Schedule of Activities in 
Appendix 1).  For further details, see Appendix 10. 

 
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4.5.6 
Tumor and Response Evaluations 
Screening and subsequent tumor assessments must include CT scans (with oral and/or 
IV contrast unless contraindicated).  A CT scan of the pelvis is required at screening 
and as clinically indicated or as per local standard of care at subsequent response 
evaluations.  MRI scans with contrast of the chest, abdomen, and pelvis with 
a non-contrast CT scan of the chest may 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) or MRI scan with contrast (if CT contrast is contraindicated) of the 
head must be done at screening to evaluate CNS metastasis in all patients.  If CT with 
contrast is performed and the presence of brain metastases is considered equivocal, 
an MRI scan of the brain is required to confirm or refute the diagnosis of CNS 
metastases at baseline.   
Patients with active or untreated symptomatic CNS metastases are not eligible for the 
study (see Section 4.1.2).  Patients with untreated asymptomatic CNS metastasis at 
screening may be eligible.  For untreated patients, brain MRI scan with contrast at 
screening is required, and need to meet all eligibility criteria as specified in Section 4.1.2. 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a full 
contrast diagnostic CT scan. 
Further investigations such as bone scans and CT scans of the neck should also be 
performed if clinically indicated.  At the investigator's discretion, other methods of 
assessment of measurable disease as per RECIST v1.1 may be used. 
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days of Cycle 1, Day 1 may be used rather than repeating tests.  All known 
sites of disease, including measurable and/or non-measurable disease, must be 
documented at screening and re-assessed at each subsequent tumor evaluation. 
At subsequent (post-screening) tumor assessments, patients with a history of treated 
brain metastases at screening are not required to undergo brain scans unless clinically 
indicated (e.g., in patients with neurological symptoms).  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). 

 
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For patients with previously untreated CNS metastases, a brain MRI scan with contrast 
is required at screening and is the preferred modality for all subsequent scheduled 
follow-up tumor assessments. 
Note:  CT scan with contrast may be acceptable for all subsequent scheduled follow-up 
tumor assessments if the following criteria are met: 
 
Both brain MRI and CT scan with contrast must be performed at screening to 
assess untreated CNS disease, and  
 
The CT scan with contrast can be used to reliably evaluate lesions identified on the 
screening MRI with contrast.  If CT scan with contrast cannot be used to reliably 
evaluate lesions identified on the screening MRI with contrast, then MRI scan with 
contrast must be used at all subsequent scheduled follow-up tumor assessments.  
The same modality must be used at every tumor assessment. 
 
Untreated CNS disease must be recorded in the Tumor Assessment eCRF per 
RECIST v1.1 at screening as well as at subsequent scheduled follow-up tumor 
assessments. 
Patients will undergo tumor assessments at baseline and at every 6 weeks ( 7 days) for 
48 weeks following Day 1 of Cycle 1, regardless of treatment delays.  After the 
completion of the Week 48 tumor assessment, tumor assessment will be required every 
9 weeks ( 7 days) regardless of treatment delays, until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for patients who continue study 
treatment after disease progression per RECIST v1.1), withdrawal of consent, death, or 
study termination by the Sponsor, whichever occurs first (see Section 3.1.2).  At the 
investigator's discretion, scans may be performed at any time if progressive disease or 
loss of clinical benefit is suspected.  After the CCOD (31 August 2023) of primary 
analysis, we will continue to follow ongoing patients under treatment in the study for 
limited information.  Tumor assessments will no longer be required and investigators 
may continue to report tumor assessment results based on the frequency as per local 
practices to determine if patients have disease progression per RECIST v1.1. 
Response will be assessed by the investigator on the imaging modalities detailed above, 
using RECIST v1.1 (see Appendix 4).  The investigator's assessment of overall tumor 
response at all timepoints should only be based on RECIST v1.1.  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. 
Study treatment may be continued as long as patients are experiencing clinical benefit 
as assessed by the investigator in the absence of unacceptable toxicity or symptomatic 
deterioration attributed to disease progression after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status.  Patients who meet 
criteria for disease progression per RECIST v1.1 will be permitted to continue study 
treatment if they meet all of the criteria specified in Section 3.1.2. 

 
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Patients who discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue 
scheduled tumor assessments at the frequency described above until radiographic 
disease progression per RECIST v1.1, withdrawal of consent, death, or study 
termination by Sponsor, whichever occurs first. 
After the CCOD (31 August 2023) of primary analysis, we will only continue to follow 
ongoing patients under treatment in the study for limited information, and tumor 
assessments are performed to determine if they have disease progression per 
RECIST v1.1.  Tumor assessments will no longer be required for patients who 
discontinue treatment, no matter what the reasons are. 
Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 will continue tumor assessments at the frequency 
described above until radiographic disease progression per RECIST v1.1, withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first. 
Investigator assessment of overall tumor response at all timepoints will be only based on 
RECIST v1.1.  The Sponsor will derive the overall tumor assessment as per iRECIST 
based on entries for all target lesions, non-target lesions, and new lesions.  To facilitate 
evaluation of response per iRECIST, tumor assessments must be continued after 
disease progression per RECIST v1.1 for patients who receive study treatment beyond 
progression.  This includes continued measurement of target lesions, evaluation of 
non-target lesions (including monitoring for further worsening of any non-target lesions 
that have shown unequivocal progression), and evaluation of any newly identified 
lesions (including measurements, if lesions are measurable; see Appendix 4) at all 
subsequent assessments.  
4.5.7 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis.  Central laboratory analysis will be permitted only if local laboratory testing 
is not available. 
 
Hematology:  WBC count with differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes), RBC count, hemoglobin, hematocrit, platelet count, and 
differential count 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, magnesium, potassium, 
calcium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, 
phosphate, total bilirubin, ALP, ALT, AST, and LDH 
 
Coagulation:  INR, and aPTT 
 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4) 

 
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 
HIV serology 
 
HBV serology:  HBsAg, HBsAb, and total HBcAb for all patients; HBV DNA for 
patients with negative HBsAg and HBsAb tests and a positive total HBcAb 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
 
EBV serology, including the following: 
– 
EBV VCA IgM  
– 
EBV PCR (if EBV VCA IgM test not available) 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  During the study, urine pregnancy tests will be performed on Day 1 
of every cycle, and after study treatment is discontinued (see Appendix 1).  
If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood)  
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum samples for tiragolumab and atezolizumab PK analysis through use of 
validated assays 
 
Serum samples for assessment of ADAs to tiragolumab through use of 
validated assays 
 
Serum samples for analysis of autoantibodies 
Serum samples collected for the assessment of pharmacokinetics, ADAs, or 
biomarkers at baseline on Day 1 of Cycle 1 prior to the first dose of study 
treatment may be used for autoantibody testing if an immune-mediated adverse 
event develops in a patient that would warrant such an assessment. 
 
Pre-treatment tumor sample 
A representative formalin-fixed paraffin-embedded (FFPE) pre-treatment tumor 
specimen in the format of slide (10 slides) containing unstained, freshly cut, 
serial sections should be submitted along with an associated pathology report 
for
 
Patients may enroll into the study before submitting a pre-treatment tumor 
tissue sample.  A pre-treatment tumor tissue (archival or freshly obtained) 
sample should be submitted within 4 weeks after randomization unless tissue 
sample collection is not permitted by HGRAC. 
Preferred sample types include FFPE samples prepared from resections, core 
needle, excisional, incisional, punch, or forceps biopsies.  If these sample types 
are not available, any type of specimen (including fine-needle aspiration, cell 
pellet specimens [e.g., from pleural effusion and lavage samples]) is 
acceptable. 

 
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Tumor tissue should be of good quality based on total and viable tumor content.  
Tumor tissue from bone metastases that is subject to decalcification is not 
advisable. 
 
 
  Research may involve using 
next-generation sequencing methods from RNA isolated from the tissue.  
 
 
 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions: 
 
Serum and plasma samples collected for PK or immunogenicity analysis may be 
needed for additional immunogenicity characterization and for PK or immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed, or earlier 
depending on local regulations. 
 
Tumor tissue samples collected for exploratory biomarker research will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed or 
earlier depending on local regulations.  However, the storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements). 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed, or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses 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. 

