A Phase II, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Neoadjuvant and Adjuvant Tiragolumab Plus Atezolizumab, With or Without Platinum-Based Chemotherapy, in Patients With Previously Untreated Locally Advanced Resectable Stage II, IIIA, or Select IIIB Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer (NSCLC)
Sponsor: Hoffmann-La Roche

Official Title: A Phase II, Open-Label, Multicenter Study Evaluating the Safety and 
Efficacy of Neoadjuvant and Adjuvant Tiragolumab Plus Atezolizumab, 
With or Without Platinum-Based Chemotherapy, in Patients With 
Previously Untreated Locally Advanced Resectable Stage II, IIIA, or 
Select IIIB Non–Small Cell Lung Cancer 
NCT Number: NCT04832854 
Document Date: Protocol Amendment Version 5: 19-December-2023 

CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
Protocol GO42501, Version 5 
PROTOCOL 
TITLE: 
A PHASE II, OPEN-LABEL, MULTICENTER STUDY 
EVALUATING THE SAFETY AND EFFICACY OF 
NEOADJUVANT AND ADJUVANT TIRAGOLUMAB 
PLUS ATEZOLIZUMAB, WITH OR WITHOUT 
PLATINUM-BASED CHEMOTHERAPY, IN 
PATIENTS WITH PREVIOUSLY UNTREATED 
LOCALLY ADVANCED RESECTABLE STAGE II, 
IIIA, OR SELECT IIIB NONSMALL CELL LUNG 
CANCER 
PROTOCOL NUMBER: 
GO42501 
VERSION NUMBER: 
5 
REGULATORY 
AGENCY IDENTIFIERS: 
EudraCT NUMBER:  2020-002853-11 
EU CT NUMBER:  2022-502978-17-00 
IND NUMBER:  129,258 
NCT NUMBER:  NCT04832854 
TEST PRODUCTS: 
Tiragolumab (RO7092284) 
Atezolizumab (RO5541267) 
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 final page 
of this document 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
2/Protocol GO42501, Version 5 
 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
5 
See electronic date stamp on the final page of this 
document. 
4 
20 December 2022 
3 
2 February 2022 
2 
23 February 2021 
1 
19 August 2020 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
3/Protocol GO42501, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol GO42501 has been amended to align with
 
.  In 
addition, risks and management guidelines for atezolizumab have been updated to align 
with the latest Atezolizumab Investigator's Brochure ([IB] Version 20).  Substantive 
changes to the protocol, along with a rationale for each change, are summarized below: 
 
Cohort A, which was designed for the combination treatment of tiragolumab and 
atezolizumab for patients with at least
, has been closed 
early due to the changing treatment landscape which includes chemotherapy as part 
of the approved treatment regimen in the perioperative setting (Section 1.3 and 
Section 3.1.1.1, Figure 2, Section 6.1, Section 6.5).  
 
The list of approved indications for atezolizumab has been updated to include 
alveolar soft part sarcoma (Section 1.4).   
 
The analysis for the pathological response has changed from central to local 
pathology laboratory since all local pathologists were trained to follow the 
assessment guidance per the pathology manual and 
endpoints 
associated with central pathological review are removed (Section 2, Table 2, 
Section 3.1.1, Section 3.4.3, Section 4.5.7, Section 6.5.3).  
 
The chemotherapy regimen cisplatin  gemcitabine has been removed as an option 
from the protocol as no patients have been dosed with this regimen in this study 
(Sections 3.1.1, Section 4.3.2, Section 4.3.2.4, Appendix 1, Appendix 11). 
 
Clarification has been made that the last joint monitoring committee (JMC) meeting 
will be conducted after the last patient completes surgery.  However, the JMC chair 
and medical monitor can request an ad-hoc JMC if any potential safety concerns 
need further investigation (Section 3.1.2). 
 
Event-free survival (EFS) definition was updated to align to the FDA guidance 
(Section 2, Section 6.5.2) 
 
The post-surgery visit row of Appendix 2 that was mistakenly deleted due to 
formatting error has been added back in. 
 
Adverse event management guidelines have been updated to align with the 
Atezolizumab Investigator’s Brochure, Version 20 (Appendix 12) and updated 
SmPCs of chemotherapies. 
 
Additional changes have been made to align with the EU Clinical Trial Regulation 
(CTR): 
– 
Personal identifiable information (i.e., name and telephone number) for the 
Medical Monitors has been removed from the protocol (front matter and 
Section 5.4.1).   
– 
The synopsis has been simplified. 
 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
4/Protocol GO42501, Version 5 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
5/Protocol GO42501, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
1. 
BACKGROUND ............................................................................ 23 
1.1 
Background on NonSmall Cell Lung Cancer.......................... 23 
1.2 
Treatment Options for Resectable Early-Stage NSCLC .......... 23 
1.2.1 
Adjuvant Treatment for Surgically Resected Early-Stage 
NSCLC .................................................................................... 24 
1.2.2 
Neoadjuvant Treatment for Surgically Resectable NSCLC 
Population ................................................................................ 26 
1.3 
Background on Neoadjuvant Treatment with Immune 
Checkpoint Inhibitors for resectable NSCLC............................ 26 
1.4 
Background on Atezolizumab .................................................. 29 
1.5 
Background on Tiragolumab .................................................... 30 
1.6 
Background on Blockade of the Tigit Pathway in Cancer as 
a Potential Anti-Cancer Therapy .............................................. 30 
1.7 
Combined Inhibition of the TIGIT and PD-L1/PD-1 
Pathways as Potential Anti-Cancer Therapy ........................... 31 
1.8 
Combined Inhibition of TIGIT and PD-L1/PD-1 Pathways in 
Combination with Chemotherapy ............................................. 32 
1.9 
Study Rationale and BenefitRisk Assessment ....................... 33 
1.9.1 
Study Rationale ....................................................................... 33 
1.9.2 
BenefitRisk Assessment ........................................................ 35 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 38 
3. 
STUDY DESIGN ........................................................................... 42 
3.1 
Description of the Study ........................................................... 42 
3.1.1 
Overview of Study Design........................................................ 42 
3.1.1.1 
Treatment Assignment and Safety Lead-In ............................. 45 
3.1.1.2 
Surgery and Adjuvant Treatment ............................................. 47 
3.1.2 
Joint Monitoring Committee ..................................................... 47 
3.2 
End of Study and Length of Study ........................................... 48 
3.3 
Duration of participation ........................................................... 48 
3.4 
Rationale for Study Design ...................................................... 48 
....................... 48 

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3.4.2 
Rationale for Patient Population .............................................. 49 
3.4.3 
Rationale for Major Pathological Response as Primary 
Endpoint .................................................................................. 50 
................................... 52 
3.4.5 
Rationale for Patient-Reported Outcome Assessments ........... 53 
4. 
MATERIALS AND METHODS ...................................................... 54 
4.1 
Patients .................................................................................... 54 
4.1.1 
Inclusion Criteria ...................................................................... 54 
4.1.2 
Exclusion Criteria ..................................................................... 58 
4.2 
Method of Treatment Assignment ............................................ 61 
4.2.1 
Treatment Assignment ............................................................. 61 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 62 
4.3.1 
Study Treatment Formulation and Packaging .......................... 62 
4.3.1.1 
Atezolizumab ........................................................................... 62 
4.3.1.2 
Tiragolumab ............................................................................. 62 
4.3.1.3 
Carboplatin, Cisplatin, Pemetrexed, Gemcitabine, 
and Paclitaxel .......................................................................... 63 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 63 
4.3.2.1 
Atezolizumab ........................................................................... 67 
4.3.2.2 
Tiragolumab ............................................................................. 67 
4.3.2.3 
Atezolizumab and Tiragolumab Dose Delays .......................... 69 
4.3.2.4 
Chemotherapy ......................................................................... 69 
4.3.3 
Surgical Treatment Plan .......................................................... 72 
4.3.4 
Post-Operative Radiotherapy................................................... 73 
4.3.5 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 74 
4.3.6 
Continued Access to Atezolizumab and Tiragolumab .............. 74 
4.4 
Concomitant Therapy .............................................................. 75 
4.4.1 
Permitted Therapy ................................................................... 75 
4.4.2 
Cautionary Therapy for Atezolizumab- and Tiragolumab-
Treated Patients ...................................................................... 76 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and 
TNF- Inhibitors ....................................................................... 76 

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4.4.2.2 
Herbal Therapies ..................................................................... 76 
4.4.3 
Prohibited Therapy .................................................................. 76 
4.5 
Study Assessments ................................................................. 77 
4.5.1 
Informed Consent Forms and Screening Log .......................... 77 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 77 
4.5.3 
ECOG Performance Status...................................................... 78 
4.5.4 
Physical Examinations ............................................................. 78 
4.5.5 
Vital Signs ................................................................................ 78 
4.5.6 
Tumor Response and Disease Status Follow-Up 
Evaluations .............................................................................. 78 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 80 
4.5.8 
Electrocardiograms .................................................................. 84 
4.5.9 
Clinical Outcome Assessments ............................................... 84 
4.5.9.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 84 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments ....... 85 
4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................ 86 
4.5.11 
Optional Procedures ................................................................ 87 
4.5.11.1 
Optional Tumor Biopsies ......................................................... 87 
4.5.12 
Optional Samples for Research Biosample Repository ........... 88 
4.5.12.1 
Overview of the Research Biosample Repository .................... 88 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 88 
4.5.12.3 
Sample Collection .................................................................... 89 
4.5.12.4 
Confidentiality .......................................................................... 89 
4.5.12.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 90 
4.5.12.6 
Withdrawal from the Research Biosample Repository ............. 90 
4.5.12.7 
Monitoring and Oversight ......................................................... 91 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 91 
4.6.1 
Study Treatment Discontinuation ............................................. 91 
4.6.2 
Patient Discontinuation from the Study .................................... 92 
4.6.3 
Study Discontinuation .............................................................. 93 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
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4.6.4 
Site Discontinuation ................................................................. 93 
5. 
ASSESSMENT OF SAFETY ......................................................... 93 
5.1 
Safety Plan .............................................................................. 93 
5.1.1 
Risks Associated with Atezolizumab ........................................ 94 
5.1.2 
Risks Associated with Tiragolumab ......................................... 94 
5.1.2.1 
Infusion-Related Reactions ...................................................... 95 
.................................................... 95 
5.1.2.3 
Lymphopenia ........................................................................... 95 
5.1.2.4 
Immune-Mediated Adverse Events .......................................... 95 
5.1.2.5 
Embryofetal Toxicity ................................................................ 96 
5.1.3 
Risks Associated with the Combination of Atezolizumab 
and Tiragolumab ...................................................................... 96 
5.1.4 
Risks Associated with Cisplatin ............................................... 97 
5.1.5 
Risks Associated with Carboplatin ........................................... 97 
5.1.6 
Risks Associated with Pemetrexed .......................................... 97 
5.1.7 
Risks Associated with Paclitaxel .............................................. 98 
5.1.8 
Risks Associated with Gemcitabine ......................................... 98 
5.1.9 
Management of Adverse Events .............................................. 98 
5.1.9.1 
Dose Modification, Treatment Interruption, or Treatment 
Discontinuation for Atezolizumab or Tiragolumab .................... 98 
5.1.9.2 
Management Guidelines for Atezolizumab- and 
Tiragolumab-Specific Adverse Events ..................................... 99 
5.1.9.3 
Dose Modifications, Treatment Delays, or Treatment 
Discontinuation and Management of Specific Adverse 
Events for Chemotherapies ................................................... 100 
5.1.10 
Potential Overlapping Toxicities ............................................. 100 
5.2 
Safety Parameters and Definitions ........................................ 101 
5.2.1 
Adverse Events ...................................................................... 101 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) ................................................................................ 101 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 102 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................. 103 
5.3.1 
Adverse Event Reporting Period ............................................ 103 

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9/Protocol GO42501, Version 5 
5.3.2 
Eliciting Adverse Event Information ....................................... 104 
5.3.3 
Assessment of Severity of Adverse Events ........................... 104 
5.3.4 
Assessment of Causality of Adverse Events.......................... 106 
5.3.5 
Procedures for Recording Adverse Events ............................ 107 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release 
Syndrome .............................................................................. 107 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................. 108 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ........... 108 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 109 
5.3.5.5 
Abnormal Laboratory Values ................................................. 109 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 110 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 110 
5.3.5.8 
Deaths ................................................................................... 111 
5.3.5.9 
Preexisting Medical Conditions .............................................. 111 
5.3.5.10 
Lack of Efficacy or Worsening of NonSmall Cell Lung 
Cancer ................................................................................... 112 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 112 
5.3.5.12 
Cases of Accidental Overdose or Medication Error ............... 112 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 113 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 114 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............. 114 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 114 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ........... 114 
5.4.2.2 
Events That Occur after Study Treatment Initiation ............... 115 
5.4.3 
Reporting Requirements for Pregnancies .............................. 115 
5.4.3.1 
Pregnancies in Female Patients ............................................ 115 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 116 
5.4.3.3 
Abortions................................................................................ 116 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 116 
5.5 
Follow-Up of Patients after Adverse Events........................... 117 
5.5.1 
Investigator Follow-Up ........................................................... 117 
5.5.2 
Sponsor Follow-Up ................................................................ 117 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
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5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 117 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 117 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 118 
6.1 
Determination of Sample Size ............................................... 118 
6.2 
Summaries of Conduct of Study ............................................ 119 
6.3 
Summaries of Demographic and Baseline Characteristics .... 119 
6.4 
Safety Analyses ..................................................................... 119 
6.5 
Efficacy Analyses ................................................................... 120 
6.5.1 
Primary Efficacy Endpoint ...................................................... 120 
6.5.2 
Secondary Efficacy Endpoints ............................................... 120 
.............................................. 120 
6.6 
Pharmacokinetic analyses ..................................................... 120 
6.7 
Immunogenicity analyses ...................................................... 121 
............... 121 
............... 121 
................................................................... 122 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 122 
7.1 
Data Quality Assurance ......................................................... 122 
7.2 
Electronic Case Report Forms ............................................... 122 
7.3 
Source Data Documentation .................................................. 123 
7.4 
Use of Computerized Systems .............................................. 123 
7.5 
Retention of Records ............................................................. 124 
8. 
ETHICAL CONSIDERATIONS .................................................... 124 
8.1 
Compliance with Laws and Regulations ................................ 124 
8.2 
Informed Consent .................................................................. 124 
8.3 
Institutional Review Board or Ethics Committee .................... 125 
8.4 
Confidentiality ........................................................................ 126 
8.5 
Financial Disclosure ............................................................... 127 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 127 
9.1 
Study Documentation ............................................................ 127 

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9.2 
Protocol Deviations ................................................................ 127 
9.3 
Management of Study Quality ................................................ 127 
9.4 
Site Inspections ..................................................................... 128 
9.5 
Administrative Structure ......................................................... 128 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 128 
9.7 
Protocol Amendments ........................................................... 129 
10. 
REFERENCES............................................................................ 130 
 
 
LIST OF TABLES 
 
Table 1 
Study treatments administered ................................................... 38 
Table 2 
Objectives and Corresponding Endpoints ................................... 39 
Table 3 
Study Treatment Component Regimens ..................................... 64 
Table 4 
Premedication for Pemetrexed .................................................... 65 
Table 5 
Administration of First and Subsequent Infusions 
of Atezolizumab and Tiragolumab ............................................... 67 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 105 
............................................ 106 
Table 8 
Causal Attribution Guidance ..................................................... 107 
 
LIST OF FIGURES 
 
Figure 1 
Study Schema ............................................................................. 44 
........................................................ 46 
Figure 3 
Overall Survival by Clinical Response and by Pathological 
Response .................................................................................... 51 
 
 
 
 
 

Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
13/Protocol GO42501, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, OPEN-LABEL, MULTICENTER STUDY 
EVALUATING THE SAFETY AND EFFICACY OF 
NEOADJUVANT AND ADJUVANT TIRAGOLUMAB 
PLUS ATEZOLIZUMAB, WITH OR WITHOUT 
PLATINUM-BASED CHEMOTHERAPY, IN 
PATIENTS WITH PREVIOUSLY UNTREATED 
LOCALLY ADVANCED RESECTABLE STAGE II, 
IIIA, OR SELECT IIIB NONSMALL CELL LUNG 
CANCER 
PROTOCOL NUMBER: GO42501 
VERSION NUMBER: 
5 
REGULATORY 
AGENCY IDENTIFIERS: 
EudraCT NUMBER:  2020-002853-11 
EU CT NUMBER:  2022-502978-17-00 
IND NUMBER:  129,258 
NCT NUMBER:  NCT04832854 
TEST PRODUCT: 
Tiragolumab (RO7092284) 
Atezolizumab (RO5541267) 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. HoffmannLa Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
 
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 its designee  
 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
14/Protocol GO42501, Version 5 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE: 
A PHASE II, OPEN-LABEL, MULTICENTER STUDY 
EVALUATING THE SAFETY AND EFFICACY OF NEOADJUVANT 
AND ADJUVANT TIRAGOLUMAB PLUS ATEZOLIZUMAB, WITH 
OR WITHOUT PLATINUM-BASED CHEMOTHERAPY, IN 
PATIENTS WITH PREVIOUSLY UNTREATED LOCALLY 
ADVANCED RESECTABLE STAGE II, IIIA, OR SELECT IIIB 
NON-SMALL CELL LUNG CANCER 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
EudraCT Number:  2020-002853-11 
EU CT Number:  2022-502978-17-00  
IND Number:  129,258 
NCT Number: NCT04832854 
 
STUDY RATIONALE 
In light of the evidence of clinical activity of atezolizumab plus tiragolumab in 
NSCLC and the need to improve survival and decrease recurrence rates for patients 
with resectable early-stage NSCLC, the Sponsor is conducting this Phase II study.  
This study will evaluate the surgical safety and feasibility of atezolizumab plus 
tiragolumab alone (Atezo  +  Tira) or in combination with platinum-based 
chemotherapy (Atezo  +  Tira  +  Chemo) as neoadjuvant treatment for patients with 
previously-untreated locally advanced non-small cell lung cancer (NSCLC).  The 
study will also evaluate the efficacy, pharmacokinetics, immunogenicity, and safety 
of neoadjuvant Atezo  +  Tira or Atezo  +  Tira  +  Chemo, followed by adjuvant 
Atezo  +  Tira or adjuvant platinum-based chemotherapy.   
 