 
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4.5.8 
Electrocardiograms 
ECG is required at screening and as clinically indicated during the study.  ECGs should 
be obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review all ECG tracings.  
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. 
4.5.9 
Clinical Outcome Assessments 
PRO data will be collected to document the treatment benefit and more fully characterize 
the clinical profile of tiragolumab plus atezolizumab.  PRO data will be collected using 
the following instruments:  EORTC QLQ-C30, single-item EORTC IL46, select items 
from the PRO-CTCAE, and the EQ-5D-5L.  PRO instrument completion is applicable 
through CCOD (31 August 2023) for the primary analysis. 
4.5.9.1 
Data Collection Methods for Clinical Outcome Assessments 
Paper versions of the PRO instruments will be self-administered during the treatment 
visits and interviewer administered by site personnel to the patient over the telephone 
during follow-up visits so that data can be collected without mandating patients' travel to 
the clinical site (see Schedule of Activities in Appendix 1).  PRO data will be entered into 
the study database by the site personnel.  The questionnaires will be translated into the 
local language as required.  For patients who are unable to return to the clinic because 
of government restrictions or personal safety, PROs may be completed by means of 
a telephone call; source documentation should be obtained that includes, among other 
information, the questionnaires administered via telephone. 
To ensure instrument validity and that data standards meet health authority 
requirements, questionnaires scheduled for administration during a clinic visit will be 
completed in their entirety by the patient prior to receiving any information on disease 
status, prior to the performance of non-PRO assessments that could bias patients' 
answers, and prior to the administration of study treatment, unless otherwise specified. 
PROs should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 

 
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 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should not interpret or explain questions but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  
If a response is missing, site staff should ask the patient to complete the item or 
confirm that the item was intentionally left blank. 
 
The questionnaires (EORTC QLQ-C30, EORTC IL46, PRO-CTCAE [select items], 
and EQ-5D-5L) will be completed during the induction phase at Cycle 1, Day 1 
(baseline) prior to administration of study drug; then at every study treatment cycle 
prior to administration of study drug (i.e., on Cycle 2, Day 1; Cycle 3, Day 1; and 
Cycle 4, Day 1). 
Starting at Cycle 5, the questionnaires will be completed at every other study treatment 
cycle prior to administration of study drug (i.e., on Cycle 5, Day 1; Cycle 7, Day 1; 
Cycle 9, Day 1; and so forth), and at the study treatment discontinuation visit 
(see Appendix 1). 
Patients who discontinue study treatment for any reason other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete the 
EORTC QLQ-C30, PRO-CTCAE (select items), and EQ-5D-5L at each tumor 
assessment visit until radiographic disease progression per RECIST v1.1, death, loss 
to follow-up, consent withdrawal, or study termination by the Sponsor, whichever 
occurs first.  Patients who continue to receive treatment after the confirmation of disease 
progression per RECIST v1.1 will complete the questionnaires at every other study 
treatment cycle until study treatment discontinuation. 
During survival follow-up, for patients with radiographic disease progression per 
RECIST v1.1, the PRO questionnaires will be completed at 3 months ( 30 days) and 
6 months ( 30 days) following the visit in which progressive disease was confirmed.  
For patients who continued treatment after disease progression per RECIST v1.1), 
PRO questionnaires will be completed at 3 months [ 30 days] and 6 months [ 30 days] 
following the study treatment discontinuation visit. 
Patients whose native language is not available with the questionnaires are exempted 
from completing all PRO assessments. 
The Sponsor will not derive adverse events reports from PRO data.  

 
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4.5.9.2 
Description of Clinical Outcome Assessment Instruments 
EORTC QLQ-C30  
The EORTC QLQ-C30 is a validated, reliable self-reported measure (Aaronson et al. 
1993; Fitzsimmons et al. 1999) (see Appendix 6).  It consists of 30 questions that assess 
five aspects of patient functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, and six 
single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties) with a recall period of the previous week.  Scale scores can be obtained for 
the multi-item scales.  The functioning and symptoms items are scored on a 4-point 
scale that ranges from "not at all" to "very much," and the GHS and QoL items are 
scored on a 7-point scale that ranges from "very poor" to "excellent."  The EORTC 
QLQ-C30 module takes approximately 15 minutes to complete.   
EORTC IL46 
EORTC IL46 is a validated single-item question assesses overall side-effect impact 
(Appendix 7). 
PRO-CTCAE 
The PRO-CTCAE is a validated item bank that is used to characterize presence, 
frequency, severity, and interference with daily function of 78 patient-reportable 
symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 2015).  
The PRO-CTCAE contains 124 questions that are rated on either a 5-point Likert scale 
(frequency, severity and interference) or dichotomously (presence/absence).  
Included treatment toxicity terms can be subjective, with or without observable 
components (e.g., vomiting and nausea, respectively), or primarily observable with 
subjective components (e.g., rash).  The standard PRO-CTCAE recall period is "the past 
7 days."  A subset of three symptoms that were deemed most applicable to the current 
treatments were selected for this study (Appendix 8). 
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) (see Appendix 9).  
There are two components to the EQ-5D-5L:  a five-item health state profile that 
assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as 
well as a visual analogue scale that measures health state.  The EQ-5D-5L is designed 
to capture the patient's current health status.  Published weighting systems allow for 
creation of a single composite score of the patient's health status.  The EQ-5D-5L takes 
approximately 3 minutes to complete.  It will be used in this study for informing 
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4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
 
Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results if 
available, and the patient's clinical status 
 
Intolerable toxicity related to study 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 
 
Any medical condition that may jeopardize the patient's safety if he or she continues 
on study treatment 
 
Use of another nonprotocol-specified anti-cancer therapy (NPT) 
(see Section 4.4.3) 
 
Pregnancy 
 
Radiographic disease progression per RECIST v1.1 (unless treating beyond 
radiographic progression; see below) 
 
However, to better accommodate standard clinical practice which is guided by the fact 
that patients with ES-SCLC whose disease progresses after 1L treatment have limited 
treatment options and such options also have limited efficacy and significant toxicity, 
patients may be considered for treatment beyond radiographic progression per 
RECIST v1.1 at the discretion of the investigator and after appropriate discussion with 
the patient, only if all of the following criteria are met: 
 
Evidence of clinical benefit as assessed by the investigator 
 
No decline in ECOG Performance Status that can be attributed to disease 
progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Treatment should be discontinued if patients experience any of the following:  
 
Loss of clinical benefit (if treatment with tiragolumab or placebo and atezolizumab) 
or clinical deterioration due to disease progression occurs at any time or if persistent 
disease growth is confirmed as determined by investigator after an integrated 
assessment of radiographic and biochemical data, clinical status, and local biopsy 
results (if available)  
 
Unacceptable toxicity  
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 

 
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Patients will return to the clinic for a treatment discontinuation visit  30 days after the 
final dose of study treatment (see Appendix 1).  The visit at which response assessment 
shows progressive disease may be used as the treatment discontinuation visit.  Patients 
who discontinue study treatment for any reason other than progressive disease or loss 
of clinical benefit will continue to undergo tumor response assessments and PRO 
assessments as outlined in the Schedule of Activities (see Appendix 1).  PRO 
instrument completion is applicable through CCOD (31 August 2023) for the primary 
analysis. 
After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study) (see Appendix 1).  Information on subsequent anti-cancer 
therapies will include systemic therapies (e.g., chemotherapy, targeted therapy, 
hormonal therapy, or cancer immune therapy), surgery (e.g., resection of metastatic 
disease), and radiation procedures (e.g., radiotherapy to a tumor lesion).  Follow-up 
activities completion is applicable through CCOD (31 August 2023) for the primary 
analysis. 
4.6.2 
Patient Discontinuation from the Study 
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 patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 

 
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Patients who have discontinued from treatment and are in survival follow-up before 
CCOD (31 August 2023) will have an end of study visit/call after Protocol Version 6 
(or protocol clarification letter) is effective, whichever occurs earlier. 
4.6.3 
Study 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. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the ICH guideline for Good Clinical Practice (GCP) 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on anticipated mechanism of action, 
results from nonclinical studies, published data on similar molecules, clinical experience 
with tiragolumab alone and in combination with atezolizumab in Phase I and II studies, 
and the clinical safety profile of atezolizumab as a single agent.  The anticipated 
important safety risks for tiragolumab and atezolizumab are outlined below 
(see Sections 5.1.1, 5.1.2, and 5.1.3).  Refer to the Tiragolumab Investigator's Brochure 
and the Atezolizumab Investigator's Brochure for a complete summary of safety 
information for each respective study drug. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  An iDMC has also been incorporated into the study design to 
periodically review safety data (see the iDMC Charter for a detailed monitoring plan). 
Administration of study treatment will be performed in a monitored setting in which there 
is immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  Guidelines for managing patients who 

 
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experience anticipated adverse events, including criteria for treatment interruption or 
discontinuation, are provided in Appendix 13 and Appendix 14.  Refer to 
Sections 5.25.6 for details on safety reporting (e.g., adverse events, pregnancies) for 
this study. 
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 
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 Tiragolumab 
 
 
 Although clinical evaluation of tiragolumab is 
limited and not all risks are known, as an antagonist of TIGIT, tiragolumab is anticipated 
to enhance T-cell and NK-cell proliferation, survival, and function.  Therefore, 
tiragolumab may increase the risk of autoimmune inflammation (also described as 
immune-mediated adverse events).   
Refer to Appendix 14 of the protocol and Section 6 of the Tiragolumab Investigator's 
Brochure for a detailed description of anticipated safety risks for tiragolumab. 
5.1.1.1 
Infusion-Related Reactions 
Because tiragolumab is a therapeutic monoclonal antibody and targets immune cells, 
IRRs associated with hypersensitivity reactions and/or target-mediated cytokine release 
may occur.  Clinical signs and symptoms of such reactions may include rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. 
IRRs have been reported in patients treated with tiragolumab with or without 
atezolizumab.  The majority of events were mild to moderate and manageable. 
To minimize the risk and sequelae of IRRs, the initial dose of tiragolumab/placebo will be 
administered over 60 minutes followed by a 60-minute observation period, and 
subsequent infusions as well as observation times may be shortened only if the dose 
administration is well tolerated.  All infusions will be administered in an appropriate 

 
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medical setting.  Please see Sections 4.3.2.1 and 4.3.2.2 for detailed guidance on 
administration of atezolizumab and tiragolumab/placebo in this study.  Please see 
Appendix 11 for guidance on anaphylaxis precautions, and see Appendix 14 for 
guidance on management of IRRs and risks associated with tiragolumab. 
 