OBJECTIVES AND ENDPOINTS 
Primary Safety Objectives 
Corresponding Endpoints 
 
To evaluate the safety of 
Atezo   Tira as neoadjuvant 
treatment followed by either 
Atezo   Tira or chemo as 
adjuvant treatment 
 
To evaluate the safety of 
Atezo   Tira   Chemo as 
neoadjuvant treatment followed 
by Atezo   Tira as adjuvant 
treatment 
 
Incidence and length of surgical delays, 
incidence of operative and post-operative 
complications, and/or number of 
surgical cancellations related to study 
treatment  
 
Incidence and severity of adverse events, 
with severity determined according to 
NCI CTCAE v5.0 
 
 
 
Primary Efficacy Objective 
Corresponding Endpoint 
 
To evaluate the efficacy of 
Atezo   Tira or 
Atezo  +  Tira  +  Chemo as 
neoadjuvant treatment 
 
MPR rate, defined as the proportion of 
patients who achieve MPR, with MPR, 
defined as   10% residual viable tumor 
at the time of surgical resection in the 
primary tumor, as assessed by the local 
pathology laboratory 
Secondary Efficacy Objectives 
Corresponding Endpoints 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
15/Protocol GO42501, Version 5 
 
To evaluate the efficacy of 
Atezo   Tira or 
Atezo  +  Tira  +  Chemo as 
neoadjuvant treatment 
 
pCR, defined as the absence of any viable 
tumor cells in both the primary tumor 
and all sampled lymph nodes at the time 
of surgical resection, as assessed by the 
local pathology laboratory 
 
To evaluate the efficacy of 
Atezo   Tira as neoadjuvant 
treatment followed by either 
Atezo   Tira or chemotherapy 
as adjuvant treatment 
 
To evaluate the efficacy of 
Atezo  +  Tira  +  Chemo as 
neoadjuvant treatment followed 
by Atezo   Tira as adjuvant 
treatment 
 
EFS, defined as the time from first dose 
of study drug to any of the following 
events, whichever occurs first:  disease 
progression that precludes surgical 
resection, as assessed by the 
investigator, or local or distant disease 
recurrence after surgery, including the 
occurrence of a new primary NSCLC, or 
death from any cause 
ADA  =  anti-drug antibody; 
 Atezo  +  Tira  =  atezolizumab plus tiragolumab; 
Atezo  +  Tira  +  Chemo  =  atezolizumab plus tiragolumab plus platinum -based 
chemotherapy; CRS  =  cytokine-release syndrome; EFS  =  event-free survival; 
EORTC  =  European Organisation for Research and Treatment of Cancer; 
MPR  =  major pathological response; NCI CTCAE v5.0  =  National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0; NSCLC  =  non-small 
cell lung cancer; pCR  =  pathological complete response;. 
 
OVERALL DESIGN AND STUDY POPULATION 
This is a global Phase II, open-label, multicenter study evaluating the safety and 
efficacy of neoadjuvant and adjuvant atezolizumab plus tiragolumab, with or 
without platinum-based chemotherapy, in patients with previously untreated, 
histologically or cytologically confirmed resectable Stage II, IIIA, or select IIIB 
(T3N2 only) NSCLC.   
This study is designed to establish proof-of-concept clinical data that neoadjuvant 
treatment with Atezo  +  Tira or Atezo  +  Tira  +  Chemo is safe, tolerable and does not 
have a clinically significant negative effect on surgical outcomes in patients with 
early-stage resectable NSCLC.  This study is also designed to evaluate potential 
anti-tumor effects of neoadjuvant Atezo  +  Tira or Atezo  +  Tira  +  Chemo, as measured 
by major pathological response (MPR).  The study is designed with the flexibility to 
open new cohorts as new treatment combinations become available.  
Patients will be assigned to a cohort on the basis of PD-L1 status (see below) and 
will receive treatment as follows: 
 
Cohort A (PD-L1 high):  neoadjuvant Atezo  +  Tira for 4 cycles, followed by 
surgical resection and either adjuvant Atezo  +  Tira for 16 cycles or adjuvant 
chemotherapy for 4 cycles 
 
Cohort B (PD-L1 all comers):  neoadjuvant Atezo  +  Tira  +  Chemo for 4 cycles, 
followed by surgical resection and adjuvant Atezo  +  Tira for 16 cycles 
Selection of the platinum-based chemotherapy regimen will be at the  discretion of 
the investigator, based on histology subtypes and documented at the time of 
initiation.  The following platinum-based chemotherapy options are permitted for 
this study. 
For Non-squamous NSCLC 
For Squamous NSCLC 
Cisplatin  +  pemetrexed 
Carboplatin  +  pemetrexed  
Carboplatin  +  paclitaxel 
Carboplatin  +  gemcitabine  
Carboplatin  +  paclitaxel 

 
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NSCLC  =  non-small cell lung cancer. 
 
Surgical specimens will be assessed for pathological response (MPR and pathological 
complete response [pCR]) by an independent central pathology laboratory as well as 
by the investigator’s site pathology laboratory.  In addition, exploratory biomarker 
analyses will be performed on remaining FFPE tissue (primary tumor tissue and 
dissected lymph nodes) post MPR assessment.  
Postoperative radiotherapy (PORT) will be allowed for patients with confirmed, 
pathological N2  +  disease or positive tumor margins present at the time of surgical 
resection (ypN2 and/or R1/R2) and must be administered prior to adjuvant 
Atezo  +  Tira treatment or after adjuvant platinum-based chemotherapy. 
Patients must be eligible for R0 resection with curative intent at screening and must 
meet all eligibility criteria.  Patients who do not meet the criteria for participation 
in this study (screen failures) may quali fy for two re-screening opportunities (for a 
total of three screenings per participant) at the investigator's discretion.  Patients 
must re-sign the Informed Consent Form prior to re-screening.  The investigator 
will record reasons for screen failure in th e screening log. 
Treatment Assignment and Safety Lead-In Based on Tumor PD-L1 Status 
After providing informed consent, patients will undergo screening procedures, 
including central assessment of PD-L1 status by 
 
.  High PD-L1 expression is defined as ³
of 
tumor cells with membrane positivity for PD -L1 at any intensity above background 
staining as noted on the corresponding negative control.  Enrollment will be 
completed in a stepwise manner as follows, with approximately
patients enrolled 
in each of the cohorts.  Cohort A enrollment was closed in September 2023:  
 
Initially there will be a safety lead-in:   
- 
- 
 
The Joint Monitoring Committee (JMC) will evaluate the safety of each cohort, 
and if deemed to be safe:  
- 
- 
 
 
Safety Lead-In 
To account for potential surgical delays, cancellations or complications related to 
study treatment, enrollment within each cohort will be suspended to allow for a 
safety evaluation after approximately 6 patients have completed neoadjuvant 
treatment and either completed surgery or had their surgery plan changed.  The 
cohorts may not enroll at the same speed, and each cohort will be evaluated 
separately and independently.  The safety evaluat ion will be based on safety and 
surgical data and reviewed by the JMC, who will recommend either continuing 
enrollment into that cohort or closing the cohort.  During this safety lead -in period, 
a patient may be replaced if he or she does not proceed to su rgery for reasons other 
than an adverse event of special interest or disease progression.  
 
 

 
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Surgery and Adjuvant Treatment 
Patients will undergo surgical resection of their tumor upon completion of four 
cycles of neoadjuvant therapy.  Prior to the surgery, the attending surgeon and 
medical oncologist will reassess the patient.  
The pre-surgery visit should occur within 30 days after the last dose of neoadjuvant 
treatment; repeat pulmonary function tests (PFTs) (if clinically indicated), as well 
as associated assessments should be performed in accordance with local institutional 
practice.  The surgical procedure should be performed within 30 days after the 
pre-surgery visit if judged clinically feasible by both the attending surgeon and 
medical oncologist.    Surgical data should be entered on the corresponding 
electronic Case Report Form (eCRF) as soon as po ssible after surgery, especially 
during the safety lead-in, so that assessment of surgical delays, cancellations, or 
complications can be completed in a timely manner.  
Patients who are found to have disease progression at scheduled tumor assessments 
(after Cycle 2 and Cycle 4) or at any time during neoadjuvant treatment and are 
still deemed resectable and non-metastatic will proceed to surgery if amenable and 
will remain eligible for all study treatment and evaluations.  
Patients who discontinue neoadjuvant treatment early because of disease progression 
and do not proceed to surgery will be discontinued from additional clinic study 
procedures and will proceed to receive other treatment as determined by the 
investigator.  Such patients will remain in the study  for survival follow-up.  For 
patients who are responding to neoadjuvant therapy but cannot proceed to surgery 
due to an unforeseen medical issue (e.g., pulmonary embolism or myocardial 
infarction), and the patient can continue protocol-specified treatment, such as 
chemotherapy (Cohort A [PD-L1 high]) or Atezo  +  Tira (Cohort A or B) and 
radiotherapy.  
After surgical resection, patients will continue to receive adjuvant Atezo  +  Tira or 
adjuvant chemotherapy (Cohort A [PD-L1 high] only) until one of the follo wing 
occurs:  administration of up to four cycles of adjuvant chemotherapy per local 
standard of care, 16 cycles of adjuvant Atezo  +  Tira, unacceptable toxicity, disease 
recurrence, death, or patient and/or physician decision to discontinue study 
treatment. 
 
Several key aspects of the study design and study population are summarized below.  
Phase: 
II 
Population Type: 
Adult patients 
Control Method: 
None 
Population 
Diagnosis or 
Condition: 
Stage IISelect 
stage IIIB NSCLC 
Interventional 
Model: 
Parallel group 
Population Age: 
  18 years 
Test 
Compound{s}: 
Atezolizumab plus 
tiragolumab 
Site Distribution: 
Multisite 
Active 
Comparator: 
None 
Study Intervention 
Assignment Method: 
Assigned 
Number of 
Cohorts: 
2 
Number of 
Participants to Be 
Enrolled: 
Approximately 50 
 

 
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STUDY TREATMENT 
Patients will be assigned to a cohort on the basis of PD -L1 status (see below) and 
will receive treatment as follows: 
 
Cohort A (PD-L1 high):  neoadjuvant Atezo   Tira for 4 cycles, followed by 
surgical resection and either adjuvant Atezo   Tira for 16 cycles or adjuvant 
chemotherapy for 4 cycles 
 
Cohort B (PD-L1 all comers):  neoadjuvant Atezo   Tira   Chemo for 4 cycles, 
followed by surgical resection and adjuvant Atezo   Tira for 16 cycles 
Selection of the platinum-based chemotherapy regimen will be at the  discretion of 
the investigator, based on histology subtypes and  documented at the time of 
initiation.  The following platinum-based chemotherapy options are permitted for 
this study. 
For Non-squamous NSCLC 
For Squamous NSCLC 
Cisplatin   pemetrexed 
Carboplatin   pemetrexed  
Carboplatin   paclitaxel 
Carboplatin   gemcitabine  
Carboplatin   paclitaxel 
 
DURATION OF PARTICIPATION 
The total duration of study participation for each individual from screening until 
completion may vary.  The total duration of study participation for each individual 
is expected to range from 1 day to more than 5 years. 
COMMITTEES 
Independent 
Committees: 
Not applicable 
Other Committees: 
Joint Monitoring Committee 
 
 
 
 

  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell cytotoxicity 
ALK 
anaplastic lymphoma kinase 
Atezo 
atezolizumab 
AUC 
area under the concentration-time curve 
AxMP 
auxiliary medicinal product 
CAP 
College of American Pathologists 
CE 
Conformitè Europëenne 
Chemo 
platinum-based chemotherapy 
CIT 
cancer immunotherapy 
CLIA 
Clinical Laboratory Improvement Amendments 
COPD 
chronic obstructive pulmonary disease 
CPI 
checkpoint inhibitor 
CR 
complete response 
CrCl 
creatinine clearance 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DFS 
disease-free survival 
DLCO 
diffusion capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
EAE 
experimental autoimmune encephalitis 
EBUS 
endobronchial ultrasound 
EBUS TBNA 
EBUS-guided transbronchial needle aspirations 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
Event free survival 
EGFR 
epidermal growth factor receptor 

  
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Abbreviation 
Definition 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EUS 
endoscopic ultrasound 
EUS-FNA 
EUS-guided fine-needle aspirations 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FFPE 
formalin-fixed, paraffin-embedded 
GFR 
glomerular filtration rate 
GGO 
ground-glass opacity 
GHS 
global health status 
Gy 
grays 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
IFN- 
interferon- 
IHC 
immunohistochemistry 
IL 
interleukin 
IL 
Item List 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ITT 
intent-to-treat 
IxRS 
interactive voice or web-based response system 
JMC 
joint monitoring committee 
LACE 
Lung Adjuvant Cisplatin Evaluation 
mAb 
monoclonal antibody 
MAS 
macrophage activation syndrome 

  
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Abbreviation 
Definition 
MPR 
major pathological response 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
N 
nivolimab 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NI 
nivolimab and ipilimumab 
NK 
natural killer 
NSCLC 
nonsmall cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
pCR 
pathological complete response 
PD-1 
programmed death1 
PD-L1 
programmed deathligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
ppo 
predicted postoperative 
PORT 
postoperative radiotherapy 
PR 
partial response 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
PVR 
poliovirus receptor 
Q3W 
every 3 weeks 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
c-ros proto-oncogene 1, receptor tyrosine kinase 
SCLC 
small cell lung cancer 
SOC 
standard of care 
TC 
tumor cell 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
Tira 
tiragolumab 

  
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Abbreviation 
Definition 
TNF- 
tumor necrosis factor 
TPS 
tumor proportion score 
ULN 
upper limit of normal 
V20 
percentage of lung volume that receives radiation 
doses of 20 Gy or more 
VATS 
video-assisted thoracic surgery 
VCA 
viral capsid antigen 
VO2max 
maximal oxygen consumption 
VQ scan 
ventilation/perfusion scan 
 
 

  
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1. 
BACKGROUND 
1.1 
BACKGROUND ON NONSMALL CELL LUNG CANCER 
Lung cancer remains the leading cause of cancer deaths worldwide.  In the 
United States, it is the most common cancer in both men and women and accounts for 
12%14% of all new cancer cases.  In 2020, there will be an estimated 228,820 new 
cases of lung cancer, resulting in 135,720 deaths in the United States (Siegel et al. 
2020). 
Nonsmall cell lung cancer (NSCLC) is the predominant subtype of lung cancer, 
accounting for approximately 80%85% of all cases (Osmani et al. 2018).  NSCLC can 
be divided into two major histologic types:  adenocarcinoma and squamous cell 
carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for approximately 
40%50% of all NSCLC, while squamous cell histology accounts for approximately 
20%-30% of NSCLC (Osmani et al. 2018).  The remaining cases of NSCLC are 
represented by large cell carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, 
and are of poorly differentiated histology. 
The overall 5-year survival rate for advanced disease (Stage IVA and IVB) is 0%10%, 
(Goldstraw et al. 2016).  Poor prognostic factors for survival in patients with NSCLC 
include advanced stage of disease at the time of initial diagnosis, poor performance 
status, and a history of unintentional weight loss.  More than one-half of patients with 
NSCLC are diagnosed with metastatic disease, which directly contributes to poor 
survival prospects. 
1.2 
TREATMENT OPTIONS FOR RESECTABLE EARLY-STAGE 
NSCLC 
In its early stages, NSCLC is treated surgically with curative intent.  However, 30%70% 
of patients undergoing resection develop recurrence and die as a result of disease 
progression (Siegel et al. 2020).  Radiation therapy is no longer recommended after 
surgery as an adjuvant treatment option for patients with Stage I and II NSCLC because 
it has been shown to have a deleterious effect on long-term survival (Pezzi et al. 2017). 
For patients with Stage I disease with tumors measuring  4 cm, surgical treatment alone 
is the standard of care (SOC).  For Stage II to IIIB disease, the development of 
platinum-based chemotherapy has led to its use as adjuvant or neoadjuvant therapy 
together with surgery to improve survival outcome compared with surgery alone.  
Adjuvant platinum-based chemotherapy is now the SOC for fully resected (Stage II to 
IIIB) NSCLC, and neoadjuvant platinum-based chemotherapy is also a widely accepted 
option as per the National Comprehensive Cancer Network [NCCN] guidelines (NCCN 
2020).  Chemotherapy regimens used in the adjuvant and neoadjuvant settings involve 
platinum-based doublets, which are similar to those used in metastatic settings.  Agents 
that have been partnered with either cisplatin or carboplatin for the treatment of NSCLC 
include taxanes (paclitaxel, nab-paclitaxel, docetaxel), vinorelbine, gemcitabine, 

  
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etoposide and pemetrexed.  Combinations of these drugs with platinum analogs are 
superior to single-agent therapy and have been shown to prolong survival, despite 
notably increased toxicity (Azzoli et al. 2009). 
1.2.1 
Adjuvant Treatment for Surgically Resected Early-Stage 
NSCLC  
Adjuvant Systemic Treatment 
Adjuvant chemotherapy is the SOC for fully resected (Stage II, IIIA, or select IIIB [T3N2]) 
NSCLC (8th edition TNM staging; Detterbeck et al. 2017) (see Appendix 4).  The Lung 
Adjuvant Cisplatin Evaluation (LACE) reported on the results of a pooled analysis of data 
from five large Phase III trials comparing cisplatin-based adjuvant chemotherapy with no 
chemotherapy in patients with resected Stage IIII (7th edition TNM staging) NSCLC 
(Pignon et al. 2008).  The analysis was designed to identify treatment options associated 
with a higher degree of benefit or groups of patients benefiting more from adjuvant 
treatment.  With a median follow-up time of 5.2 years, the hazard ratio (HR) for overall 
survival (OS) was 0.89 (95% CI: 0.82 to 0.96; p  0.005), corresponding to a 5-year 
absolute benefit of 5.4% from chemotherapy.  The survival benefit varied with stage, with 
the strongest effect seen in Stages II and III and a potential deleterious effect in 
Stage IA.  The effect of chemotherapy on OS did not vary significantly (test for 
interaction with p  0.11) with the associated drugs, including vinorelbine (HR  0.80; 
95% CI: 0.70 to 0.91), etoposide or vinca alkaloid (HR  0.92; 95% CI: 0.80 to 1.07), or 
other (HR  0.97; 95% CI: 0.84 to 1.13).  In addition, there was no correlation between 
chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or 
planned total dose of cisplatin. 
In the Phase III Cancer and Leukemia Group B 9633 study of adjuvant chemotherapy in 
Stage IB NSCLC, a survival advantage was not observed with paclitaxel and carboplatin 
in the intent-to-treat (ITT) Stage IB population (Strauss et al. 2008).  However, 
exploratory analysis demonstrated a significant survival difference in favor of adjuvant 
chemotherapy for patients who had tumors  4 cm in diameter (HR  0.69; 95% CI: 0.48 
to 0.99). 
The Phase III adjuvant E1505 study and the JIPANG study suggest that platinum-based 
chemotherapy continues to be the current SOC in an unselected early-stage resectable 
patient population (Wakelee et al. 2017; Kenmotsu et al. 2020).  The results from the 
E1505 study did not demonstrate improved disease-free survival (DFS) or OS with the 
addition of bevacizumab to platinum-based chemotherapy.   
Recently however, for a select patient population with early-stage resectable NSCLC, 
targeting a specific oncogenic driver, it was shown that improvements upon the marginal 
benefit of platinum-based chemotherapy can be achieved in the adjuvant setting.  The 
ADAURA trial demonstrated that patients whose NSCLC had an epidermal growth factor 
receptor (EGFR) mutation achieved significant improvements in median DFS (HR  0.21; 

  
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p  0.0001) with the addition of adjuvant osimertinib with or without platinum-based 
chemotherapy after surgery (Herbst et al. 2020).  
In addition, with the successful development of cancer immunotherapy (CIT) in 
advanced NSCLC, Phase III adjuvant studies of antiprogrammed death-ligand 1 
(PD-L1)/antiprogrammed death1 (antiPD-1) inhibitors (atezolizumab, nivolumab, 
pembrolizumab, and durvalumab) are currently being conducted in patients with 
resectable early-stage NSCLC, and perhaps may improve upon the modest survival 
benefit of platinum-based chemotherapy alone when combined or sequentially 
administered with platinum-based chemotherapy. 
Immune checkpoint inhibitors have transformed the treatment paradigm of solid tumors, 
including NSCLC, but approvals for NSCLC were previously limited to advanced or 
metastatic disease settings.  Atezolizumab was the first immunotherapy approved for the 
adjuvant treatment of early-stage resectable PD-L1+ stage II-IIIA NSCLC based on the 
IMpower010 trial.  At the planned interim analysis of the DFS primary endpoint, 
IMpower010 demonstrated a statistically significant improvement in DFS in the 
stage II-IIIA PD-L1   1% TC analysis population with a hazard ratio (HR) of 0.66 (95% 
CI: 0.5, 0.88).  Median DFS was not reached (95% CI 36.1, not estimable [NE]) in the 
atezolizumab arm and was 35.3 months (95% CI 29.0, NE) in the BSC arm  
(Felip et al. 2021).  In the PD-L1 SP263   50% TC Stage II-IIIA population the 
unstratified HR was 0.49 (95% CI: 0.29, 0.81) without EGFR mutations or ALK 
rearrangements.  At a later pre-specified exploratory analysis of OS suggested a trend in 
favor of atezolizumab over BSC in the PD-L1 SP263   1% TC Stage II-IIIA population 
(stratified HR=0.77; 95% CI: 0.51, 1.17) and a clinically meaningful improvement in the 
PD-L1 SP263   50% TC Stage II-IIIA population without EGFR mutations or ALK 
rearrangements (unstratified HR = 0.42; 95% CI: 0.23, 0.78) was reported (Felip et al. 
2021). 
Adjuvant Postoperative Radiotherapy 
Postoperative radiotherapy (PORT) is no longer recommended as a treatment option for 
patients with Stage I and II disease, because it has been shown to have a deleterious 
effect on long-term survival (PORT Meta-Analysis Trialists Group 1998).  On the other 
hand, PORT may help improve locoregional recurrence rates and/or survival in carefully 
selected patients, such as those with pathologically confirmed N2 disease or positive 
surgical margins (Decker and Wilson 2008).  In the Phase III LungART trial evaluating 
modern conformal PORT versus no PORT after complete resection of Stage IIIA N2 
NSCLC, no significant difference in 3-year DFS was observed (Le Péchoux et al. 2020).  
However, mediastinal relapse was reduced with PORT (25%) compared with the control 
arm (46%).  The LungART trial results suggest that while PORT should not be 
recommended for all patients with completely resected Stage IIIA N2 NSCLC, it is 
possible that select patients may benefit from PORT due to reduced risk of mediastinal 
relapse. 

  
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1.2.2 
Neoadjuvant Treatment for Surgically Resectable NSCLC 
Population 
Neoadjuvant chemotherapy is another approach to the treatment of resectable 
early-stage NSCLC, with survival benefits comparable to those achieved with adjuvant 
chemotherapy.  A meta-analysis reported an indirect comparison of neoadjuvant and 
adjuvant chemotherapy and concluded that there were no differences in both OS and 
DFS between neoadjuvant and adjuvant chemotherapy (Lim et al. 2009).  The data 
included 32 randomized trials (10 neoadjuvant and 22 adjuvant) involving more than 
10,000 participants.  For OS, the HR of adjuvant chemotherapy compared with 
neoadjuvant chemotherapy was 0.99 (95% CI: 0.81 to 1.21), and for DFS the HR was 
0.96 (95% CI: 0.77 to 1.20). 
A review of 15 neoadjuvant trials showed an absolute survival improvement of 5% at 
5 years and a 13% reduction in the relative risk of death (OS HR  0.87; 95% CI: 0.78 to 
0.96) with neoadjuvant chemotherapy compared with surgery alone (NSCLC 
Meta-Analysis Collaborative Group 2014).  There were no notable differences in survival 
between different chemotherapy regimens or scheduling, platinum agents, age, sex, 
performance status, histology, and whether or not PORT was given.  Time-to-distant 
recurrence was also significantly longer for patients who received neoadjuvant treatment 
versus surgery alone (HR  0.69; 95% CI: 0.58 to 0.82). 
It is important to note that many Phase III neoadjuvant studies were closed early 
because of positive outcomes in Phase III adjuvant trials.  Nevertheless, as a result of 
these reports, neoadjuvant platinum-based chemotherapy is considered another SOC 
option for patients with resectable early-stage NSCLC. 
1.3 
BACKGROUND ON NEOADJUVANT TREATMENT WITH 
IMMUNE CHECKPOINT INHIBITORS FOR RESECTABLE 
NSCLC 
In the Phase II AAAQ3153 study, 30 patients with resectable early-stage NSCLC 
received four cycles of neoadjuvant atezolizumab concurrently with carboplatin and 
nab-paclitaxel.  Seventy-seven percent of these patients had Stage IIIA disease.  The 
results were encouraging, with 17 patients (57%) experiencing a major pathological 
response (MPR) and 10 patients (33%) experiencing a pathological complete response 
(pCR) and supported further study of combining atezolizumab with chemotherapy as 
neoadjuvant treatment (Shu et al. 2020). 
In the Phase II Study ML39236 (LCMC3) patients with resectable early-stage NSCLC 
received two cycles of single agent neoadjuvant atezolizumab.  The results were 
encouraging with 30 patients (21%) of the primary efficacy population (n  144) 
experiencing a MPR.  Four patients (3%) experienced treatment-related delays of their 
surgery (surgery performed  28 days after last dose of neoadjuvant atezolizumab) and 
5 patients (3%) experienced intraoperative complications.  An R0 resection rate of 92% 
was observed (Lee et al. 2021). 

  
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In the Phase II GECP 16/03 (NADIM) study conducted in Spain, patients with Stage IIIA 
NSCLC were treated with three cycles of neoadjuvant paclitaxel, carboplatin and 
nivolumab which was well tolerated, with 41 patients (89%) proceeding to surgery with 
no delays and all undergoing successful R0 resections.  Of these 41 patients, 
34 patients (83%) achieved a MPR, with 26 patients (63%) achieving a pCR (Provencio 
et al. 2020). 
In a U.S. study (NCT02259621), 21 patients received two cycles of single agent 
neoadjuvant nivolumab without reported treatment-related surgical delays.  The median 
time from the administration of the second dose of nivolumab to surgery was 18 days 
(range:  1129 days), and 20 of the 21 eligible patients (95%) underwent R0 tumor 
resection.  A MPR was seen in 9/20 of patients (45%) who underwent resection.  One 
patient with Stage IIIA disease had tracheal invasion discovered during surgery, and a 
complete tumor resection could not be performed (Forde et al. 2018). 
In the Phase II NEOSTAR study, 44 patients were randomized to receive three doses of 
either single agent nivolumab (N) or the combination of nivolumab and ipilimumab (NI) 
prior to surgery.  Of 37 evaluable patients, 11 patients (30%) achieved a MPR (19% N; 
and 44% NI) and a pCR was seen in 22% of patients (10% N; and 38% NI).  No 
unacceptable toxicity or increased peri-operative morbidity/mortality were noted 
(Cascone et al. 2019). 
These data provide proof-of-concept evidence that use of single agent checkpoint 
inhibitors (CPIs) or combination of CPIs, with or without chemotherapy, in the 
neoadjuvant setting is clinically promising and provides a strong rationale for further 
investigation. 
With the successful development of CIT in advanced NSCLC, several neoadjuvant and 
perioperative studies of antiPD-L1/PD-1 inhibitors (atezolizumab, nivolumab, 
pembrolizumab, and durvalumab) are currently being conducted in early stage 
resectable NSCLC, and perhaps may improve upon the modest survival benefit of 
platinum-b ased chemotherapy alone when combined with and/or sequentially 
administered with platinum-based chemotherapy. 
In the Phase III CheckMate 816 trial, 385 patients were randomized to receive three 
cycles of neoadjuvant nivolumab plus chemotherapy or chemotherapy alone.  A 
statistically significant improvement in the primary endpoint of pCR was observed (OR  
13.94 [99% CI: 3.4955.75]; p 0.0001) with 24% of patients in the nivolumab plus 
chemotherapy arm achieving pCR compared with 2.2% of patients in the chemotherapy 
alone arm (Forde et al. 2021).  The pCR benefit was consistent across disease stages, 
histologies, and PD-L1 expression levels.  Likewise, significant improvement in MPR 
was also observed with 36.9% of patients in the nivolumab plus chemotherapy arm 
achieving MPR versus 8.9% in the chemotherapy alone arm (OR 5.70 [95% CI: 
3.1610.26]).  Importantly, nivolumab plus chemotherapy was tolerable, and the addition 

  
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of nivolumab to chemotherapy did not increase post-surgical complication (Spicer et al. 
2021).  Numerically, a greater percentage of patients treated with nivolumab plus 
chemotherapy had definitive surgery and complete resection, and fewer patients 
underwent pneumonectomy.  
KEYNOTE-671 is a Phase III, randomized, double blinded trial evaluating neoadjuvant 
pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in resectable 
Stage IIA to IIIB NSCLC with dual primary endpoints of event-free survival (EFS) and 
OS.  With a median follow-up of 25.2 months, the results demonstrated a median EFS 
of not yet reached (95% CI: 34.1-not yet reached) in the pembrolizumab arm compared 
with 17.0 months (95% CI: 14.3-22.0) in the control arm (HR    0.58 [95% CI: 
0.46-0.72], p  0.00001), and a median OS of not yet reached in the pembrolizumab arm 
(95% CI: not yet reached-not yet reached) compared with 45.5 months (95% CI: 
42.0-not yet reached) in the control arm (HR=0.73 [95% CI: 0.54-0.99], p 
 0.02124).  
Regarding resectability, 82.1% of patients in the treatment arm and 79.4% of patients 
in control arm underwent definitive surgery.  For the key secondary endpoints, the pCR 
rate among patients who received pembrolizumab was 18.1% (95% CI: 14.5%22.3%) 
versus 4% (95% CI: 2.3%6.4%) for those who received chemotherapy alone (overall 
response [OR], 14.2; 95% CI: 10.118.7, p   0.00001) (Wakelee et al. 2023).  The 
treatment regimen was approved by the FDA. 
Another perioperative Phase III trial AEGEAN is a randomized, double blinded trial 
evaluating neoadjuvant durvalumab plus chemotherapy followed by adjuvant 
durvalumab in resectable Stage IIA to IIIB NSCLC with dual primary endpoints of pCR 
and EFS. With a median follow-up of 11.7 months, the results demonstrated a median 
EFS of not yet reached (95% CI:31.9-not yet reached) in the durvalumab arm compared 
with 25.9 months (95% CI: 18.9-not yet reached) in the control arm (HR0.68 [95% 
CI: 0.53-0.88], p0.003902).  The pCR rate among patients who received durvalumab 
was 17.2% versus 4.3% for those who received chemotherapy alone (OR, 13.0; 9.5% CI: 
8.7-17.6, p  0.000036).  Regarding resectability, 80.6% of patients in the treatment 
arm and 80.7% of patients in the control arm underwent definitive surgery (Heymach 
et al. 2023).  These results show that perioperative durvalumab is a potential new 
treatment option for stage II to IIIB NSCLC before and after surgery, however, there 
have not been any Health Authority approvals to date. 
China only Phase III Neotorch trial is randomized, double-blinded trial evaluating 
neoadjuvant toripalumab plus chemotherapy followed by one cycle of adjuvant 
toripalumab plus chemotherapy and then adjuvant toripalimab monotherapy in 
resectable stage II-III NSCLC.  The primary efficacy endpoints are EFS for stage III, 
EFS for ITT, major pathological response (MPR) for Stage III, and MPR for ITT.  The 
first interim analysis was only for Stage III patients.  With a median follow-up of 
18.25 months, the results demonstrated a median EFS of not reached (95% CI: 24.4-not 
yet reached) in the toripalimab arm compared with 15.1 months (95% CI: 10.621.9) in 
the control arm (HR 0.40 [95% CI:0.277-0.565], p  0.0001) for Stage III patients.  

  
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The MPR rate among patients with Stage III disease who received toripalimab was 
48.5% (95% CI: 41.455.6) versus 8.4% (95% CI: 5.013.1) for those who received 
chemotherapy alone (OR, 40.2 [95% CI: 32.248.1], p   0.0001].  Regarding 
resectability, 82.2% of patients in the treatment arm and 73.3% of patients in the 
control arm underwent surgery, with 95.8% and 92.6% of patients with R0 resection, 
respectively.  The addition of toripalimab to perioperative chemotherapy showed 
statistically significant improvements in EFS for patients with Stage III NSCLC with a 
manageable safety profile (Lu et al. 2023). 
CheckMate-77T is a Phase III, randomized, double blinded trial evaluating neoadjuvant 
nivolumab plus chemotherapy followed by adjuvant nivolumab in resectable Stage IIA 
to IIIB NSCLC.  The study met its primary endpoint of improved EFS at the first 
interim analysis assessed by blinded Independent Central Review (Cascone et al. 2023).  
With a median follow up of 25.4 months, the results demonstrated a median EFS of not 
yet reached (95% CI: 28.9-not yet reached) in the nivolumab arm compared with 
18.4 months (95% CI: 13.6-28.1) in the control arm (HR  0.58 [9.5% CI: 0.43-0.81], 
p  0.00025).  The MPR rate among patients who received nivolumab was 35.4% (95% 
CI: 29.2-41.9%) versus 12.1% (95% CI: 8.2-17.0) for those who received chemotherapy 
alone (OR, 4.01 [95% CI: 2.48-6.49).  The pCR rate among patients who received 
nivolumab was 25.5% (95% CI: 19.8-31.5) versus 4.7% (95% CI, 2.4-8.3) for those 
who received chemotherapy alone (OR, 6.64 [95% CI: 3.40-12.97]. 
1.4 
BACKGROUND ON 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 fragment crystallizable (Fc) receptors, thus eliminating detectable Fc-effector function 
and associated antibody-mediated clearance of activated effector T cells. 
 