 
 
 
 
 
 
5.1.1.3 
Immune-Mediated Adverse Events 
Nonclinical models have suggested a role of TIGIT signaling interruption in 
autoimmunity.  In a knockout model (TIGIT/), loss of TIGIT signaling resulted in 
hyperproliferative T-cell responses and exacerbation of experimental autoimmune 
encephalitis (EAE).  TIGIT/ and wild-type B6 mice were immunized with myelin 
oligodendrocyte glycoprotein peptide in an EAE using suboptimal doses.  In contrast to 
the wild-type B6 mice, the majority of the TIGIT/ mice developed severe EAE 
(Joller et al. 2011). 
Clinical experience with therapeutics intended to enhance anti-tumor T-cell responses 
has demonstrated that development of autoimmune inflammatory conditions is a general 
risk and may therefore be considered a potential risk of tiragolumab.  Such 
immune-mediated adverse events have been described for virtually all organ systems 
and include, but are not limited to, colitis, pneumonitis, endocrinopathies, ocular toxicity, 
pancreatic toxicity, neurologic toxicity, cardiac toxicity, nephritis, myositis, and severe 
cutaneous adverse reactions.  Refer to the Tiragolumab Investigator's Brochure for more 
details on these adverse events. 
Patients with a history of autoimmune disease will be excluded from this study 
(see Section 4.1.2). 
Management guidelines for individual suspected immune-mediated adverse events are 
provided in Appendix 14. 
 
 
 
 
 

 
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5.1.1.5 
Embryofetal Toxicity 
Embryofetal toxicity is a potential risk with tiragolumab.  Administration of tiragolumab is 
expected to have adverse effects on pregnancy based on the expression of TIGIT on 
decidual NK and CD8  T cells (Powell et al. 2017; van der Zwan et al. 2018; 
Vento-Tormo et al. 2018), and the expected role of these cells in the recognition and 
response to foreign fetal, placental, and viral antigens at the maternal-fetal interface as 
well as maintenance of maternal-fetal tolerance.  No reproductive or teratogenicity 
studies in animals have been conducted with tiragolumab.  There are no clinical studies 
of tiragolumab in pregnant women.  Tiragolumab should not be administered to pregnant 
women. 
Refer to Section 6 of the Tiragolumab Investigator's Brochure for a detailed description 
of embryofetal toxicity. 
5.1.2 
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 14 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab.   
5.1.3 
Risks Associated with Combination Use of Tiragolumab and 
Atezolizumab 
Based on clinical data with tiragolumab and atezolizumab, there are known and potential 
overlapping toxicities in patients treated with tiragolumab plus atezolizumab.  Because 
the expected pharmacologic activity of these two molecules is to increase adaptive T-cell 
immune responses, there is the possibility of heightened immune responses.   
Refer to Section 6 of the Tiragolumab Investigator's Brochure for a list of identified risks 
associated with tiragolumab in combination with atezolizumab.  Based on the 
mechanism of action of tiragolumab and atezolizumab, additional immune-mediated 
adverse events are potential overlapping toxicities associated with combination use of 
tiragolumab plus atezolizumab. 

 
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Based on clinical experience to date, it is anticipated that immune-mediated adverse 
events following treatment with tiragolumab and atezolizumab will be amenable to 
monitoring and manageable in the setting of this combination study.  The extensive 
experience with immune checkpoint inhibitors to date has been incorporated into the 
design and safety management plan (see Section 5.1) in order to reduce the potential 
risks to participating patients.  Patients with a history of autoimmune disease will be 
excluded from this study (other than autoimmune thyroid disease managed with 
thyroid-hormone replacement or vitiligo, see Section 4.1.2).  Patients previously treated 
with approved or experimental cancer immune therapies will also be excluded from 
participation in this study. 
Owing to the risks of active viral infection and viral reactivation, patients with active 
infection (including, but not limited to, HIV, HBV, HCV, EBV, known and/or suspected 
chronic active EBV infection, or tuberculosis) and/or patients with recent severe 
infections will be excluded from this study (see Section 4.1.2). 
5.1.4 
Risks Associated with Etoposide 
The risk of overlapping toxicities between tiragolumab plus atezolizumab and etoposide 
is thought to be minimal (see Section 5.1.7).  Etoposide is known to cause bone marrow 
suppression including myelosuppression, anemia, thrombocytopenia, gastrointestinal 
symptoms (e.g., nausea, vomiting, diarrhea), hepatotoxicity, and alopecia.  
Etoposide-based chemotherapy is considered to be moderately emetogenic.  
Etoposide carries a risk of secondary hematologic malignancy.  Patients will be 
monitored for etoposide-related adverse events. 
For more details regarding the safety profile of etoposide, refer to the local etoposide 
prescribing information. 
5.1.5 
Risks Associated with Carboplatin 
The risk of overlapping toxicities between tiragolumab plus atezolizumab and carboplatin 
is thought to be minimal (see Section 5.1.7).  Carboplatin is known to cause bone 
marrow suppression including myelosuppression, anemia, and thrombocytopenia.  
Carboplatin-based chemotherapy is considered to be moderately emetogenic.  
Patients will be monitored for carboplatin-related adverse events. 
For more details regarding the safety profile of carboplatin, refer to the local carboplatin 
prescribing information. 
5.1.6 
Management of Patients Who Experience Adverse Events 
5.1.6.1 
Dose Modification 
 
 
  

 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.6.2 
Tiragolumab and/or Atezolizumab Dose Modification, 
Treatment Interruption, or Treatment Discontinuation 
Dose Modifications 
 
 
Treatment Interruption 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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5.1.6.4 
Chemotherapy Dose Modifications, Treatment Delays, or 
Treatment Discontinuation and Management of Specific 
Adverse Events 
Refer to Appendix 13 for details on chemotherapy dose modifications, treatment delays, 
or treatment discontinuation and management of specific adverse events. 
5.1.7 
Potential Overlapping Toxicities 
Based on nonclinical and/or clinical studies with tiragolumab or atezolizumab as a single 
agent, clinical data from studies with tiragolumab and atezolizumab as a combination 
therapy, and data from molecules with similar mechanisms of action, there is a potential 
for overlapping toxicity in patients treated with tiragolumab plus atezolizumab.  Because 
the expected pharmacologic activity of these two molecules is to increase adaptive T‑cell 
immune responses, there is the possibility of heightened immune responses.  
The following adverse events are potential overlapping toxicities associated with 
combination use of tiragolumab plus atezolizumab:  immune-mediated pulmonary, 
hepatic, gastrointestinal, renal, endocrine, ocular, pericardial disorders, pancreatic, 
dermatologic, neurologic adverse events, HLH, and MAS, as well as immune-mediated 
myocarditis, meningoencephalitis, myositis, and severe cutaneous adverse reactions. 
Based on the clinical experience to date, it is anticipated that immune-mediated adverse 
events following treatment with tiragolumab and atezolizumab will be amenable to 
monitoring and manageable in the setting of this combination study.  The extensive 
experience with immune checkpoint inhibitors to date has been incorporated into the 
design and safety management plan (see Section 5.1) in order to reduce the potential 
risks to participating patients.  Patients with a history of autoimmune disease will be 
excluded from this study (see Section 4.1.2).  Patients previously treated with approved 
or experimental cancer immune therapy will also be excluded from participation in this 
study.  Due to the risks of active viral infection and viral reactivation, patients with active 
infection (including, but not limited to, HIV, HBV, HCV, EBV, known and/or suspected 
chronic active EBV infection, or tuberculosis) and/or patients with recent severe 
infections will be excluded from this study (see Sections 4.1.1 and 4.1.2). 
The risk of overlapping toxicities between tiragolumab plus atezolizumab and carboplatin 
and etoposide is thought to be minimal.  Nevertheless, the attribution and management 
of certain adverse events that have been associated with each agent separately 
(e.g., hepatotoxicity, skin and gastrointestinal toxicity) may be ambiguous when the 
agents are administered together.  It is theoretically possible that allergic or inflammatory 
adverse events associated with carboplatin and etoposide (e.g., dermatitis, 
infusion-associated symptoms) could be exacerbated by the immunostimulatory activity 
of tiragolumab and/or atezolizumab. 
Toxicities should initially be managed according to the recommendations in 
Sections 5.1.5 and 5.1.6 and Appendix 13, with dose holds and modifications 
(if applicable) applied to the component of the study drug judged to be the primary 