  
 
 
Atezolizumab is approved for the treatment of urothelial carcinoma, NSCLC, small-cell 
lung cancer, 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. 

  
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1.5 
BACKGROUND ON TIRAGOLUMAB 
Tiragolumab is a fully human IgG1/ monoclonal antibody that binds T-cell 
immunoreceptor with Ig and ITIM domains (TIGIT), an immune inhibitory receptor that is 
expressed on the surface of activated T-cell and natural killer (NK)-cell subsets and 
interacts with high affinity with CD155 (also known as poliovirus receptor [PVR]) (Yu et 
al. 2009).  Genetic ablation of TIGIT in T cells in mice results in exacerbated T-cell 
responses, demonstrating the role of TIGIT in inhibiting T-cell responses (Joller et al. 
2011; Johnston et al. 2014).  Therapeutic blockade of TIGIT by tiragolumab represents 
an attractive strategy for cancer therapy and is expected to enhance the magnitude and 
quality of tumor-specific T-cell responses, which may result in improved meaningful 
anti-tumor activity when tiragolumab is combined with other CIT and chemotherapy.  The 
available nonclinical and clinical data provide a strong rationale for evaluating the 
potential clinical benefit of tiragolumab in patients with cancer. 
Refer to the Tiragolumab Investigator’s Brochure for details on the nonclinical and 
clinical studies for tiragolumab. 
1.6 
BACKGROUND ON BLOCKADE OF THE TIGIT PATHWAY IN 
CANCER AS A POTENTIAL ANTI-CANCER THERAPY 
TIGIT is a novel immune inhibitory receptor that is a member of the Ig super family 
(Yu et al. 2009; Manieri et al. 2017).  TIGIT expression is elevated in the tumor 
microenvironment in many human tumors, is coordinately expressed with other 
checkpoint immune receptors such as PD-1 and is associated with impaired T-cell 
function and anti-tumor immunity (Johnston et al. 2014).  Activation of TIGIT on T-cells 
and NK-cells limits cellular proliferation, effector cytokine production, and killing of target 
tumor cells (TCs) (Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; 
Wang et al. 2015; Manieri et al. 2017). 
TIGIT is expressed in a wide variety of human tumors, including NSCLC, and is highly 
correlated with T-cell infiltration and PD-1 expression (Johnston et al. 2014).  
Fluorescence-activated cell sorting analysis of fresh tumor samples showed that TIGIT 
and PD-1 are also co-expressed on tumor-infiltrating T cells.  TIGIT expression ranges 
from 30% to 80% and from 50% to 80% on tumor-infiltrating CD4   and CD8   T cells, 
respectively (Johnston et al. 2014).  It has also been reported that tumor-infiltrating 
lymphocytes from early-stage primary NSCLCs co-express TIGIT with PD-1, suggesting 
that TIGIT expression may be important throughout the development of NSCLC 
(Tassi et al. 2017). 
Therefore, TIGIT is a potential target for therapeutic intervention aimed at restoring the 
immune response against the tumor, especially in NSCLC.  Agents that inhibit the 
activity 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, an inhibitor of PD-L1.  Early nonclinical results using genetically deficient 

  
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mice and blocking antibodies reveal a key role for TIGIT in regulating T-cell responses.  
Together the data support the hypothesis that antiTIGIT in combination with antiPD-L1 
may reactivate anti-tumor immunity in NSCLC to provide clinical benefit to patients.  
1.7 
COMBINED INHIBITION OF THE TIGIT AND PD-L1/PD-1 
PATHWAYS AS POTENTIAL ANTI-CANCER THERAPY 
The inhibitory immunoreceptor TIGIT has been shown to limit the effector function of 
tumor-associated lymphocytes.  Activation of TIGIT on T cells and NK cells limits 
proliferation, effector cytokine production, and killing of target TCs.  Therefore, in the 
context of the tumor microenvironment, TIGIT acts to limit anti-tumor immune responses.  
Interference with TIGITPVR interaction may enhance the magnitude and quality of the 
tumor-specific T-cell responses through increased expansion of T cells as well as 
improved T-cell priming and/or effector function.  Because TIGIT and PD-1 are 
co-expressed by infiltrating T cells in several human tumors, inhibition of the TIGIT/PVR 
pathway may complement and potentiate the anti-tumor activity of a PD-L1 pathway 
inhibitor such as atezolizumab. 
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 I 
Study GO30103 and the Phase II Study GO40290 (hereafter referred to as 
CITYSCAPE).  Study GO30103 is a first-in-human, combined Phase Ia/Phase Ib, 
open-label, dose-escalation, multicenter study.  The study evaluated the safety, 
tolerability, immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and 
preliminary evidence of biologic activity of tiragolumab administered as a single agent 
(Phase Ia) or in combination with atezolizumab (Phase Ib) to patients with locally 
advanced or metastatic malignancies.  
 
 
 
 
 
 
Tiragolumab was further evaluated in patients with PD-L1 selected advanced NSCLC 
(tumor proportion score [TPS]  1%) in the Phase II, global, randomized, double-blind, 
placebo-controlled CITYSCAPE study.  As of the clinical cutoff date of 
2 December 2019, the confirmed objective response rate (ORR) in the ITT population 
was higher in the tiragolumab combined with atezolizumab arm (37%) than in the 
placebo combined with atezolizumab arm (21%).  Investigator-assessed 
progression-free survival (PFS) was also improved with a stratified HR of 0.58 (95% CI: 
0.38 to 0.89), with a median PFS not estimable and 3.9 months in the tiragolumab 
combined with atezolizumab arm compared to the placebo combined with atezolizumab 

  
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Tiragolumab is being investigated in clinical studies as a potential therapy against 
various tumor types.  Refer to the Tiragolumab Investigator’s Brochure for details on the 
nonclinical and clinical studies for tiragolumab. 
1.8 
COMBINED INHIBITION OF TIGIT AND PD-L1/PD-1 PATHWAYS 
IN COMBINATION WITH CHEMOTHERAPY 
Several Phase III metastatic studies, including MK-3475-189 (KEYNOTE-189), 
MK-3475-407 (KEYNOTE-407), GO29436 (IMpower150), and GO29537 (IMpower130), 
have documented that, when co-administered with chemotherapy, the efficacy benefit of 
PD-L1/PD-1 inhibitors extends across all PD-L1 expression subgroups (Gandhi et al. 
2018; Paz-Ares et al. 2018; Socinski et al. 2018; Gadgeel et al. 2019; West et al. 2019). 
The data are consistent with the known effects of chemotherapy on the tumor 
microenvironment that may potentiate the effects of immunotherapies.  In addition to 
direct cytotoxicity, which increases release of tumor antigens and enhances 
immunogenicity, chemotherapy has been shown to increase expression of PD-L1 
(Zhang et al. 2008) and increase levels of CD155 (PVR), the ligand for TIGIT (Yoshida 
et al. 2019).  The expectation that tiragolumab will further enhance atezolizumab efficacy 
in the context of chemotherapy is supported by nonclinical evidence that the TIGIT 
pathway is associated with immune dysfunction and chemoresistance (Blake et al. 2016; 
Burugu et al. 2018).  In lung cancer models, TIGIT expression on T cells contributed to 

  
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carboplatin chemoresistance through the upregulation of CD155 and subsequent T-cell 
dysfunction (Anestakis et al. 2020). 
Furthermore, an exploratory study in gastric cancer has shown that after treatment with 
platinum chemotherapy, patients with a higher percentage of CD8  TIGIT  T cells had 
increased rates of cancer relapse and shorter DFS (Tang et al. 2019).  Because the 
TIGIT pathway is associated with immune dysfunction and chemoresistance, these 
findings suggest that TIGIT blockade to restore T-cell function could potentially improve 
outcomes for patients undergoing chemotherapy.  In support of this hypothesis, in vitro 
studies have shown that TIGIT blockade countered the suppression of T-cell proliferation 
and activation following chemotherapy (Tang et al. 2019). 
Collectively, the data and preliminary results of Study GO30103 and CITYSCAPE have 
led to the hypothesis that antiTIGIT treatment (tiragolumab) in combination with 
antiPD-L1 treatment (atezolizumab) plus chemotherapy may result in enhanced and 
more durable responses.  This combination is currently under evaluation in other 
indications. 
1.9 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
1.9.1 
Study Rationale  
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 NSCLC.  In the Phase Ib portion of Study GO30103, evaluating tiragolumab in 
combination with atezolizumab PRs occurred in patients with metastatic cancers, 
including NSCLC, with varying degrees of PD-L1 and/or TIGIT expression (Bendell et al. 
2020).  The combination of atezolizumab with tiragolumab was tolerated in the Phase Ib 
portion of the study, with a safety profile consistent with prior observations of 
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Consistent with the Phase Ib portion of Study GO30103, the combination of 
atezolizumab with tiragolumab was tolerated in the Phase II study (for more details, refer 
to the Tiragolumab Investigator’s Brochure).  Atezolizumab plus tiragolumab 
demonstrated an overall safety profile similar to that of atezolizumab alone in terms of all 
Grade adverse events, Grade 3 and 4 adverse events, serious adverse events and 
adverse events leading to study treatment discontinuation.  While adverse events related 
to any study treatment and adverse events leading to dose interruption of any study 
treatment were higher in the tiragolumab plus atezolizumab arm, there was no increase 
in Grade 5 adverse events (see the Tiragolumab Investigator’s Brochure).  Adverse 
events with potentially immune-mediated causes have been observed with a higher 
frequency for tiragolumab in combination with atezolizumab in CITYSCAPE.  However, 
the imbalance was mostly attributed to Grade 1 and 2 rashes and infusion-related 
reactions (IRRs).  Grade 3 and 4 immune-mediated adverse events were similar 
between the tiragolumab plus atezolizumab treatment group compared with 
atezolizumab treatment alone.  To date, immune-mediated adverse events have been 
manageable with standard medical practice supplemented with corticosteroids, 
immunosuppressive agents, and/or hormone replacement therapy. 
In light of the evidence of clinical activity of atezolizumab plus tiragolumab in NSCLC 
and the need to improve survival and decrease recurrence rates for patients with 
resectable early-stage NSCLC, the Sponsor is conducting this Phase II study GO42501.  
The study is designed to evaluate whether neoadjuvant therapy with the combination of 
atezolizumab and tiragolumab, with or without platinum-based chemotherapy, is safe 
and tolerable and does not have a deleterious effect on surgical outcomes in patients 
with resectable Stage II, IIIA, and select IIIB (T3N2) NSCLC.  This study is also designed 
to evaluate potential anti-tumor effects of neoadjuvant atezolizumab plus tiragolumab 
alone (Cohort A) or with platinum-based chemotherapy (Cohort B), as measured by 
MPR. 
Given that the additional atezolizumab plus tiragolumab benefit relative to atezolizumab 
alone was primarily observed in patients with high PD-L1 expression in CITYSCAPE, 
Cohort A will include only patients with tumors having high PD-L1 expression 
  Patients in Cohort A (hereafter referred to as Cohort A [PD-L1 high]) will 
receive atezolizumab plus tiragolumab as neoadjuvant treatment.  After surgery, patients 
will receive adjuvant treatment with either additional cycles of atezolizumab plus 
tiragolumab or platinum-based chemotherapy (physician’s choice of protocol-defined 
regimen) to ensure all patients have the opportunity for SOC treatment with 
chemotherapy. 
The clinical benefit of chemotherapy combined with PD-L1/PD-1 inhibitors has been 
documented by improved OS and PFS in metastatic NSCLC patients throughout all 
PD-L1 subgroups (Gandhi et al. 2018; Paz-Ares et al. 2018; Socinski et al. 2018; 
Gadgeel et al. 2019; West et al. 2019) and is being further studied in ongoing 
early-stage NSCLC studies.  The expectation that tiragolumab will enhance 

  
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atezolizumab efficacy in the context of chemotherapy in NSCLC is supported by 
preclinical evidence that the TIGIT pathway is associated with immune dysfunction and 
chemoresistance.  Thus, TIGIT blockade may restore T-cell function and improve 
outcomes in patients treated with chemotherapy (see Section 1.8).  This evidence, as 
well as data from CITYSCAPE, support the hypothesis that tiragolumab in combination 
with atezolizumab and chemotherapy may result in enhanced and more durable 
responses across PD-L1 subgroups.  To further study this hypothesis, patients in Cohort 
B will include patients across all PD-L1 subgroups who will receive atezolizumab plus 
tiragolumab plus platinum-based chemotherapy (physician’s choice of protocol-defined 
regimen) as neoadjuvant treatment.  After surgery, patients in Cohort B (hereafter 
referred to as Cohort B [PD-L1 all comers]) will receive additional cycles of atezolizumab 
plus tiragolumab. 
Because the safety of the combination of atezolizumab plus tiragolumab in the 
neoadjuvant setting has yet to be determined, the study will enroll in a stepwise fashion 
with limited patients for initial evaluation at a limited number of clinical sites (see 
Section 4.2.1), and the Medical Monitor and a Joint Monitoring Committee (JMC; see 
Section 3.1.2) will closely monitor surgical outcomes and preliminary efficacy data. 
1.9.2 
BenefitRisk Assessment 
Data from CITYSCAPE indicate that combination therapy of atezolizumab plus 
tiragolumab may confer increased efficacy benefit in NSCLC relative to atezolizumab 
monotherapy in PD-L1 high patients.  To date, there is evidence of improved 
radiographic and pathological responses when combining CPI with chemotherapy in the 
neoadjuvant setting compared with chemotherapy alone (Provencio et al. 2020; Shu et 
al. 2020).  In addition, there are ongoing safety and efficacy clinical trials of atezolizumab 
plus tiragolumab, with and without platinum-based chemotherapy, as well as clinical 
trials of neoadjuvant and adjuvant CPI treatment, with and without platinum-based 
chemotherapy in NSCLC. 
Based on these observations, neoadjuvant therapy with atezolizumab plus tiragolumab, 
with or without chemotherapy, may improve efficacy outcomes in patients with 
resectable early-stage NSCLC relative to neoadjuvant chemotherapy alone.  
The combination of atezolizumab plus tiragolumab was tolerated in both Study GO30103 
and CITYSCAPE.  The toxicities of atezolizumab alone and the combination of 
atezolizumab plus tiragolumab are expected to be similar.  Immune-mediated adverse 
events, although reported at a higher frequency for the atezolizumab plus tiragolumab 
arm in CITYSCAPE, are generally mild, transient, monitorable, and manageable in 
nature.  The toxicities of the combination of atezolizumab and tiragolumab plus 
chemotherapy are also expected to be similar to the combination of atezolizumab plus 
chemotherapy. 
This study includes eligibility criteria, baseline measurements, and recommendations for 
management of adverse events, including guidelines for dose modifications, delays, and 

  
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discontinuation of one or more of the study drugs that are designed to enhance the 
safety of patients in this trial.  Oversight of this study will be provided by the Sponsor’s 
Medical Monitor (see Section 5.4.1).  Additionally, a JMC, 
 
, will be formed to evaluate safety data 
during the study. 
Currently available clinical data also indicate that the therapeutic value of tiragolumab is 
in combination with atezolizumab.  Patients who received atezolizumab and tiragolumab 
as participants in the Phase Ib portion of Study GO30103 (solid tumors, including 
metastatic NSCLC) and in CITYSCAPE (in metastatic NSCLC) achieved encouraging 
efficacy outcomes (detailed in Section 1.7). 
Given that the addition of tiragolumab to atezolizumab improved efficacy outcomes in 
metastatic NSCLC in CITYSCAPE (see Section 1.7), it is anticipated that this combined 
regimen may potentially also improve efficacy in resectable early stage NSCLC.  There 
are ongoing Phase Ib, II, and III studies investigating the combination of atezolizumab 
and tiragolumab, with and without platinum-based chemotherapy in lung cancer, which 
will generate additional safety and efficacy data as this study is enrolling 
(Studies GO41717, GO41767, GO41854, and BO42592). 
Given the unmet need that still exists in resectable early stage NSCLC, the strength of 
the scientific hypothesis and the compelling clinical data supporting this study as well as 
the rigorous safety monitoring proposed, Study GO42501 will provide an initial 
evaluation of the benefitrisk profile of neoadjuvant atezolizumab plus tiragolumab with 
or without platinum-based chemotherapy. 
This trial will enroll patients with previously untreated resectable Stage II, IIIA, or select 
IIIB NSCLC.  Given the relatively poor prognosis, limited treatment options and more 
than a decade of little to no improvement in the treatment landscape for these patients, 
this population is considered appropriate for trials of novel therapeutic candidates.  The 
benefitrisk ratio for atezolizumab in combination with tiragolumab, with or without 
platinum-based chemotherapy, is expected to be acceptable in this setting. 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with lung cancer, are considered a more vulnerable 
population, with the potential for more severe clinical outcomes from severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear 
whether or how systemic cancer therapies such as chemotherapy, targeted therapy, or 
immunotherapy impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of CPI treatment 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-L1/PD-1 blockade appears to be 
associated with serious exacerbation of inflammation in the setting of acute (as opposed 

  
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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 SARS-CoV-2 infection is altered by 
cancer immunotherapy. 
Severe SARS-CoV-2 infection appears to be associated with a cytokine-release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon- (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 acute 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 SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with CPIs and clinical and radiologic features for 
SARS-CoV-2related interstitial pneumonia.  Thus, investigators should use their clinical 
judgment when evaluating and managing patients with pulmonary symptoms. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab and tiragolumab in 
combination with chemotherapy. 
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 National Comprehensive Cancer Network® (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune checkpoint inhibitors), 
with the understanding that there are limited safety and efficacy data in such patients 
(NCCN 2021).  Given the lack of clinical data, currently no recommendations can be 
made regarding the optimal sequence of COVID-19 vaccination in patients who are 
receiving cancer immunotherapy (SITC 2020).  For patients enrolling in this study and 
receiving atezolizumab and tiragolumab treatment, a decision to administer the vaccine 
to a patient, should be made on an individual basis by the investigator in consultation 
with the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab and tiragolumab 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 

  
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severity of COVID-19 outbreak in a given area or region.  SITC and NCCN 
recommendations along with institutional guidelines should be used by the investigator 
when deciding on administering COVID-19 vaccines.  When administered, COVID-19 
vaccines must be given in accordance with the approved or authorized vaccine label. 
Receipt of the COVID-19 vaccine is considered a concomitant medication and should be 
documented as such. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the surgical safety and feasibility of atezolizumab plus 
tiragolumab alone (Atezo  Tira) or in combination with platinum-based chemotherapy 
(Atezo  Tira  Chemo) as neoadjuvant treatment for patients with previously untreated 
locally advanced NSCLC.  The study will also evaluate the efficacy, pharmacokinetics, 
immunogenicity, and safety of neoadjuvant Atezo  Tira or Atezo  Tira  Chemo, followed 
by adjuvant Atezo  Tira or adjuvant platinum-based chemotherapy (Chemo) as indicated 
below and detailed in Section 3.1.1.  
Table 1 
Study treatments administered 
Cohort 
Neoadjuvant Treatment 
Adjuvant Treatment 
A (PD-L1 high) 
Atezo  Tira 
Atezo  Tira 
Chemo a 
B (PD-L1 all comers) 
Atezo  Tira  Chemo 
Atezo  Tira 
Atezo  atezolizumab; Chemo  platinum-based chemotherapy; PD-L1  programmed 
deathligand 1; Tira  tiragolumab. 
a 
Investigator’s choice to administer chemotherapy as adjuvant treatment. 
  
In this protocol, “study treatment” refers to the combination of treatments assigned to 
patients as part of this study (i.e., Atezo  Tira, Atezo  Tira  Chemo or chemotherapy). 
Specific objectives and corresponding endpoints for the study are outlined in Table 2. 
 
 

  
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design  
This is a global Phase II, open-label, multicenter study evaluating the safety and efficacy 
of neoadjuvant and adjuvant atezolizumab plus tiragolumab, with or without 
platinum-based chemotherapy, in patients with previously untreated, histologically or 
cytologically confirmed resectable Stage II, IIIA, or select IIIB (T3N2 only) NSCLC. 
This study is designed to establish proof-of-concept clinical data that neoadjuvant 
treatment with Atezo  Tira or Atezo  Tira  Chemo is safe, tolerable and does not have a 
clinically significant negative effect on surgical outcomes in patients with early-stage 
resectable NSCLC.  This study is also designed to evaluate potential anti-tumor effects 
of neoadjuvant Atezo  Tira or Atezo  Tira  Chemo, as measured by MPR.  The study is 
designed with the flexibility to open new cohorts as new treatment combinations become 
available. 
This study will involve the use of an investigational diagnostic device.  PD-L1 status of 
the NSCLC tumor specimens will be evaluated by a College of American pathologists 
(CAP) and Clinical Laboratory Improvement Amendments (CLIA)-accredited laboratory 
using the commercially available 
 
 
 
 
Patients will be assigned to a cohort on the basis of PD-L1 status as outlined in 
Section 4.2.1 and will receive treatment as follows: 
 
Cohort A (PD-L1 high):  neoadjuvant Atezo  Tira for 4 cycles, followed by surgical 
resection and either adjuvant Atezo  Tira for 16 cycles or adjuvant chemotherapy 
for 4 cycles 
 
Cohort B (PD-L1 all comers):  neoadjuvant Atezo  Tira  Chemo for 4 cycles, 
followed by surgical resection and adjuvant Atezo  Tira for 16 cycles 
 

  
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Selection of the platinum-based chemotherapy regimen will be at the discretion of the 
investigator, based on histology subtypes and documented at the time of initiation.  The 
following platinum-based chemotherapy options are permitted for this study. 
 
For non-squamous NSCLC: 
– 
Cisplatin  pemetrexed 
– 
Carboplatin  pemetrexed 
– 
Carboplatin  paclitaxel 
 
For squamous NSCLC: 
– 
Carboplatin  gemcitabine 
– 
Carboplatin  paclitaxel 
 
Surgical specimens will be assessed for pathological response (MPR and pCR) by the 
investigator’s site pathology laboratory.  In addition, 
 
 
   
All patients will complete scheduled tumor assessments of the chest and abdomen by 
both computed tomography (CT) and positron emission tomography (PET) at screening 
and by CT only after Cycles 2 and 4 of neoadjuvant treatment.  Tumor assessments will 
continue after surgery until recurrence (see Section 4.5.6).  If a disease follow-up 
assessment shows evidence of disease recurrence, it should be confirmed 
pathologically and/or by unequivocal radiographic evidence from the scan.  
 
 
 
 In the absence of disease recurrence, disease follow-up assessments 
should continue until disease recurrence, withdrawal of consent, death, loss to follow-up, 
or study termination by the Sponsor, whichever occurs first (see Section 4.5.6 and 
Appendix 1 for details). 

  
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3.1.1.1 
Treatment Assignment and Safety Lead-In 
Patients must be eligible for R0 resection with curative intent at screening and must 
meet all eligibility criteria specified in Section 4.1.  Patients who do not meet the criteria 
for participation in this study (screen failures) may qualify for two re-screening 
opportunities (for a total of three screenings per participant) at the investigator's 
discretion.  Patients must re-sign the Informed Consent Form prior to re-screening.  The 
investigator will record reasons for screen failure in the screening log (see 
Section 4.5.1). 
Treatment Assignment and Safety Lead-In Based on Tumor PD-L1 Status 
After providing informed consent, patients will undergo screening procedures, including 
central assessment of PD-L1 status by the investigational 
 
 
  Enrollment will be 
completed in a step-wise manner as follows (see Figure 2), with approximately
patients enrolled in each of the cohorts.  Cohort A enrollment was closed in September 
2023: 
1. 
Initially there will be a safety lead-in: 
– 
– 
2. 
The JMC will evaluate the safety of each cohort, and if deemed to be safe:  
– 
– 
3. 
 

  
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3.1.1.2 
Surgery and Adjuvant Treatment 
Patients will undergo surgical resection of their tumor upon completion of four cycles of 
neoadjuvant therapy.  
 
 
The pre-surgery visit should occur within
days after the last dose of neoadjuvant 
treatment; repeat pulmonary function tests (PFTs) (if clinically indicated), as well as 
associated assessments (see Appendix 1) should be performed in accordance with local 
institutional practice.  The surgical procedure should be performed within
days after 
the pre-surgery visit if judged clinically feasible by both the attending surgeon and 
medical oncologist.  Surgical data should be entered on the corresponding electronic 
Case Report Form (eCRF) as soon as possible after surgery, especially during the 
safety lead-in, so that assessment of surgical delays, cancellations, or complications can 
be completed in a timely manner.  See Section 4.3.3 for guidance on the surgical 
treatment plan. 
Patients who are found to have disease progression at scheduled tumor assessments 
(after Cycle 2 and Cycle 4) or at any time during neoadjuvant treatment and are still 
deemed resectable and non-metastatic will proceed to surgery if amenable and will 
remain eligible for all study treatment and evaluations. 
Patients who discontinue neoadjuvant treatment early because of disease progression 
and do not proceed to surgery will be discontinued from additional in-clinic study 
procedures and will proceed to receive other treatment as determined by the 
investigator.  
 
 
 
After surgical resection, patients will continue to receive adjuvant Atezo  Tira or adjuvant 
chemotherapy (Cohort A [PD-L1 high] only) until one of the following occurs:  
administration of up to four cycles of adjuvant chemotherapy per local SOC, 16 cycles of 
adjuvant Atezo  Tira, unacceptable toxicity, disease recurrence, death, or patient and/or 
physician decision to discontinue study treatment. 
3.1.2 
Joint Monitoring Committee  
A JMC, 
, will be formed to evaluate 
safety data during the study.  The external experts share with the Sponsor the 
responsibility for trial monitoring and are invited to attend all review meetings and 
participate in all data reviews.  
 
  The JMC will follow a charter that outlines the JMC’s 
roles and responsibilities. 

  
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The JMC will review data to assess potential surgical delays, cancellations, or 
complications related to study treatment during the safety lead-in as described in 
Section 3.1.1.1.  After the safety lead-in, safety data will be reviewed on a periodic basis 
 
 
 
 
After reviewing the data, the JMC will provide a recommendation to the Sponsor as 
described in the JMC Charter.  
 
 
 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs, which 
is expected to occur approximately 3 years after the last patient receives the final dose 
of study drugs after surgery. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 56 years. 
3.3 
DURATION OF PARTICIPATION 
Participation will continue until withdrawal or death due to any cause.   
3.4 
RATIONALE FOR STUDY DESIGN 
This study will evaluate the surgical safety and feasibility of Atezo  Tira or 
Atezo  Tira  Chemo as neoadjuvant treatment for patients with previously untreated 
locally advanced NSCLC.  The study will also evaluate the efficacy, pharmacokinetics, 
immunogenicity, and safety of neoadjuvant Atezo  Tira or Atezo  Tira  Chemo followed 
by adjuvant Atezo  Tira or adjuvant chemotherapy. 

  
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3.4.2 
Rationale for Patient Population 
This study will enroll patients with resectable Stage II, IIIA, and select IIIB (T3N2 only) 
NSCLC as determined at screening.  
 
) will be enrolled in Cohort A (PD-L1 high), while all comers (regardless 
of PD-L1 expression level) will be enrolled in Cohort B (PD-L1 all comers). 
Neoadjuvant and adjuvant chemotherapy has shown significant but modest benefit for 
patients with early-stage resectable NSCLC, but there is still a substantial unmet need 
for improvement in outcomes in this treatment setting. 
Tumor-cell killing by cytotoxic chemotherapy may expose the immune system to high 
levels of tumor antigens.  Boosting tumor-specific T-cell immunity in this setting by 
blocking the PD-L1 and TIGIT pathways may result in deeper and more durable 
responses than those observed with standard chemotherapy alone (Merritt et al. 2003; 

  
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Apetoh et al. 2007), and this may reasonably occur in tumors regardless of PD-L1 
expression.  
Given the strong data from CITYSCAPE showing the magnitude of benefit in the PD-L1 
TPS  50% population, and the need to improve survival and decrease recurrence rates 
for patients with resectable early-stage NSCLC, this study will examine the efficacy of 
Atezo  Tira combination as a chemotherapy-free option.  A chemotherapy-free option for 
patients with resectable NSCLC would be a landmark improvement for patients and may 
spare patients the early and late toxicity associated with chemotherapy. 
3.4.3 
Rationale for Major Pathological Response as Primary 
Endpoint 
The primary efficacy objective of this study is to evaluate the efficacy of neoadjuvant 
treatment with Atezo  Tira or Atezo  Tira  Chemo in patients with resectable Stage II, 
IIIA, or select IIIB (T3N2 only) NSCLC as measured by local pathology laboratory 
assessed-MPR. 
While OS is the standard in evaluating clinical benefit in adjuvant and neoadjuvant 
NSCLC trials, readout of OS often takes many years, especially in early-stage disease.  
Thus, adopting meaningful surrogate endpoints may expedite the evaluation of new 
therapies and bring new treatments to NSCLC patients sooner.  Pathological response 
after surgical resection of NSCLC has been proposed as a surrogate endpoint for OS 
(Hellmann et al. 2014).  Hellmann et al. (2014) cited the U.S. Food and Drug 
Administration’s (FDA’s) definition of the surrogate endpoint in which the endpoint 
should be “reasonably likely to predict clinical benefit”.  They advocate that using 
pathological response in the neoadjuvant setting meets this definition based on three 
findings:  1) pathological response strongly correlates to OS; 2) pathological response is 
reflective of neoadjuvant chemotherapy; and 3) the degree of pathological response 
correlates with the degree of OS benefit. 
Use of pathological response as a surrogate endpoint is not without precedent.  Trials for 
breast cancer have used pCR to evaluate the efficacy of neoadjuvant treatment.  
However, pCR rates have varied in neoadjuvant NSCLC studies.  Furthermore, relatively 
low pCR rates reported in NSCLC may not translate into a clinically significant OS 
benefit, hence restricting the utility of pCR as a surrogate survival endpoint in NSCLC 
trials.  In fact, few trials have reported corollary survival data for pCR in NSCLC because 
of low pCR rates (median rate 4%) (Hellmann et al. 2014). 
Instead of pCR, Hellman et al. (2014) proposed the use of MPR, defined as  10% 
residual viable tumor tissue, as a survival surrogate for patients with resectable NSCLC 
receiving neoadjuvant chemotherapy treatment.  This is based on studies in which 
investigators, in acknowledgment of the rarity of pCR in NSCLC, considered other 
definitions of pathological response, including residual viable tumor as a surrogate 
survival endpoint.  Junker et al. (1997) performed pathological analysis of 40 tumors 

  
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from patients with Stage IIIA and IIIB disease who were given sequential neoadjuvant 
chemotherapy treatment, chemoradiotherapy, and surgical resection.  Patients with 
 10% residual tumor in this group had a median survival of 36 months, while patients 
who had  10% residual viable tumor tissue had a median survival of 14 months. 
Two prospective trials reported an MPR rate of approximately 22% with neoadjuvant 
chemotherapy in NSCLC.  The first study noted that of the 90 patients with Stage IIIA 
disease who received neoadjuvant chemotherapy (cisplatin  docetaxel), the median 
pathological response (amount of tumor necrosis and fibrosis) was 60%, with a median 
OS of 61 months compared with 22 months in patients with  60% pathological response 
(Betticher et al. 2006).  Another study showed that of the 50 patients who received 
neoadjuvant chemotherapy (cisplatin  docetaxel) in combination with bevacizumab, 
patients with MPR had a significantly longer 3-year survival rate compared with patients 
who did not achieve MPR (61 months vs. 22 months, respectively) (Chaft et al. 2013).  A 
retrospective study from the MD Anderson Cancer Center by William and colleagues 
(William et al. 2013) showed that in 160 patients who received neoadjuvant 
platinum-based chemotherapy, MPR was a stronger predictor of OS than clinical 
Response Evaluation Criteria in Solid Tumors (RECIST) response (see Figure 3). 
Figure 3 Overall Survival by Clinical Response and by Pathological 
Response 
 
CR/PR  complete response/partial response; CT RECIST  computed tomography Response 
Evaluation Criteria in Solid Tumors; SD/PD  stable disease/progressive disease. 
Source: William et al. 2013. 
 
The Sponsor believes that there is a significant rationale for the use of MPR as a 
surrogate endpoint based on its correlation to the magnitude of improvement in OS.  
Currently, there are ongoing global Phase III neoadjuvant registrational trials of 
chemotherapy plus PD-L1/PD-1 inhibitors vs. chemotherapy alone assessing MPR as a 
primary or secondary objective.  Use of MPR as a surrogate endpoint has the potential 
to increase the effectiveness of clinical studies and to accelerate new therapies for 

  
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3.4.5 
Rationale for Patient-Reported Outcome Assessments 
The long-term goals of lung cancer surgery include improved length and quality of life 
(Win et al. 2005).  Although lung resection remains the most effective treatment for 
patients with resectable NSCLC, these patients are at increased risk of complications 
from surgery and of functional impairment post-operatively (Win et al. 2005). 
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic adverse events.  Recent research has shown that clinicians may 
underreport the incidence and severity of symptoms experienced by patients receiving 
treatment for cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; 
Basch 2010; Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014).  Collecting 

  
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adverse event information directly from patients can provide a better understanding of 
treatment characteristics and their effects. 
Previous studies have shown that patients with resectable lung cancer present with mild 
to moderate symptoms of fatigue, dyspnea, and cough and that patients’ health-related 
quality of life (HRQoL) scores tend to return to preoperative levels 69 months after 
surgery.  To comprehensively capture disease and treatment burden from the patients’ 
perspective, patient-relevant endpoints of symptom severity and their impact on function 
and HRQoL will be collected using validated patient-reported measures.  
 