 
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cause.  For severe (Grade 3) or persistent Grade 12 diarrhea, an endoscopic 
evaluation should be considered.  Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology for adverse events 
listed above.  If, in the opinion of the investigator, tiragolumab and/or atezolizumab is 
a potential inciting factor, the dose of tiragolumab and/or atezolizumab may be held for 
a maximum of 12 weeks (or 4 cycles) after event onset (see Appendix 13).  
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.  Prompt symptomatic management is appropriate for mild 
immune-mediated adverse events.  In severe cases, immune-mediated toxicities may be 
acutely managed with systemic corticosteroids or TNF- inhibitors.  These cases should 
be discussed with the Medical Monitor. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and 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) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
 
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 treatment 
 
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) 
 

 
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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 treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
 
 
 
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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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). 

 
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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained, but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 
 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events will continue to be reported until 
 days after the final dose of study treatment or until initiation of new systemic 
anti-cancer therapy, whichever occurs first.  In addition, adverse events of special 
interest will continue to be reported until 
 days after the final dose of study treatment, 
regardless of initiation of new systemic anti-cancer therapy. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 

 
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5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated  
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
  

 
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The ASTCT CRS consensus grading scale (see Table 5) should be used in addition 
to NCI CTCAE when reporting severity of CRS (see Section 5.3.5.1 for details on 
CRS reporting). 
Table 5 
ASTCT CRS Consensus Grading 
Grade 
Symptoms 
1 
 Fever a with or without constitutional symptoms (such as myalgia, arthralgia, 
or malaise) 
 No hypotension 
 No hypoxia 
2 
 Fever a combined with at least one of the following: 
– Hypotension not requiring vasopressors 
– Hypoxia requiring low-flow oxygen b by nasal cannula or blow-by 
3 
 Fever a combined with at least one of the following: 
– Hypotension requiring one vasopressor c 
– Hypoxia requiring high-flow oxygen b by nasal cannula, face mask, 
non-rebreather mask, or Venturi mask 
4 
 Fever a combined with at least one of the following: 
– Hypotension requiring two or more vasopressors  
– Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, 
intubation and mechanical ventilation) 
5 
 Death due to CRS in which another cause is not the principal factor leading 
to this outcome 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive 
airway pressure; CPAP  continuous positive airway pressure; CRS  cytokine-release 
syndrome. 
a Fever is defined as temperature  38C not attributable to any other cause.  In patients who 
develop CRS and then receive antipyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining CRS severity (grade).  In this case, the CRS 
grade is driven by the presence of hypotension and/or hypoxia. 
b Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at  6 L/min. 
   

 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 6): 
 
Temporal relationship of event onset to the initiation of study treatment 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment 
(as applicable) 
 
Known association of the event with study treatment or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 6 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
  
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. 

 
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5.3.5.1 
Infusion-Related Reactions and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and CRS.  While IRRs 
occur during or within 24 hours after treatment administration, time to onset of CRS may 
vary.  Differential diagnosis should be applied, particularly for late-onset CRS (occurring 
more than 24 hours after treatment administration), to rule out other etiologies such as 
delayed hypersensitivity reactions, sepsis or infections, HLH, tumor lysis syndrome, 
early disease progression, or other manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration 
and are judged to be related to study treatment infusion should be captured as a 
diagnosis (e.g., "infusion-related reaction" or "cytokine-release syndrome") on the 
Adverse Event eCRF.  Avoid ambiguous terms such as "systemic reaction."  Cases of 
late-onset CRS should be reported as "cytokine-release syndrome" on the Adverse Event 
eCRF.  Associated signs and symptoms should be recorded on the dedicated 
Infusion-Related Reaction eCRF or Cytokine-Release Syndrome eCRF, as appropriate.  
If a patient experiences both a local and systemic reaction to the same dose of study 
treatment, each reaction should be recorded separately on the Adverse Event eCRF, with 
signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF or Cytokine-Release Syndrome eCRF. 
NCI CTCAE v5.0 and the ASTCT CRS consensus grading scale (see Section 5.3.3) 
should be used when reporting severity of CRS on the Adverse Event eCRF.  
NCI CTCAE v5.0 should be used when reporting severity of organ toxicities associated 
with CRS on the dedicated Cytokine-Release Syndrome eCRF.  Organ toxicities 
associated with CRS should not influence overall CRS grading. 
Guidelines for medical management of IRRs and CRS are provided in Table 7 and 
Table 8, respectively, of Appendix 14. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF, rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 

 
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5.3.5.3 
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. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
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 meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 

 
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Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
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. 
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 meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 

 
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Observations of the same clinically significant vital sign abnormality from visit to visit 
should 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  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  ULN 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 SCLC should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the 
adverse event reporting period, regardless of relationship to study treatment, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2).  An iDMC will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 

 
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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"). 
5.3.5.10 
Lack of Efficacy or Worsening of SCLC 
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.  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 treatment 
administration or performance of an efficacy measurement for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
Hospitalization due solely to progression of the underlying cancer 
 

 
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (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 
 
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. 
 
Special situations are not in 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 tiragolumab (or matching placebo) and atezolizumab, 
adverse events associated with special situations should be recorded as described 
below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
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 "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with tiragolumab (or matching placebo) and 
atezolizumab, regardless of whether they result in an adverse event, should be recorded 
on the Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
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 "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 

 
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 
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. 
 
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 "Accidental 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-CTCAE or other PRO data by the 
Sponsor.  In addition, the Sponsor will make no attempt to reconcile patient reports of 
treatment-related symptoms (via PRO-CTCAE) with investigator reports of adverse 
events.  Sites are not expected to review the PRO-CTCAE or other PRO data for 
adverse events.  
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information 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. 

 
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5.4.1 
Medical Monitor and Emergency Medical Contact 
Contact Information for All Sites 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators.  
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. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained, but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting 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. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events will be reported until 
 days 
after the final dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first.  In addition, adverse events of special interest will 
continue to be reported until 
 days after the final dose of study treatment, regardless 
of initiation of new systemic anti-cancer therapy.  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 paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting 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. 

 
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Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study, or 
within 90 days after final dose of tiragolumab or placebo, 5 months after the final dose of 
atezolizumab, or 6 months after the final dose of carboplatin or etoposide, whichever is 
later.  A paper 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 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  
In addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant while receiving chemotherapy 
study treatment (i.e., carboplatin and etoposide) or within 90 days after the final dose of 
tiragolumab or placebo, or 6 months after the final dose of chemotherapy study 
treatment, whichever is later.  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 treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form 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. 

 
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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 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study treatment 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, email, 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. 

 
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5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (as defined in Section 5.3.1), all deaths, regardless of cause, should be 
reported through use of the Long-Term Survival Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety 
of a study treatment under clinical investigation.  The Sponsor will comply with 
regulatory requirements for expedited safety reporting to regulatory authorities (which 
includes the use of applicable systems, such as EudraVigilance), IRBs, ECs, and 
investigators. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Tiragolumab 
Tiragolumab Investigator's Brochure 
Atezolizumab 
Atezolizumab Investigator's Brochure 
  
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 

 
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 
PFS curve following one-piece exponential distributions  
 
Median PFS of 
 months in Arm A and 
 months Arm B, corresponding to 
a target HR of 
   
 
Dropout rate of 
 over 12 months for PFS  
 
6.1.2 
Co-Primary Endpoint:  Overall Survival in the Primary 
Analysis Set 
 
 
 
OS curve following one-piece exponential distributions  
 
Median OS of 
 months for Arm A and 
 months for Arm B, corresponding to 
a target HR of 
 