 
 
 
 
In order to evaluate the tolerability of neoadjuvant and adjuvant Atezo  Tira, patients will 
be asked to report on their experience related to study treatment-related symptoms by 
 (see Appendix 8).  These 
symptoms were identified as being salient to patients' experience with Atezo  Tira on the 
basis of the combined safety profile.  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 benefit-risk profile of Atezo  Tira. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately
patients with Stage II, IIIA, or select IIIB (T3N2 only) will be enrolled in 
this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the inclusion criteria listed below 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 
 
Histologically or cytologically confirmed Stage II, IIIA, or select IIIB (T3N2 only) 
NSCLC of squamous or non-squamous histology 

  
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– 
 
– 
– 
 
 
 
 
 
 
 
 
 
 
Solid or subsolid appearance of NSCLC on CT scan with no appearance of purely 
ground-glass opacity (GGO) 
For subsolid lesions, the tumor size (i.e., clinical T stage) should be measured 
based on solid component only, exclusive of the GGO component. 
 
Eligible for R0 resection with curative intent at the time of screening, as confirmed 
by the operating attending surgeon and involved medical oncologist prior to study 
enrollment (see Section 4.3.3) 
 
Adequate pulmonary function to be eligible for surgical resection with curative intent, 
as assessed by PFTs performed within 6 months of planned resection and repeated 
at screening, if clinically indicated, including lung volumes, spirometry, and a 
diffusion capacity; and meeting at least one of the following criteria: 
– 
 
 
 
 
– 
o 
o 

  
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 
Eligible to receive a platinum-based chemotherapy regimen 
 
 
 
Measurable disease, as assessed by the investigator per RECIST v1.1 (see 
Appendix 3) 
 
 
 
 
 
 
 
 
 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
 
Normal life expectancy, excluding lung cancer mortality risk 
 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
– 
– 
– 
– 
– 
– 
– 
– 
– 
 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 

  
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 
Negative HIV test at screening 
 
 
 
 
 
– 
– 
 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening 
 
 
 
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, 5 months after the final dose of atezolizumab, and 6 months 
after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin or 
cisplatin.  Women must refrain from donating eggs during this same period. 
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. 
Women who would like to become pregnant after study treatment 
discontinuation should seek advice on oocyte cryopreservation prior to initiation 

  
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of study treatment because of the possibility of irreversible infertility due to 
treatment with cisplatin and carboplatin.  
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential, 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, for 90 days after the final dose of tiragolumab, and for 
6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, 
carboplatin or cisplatin.  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, and 
for 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, 
carboplatin or cisplatin 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 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. 
Men who would like to father a child after study treatment initiation should be 
advised regarding the conservation of sperm prior to treatment because of the 
possibility of irreversible infertility resulting from chemotherapies used in this 
study. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the criteria listed below will be excluded from study entry. 
 
NSCLC with histology of large cell neuroendocrine carcinoma, sarcomatoid 
carcinoma, or NSCLC not otherwise specified 
 
Small cell lung cancer (SCLC) histology or NSCLC with any component of SCLC 
 
Illness or condition that may interfere with a patient’s capacity to understand, follow, 
and/or comply with study procedures 
 
Any prior therapy for lung cancer, including immunotherapy, chemotherapy, or 
radiotherapy 

  
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 
Active or history of autoimmune disease or immune deficiency, 
 
 
 
 
 
 
 
 
 
 
 
 
– 
– 
– 
 
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 
 
Active tuberculosis 
 
Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable 
angina 
 
Major surgical procedure, within 4 weeks prior to initiation of study treatment, or 
anticipation of need for a major surgical procedure during the study 
 
NSCLC with an activating EGFR mutation or ALK fusion oncogene 

  
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ALK and/or EGFR status may be assessed locally or submitted for central 
laboratory testing. 
- 
- 
 
Known c-ros oncogene 1 (ROS1) rearrangement  
 
 
 
History of malignancy other than NSCLC within 5 years prior to screening, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year 
OS rate  90%), such as adequately treated carcinoma in situ of the cervix, 
non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, 
or Stage I uterine cancer 
 
Severe 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 
 
 
 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during study treatment, within 
90 days after the final dose of tiragolumab, or within 5 months after the final dose of 
atezolizumab 
 
 
 
 
  
 
 

  
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 
 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including antiCTLA-4, antiPD-1, antiTIGIT, and antiPD-L1 therapeutic 
antibodies. 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is 
longer) prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [TNF-] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during study treatment, with the following exceptions: 
– 
– 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab or tiragolumab formulation 
 
Known allergy or hypersensitivity to any component of the chemotherapy regimen 
the patient may receive during the study 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during study 
treatment, within 90 days after the final dose of tiragolumab, 5 months after the final 
dose of atezolizumab, or 6 months after the final dose of pemetrexed, gemcitabine, 
paclitaxel, carboplatin, or cisplatin 
 
 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
4.2.1 
Treatment Assignment  
This is an open-label study.  After written informed consent has been obtained, a patient 
will be assigned a screening number from the interactive voice or web-based response 
system (IxRS). Upon completion of all screening procedures and assessments have 
been completed, the Surgical Feasibility Form has been reviewed and confirmed by the 
Sponsor, and eligibility has been established for a patient, the study site will obtain the 

  
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patient's identification number (distinct from the screening number) and treatment 
assignment from the IxRS.  
at the 
) will be enrolled in Cohort 
A (PD-L1 high) while all comers (regardless of PD-L1 expression level) will be enrolled in 
the Cohort B (PD-L1 all comers) (see Section 3.4.2).  Enrollment will be completed in a 
step-wise manner as follows (see Figure 2), with approximately
patients enrolled in 
each of the cohorts: 
1. 
Initially there will be a safety lead-in: 
– 
– 
2. 
The JMC will evaluate the safety of each cohort, and if deemed to be safe:  
– 
– 
3. 
 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab and 
tiragolumab.  Gemcitabine, paclitaxel, pemetrexed, carboplatin, and cisplatin are 
considered non-investigational medicinal products. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Atezolizumab  
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. 
For information on the atezolizumab formulation, see the pharmacy manual and the 
Atezolizumab Investigator's Brochure. 
4.3.1.2 
Tiragolumab  
Tiragolumab 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. 

  
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For further information on the tiragolumab formulation, refer to the pharmacy manual and 
the Tiragolumab Investigator’s Brochure. 
4.3.1.3 
Carboplatin, Cisplatin, Pemetrexed, Gemcitabine, 
and Paclitaxel 
Carboplatin, cisplatin, pemetrexed, gemcitabine, and paclitaxel will be used in the 
commercially available formulation where allowed by local regulations. 
For more information on the formulation and packaging of carboplatin, cisplatin, 
pemetrexed, gemcitabine, and paclitaxel, please refer to the local prescribing information 
for each drug. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Each study treatment component will be administered at the doses and frequency 
specified in Table 3. 
 
 

  
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The neoadjuvant treatment phase will consist of four cycles of Atezo  Tira or 
Atezo  Tira  Chemo.  Each cycle will be 21 days in duration.  On Day 1 of each cycle, 
all eligible patients will be administered study drug infusions in the following order: 
 
Cohort A (PD-L1 high): 
 
Cohort B (PD-L1 all comers):  Investigator will administer one of the listed 
regimens based on histology subtype and local SOC. 
– 
– 
– 
Atezolizumab (1200 mg) and tiragolumab (600 mg) will be administered at a fixed dose. 
 
 
 
For Cycle 1, premedication for primary prophylaxis (antihistamines, antipyretic 
medications, and/or analgesics) of atezolizumab and tiragolumab is not permitted.  
Patients should receive anti-emetics and IV hydration for the selected chemotherapy 
backbone regimen according to the local SOC 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 4.4.2.1).  A list of premedication for pemetrexed is provided in Table 4.  All 
medications must be recorded on the appropriate Concomitant Medications eCRF. 
Table 4 
Premedication for Pemetrexed 
Premedication 
Dose and Route 
Timing 
Folic acid 
350–1000 g PO 
Once daily beginning at least 5–7 days before 
Cycle 1, Day 1 and continuing until 3 weeks after 
discontinuation of pemetrexed 
Vitamin B12 
1000 g IM 
Q9W beginning with the week preceding Cycle 1, 
Day 1 and continuing until 3 weeks after 
discontinuation of pemetrexed 
Dexamethasone 
(suggested) 
4 mg PO 
Twice daily the day before, the day of, and the day 
after pemetrexed administration 
IM  intramuscular; PO  oral; Q9W  every 9 weeks 
 
 
.  If the investigator prefers to treat a 
patient in Cohort A with adjuvant chemotherapy the reason must be documented in the 
patient’s medical record and entered in the appropriate eCRF.  If adjuvant chemotherapy 
is to be administered, treatment should begin within 2872 days after surgery followed 
by PORT (if chosen) to begin within 2160 days after adjuvant chemotherapy.   

  
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During post-operative adjuvant treatment, infusions will be administered in the following 
order (one regimen per patient).  The choice of Cohort A (PD-L1 high) regimen is at the 
investigator’s discretion for each patient. 
Cohort A (PD-L1 high):  The investigator will administer one of the regimens 
listed below. 
– 
– 
– 
– 
Cohort B (PD-L1 all comers): 
Cases of accidental overdose or medication error associated with atezolizumab or 
tiragolumab, along with any associated adverse events, should be reported as described 
in Section 5.3.5.12. 
Administration of study treatment 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 10.  
Atezolizumab and tiragolumab infusions will be administered per the instructions outlined 
in Table 5. 
Details on treatment administration (e.g., dose and timing) 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. 
.  No dose 
modification for study treatment is allowed. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 4.6.1, Section 5.1.9, 
Appendix 11 (for chemotherapy), and Appendix 12 (for CPI). 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
 
 

  
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4.3.2.1 
Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle (see Section 3.1.1 for details).  The dose of atezolizumab is fixed and 
is not dependent on body weight.  Dose reductions are not allowed. 
Guidelines for treatment interruption or discontinuation are provided in Section 4.6.1, 
Section 5.1.9, and the Atezolizumab Investigator’s Brochure.  Guidelines for study drug 
administration in the context of management of specific adverse events are provided in 
Appendix 11. 
4.3.2.2 
Tiragolumab 
Following the administration of atezolizumab and an observation period (see Table 5), 
patients will receive 600 mg tiragolumab administered by IV infusion on Day 1 of each 
21-day cycle (see Section 3.4.1).  The tiragolumab dose is fixed and is not dependent on 
body weight.  Dose reductions are not allowed. 
Tiragolumab infusions will be administered per the instructions outlined in Table 5. 
Guidelines for treatment interruption or discontinuation are provided in Section 4.6.1 and 
Section 5.1.9.  Guidelines for study drug administration in the context of management of 
specific adverse events are provided in Appendix 12. 
 Table 5 
Administration of First and Subsequent Infusions 
of Atezolizumab and Tiragolumab 
Study drug 
First Infusion 
Subsequent Infusions 
Atezolizumab 
infusion 
 No premedication is permitted 
prior to the atezolizumab 
infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood 
pressure, and temperature) 
should be recorded within 
60 minutes prior to the infusion. 
 Atezolizumab should be 
infused over 60 ( 15) minutes. 
 If clinically indicated, vital signs 
should be recorded 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 medications may be 
administered for subsequent doses at 
the discretion of the investigator. 
 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 clinically indicated, vital signs should 
be recorded during the infusion. 
IRR  infusion-related reaction. 
 
 
 

  
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Table 5 
Administration of First and Subsequent Infusions 
of Atezolizumab and Tiragolumab (cont.) 
Study drug 
First Infusion 
Subsequent Infusions 
Observation 
period after 
infusion of 
atezolizumab 
 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 will be informed about 
the possibility of delayed post-
infusion symptoms and 
instructed to contact their study 
physician if they develop such 
symptoms. 
 If the patient 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. 
Infusion of 
tiragolumab 
 No premedication is permitted 
prior to the tiragolumab 
infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood pressure, 
and temperature) should be 
recorded within
 minutes 
prior to the infusion. 
 Tiragolumab should be infused 
over
minutes. 
 Vital signs should be recorded 
every
minutes during 
the infusion. 
 If the patient experienced an IRR during 
any previous infusion of tiragolumab, 
 may be 
administered for subsequent doses, at 
the discretion of the investigator. 
 Vital signs should be recorded within 
 minutes prior to the tiragolumab 
infusion. 
 Tiragolumab should be infused over 
 minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or
 minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
 Vital signs should be recorded during the 
infusion if clinically indicated. 
IRR  infusion-related reaction. 
 
 
 

  
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Table 5 
Administration of First and Subsequent Infusions 
of Atezolizumab and Tiragolumab (cont.) 
Study drug 
First Infusion 
Subsequent Infusions 
Observation 
period after 
infusion of 
tiragolumab 
 After the infusion of 
tiragolumab, the patient begins 
a 
-minute observation period. 
 Vital signs should be recorded 
at
minutes after the 
infusion of tiragolumab. 
 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 well without 
infusion-associated adverse events, the 
observation period may be reduced to 
minutes. 
 If the patient experienced an infusion-
associated adverse event in the previous 
infusion, the observation period should 
be
minutes. 
 If clinically indicated, vital signs should 
be recorded at
minutes after the 
infusion of tiragolumab. 
 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. 
 
4.3.2.3 
Atezolizumab and Tiragolumab Dose Delays 
The following rules apply as long as neither atezolizumab nor tiragolumab has been 
permanently discontinued:  
 
Treatment cycles will normally begin with dosing of atezolizumab and tiragolumab 
on Day 1 of each 21-day cycle.  If either study drug is delayed for a related toxicity, 
it is recommended that the other study drug is also delayed since the safety profiles 
for atezolizumab and tiragolumab are similar. 
 
In case of delays in dosing of one study drug for drug-related toxicity while the other 
study drug 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). 
 
4.3.2.4 
Chemotherapy 
Sites should adhere to the information below and to local prescribing information.  In 
general, sites should also follow their institutional and local SOC for determining dose 
adjustments in the event of patient weight changes.  If a treatment cycle is delayed or 
interrupted because of toxicity resulting from either component of the chemotherapy 
regimen, both chemotherapy components should be held and if resumed, both should be 
resumed to remain synchronized. 
Guidelines for dose modification and treatment interruption or discontinuation for 
chemotherapy are provided in Appendix 11. 

  
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Paclitaxel 
 
 
 
 
 
 
 
 
 
 
Paclitaxel injection must be diluted prior to infusion.  Paclitaxel should be diluted in 
0.9% Sodium Chloride USP; 5% Dextrose Injection, USP; 5% Dextrose and 
0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2 mg/mL.  The infusion site should be closely monitored for 
possible infiltration during drug administration. 
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment 
or devices used to prepare solutions for infusion is not recommended.  Paclitaxel should 
be administered through an in-line filter with a microporous membrane not greater than 
0.22 m.  Use of filter devices such as IVEX-2® filters, which incorporate short inlet and 
outlet PVCcoated tubing, has not resulted in significant leaching of 
bis(2-ethylhexyl)phthalate. 
Sites should follow their institutional SOC guidelines for determining the paclitaxel dose 
adjustments in the event of patient weight changes.  For paclitaxel infusion, exceptions 
to the infusion time of 3 hours will be allowed for sites that have an institutional policy of 
infusing paclitaxel more quickly (over 90 minutes) or more slowly (up to 4 hours for 
the first infusion). 
See the prescribing information for paclitaxel for more information. 
Pemetrexed 
Institutions should follow their standard administration procedures for pemetrexed.  
Administration of pemetrexed should be administered by IV infusion over at least 
10 minutes.  The premedication doses administered should be in compliance with the 
prescribing information (see Table 4).  All patients eligible for pemetrexed therapy should 
avoid taking non-steroidal anti-inflammatory drugs with long drug-elimination half-lives 
for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed 
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Gemcitabine 
Gemcitabine should be administered by IV infusion over 30 minutes prior to carboplatin.  
Please refer to Table 3 for the appropriate gemcitabine dosing.  Gemcitabine must be 
diluted prior to infusion.  The recommended diluent for reconstitution of gemcitabine is 
0.9% Sodium Chloride Injection, USP, without preservatives.  The administration of 
gemcitabine should be done in accordance with local practice and the prescribing 
information. 
See prescribing information for gemcitabine for more information. 
Carboplatin 
Carboplatin should be administered by IV infusion, immediately after the completion of 
paclitaxel or pemetrexed administration, over 1530 minutes to achieve an initial target 
area under the concentration-time curve (AUC) of 5 or 6 mg/mL/min (Calvert formula 
dosing) and with standard anti-emetic medications per local practice guidelines. 
The carboplatin dose of AUC 5 or 6 mg/mL/min 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 study, the GFR is considered to be equivalent to the creatinine 
clearance (CrCl).  The CrCl is calculated by institutional guidelines or by the method of 
Cockcroft and Gault (1976) using the following formula: 
CrCl =   (140  age)  (wt) ( 0.85 if female) 
72  Scr 
 
Where: 
CrCl = creatinine clearance in mL/min 
  
age = patient's age in years  
  
wt = patient’s weight in kg 
  
Scr = serum creatinine in mg/dL 
 
If a patient’s GFR is estimated based on serum creatinine measurements by the isotope 
dilution mass spectroscopy method, the FDA recommends that physicians consider 
capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity 
due to overdosing.  Based on the Calvert formula described in the carboplatin label, the 
maximum doses can be calculated as follows: 
Maximum carboplatin dose (mg) = target AUC (mg  min/mL)  (GFR  25 mL/min) 
 

  
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The maximum dose is based on a GFR estimate that is capped at 125 mL/min for 
patients with normal renal function.  No higher estimated GFR values should be used. 
For a target AUC = 6, the maximum dose is 6  (125  25) = 900 mg. 
For a target AUC = 5, the maximum dose is 5  (125  25) = 750 mg. 
For a target AUC = 4, the maximum dose is 4  (125  25) = 600 mg. 
Cisplatin 
Cisplatin should be administered by IV infusion, approximately 30 minutes after 
completion of the pemetrexed or per SOC at the institution.  Patients must receive 
adequate antiemetic treatment and appropriate hydration prior to and after receiving 
cisplatin. 
Refer to local clinical practice guidelines for further details. 
4.3.3 
Surgical Treatment Plan 
An attending thoracic surgeon with experience in early-stage resectable NSCLC should 
evaluate patients at screening to determine surgical fitness and eligibility for surgical 
resection.  Patients must be eligible for an R0 resection with curative intent at time of 
screening.  The intent to downstage in order to render patient operable is not permitted. 
At screening, patients must be confirmed for surgical fitness based on their PFTs as 
outlined in the inclusion criteria (see Section 4.1.1).  ppoFEV1 and ppoDLCO should be 
calculated using the following methodology (Brunelli et al. 2013): 
 
 
 
 
Patients must be reassessed after completion of neoadjuvant treatment and prior to 
surgery by the attending surgeon and medical oncologist.  Preoperative evaluation, 
including, but not limited to, blood tests, coagulation, cardiac tests or PFTs (if indicated), 
anesthesia assessment, and other evaluation procedures, should be performed per local 
SOC. 
The surgical procedure should be performed within
days after the pre-surgery visit as 
best as possible.  
 