 
Dropout rate of 
 over 24 months for OS  
 

 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, study drug administration, reasons for study drug discontinuation, and 
reasons for study termination will be summarized by treatment arm.  Major protocol 
deviations, including major deviations of inclusion/exclusion criteria, will be reported and 
summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG Performance Status) will be summarized by treatment arm.  
Descriptive statistics (mean, median, standard deviation, and range) will be presented 
for continuous data, and frequencies and percentages will be presented for categorical 
data, as appropriate. 
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of protocol treatment. 
6.4 
EFFICACY ANALYSES 
Unstratified analysis will be considered as primary results given the potential small 
sample size within each stratum.  The stratified analysis will also be provided.  
The stratification factors will be the same as the randomization stratification factors used 
for IxRS (ECOG Performance Status and LDH) and applied to all endpoints where 
stratification analyses are planned.  Stratification factor(s) may be removed from the 
stratified analyses if there is risk of overstratification.  Analyses based on stratification 
factors recorded on the eCRF will also be provided if considerable discrepancy is 
observed between IxRS and eCRF records. 
6.4.1 
Co-Primary Efficacy Endpoints 
The co-primary efficacy endpoints are PFS (as assessed by the investigator according to 
RECIST v1.1) and OS in the PAS. 
PFS is defined as the time between the date of randomization and the date of first 
documented disease progression (as assessed by investigators according to 
RECIST v1.1) or death, whichever occurs first.  Patients who have not experienced 
disease progression and have not died by the time of analysis will be censored at the 
time of the last tumor assessment.  Patients with no post-baseline tumor assessment will 
be censored at the date of randomization. 
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Data for patients who are not reported as having died by the date of analysis will be 
censored at the date when they were last known to be alive.  Data for patients who do not 
have post-baseline information will be censored at the date of randomization. 
PFS and OS will be compared between treatment arms with use of the unstratified 
log-rank test.  The HR for PFS and OS will be estimated using both unstratified and 
stratified Cox proportional hazards model.  The 95% CI for the HR will be provided. 
 
 
 
 
  The investigator-assessed 
PFS rates at 6 months and at 1 year and OS rates at 1 year, 18 months, and 2 years 
after randomization will be estimated using Kaplan-Meier methodology for each 
treatment arm, along with 95% CIs calculated using the standard error derived from 
Greenwood's formula.  The 95% CI for the difference in PFS rates and OS rates 
between the two treatment arms will be estimated using the normal approximation 
method. 
The timing of the final PFS analysis is described in Section 6.1.1 and the analysis timing 
for OS is described in Section 6.1.2. 
6.4.2 
Secondary Efficacy Endpoints 
6.4.2.1 
Progression-Free Survival and Overall Survival in the Full 
Analysis Set 
PFS and OS in the FAS will be analyzed at the same time with the PAS, using the same 
methods as described in Section 6.4.1. 
6.4.2.2 
Objective Response Rate 
A confirmed objective response is defined as either a confirmed CR or a PR, on two 
consecutive occasions  4 weeks apart, as determined by the investigator using 
RECIST v1.1.  Patients not meeting these criteria, including patients without any 
post-baseline tumor assessment, will be considered non-responders. 
Confirmed ORR is defined as the proportion of patients who had a confirmed objective 
response.  The analysis population for confirmed ORR will be the PAS and the FAS with 
measurable disease at baseline.  An estimate of confirmed ORR and its 95% CI will be 
calculated using the Wilson score method for each treatment arm.  CIs for the difference 
in confirmed ORRs between the two treatment arms will be determined using the 
Newcombe method. 

 
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6.4.2.3 
Duration of Response 
DOR will be assessed in patients who had a confirmed objective response as 
determined by the investigator using RECIST v1.1 in the PAS and the FAS.  DOR is 
defined as the time interval from the date of the first occurrence of a confirmed objective 
response until the first date that progressive disease as determined by the investigator 
using RECIST v1.1 or death is documented, whichever occurs first.  Patients who have 
not progressed and who have not died at the time of analysis will be censored at the 
time of last tumor assessment date.  DOR is based on a non-randomized subset of 
patients (specifically, patients who achieved an objective response); therefore, formal 
hypothesis testing will not be performed for this endpoint.  Comparisons between 
treatment arms will be made for descriptive purposes.  The methodologies detailed for 
the PFS analysis will be used for the DOR analysis. 
6.4.2.4 
Patient-Reported Outcomes 
TTCD in the PAS and the FAS for physical functioning and GHS using the EORTC 
QLQ-C30 is defined as the time from the date of randomization until the first confirmed 
clinically meaningful deterioration.  Confirmed clinically meaningful deterioration for GHS 
and physical functioning is defined as a clinically meaningful decrease from baseline in 
GHS or physical functioning scale score that must be held for at least two consecutive 
assessments or an initial clinically meaningful decrease above baseline followed by 
death.  A score change of  10-point is considered to be clinically meaningful by 
patients for lung cancer-related symptoms, GHS and physical functioning subscale score 
(Osaba et al. 1998). 
For TTCD, data for patients will be censored at the last time when they completed an 
assessment if they have not experienced a confirmed clinically meaningful deterioration 
event at the CCOD.  If no baseline or post-baseline assessment is performed, patients 
will be censored at the randomization date.  TTCD using the EORTC scale will be 
analyzed using the same methods as for PFS.  Further details regarding the TTCD 
analyses for the EORTC measures will be described in the SAP. 
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) and the 
mean change from baseline of linear-transformed scores will be reported for all of the 
items and subscales of the EORTC QLQ-C30 and EORTC IL46 (an item for troubled by 
side effects) questionnaires at each timepoint, the end of treatment, at the time of 
progression (per RECIST criteria), and at the time of clinical progression (if different from 
time to progression).  In addition, mean scores for GHS, physical functioning, and 
selected symptom scales will be presented for the induction phase and the 
maintenance phase. 
PRO-CTCAE data will be analyzed by treatment arm, the number (percentage) of 
patients reporting symptom by "frequency," "severity," "interference," and "presence" at 
each assessment.  In addition, the frequency of symptoms will be cross tabulated with 
the severity of the symptom to explore the impact of the symptom when it occurred.  

 
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A summary table of the percentage of patients reporting severity of a symptom as 
'severe' or 'very severe' over the course of the study by treatment arm will also be 
provided.  Finally, a longitudinal analysis of change may be employed to understand how 
symptoms may have changed over the course of treatment. 
Completion and compliance rates will be summarized at each timepoint by 
treatment arm. 
6.5 
SAFETY ANALYSES 
Safety analyses will be conducted in all randomized patients who received at least one 
dose of study treatment. 
Safety analyses will be performed by treatment arm and will be based on actual 
treatment received.  Specifically, a patient will be included in the tiragolumab containing 
arm in the safety analyses if the patient receives any amount of tiragolumab, regardless 
of the initial treatment assignment at randomization. 
Drug exposure will be summarized, including duration, dosage, and dose intensity. 
Verbatim description of adverse events will be mapped to the MedDRA thesaurus terms.  
Severity for all adverse events will be graded by the investigator according to the 
NCI CTCAE v5.0, and severity for CRS will also be graded by the investigator according 
to the ASTCT consensus grading scale.  All adverse will be summarized by treatment 
arm and NCI CTCAE grade.  CRS will also be summarized by treatment arm and the 
ASTCT consensus grade.  In addition, serious adverse events and adverse events 
leading to study treatment discontinuation or interruption will be summarized 
accordingly.  Multiple occurrences of the same event will be counted once at the 
maximum severity.  Laboratory data with values outside of the normal ranges will be 
identified.  Additionally, selected laboratory data, including ADA results, will be 
summarized by treatment arm and grade.  Vital signs will also be summarized by 
treatment arm and visit.  Deaths and causes of deaths will be summarized. 
Completion and compliance rates will be summarized at each timepoint by treatment 
arm.  The analysis populations for PROs will be all randomized patients.  The analysis 
populations for PRO changes will be all randomized patients with a non-missing baseline 
assessment and at least one non-missing post-baseline assessment. 
6.6 
PHARMACOKINETIC ANALYSES 
Samples will be collected for PK analyses and to compare exposure in this study with 
that attained in previous studies.  Serum concentrations of tiragolumab and 
atezolizumab will be reported as individual values and summarized (mean, standard 
deviation, coefficient of variation, median, range, geometric mean, and geometric mean 
coefficient of variation) by treatment arm and cycle, when appropriate and as data allow.  
Individual and median serum tiragolumab and atezolizumab concentrations will be 

 
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plotted by treatment arm and day.  Tiragolumab and atezolizumab concentration data 
may be pooled with data from other studies using an established population-PK model to 
derive PK parameters such as clearance, volume of distribution, and AUC, as warranted 
by the data.  Potential correlations of relevant PK parameters with safety, efficacy, or 
biomarker outcomes may be explored. 
Schedule for collection of PK samples is outlined in Appendix 2. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with any ADA assessments, with 
patients grouped according to treatment received. 
The numbers and proportions of treatment-emergent ADA-positive patients and 
ADA-negative patients during both the treatment and follow-up periods for tiragolumab 
will be summarized by treatment arm. 
The relationship between ADA status and safety, efficacy, and PK endpoints may be 
analyzed and reported via descriptive statistics. 
6.8 
BIOMARKER ANALYSES 
No formal statistical testing will be conducted for the exploratory biomarker analyses.  
Results of these analyses may be reported separately from the Clinical Study Report. 
6.9 
EXPLORATORY ANALYSES 
 
 
 
 
  
 
 
 
6.9.1.2 
Safety Monitoring 
An external iDMC will be set up to evaluate safety data on an ongoing basis.  
All summaries/analyses by treatment arm for the iDMC's review will be prepared by an 
iDCC.  Members of the iDMC will be external to the Sponsor and will follow a charter that 

 
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outlines their roles and responsibilities.  Any outcomes of these safety reviews that affect 
study conduct will be communicated in a timely manner to the investigators for 
notification of the IRBs/ECs.  A detailed plan will be included in the iDMC Charter. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in 
a readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review 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. 