  
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The surgical procedure performed should be documented and reported on the eCRF.  If, 
after neoadjuvant treatment or during the operation, the surgeon determines that the 
patient should not proceed with the planned surgery, the reason should be documented 
and reported in the eCRF as well. 
After surgery and following review of the pathology report, the attending surgeon should 
complete the Thoracic Surgery Questionnaire. 
4.3.4 
Post-Operative Radiotherapy 

  
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4.3.5 
Investigational Medicinal Product Handling and 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, using the IxRS 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. 
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 the applicable Investigator's Brochure for information 
on IMP handling, including preparation and storage, and accountability. 
4.3.6 
Continued Access to Atezolizumab and Tiragolumab  
Currently, the Sponsor does not have any plans to provide Roche IMPs (atezolizumab 
and tiragolumab) or any other study treatments to patients who have completed the 
study.  The Sponsor may evaluate whether to continue providing atezolizumab and 

  
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tiragolumab in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, 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 in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug 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  
Patients are permitted to use the following therapies during the study: 
 
 
 
 
  
 
 
 
 
 
 
 
. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2 and 4.4.3) as clinically indicated, per local 
standard practice.  Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or 
H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusionassociated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists; see Appendix 10). 

  
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4.4.2 
Cautionary Therapy for Atezolizumab- and Tiragolumab-
Treated Patients 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and TNF- 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF- inhibitors may 
attenuate potential beneficial immunologic effects of treatment with 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 atezolizumab and/or tiragolumab therapy (refer to Appendix 12 for 
details). 
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 
Use of the following concomitant therapies is prohibited as described below: 
 
 
 
 
 
. 
 
 
 
 
 
 

  
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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. 
All treatment visits must occur  3 days from the scheduled date unless otherwise noted 
(see Appendix 1).  All assessments should be performed on the day of the specified visit 
unless a time window is specified.  Patients must be assessed for toxicity prior to each 
dose; dosing will occur only if the clinical assessment and local laboratory test values 
are acceptable.  Assessments scheduled on the day of study treatment administration 
should be performed prior to dosing, unless otherwise specified. 
 
 
 
 
 
 
 
 
 
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 enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History, 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 

  
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will be recorded at baseline.  In addition, all 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. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
ECOG Performance Status 
Performance status will be measured using the ECOG Performance Status Scale at the 
timepoints specified in the schedule of activities in Appendix 1. 
4.5.4 
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 
postbaseline 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. 
4.5.5 
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. 
Refer to Table 5 and Appendix 1 for details on the measurements of vital signs during 
study treatment.  
4.5.6 
Tumor Response and Disease Status Follow-Up Evaluations 
Screening assessments must include PET (whole body, or skull base to mid-thighs) with 
CT scans (with oral/IV contrast) of the chest and abdomen.  A spiral CT scan of the 
chest may be obtained but is not a requirement.  If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance or a severe allergy), a 
non-contrast CT scan of the chest and abdomen may be performed along with the PET 
scan (whole body, or skull base to mid-thighs).  A CT scan with contrast or magnetic 
resonance imaging (MRI) scan of the head must be done at screening to evaluate the 
presence of CNS metastasis in all patients to ensure eligibility (MRI scan must be 
performed if CT scan is contraindicated).  An MRI scan of the head is required to confirm 

  
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Tumor or disease status follow-up assessments should continue in patients who 
discontinue treatment early for reasons other than disease progression or recurrence 
(e.g., because of toxicity).  In the absence of disease progression or recurrence, tumor 
or disease status follow-up assessments should continue in all patients, regardless of 
whether they start new anti-cancer therapy, until disease progression or recurrence, 
withdrawal of consent, death, loss to follow-up, or study termination by the Sponsor, 
whichever occurs first. 
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 (see Appendix 1 and Appendix 2).  Results must be reviewed prior to 
dosing: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered SOC for the region), sodium, potassium, magnesium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, 
ALP, ALT, AST, and LDH 
 
Coagulation:  INR, and aPTT (see Appendix 1) 
 
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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 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  During the study, urine pregnancy tests will be performed at 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 (see 
Appendix 1). 
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). 
 
Urinalysis:  pH, specific gravity, glucose, protein, ketones, and blood; dipstick 
permitted 
 
.   
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis.  Please refer to the laboratory or pathology manual 
for additional details (e.g., kits to be used, sample handling, etc.): 
 
Serum sample for analysis of autoantibodies (if deemed necessary by the sponsor 
in cases of an immune-related adverse event):  anti-nuclear antibody, 
antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and 
perinuclear anti-neutrophil cytoplasmic antibody 
 
Serum samples for atezolizumab and tiragolumab PK analysis through use of a 
validated assay 
 
Serum samples for assessment of anti-drug antibodies (ADAs) to atezolizumab and 
tiragolumab through use of a validated assay 
 
For patients with non-squamous NSCLC, if EGFR and/or ALK status is unknown, 
status must be assessed locally or at a central laboratory for determination of study 
eligibility (see Section 4.1.2 for exclusion criteria). 
 
 
 

  
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 
 
 
 
 
 
 
 
 
 
 
 
Screening blood and tumor tissue samples, including those collected from patients who 
do not enroll in the study, may be used for future research and/or development of 
disease-related tests or tools. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of 
, 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. 
4.5.8 
Electrocardiograms 
An ECG is required at screening and when clinically indicated.  ECGs for each patient 
should be obtained from the same machine wherever possible.  Lead placement should 
be as consistent as possible.  ECG recordings must be performed after the patient has 
been resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.9 
Clinical Outcome Assessments  
PRO instruments will be completed to more fully characterize the clinical profile of 
Atezo  Tira.  In addition, PRO instruments will enable the capture of each patient’s direct 
experience with Atezo  Tira. 
PRO data will be collected through use of the following instruments:  
 
 
  
4.5.9.1 
Data Collection Methods for Clinical Outcome Assessments 
Paper versions of the PRO instruments will be self-administered by patients during the 
treatment period (see Schedule of Activities in Appendix 1).  
 
 
 
 
 
 

  
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 
 
 
 
 
 
 
 
 
 
 will be completed at 
baseline and at every treatment cycle through Cycle 4.  The questionnaires will be 
collected at the pre-surgery visit and post-surgery visit.  After surgery, from Cycle 5 on, 
the questionnaires will be completed at every other study treatment cycle until the study 
treatment discontinuation visit, and at the study treatment discontinuation visit (see 
Appendix 1). 
Patients whose native language is not available with the questionnaires are exempted 
from completing all PRO assessments. 
The Sponsor will not derive adverse event reports from PRO data (see 
Section 5.3.5.13). 
 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments 
 
 
 
 

  
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4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) 
At participating sites, blood samples may be collected for DNA extraction to enable 
 
 to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  Research will be aimed at exploring inherited characteristics.  DNA 
extracted from blood may be compared with DNA extracted from tissue to identify 

  
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somatic variants by distinguishing germline variants from somatic variants.  The samples 
may be sent to one or more laboratories for analysis. 
Collection and submission of blood samples for 
 or 
 is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for 
 
, this section of the protocol (Section 4.5.10) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
 provide a comprehensive characterization of the genome and exome, 
respectively and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for 
 are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
Refer to Section 4.5.7 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
4.5.11 
Optional Procedures 
4.5.11.1 
Optional Tumor Biopsies 
Consenting patients will undergo optional tumor biopsies at screening before treatment if 
clinically feasible, and at disease progression, as assessed by the investigator per 
RECIST v1.1, during neoadjuvant treatment.  Patients may also undergo additional on-
treatment biopsies at any other time at the investigator's discretion.  Samples collected 
via resection (3 cores preferred, recommended minimum of 18-gauge needle, 
embedded in a single paraffin block), or excisional, incisional, punch, or forceps biopsy 
are preferred. 
 
 
.  Fresh 
samples need to be processed and shipped immediately (refer to the laboratory manual 
for details). 

  
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The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF. 
  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.7 for details on duration of sample storage, use 
of samples after patient withdrawal, confidentiality standards for data, and availability of 
data from 
. 
4.5.12 
Optional Samples for Research Biosample Repository 
4.5.12.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's Institutional IRB/EC and, if applicable, an appropriate regulatory body.  If a 
site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.12.2) will not be applicable at that site. 

  
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4.5.12.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on 
 related to atezolizumab, 
tiragolumab, NSCLC, or drug safety: 
 
 
 
 
 
 
 
 
 
  
 
 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via 
, whole metagenomic sequencing for comprehensive 
analysis of the microbiome, or other genomic analysis methods.  Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  
 
 provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the IRB/EC 
approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.12.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 

  
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authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and 
 nature of the analyses of RBR samples, 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. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.12.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.12.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 

  
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the Sponsor by emailing the study number and patient number to the following email 
address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.12.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Intolerable toxicity related to atezolizumab or tiragolumab, including development of 
an immune-mediated adverse event determined by the investigator to be 
unacceptable given the individual patient's potential response to therapy 
and severity of the event 
 
 
 
Intolerable toxicity related to other components of the study treatment 
 
 
 
 
Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Use of another nonprotocol-specified anti-cancer therapy 
 
Pregnancy 
 
Unequivocal radiographic disease progression per RECIST v1.1 during the 
neoadjuvant treatment phase  

  
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 
Pathologically confirmed or unequivocal radiographic evidence of disease 
recurrence during the adjuvant treatment phase 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
 
 
 
 
 
 
 
 
 
 
Patients will return to the clinic for a treatment discontinuation visit
days after the 
final dose of study treatment.  The visit at which the disease assessment shows 
progressive disease or confirms disease recurrence may be used as the treatment 
discontinuation visit.  Patients who discontinue study treatment for any reason other than 
progressive disease or recurrence will continue to undergo tumor or disease status 
assessments as outlined in the schedule of activities (see Appendix 1). 
 
 
 
 
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 
 
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 (withdrawal 

  
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of consent), this request must be documented in the source documents and signed by 
the investigator.  Patients who withdraw consent from participation in 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. 
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 International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
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.  The anticipated important safety risks for 
atezolizumab, tiragolumab, and atezolizumab in combination with tiragolumab are 
outlined below (see Sections 5.1.1, 5.1.2, and 5.1.3, respectively).  Refer to the 
Atezolizumab Investigator’s Brochure and the Tiragolumab Investigator’s Brochure for a 
complete summary of safety information for each 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.  Administration of atezolizumab and tiragolumab will be 
performed in a monitored setting in which there is immediate access to trained personnel 

  
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and adequate equipment and medicine to manage potentially serious reactions.  
Guidelines for managing patients who experience anticipated adverse events, including 
criteria for treatment interruption or discontinuation, are provided in Appendix 12.  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 SARS-CoV-2 infection 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 
SARS-CoV-2 infection, 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 SARS-CoV-2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
A JMC will periodically review safety data during the study (see Section 3.1.2). 
5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, 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 12 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure 
for a detailed description of anticipated safety risks for atezolizumab.   
5.1.2 
Risks Associated with 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 12 of the protocol and Section 6 of the Tiragolumab Investigator's 
Brochure for a detailed description of anticipated safety risks for tiragolumab. 

  
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5.1.2.1 
Infusion-Related Reactions 
Because tiragolumab is a therapeutic monoclonal antibody (mAb) 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 will be 
administered over 
 minutes followed by a 
-minute observation period, and 
subsequent infusions as well as observation times may be shortened only if the 
preceding infusion was well tolerated.  All infusions will be administered in an 
appropriate medical setting. 
Refer to Section 4.3.2 for detailed guidance on administration of tiragolumab in this 
study.  Refer to Appendix 10 for guidance on anaphylaxis precautions, 
 
 
 
 
 
. 
 
5.1.2.3 
Lymphopenia 
 
 
   
 
 
Patients with a lymphocyte count  500 cells/L will be excluded from this study 
(see Section 4.1.1), and CBCs will be monitored regularly during the study 
(see Appendix 1). 
5.1.2.4 
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 

  
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oligodendrocyte glycoprotein peptide for induction of 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 therapeutic agents 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.   
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 12. 
5.1.2.5 
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. 
5.1.3 
Risks Associated with the Combination of Atezolizumab and 
Tiragolumab 
Based on results from clinical data with tiragolumab and, there are known and potential 
for 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 atezolizumab and tiragolumab, additional immune-mediated 

  
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adverse events are potential overlapping toxicities associated with combination use of 
tiragolumab plus atezolizumab. 
Based on clinical experience to date, it is anticipated that immune-mediated adverse 
events following treatment with atezolizumab and tiragolumab will be amenable to 
monitoring and manageable in the setting of this combination study.  The extensive 
experience with immune CPIs 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 therapies will also be excluded from participation in this study.  
 
 
 
 
5.1.4 
Risks Associated with Cisplatin 
Cisplatin is known to cause nephrotoxicity, neuropathies, ototoxicity and bone marrow 
suppression.  Anaphylactic-like reactions to cisplatin have been reported.  Nausea and 
vomiting may be intense and require adequate antiemetic treatment. 
Patients will be monitored for cisplatin-related adverse events.  For more details 
regarding the safety profile of cisplatin, refer to the cisplatin prescribing information. 
5.1.5 
Risks Associated with Carboplatin 
Carboplatin is known to cause myelosuppression, nephrotoxicity, allergic reactions, 
neurologic toxicity, hemolytic-uremic syndrome, reversible posterior 
leukoencephalopathy syndrome, venoocclusive liver disease, and tumor lysis syndrome. 
Patients will be monitored for carboplatin-related adverse events.  For more details 
regarding the safety profile of carboplatin, refer to the carboplatin prescribing 
information. 
5.1.6 
Risks Associated with Pemetrexed 
Pemetrexed is known to cause myelosuppression, nephrotoxicity, skin reactions, 
gastrointestinal toxicity, and cardiovascular toxicity. 
Patients will be monitored for pemetrexed-related adverse events.  For more details 
regarding the safety profile of pemetrexed, refer to the pemetrexed prescribing 
information. 

  
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5.1.7 
Risks Associated with Paclitaxel 
Paclitaxel is known to cause myelosuppression, alopecia, peripheral neuropathy, 
myalgia, arthralgia, diarrhea, nausea, and vomiting.  Less commonly reported adverse 
events are hypersensitivity reactions, infections, bleeding, pseudomembranous colitis, 
mucositis, liver function test elevations, injection-site reactions, and cardiovascular 
effects such as hypotension, bradycardia, hypertension, arrhythmias, other ECG 
abnormalities, syncope, and venous thrombosis. 
For more details regarding the safety profile of paclitaxel, refer to the prescribing 
information for paclitaxel. 
5.1.8 
Risks Associated with Gemcitabine 
Gemcitabine infusion times that are longer than 60 minutes or gemcitabine 
administration that occurs more frequently than once a week have been shown to 
increase toxicity.  Pulmonary and cardiovascular toxicities have been reported with the 
use of gemcitabine.  Capillary leak syndrome, including fatal cases, and posterior 
reversible encephalopathy syndrome with potentially severe consequences, have been 
reported in patients receiving gemcitabine as single agent or in combination with other 
chemotherapeutic agents.  Myelosuppression manifested by neutropenia, 
thrombocytopenia, and anemia has been reported with gemcitabine as a single agent or 
in combination with other cytotoxic drugs.  Hemolytic-uremic syndrome and/or renal 
failure have been reported following one or more doses of gemcitabine.  Renal failure 
leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely 
reported.  Serious hepatotoxicity, including liver failure and death, has been reported 
very rarely in patients receiving gemcitabine alone or in combination with other 
potentially hepatotoxic drugs. 
Patients will be monitored for gemcitabine-related adverse events.  For more details 
regarding the safety profile of gemcitabine, refer to the gemcitabine prescribing 
information. 
5.1.9 
Management of Adverse Events 
5.1.9.1 
Dose Modification, Treatment Interruption, or Treatment 
Discontinuation for Atezolizumab or Tiragolumab 
Dose Modifications 
There will be no dose modifications, including dose reductions, for atezolizumab or 
tiragolumab in this study. 
Treatment Interruptions 
Study treatment may be temporarily suspended as appropriate for management of 
toxicity.  On the basis of the available characterization of mechanism of action, 
tiragolumab may cause adverse events similar to but independent of atezolizumab, may 
exacerbate the frequency or severity of atezolizumab-related adverse events, or may 
have non-overlapping toxicities with atezolizumab.  Because these scenarios may not be 

  
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distinguished from one another in the clinical setting, immune-mediated adverse events 
should generally be attributed to both study drugs, and dose interruptions or treatment 
discontinuation in response to immune-mediated adverse events should be applied to 
both atezolizumab and tiragolumab. 
 