 
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Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical 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 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
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. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for 15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 

 
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Roche will retain study data for 25 years after the final study results have been reported 
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 GCP 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). 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, 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. 
If the Consent Forms are revised (through an amendment or an addendum) while 
a patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 

 
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addendum, in accordance with applicable laws and IRB/EC policy.  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. 
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 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
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. 
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. 

 
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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 exploratory biomarker analyses, data 
derived from these analyses 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 
(see Section 9.6). 
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. 
Study data, which may include data on genomic variants, 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 (see Section 9.6). 
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 (see definition of end of 
study in Section 3.2). 
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. 

 
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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 GCP guidelines and require reporting to 
health authorities.  As per the Sponsor's standard operating procedures, prospective 
requests to deviate from the protocol, including requests to waive protocol eligibility 
criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks.  Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 15 sites in China will participate in the study and approximately 
128 patients will be randomized during the study.  Screening and enrollment will occur 
through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 

 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
112/Protocol YO42373, Version 6 
An iDMC will monitor and evaluate patient safety throughout the study, as detailed in 
Section 3.1.3.  An external iDCC will prepare all summaries and analyses for review by 
the iDMC. 
9.6 
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. 
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. 

 
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9.7 
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.  

 
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10. 
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Appendix 1  
Schedule of Activities 
Procedure 
Screening 
All Treatment Cycles a 
Treatment Discontinuation Visit 
Survival 
Follow-Up 
Days  28 
to  1 
Induction 
Phase 
(Cycles 
14) 
Maintenance 
Phase (Starting from Cycle 5) 
 30 Days after Last Dose of Study 
Treatment 
Every 3 Months 
after Disease 
Progression  
Every 21 
Days 
( 3 Days) b 
Every 21 Days 
( 3 Days)  
Informed consent 
x 
 
 
 
 
Screening tumor tissue specimen for 
biomarker testing  
Demographic data 
x 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
SCLC cancer history 
x 
 
 
 
 
Vital signs d 
x 
x  
x 
x  
 
Weight 
x 
x 
x 
x 
 
Height 
x 
 
 
 
 
Complete physical examination 
x 
 
 
 
 
Limited physical examination e 
 
x f 
x f 
x 
 
ECOG Performance Status 
x 
x f 
x f 
x 
 
ECG 
x 
Perform when clinically indicated  
 
Hematology g 
x h 
x f 
x f 
x 
 
Serum chemistry i  
x h 
x f 
x f 
x 
 

Appendix 1: 
Schedule of Activities 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
120/Protocol YO42373, Version 6 
Procedure 
Screening 
All Treatment Cycles a 
Treatment Discontinuation Visit 
Survival 
Follow-Up 
Days  28 
to  1 
Induction 
Phase 
(Cycles 
14) 
Maintenance 
Phase (Starting from Cycle 5) 
 30 Days after Last Dose of Study 
Treatment 
Every 3 Months 
after Disease 
Progression  
Every 21 
Days 
( 3 Days) b 
Every 21 Days 
( 3 Days)  
Coagulation test (aPTT and INR) 
x h 
 
 
x 
 
Pregnancy test (women of 
childbearing-potential only) 
x j 
x k 
x k 
x k 
 
TSH, free T3, free T4 l 
x 
x l 
x l 
x 
 
HIV, HBV, HCV, EBV serology m 
x 
 
 
 
 
Urinalysis n 
x n 
Perform when clinically indicated 
 
Induction treatment administration  
Arm A:  
atezolizumab  tiragolumab  CE 
Arm B:  atezolizumab  placebo   CE  
 
x o 
 
 
 
Maintenance treatment administration 
Arm A:  atezolizumab  tiragolumab  
Arm B:  atezolizumab  placebo 
 
 
x p 
 
 
PCI 
 
 
x p 
 
 
Tumor response assessment  
x q 
x r 
x r 
 
x s, t 

Appendix 1: 
Schedule of Activities 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
121/Protocol YO42373, Version 6 
Procedure 
Screening 
All Treatment Cycles a 
Treatment Discontinuation Visit 
Survival 
Follow-Up 
Days  28 
to  1 
Induction 
Phase 
(Cycles 
14) 
Maintenance 
Phase (Starting from Cycle 5) 
 30 Days after Last Dose of Study 
Treatment 
Every 3 Months 
after Disease 
Progression  
Every 21 
Days 
( 3 Days) b 
Every 21 Days 
( 3 Days)  
Adverse events 
x  
x 
x 
x u 
x u 
Cancer-related procedures (medical, 
surgical, and radiation) 
 
x 
x 
x 
x 
Concomitant medications  
x v 
x v 
x v 
x v 
 
Patient-reported outcomes 
(EORTC QLQ-C30, EORTC IL46, 
PRO-CTCAE [select items], and 
EQ-5D-5L) w 
 
x t, w 
x t, w 
x t, w 
x t, w 
Survival and anti-cancer therapy 
follow-up 
 
 
 
 
x t, x 
CE  carboplatin and etoposide; CT  computed tomography; EBV  Epstein-Barr virus; ECOG  Eastern Cooperative Oncology Group; 
eCRF  electronic Case Report Form; EORTC  European Organisation for Research and Treatment of Cancer; EQ-5D-5L  EuroQoL 5 Dimensions 5-Level 
Version; HBcAb  hepatitis B core antibody; HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HCV  hepatitis C virus; MRI  magnetic resonance 
imaging;  nonsmall cell lung cancer; PCI  prophylactic cranial irradiation; PCR  polymerase chain reaction; PD  pharmacodynamic;
 
PRO  Patient-Reported Outcome; QLQ-C30  Quality-of-Life Questionnaire Core 30; PRO-CTCAE = Patient-Reported Outcomes of the Common Terminology 
Criteria for Adverse Events; RECIST  Response Evaluation Criteria in Solid Tumors; SCLC  small cell lung cancer; TSH  thyroid-stimulating hormone. 

Appendix 1: 
Schedule of Activities 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
122/Protocol YO42373, Version 6 
a Assessments should be performed before study drug infusion unless otherwise noted. 
b Cycle 1 must be performed within 5 days after the patient is randomized.  Screening assessments performed  96 hours before Cycle 1, Day 1 are not required 
to be repeated for Cycle 1, Day 1. 
c A pre-treatment tumor tissue specimen is required.  This pre-treatment tumor tissue (archival or freshly obtained) sample should be submitted within 4 weeks 
after randomization unless tissue sample collection is not permitted by Human Genetic Resources Administration of China.  This specimen must be 
accompanied by the associated pathology report.  A representative formalin-fixed paraffin-embedded pre-treatment tumor specimen in the format of slide 
(10 slides) containing unstained, freshly cut, serial sections should be submitted.  See Section 4.5.7 for details. 
d Vital signs include pulse rate, respiratory rate, blood pressures, and temperature.  Vital signs should be recorded as described in Section 4.5.4. 
e Symptom-directed physical examinations; see Section 4.5.3 for details. 
f ECOG Performance Status, a limited physical examination, and local laboratory assessments may be obtained  96 hours before Day 1 of each cycle and are 
not required to be repeated on Cycle 1, Day 1. 
g Hematology includes WBC count with differential (neutrophils, eosinophils, basophils, monocytes, lymphocytes), RBC count, hemoglobin, hematocrit, platelet 
count, and differential count.  
h At screening, the patient must have adequate hematologic and end-organ function defined by laboratory test results obtained within 14 days prior to 
randomization.  See Section 4.1.1 for details. 
i Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, magnesium, potassium, 
chloride, calcium, phosphate, glucose, BUN or urea, creatinine, total  protein, albumin, total bilirubin, ALP, ALT, AST, and LDH.  
j 
Serum pregnancy test within 14 days before Cycle 1, Day 1. 
k Urine pregnancy tests; if a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test. 
l TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed  96 hours before Day 1 of Cycles 1, 5, 9, and 13, and every 
fourth cycle thereafter.  The Cycle 1 thyroid function testing does not need to performed if the previous test was performed within the screening window. 
M All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the study.  Patients with active hepatitis B 
(chronic or acute; defined as having a positive HBsAg test result at screening) will be excluded from the study.  Patients with past or resolved HBV infection 
(defined as the presence of HBcAb and absence of HBsAg) are eligible; HBV DNA should be obtained in these patients prior to randomization.  Patients with HCV 
will be excluded from the study; patients who test positive for HCV antibody are eligible only if PCR is negative for HCV RNA.  EBV serology samples will be 
collected at screening, and an EBV IgM test or EBV PCR test is required prior to randomization.  Additional EBV serology tests will be performed for patients who 
subsequently experience an acute inflammatory event, such as systemic inflammatory response syndrome, while receiving study treatment. 
n Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood).  Urinalysis is required at screening and will be obtained when clinically 
indicated. 

Appendix 1: 
Schedule of Activities 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
123/Protocol YO42373, Version 6 
o For tiragolumab/placebo and atezolizumab, the initial dose will be administered over 60 ( 15) minutes.  If the first infusion is well tolerated, subsequent infusions 
may be administered over 30 ( 10) minutes, respectively (see Sections 4.3.2.1 and 4.3.2.2).  For carboplatin and etoposide, study drug will be administered as 
described in Section 4.3.2.  Infusions should be given in the following order:  atezolizumab →tiragolumab/placebo → carboplatin → etoposide.  
p During the maintenance phase, infusions should be given in the following order:  atezolizumab → tiragolumab/placebo.  Additionally, during this phase, PCI is 
permitted as per local standard of care and will be reported on the Prophylactic Cranial Irradiation eCRF.  
q CT scans (with oral/IV contrast unless contraindicated) or MRI scans of the chest and abdomen.  A CT or MRI scan of the pelvis is required at screening and as 
clinically indicated or as per local standard of care at subsequent response evaluations.  A CT (with contrast) or MRI scan of the head must be done at screening 
to evaluate CNS metastasis in all patients.  See Section 4.5.6 for details. 
r Perform every 6 weeks ( 7 days) for 48 weeks following Cycle 1, Day 1 and then every 9 weeks ( 7 days) thereafter, after completion of the Week 48 tumor 
assessment, regardless of treatment delays, until radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for patients who continue study 
treatment after disease progression per RECIST v1.1), withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.   
s If the patient discontinues study treatment for any reason other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic 
deterioration), tumor assessments will continue at the same frequency as would have been followed if the patient had remained on study treatment (i.e., every 
6 weeks [ 7 days] for 48 weeks following Cycle 1, Day 1 and then every 9 weeks [ 7 days] thereafter) until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first, even if the patient starts another anti-cancer therapy after study 
treatment discontinuation.  See Section 4.5.6 for details. 
t Assessments and sample collections no longer required post clinical cutoff date for the primary analysis (actual date 31 Augu st 2023).  Upon reaching this 
milestone, no further data collection and analysis relating to these assessments is required for this study.  
u All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 
 days after the last dose of 
study drug or initiation of new systemic anti-cancer therapy after the last dose of study drug, whichever occurs first.  All other adverse events, regardless of 
relationship to study drug, will be reported until 
 days after the last dose of study drug or initiation of new systemic anti-cancer therapy after the last dose of 
study drug, whichever occurs first.  After this period, all deaths should continue to be reported.  In addition, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event or adverse event of special interest that is believed to be related to prior exposure to study treatment 
(see Section 5.6).  These events should be reported using the Adverse Event eCRF.   
v From 7 days before screening until the treatment discontinuation visit.  All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 

Appendix 1: 
Schedule of Activities 
  
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w EORTC QLQ-C30, EORTC IL46, PRO-CTCAE (select items), and the EQ-5D-5L questionnaires will be completed by the patients on paper prior to 
administration of study drug.  The questionnaires will be completed at Cycle 1, Day 1 (baseline); Cycle 2, Day 1; Cycle 3, Day 1; and Cycle 4, Day 1.  At Cycle 5, 
the questionnaires will be completed at every other study treatment cycle prior to the administration of study drug (i.e., on Cycle 5, Day 1; Cycle 7, Day 1; 
Cycle 9, Day 1; etc.).  PROs will be collected during the treatment period until radiographic disease progression per RECIST v1.1, and at the study treatment 
discontinuation.  Patients who continue to receive treatment after the confirmation of disease progression per RECIST v1.1 will complete the questionnaires at 
every other study treatment cycle until study treatment discontinuation.  Patients who discontinue study treatment for any reason other than radiographic 
disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will complete the questionnaires at each tumor assessment visit until 
radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.  During survival 
follow-up, for patients with radiographic disease progression per RECIST v1.1, the questionnaires will be completed at 3 months ( 30 days) and 6 months 
( 30 days) following the visit in which progressive disease was confirmed.  For patients who continue study treatment after disease progression per 
RECIST v1.1, the questionnaires will be completed at 3 months ( 30 days) and 6 months ( 30 days) following the study treatment discontinuation visit.  
Study personnel should review all questionnaires for completeness before the patient leaves the investigational site.  Patients whose native language is not 
available are exempt from all PRO assessments.  In scenario where ECOG Performance Status, limited physical examination, local laboratory assessments, and 
PRO assessments cannot be done on the scheduled days, these could be done  96 hours prior to administration of study treatment.  PRO assessments are to 
be completed as outlined in Section 4.5.9.  In scenarios where laboratory assessments (e.g., blood draws) are done at the different location than the one 
providing treatment or when they are done on a different day than study treatment administration, they can be completed before the completion of PROs as long 
as results have not been discussed with patients. 
x Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits every 3 months or more frequently until death, loss 
to follow-up, or study termination by the Sponsor, whichever occurs first.  All patients will be periodically contacted for survival and new anti-cancer therapy 
information unless the patient requests to be withdrawn from follow-up (this request must be documented in the source documents and signed by the 
investigator).  If the patient withdraws from the study, study staff may use a public information source (e.g., county records), when permissible, to obtain 
information about survival status only.  Survival follow-up information collections are no longer required post clinical cutoff date for the primary analysis 
(actual date 31 August 2023). 

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

 
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Appendix 4  
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity. 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 

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DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.   
 

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METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 

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Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
used for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to 
a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be considered non-target lesions. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and should be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis  10 mm 

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Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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but  15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having 
a short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also 
be ticked). 

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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size 
(short axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 

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Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the Schedule of Activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  
The designation of overall progression solely on the basis of change in non-target 
lesions in the face of SD or PR in target lesions will therefore be extremely rare. 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as 
a "new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 

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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease. 
  
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  
This would be most likely to happen in the case of PD.  For example, if a patient had 
a baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion.  

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Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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135/Protocol YO42373, Version 6 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not 
a descriptor of an objective response; it is a reason for stopping study therapy.  
The objective response status of such patients is to be determined by evaluation of 
target and non-target lesions as shown in Table 1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
 

 
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Appendix 5  
Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents, which can produce delayed responses that may 
be preceded by initial apparent radiographic progression, including the appearance of 
new lesions.  Therefore, immunotherapy-specific response criteria adaptations to 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1; Eisenhauer 
et al. 2009) have been developed to allow for unconventional response and progression 
patterns.  These include modified RECIST v1.1 for immune-based therapeutics 
(iRECIST; Seymour et al. 2017), which was developed by the RECIST working group in 
an effort to create a common set of criteria that the cancer immunotherapy field could 
apply to clinical trials. 
Response evaluation through use of iRECIST requires collection of tumor assessment 
data after radiographic progression per RECIST v1.1.  Details regarding lesion 
evaluation are described below.  When not otherwise specified, RECIST v1.1 
conventions will apply. 
Criteria for determining overall response at a single timepoint per iRECIST are also 
summarized below.  Of note, overall response per iRECIST will not be captured in the 
electronic Case Report Form (eCRF), but will instead be calculated programmatically by 
the Sponsor on the basis of investigator-assessed individual lesion data recorded in 
the eCRF.   
iRECIST response status is not a specific component of treatment discontinuation 
criteria, including decisions about whether to continue treatment beyond progression per 
RECIST v1.1.  Investigators should instead take into account radiologic data and clinical 
status in making such decisions, as described in Section 3.1.2. 
EVALUATION OF LESIONS TO SUPPORT iRECIST RESPONSE 
ASSESSMENT AFTER DISEASE PROGRESSION PER RECIST v1.1  
iRECIST is an extension of RECIST v1.1 that allows for response assessment following 
disease progression per RECIST v1.1.  RECIST v1.1 rules for categorizing lesions as 
measurable or non-measurable and measuring lesions (see Appendix 4) also apply to 
iRECIST.  After disease progression per RECIST v1.1, the same target and non-target 
lesions selected at baseline will continue to be followed, along with any new lesions that 
develop, to support iRECIST response evaluations, as described below and summarized 
in Table 1.  Once a lesion has been categorized as a target, non-target, or new lesion, 
it will remain classified as such. 

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Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol YO42373, Version 6 
TARGET LESIONS 
The target lesions selected at baseline should continue to be measured at all tumor 
assessment timepoints after disease progression per RECIST v1.1, according to 
RECIST v1.1 conventions. 
NON-TARGET LESIONS 
Non-target lesions selected at baseline should continue to be followed at all tumor 
assessment timepoints after disease progression per RECIST v1.1.  At each timepoint, 
non-target lesions should continue to be categorized as "absent" (complete response 
[CR]), "unequivocal progression" relative to baseline (progressive disease [PD]), or 
"present without unequivocal progression" (non-CR/non-PD), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were categorized as PD at the 
previous timepoint should be evaluated to determine whether there has been any further 
increase in size.   
NEW LESIONS 
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST v1.1 
(e.g., nonlymph node lesions must be  10 mm on the longest diameter; new lymph 
nodes must be  15 mm on the short axis [see note below]).  All new lesions 
(measurable or non-measurable) must be assessed and recorded at the time of 
identification and at all subsequent tumor assessment timepoints. 
Up to a maximum of five measurable new lesions total (with a maximum of two lesions 
per organ) should be selected and measured at each timepoint.  New lesions that are 
not measurable at first appearance but meet measurability criteria at a subsequent 
timepoint should be measured from that point on, if the maximum number of measurable 
new lesions has not been reached.  However, for calculation of the sum of diameters for 
new lesions, iRECIST excludes measurements from new lesions that were not 
measurable at first appearance. 
All non-measurable new lesions (including those that subsequently become measurable) 
and additional measurable new lesions (in excess of five total or two per organ) should 
be assessed to determine whether there is any increase in size relative to the previous 
assessment timepoint. 
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph 
node lesion is  15 mm, it will be considered a measurable new lesion.  If at first 
appearance the short axis of a lymph node lesion is  10 mm and  15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 

Appendix 5: 
Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
  
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138/Protocol YO42373, Version 6 
axis of a lymph node is  10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is  15 mm.  Measurable new lymph node lesions 
should continue to be measured at all subsequent timepoints, even if the short axis 
decreases to  15 mm (or even  10 mm). 
Table 1 
Guidelines for Evaluation of Lesions to Support iRECIST 
Response Assessment after Disease Progression per 
RECIST v1.1 
Lesion Type 
Evaluation of Lesions to Support iRECIST Response Assessment 
after Disease Progression per RECIST v1.1 
Target lesions 
 Measurements should be continued according to RECIST v1.1 
conventions. 
Non-target lesions 
 Non-target lesions should continue to be categorized as absent 
(CR), unequivocal progression (PD), or present without 
unequivocal progression (non-CR/non-PD), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were 
categorized as PD at the previous timepoint should be 
evaluated to determine whether there has been any further 
increase in size. 
New lesions 
 New lesions should be evaluated for measurability per 
RECIST v1.1. 
 All new lesions (measurable or non-measurable) must be 
assessed and recorded at the time of identification and at all 
subsequent tumor assessment timepoints. 
 Up to a maximum of five measurable new lesions total (with a 
maximum of two lesions per organ) should be selected and 
measured at each timepoint. 
 All non-measurable new lesions (including those that 
subsequently become measurable) and additional measurable 
new lesions (in excess of five total or two per organ) should be 
assessed to determine whether there is any increase in size 
relative to the previous assessment timepoint. 
CR  complete response; iRECIST  modified RECIST v1.1 for immune-based therapeutics; 
PD  progressive disease; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, 
Version 1.1. 
  

Appendix 5: 
Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
  
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SUMMARY OF CRITERIA FOR OVERALL RESPONSE AT A SINGLE 
TIMEPOINT 
Timepoint response per iRECIST will be calculated programmatically by the Sponsor.  
A complete description of the iRECIST criteria can be found in a publication by Seymour 
et al. (2017). 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
Seymour L, Bogaerts J, Perrone A, et al., on behalf of the RECIST working group. 
iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol 2017;18:e14352. 
 

 
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Appendix 9  
EuroQol EQ-5D-5L 
 

Appendix 9: 
EuroQol EQ-5D-5L 
  
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Appendix 9: 
EuroQol EQ-5D-5L 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
147/Protocol YO42373, Version 6 
 
 

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

 
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Appendix 11  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment 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 and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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Appendix 12  
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 experienced a severe 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. 
 

Appendix 13: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
  
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Atezolizumab 
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  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks (or 4 cycles) 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. 
DOSE MODIFICATIONS FOR CHEMOTHERAPY 
Dose modifications for carboplatin and etoposide are permitted for toxicity according to 
the prescribing information and local standard of care.   
Dose modification guidelines are provided below.  Once reduced, the dose cannot be 
increased back to 100%. 
Treatment with carboplatin or etoposide should be discontinued if a patient experiences 
any hematologic or non-hematologic Grade 3 or Grade 4 toxicity after two dose 
reductions or treatment is delayed for more than 63 days due to toxicities.  
Hematologic Toxicity 
At the start of each cycle, the ANC should be  1500/L and the platelet count should be 
 100,000/L.  Treatment could be delayed for up to 63 days to allow sufficient time for 
recovery.  Growth factors may be used in accordance with American Society of Clinical 
Oncology and NCCN guidelines (Smith et al. 2015; NCCN 2019).  Upon recovery, dose 
adjustments at the start of a subsequent cycle will be made on the basis of the lowest 
platelet and neutrophil values from the previous cycle (see Table 1). 
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose. 

Appendix 13: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity. 
If chemotherapy is withheld because of hematologic toxicity, full blood counts (including 
differential WBC) should be obtained weekly until the counts reach the lower limits for 
treatment as outlined.  The treatment can then be resumed. 
No dose reductions are recommended for anemia.  Patients should be supported per the 
investigator's institution's guidelines. 
Non-Hematologic Toxicity 
For a non-hematologic toxicity (see Table 2), treatment should be delayed for up to 
63 days until resolution to less than or equal to the patient's baseline value (or Grade  1 
if the patient did not have that toxicity at baseline).  Dose reductions at the start of the 
subsequent cycle should be made on the basis of non-hematologic toxicities from the 
dose administered in the preceding cycle. 
 
 

Appendix 13: Overall Guidelines for Management of Patients Who Experience 
Adverse Events 
 
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Diarrhea should be controlled with adequate anti-diarrhea medication.  Nausea and/or 
vomiting may be controlled with adequate anti-emetics.  For Grade 3 or 4 neurotoxicity 
chemotherapy should be resumed at 50% of the previous dose upon improvement or 
discontinued immediately (based on investigator's clinical judgment). 
Suggested recommendations for dose modification of etoposide for renal impairment are 
provided in Table 3.  
Table 3 
Etoposide Dose Modification for Renal Impairment 
Creatinine clearance 
(mL/min) 
Etoposide Dose 
 50 
100% 
1550 
75% of dose 
  
 

 
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Appendix 14  
Risks Associated with Tiragolumab or Atezolizumab and 
Guidelines for Management of Adverse Events Associated with 
Tiragolumab or Atezolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
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DOSE MODIFICATIONS  
 
 
 
 
 
 
 
  

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol YO42373, Version 6 
 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
158/Protocol YO42373, Version 6 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
159/Protocol YO42373, Version 6 
 
 
 
 
 
 
 
 
 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
161/Protocol YO42373, Version 6 
 
 
 
 
 
 
  

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
164/Protocol YO42373, Version 6 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
165/Protocol YO42373, Version 6 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
167/Protocol YO42373, Version 6 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
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169/Protocol YO42373, Version 6 
 
  
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
170/Protocol YO42373, Version 6 
 
 
 
  

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
172/Protocol YO42373, Version 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
174/Protocol YO42373, Version 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
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Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
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Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
180/Protocol YO42373, Version 6 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
181/Protocol YO42373, Version 6 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
183/Protocol YO42373, Version 6 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
187/Protocol YO42373, Version 6 
 
 
 
 
 
 
 
 
 
  

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
189/Protocol YO42373, Version 6 
 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
 
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
192/Protocol YO42373, Version 6 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
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 
 
 
 
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 
 
 

Appendix 14: Risks Associated with Tiragolumab or Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Tiragolumab or Atezolizumab 
  
Tiragolumab and Atezolizumab—F. Hoffmann-La Roche Ltd 
195/Protocol YO42373, Version 6 
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 - YO42373 - TIRAGOLUMAB - v6 - China - Published
System identifier: RIM-CLIN-515717
Approval Task
Company Signatory
14-Dec-2023 17:40:07 GMT+0000