 
 
After both study treatments have been discontinued, the patient will be monitored for 
safety and efficacy as defined in Section 4.6.1. 
5.1.9.2 
Management Guidelines for Atezolizumab- and 
Tiragolumab-Specific Adverse Events 
Refer to Appendix 12 for details on the management of tiragolumab- and 
atezolizumab-specific adverse events.  See Appendix 10 for precautions for anaphylaxis. 

  
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5.1.9.3 
Dose Modifications, Treatment Delays, or Treatment 
Discontinuation and Management of Specific Adverse Events 
for Chemotherapies 
Refer to Appendix 11 for details on chemotherapy dose modifications, treatment delays, 
or treatment discontinuation and management of specific adverse events. 
5.1.10 
Potential Overlapping Toxicities 
Based on nonclinical and/or clinical studies with atezolizumab or tiragolumab as a single 
agent, clinical data from studies with atezolizumab and tiragolumab as a combination 
therapy, and data from molecules with similar mechanisms of action, there is a potential 
for overlapping toxicity in patients treated with atezolizumab plus tiragolumab.  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 atezolizumab plus tiragolumab:  immune-mediated pulmonary, hepatic, 
gastrointestinal, renal, endocrine, ocular, pancreatic, dermatologic, neurologic adverse 
events, as well as immune-mediated myocarditis, meningoencephalitis, and myositis. 
Based on the clinical experience to date, it is anticipated that immune-mediated adverse 
events following treatment with atezolizumab plus tiragolumab will be amenable to 
monitoring and manageable in the setting of this combination study.  The extensive 
experience with immune CPIs 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. 
The risk of overlapping toxicities between the CIT agents (atezolizumab and 
tiragolumab) and the chemotherapy agents (cisplatin, carboplatin, pemetrexed, 
paclitaxel, gemcitabine) 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 pemetrexed and cisplatin/carboplatin 
(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 5.1.15.1.8, Appendix 11, and Appendix 12 with dose holds and modifications 
(if applicable) applied to the component of the treatment judged to be the primary cause.  
If, in the opinion of the investigator, tiragolumab or atezolizumab is a potential inciting 
factor, the dose of tiragolumab and atezolizumab may be held for a maximum of 
 during post-surgery adjuvant treatment beyond the last 
infusion (see Appendix 12).  Prompt symptomatic management is appropriate for mild 
immune-mediated adverse events.  In severe cases, immune-mediated toxicities may be 

  
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acutely managed with systemic corticosteroids or TNF- inhibitors.  The Medical Monitor 
is available to advise as needed. 
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 Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (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) 
 
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) 

  
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 
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) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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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).   
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 
 
 and serious adverse events will continue to be reported until 
 

  
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days after the final dose of study treatment 
 
.  In addition, adverse events of special interest will 
continue to be reported until 
 days after the final dose of study treatment, 
 
. 
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 nondirective 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 

  
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Table 6 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (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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a 
b 
  
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 8): 
 
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 
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 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 8 
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 rechallenge. 
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. 
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 on the Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" 
or "cytokine-release syndrome").  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. 

  
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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
 
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. 
 
 
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. 
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. 
 

  
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All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity 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) 
 
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 

  
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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. 
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 
 
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 5.3.5.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 

  
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the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
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 non-small 
cell lung cancer 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).  A JMC will monitor the 
frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
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5.3.5.10 
Lack of Efficacy or Worsening of NonSmall Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression or recurrence 
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 radiographic evidence of disease progression (per RECIST 
v1.1) or evidence of radiographic disease recurrence after surgical resection of the 
primary tumor.  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., planned surgical resection or 
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 
 
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 

  
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 
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 atezolizumab and tiragolumab, 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 atezolizumab and tiragolumab, 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. 
 
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 (on the PROCTCAE) with investigator reports of adverse 

  
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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. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study 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.  

  
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The paper Clinical Trial Adverse Event/ Special Situations 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 
 
  In addition, adverse events of special interest will 
continue to be reported until 
 days after the final dose of study treatment, 
 
.  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 Adverse Event/ 
Special Situations Form provided to investigators should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
Instructions for reporting 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, 
within 90 days after the final dose of tiragolumab, 5 months after the final dose of 
atezolizumab, and 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, 
carboplatin or cisplatin, 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 

  
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Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study treatment, 
within 90 days after the final dose of tiragolumab, and 6 months after the final dose of 
chemotherapy (cisplatin, carboplatin, pemetrexed, paclitaxel or gemcitabine), 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. 
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 
embryo-fetal 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 
embryo-fetal 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 

  
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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. 
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 Adverse Event/ Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES   
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 

  
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events 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. 
A JMC will monitor the safety data during the study.  An aggregate report of any clinically 
relevant safety signals that do not favor the test product will be submitted to health 
authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This is a global phase II, open-label, multicenter study evaluating the safety and efficacy 
of neoadjuvant and adjuvant atezolizumab plus tiragolumab, with or without 
platinum-based chemotherapy, in patients with previously untreated, histologically or 
cytologically confirmed resectable Stage II, IIIA, or select IIIB (T3N2 only) NSCLC. 
Efficacy and safety analyses will be performed on all enrolled patients who have 
received at least one dose of the study drug, for each cohort.  
6.1 
DETERMINATION OF SAMPLE SIZE 
The primary efficacy objective of this study is to evaluate MPR rate.   
Cohort A has been closed early due to the changing treatment landscape which includes 
chemotherapy as part of the approved treatment regimen in the perioperative setting 
(Section 1.3). 
Cohort B will enroll approximately
patients in this study.  
 
 
 
 

  
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Enrollment and major protocol deviations will be listed for each treatment cohort. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic information such as age and race will be tabulated.  Descriptive statistics, 
including means, standard deviations, and ranges for continuous parameters, as well as 
percentages and frequencies for categorical parameters, will be presented.  Summaries 
will be presented for overall population and for each treatment cohort. 
Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of any component of study drug, unless otherwise noted. 
6.4 
SAFETY ANALYSES 
For each cohort, the safety analyses will include all enrolled patients who receive at least 
one dose of study treatment. 
Study treatment exposure will be summarized, including treatment duration, dosage, and 
dose intensity. 
Incidence and length of surgical delays, incidence of operative and post-operative 
complications and/or number of surgical cancellations related to study treatment will be 
evaluated for each cohort. 
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, 
 
.  These summaries will be presented by treatment 
cohort.  All adverse events will be summarized by treatment cohort and NCI CTCAE 
grade.  
 
In addition, the treatment-emergent adverse events leading to withdrawal of study 
treatment, leading to dose reduction or interruption, related to study treatment, severe 
adverse events (i.e., Grade  3 adverse events), fatal adverse events (i.e., Grade 5), 
serious adverse events, and adverse events of special interest will also be summarized.  
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, and changes in vital signs will be 
summarized by treatment cohort.  Deaths and causes of deaths will be summarized. 

  
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6.5 
EFFICACY ANALYSES 
The efficacy analysis population will include all enrolled patients who received at least 
one dose of the study treatment. 
6.5.1 
Primary Efficacy Endpoint 
MPR rate is defined as the proportion of patients who have achieved MPR and will be 
estimated for each treatment cohort in the efficacy analysis population.  MPR is defined 
as  10% residual viable tumor at the time of surgical resection in the primary tumor, as 
assessed by local pathology laboratory.  Patients who do not proceed to surgery are 
considered as non-responders for MPR.  The two-sided 95% CI for MPR rate calculated 
using the Wilson score method will be reported.  
6.5.2 
Secondary Efficacy Endpoints 
pCR rate is defined as the proportion of patients who have achieved pCR.  pCR is 
defined as the absence of any viable tumor cells in both the primary tumor and all 
sampled lymph nodes at the time of surgical resection, as assessed by local pathology 
laboratory.  pCR rate will be analyzed using the same statistical methodology as MPR 
rate for each treatment cohort for the efficacy analysis population. 
Event-free survival (EFS) is defined as the time from first dose of the study drug to any 
of the following events, whichever occurs first:  disease progression that precludes 
surgery, as assessed by the investigator; local or distant disease recurrence (including 
occurrence of new primary NSCLC); or death from any cause.  Patients who have not 
experienced disease progression that precludes surgery, local or distant disease 
recurrence, or died at the time of analysis will be censored at the time of last tumor or 
disease follow-up assessment.  Patients with no post-baseline tumor assessment will be 
censored at the date of first dose of the study drug.  EFS will be evaluated using the 
Kaplan-Meier method for each treatment cohort for the efficacy analysis population. 
 
These results may be reported separately from the Clinical Study Report. 
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 atezolizumab and 

  
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tiragolumab 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 cohort and cycle, when appropriate and as data allow.  
Individual and median serum concentrations of atezolizumab and tiragolumab will be 
plotted by cohort and day.  Atezolizumab and tiragolumab 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. 
 
. 
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 for both atezolizumab and tiragolumab will be summarized by 
cohort. 
The relationship between ADA status and safety, efficacy, and PK endpoints may be 
analyzed and reported via descriptive statistics. 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 

  
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff. 
The Sponsor 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 
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 
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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. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
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. 

  
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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. 
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 Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as 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 

  
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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 
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. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 

  
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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. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
 
 
 
 
 
Data generated by this study must be available for inspection upon request by 
representatives of 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 

  
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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. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
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.  

  
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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 trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 35 sites globally will participate to enroll approximately
patients.  
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. 
A JMC will monitor and evaluate patient safety throughout the study. 
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 database 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 

  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
129/Protocol GO42501, Version 5 
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. 
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 (e.g., change in Medical Monitor or contact information). 

  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
130/Protocol GO42501, Version 5 
10. 
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138/Protocol GO42501, Version 5 
Appendix 1  
Schedule of Activities 
Assessment 
Screening a 
Neoadjuvant 
Tx 
(21-Day 
Cycles) 
(Cycles 14)  
Pre-Surgery 
Visit d 
Surgery
e 
Post-
Surgery 
Visit f 
Adjuvant 
Tx 
(21-Day 
Cycles) 
 (Cycles 
5+) 
Tx 
DC h 
Survival 
Follow-Up 
Days 
42 
to 1 
Days 
14 
to 1 
Day 1  
( 3 days) b 
Gemcitabine:  
Day 8  
( 1 day)c 
Within 
days 
r last 
neoadjuvant 
treatment 
dose 
Within 
days 
fter 
Pre-
Surgery 
Visit 
1421 
days 
after 
surgery 
Day 1  
( 3 days) 
Gemci-
tabine:  
Day 8  
( 1 day)g 
Days 
after 
Final 
Dose 
or 
Last 
Visit 
Every
Months 
 
Informed consent(s) a, i 
x 
 
 
 
 
 
 
 
 
Surgical Feasibility Formj 
x 
 
 
 
 
 
 
 
 
ALK and/or EGFR assessment 
(if status is unknown) k 
x 
 
 
 
 
 
 
 
 
Tumor tissue and lymph node 
sample 
x l 
 
 
 
xm 
 
 
 
 
Demographics (age, sex, and 
self-reported race/ethnicity) 
x 
 
 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
 
 

Appendix 1: Schedule of Activities 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
139/Protocol GO42501, Version 5 
Assessment 
Screening a 
Neoadjuvant 
Tx 
(21-Day 
Cycles) 
(Cycles 14)  
Pre-Surgery 
Visit d 
Surgery
e 
Post-
Surgery 
Visit f 
Adjuvant 
Tx 
(21-Day 
Cycles) 
 (Cycles 
5+) 
Tx 
DC h 
Survival 
Follow-Up 
Days 
42 
to 1 
Days 
14 
to 1 
Day 1  
( 3 days) b 
Gemcitabine:  
Day 8  
( 1 day)c 
Within 
days 
after last 
neoadjuvant 
treatment 
dose 
Within 
days 
after 
Pre-
Surgery 
Visit 
1421 
days 
after 
surgery 
Day 1  
( 3 days) 
Gemci-
tabine:  
Day 8  
( 1 day)g 
Days 
after 
Final 
Dose 
or 
Last 
Visit 
Every
Months 
Thoracic surgery evaluation 
x 
 
 
x 
 
 
 
 
 
Neoadjuvant Treatment 
Administration n 
Cohort A (PD-L1 high):  
Cohort B (PD-L1 all comers):  
 
 
X 
 
 
 
 
 
 
Pathological response assessment 
 
 
 
 
x 
 
 
 
 
Thoracic Surgery Questionnaire 
 
 
 
 
x 
 
 
 
 

Appendix 1: Schedule of Activities 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
140/Protocol GO42501, Version 5 
Assessment 
Screening a 
Neoadjuvant 
Tx 
(21-Day 
Cycles) 
(Cycles 14)  
Pre-Surgery 
Visit d 
Surgery
e 
Post-
Surgery 
Visit f 
Adjuvant 
Tx 
(21-Day 
Cycles) 
 (Cycles 
5+) 
Tx 
DC h 
Survival 
Follow-Up 
Days 
42 
to 1 
Days 
14 
to 1 
Day 1  
( 3 days) b 
Gemcitabine:  
Day 8  
( 1 day)c 
Within 
days 
after last 
neoadjuvant 
treatment 
dose 
Within 
days 
after 
Pre-
Surgery 
Visit 
1421 
days 
after 
surgery 
Day 1  
( 3 days) 
Gemci-
tabine:  
Day 8  
( 1 day)g 
 
after 
Final 
Dose 
or 
Last 
Visit 
Every
Months 
Adjuvant Treatment 
Administration n, o 
Cohort A (PD-L1 high):   
Cohort B (PD-L1 all comers):   
 
 
 
 
 
 
 
x 
 
 
Patient-reported outcomes p 
 
 
 
Day 1 only of 
each cycle 
x 
 
x 
Day 1, 
Cycle 5 
and 
Day 1, 
every 
other 
cycle 
thereafter 
x 
 

Appendix 1: Schedule of Activities 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
141/Protocol GO42501, Version 5 
Assessment 
Screening a 
Neoadjuvant 
Tx 
(21-Day 
Cycles) 
(Cycles 14)  
Pre-Surgery 
Visit d 
Surgery
e 
Post-
Surgery 
Visit f 
Adjuvant 
Tx 
(21-Day 
Cycles) 
 (Cycles 
5+) 
Tx 
DC h 
Survival 
Follow-Up 
Days 
42 
to 1 
Days 
14 
to 1 
Day 1  
( 3 days) b 
Gemcitabine:  
Day 8  
( 1 day)c 
Within 
days 
after last 
neoadjuvant 
treatment 
dose 
Within 
days 
after 
Pre-
Surgery 
Visit 
1421 
days 
after 
surgery 
Day 1  
( 3 days) 
Gemci-
tabine:  
Day 8  
( 1 day)g 
Days 
after 
Final 
Dose 
or 
Last 
Visit 
Every
Months 
Vital signs q 
x 
 
X 
 
 
 
x 
x 
 
Weight 
x 
 
X 
 
 
 
x 
x 
 
Height 
x 
 
 
 
 
 
 
 
 
Complete physical examination r 
x 
 
 
 
 
 
 
 
 
Limited physical examination s 
 
 
Xw 
 
 
 
x 
 
 
Pulmonary function test t 
x 
 
 
x 
 
 
 
 
 
ECOG Performance Status 
x 
 
 
 
 
 
 
 
 
ECG u 
x 
 
X 
 
 
 
x 
 
 
Hematology v 
 
x   
x w 
 
 
 
x  
x 
 
Chemistry x 
 
x  
x w 
 
 
 
x  
x 
 
Pregnancy test y 
 
x  
Xw 
 
 
 
x 
x y 
x y 
Coagulation (INR, aPTT) 
 
x  
 
 
 
 
 
x 
 
TSH, free T3 (or total T3), free T4 z 
x 
 
x w. z  
 
 
 
x z 
x 
 

Appendix 1: Schedule of Activities 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
142/Protocol GO42501, Version 5 
Assessment 
Screening a 
Neoadjuvant 
Tx 
(21-Day 
Cycles) 
(Cycles 14)  
Pre-Surgery 
Visit d 
Surgery
e 
Post-
Surgery 
Visit f 
Adjuvant 
Tx 
(21-Day 
Cycles) 
 (Cycles 
5+) 
Tx 
DC h 
Survival 
Follow-Up 
Days 
42 
to 1 
Days 
14 
to 1 
Day 1  
( 3 days) b 
Gemcitabine:  
Day 8  
( 1 day)c 
Within 
days 
after last 
neoadjuvant 
treatment 
dose 
Within 
days 
after 
Pre-
Surgery 
Visit 
1421 
days 
after 
surgery 
Day 1  
( 3 days) 
Gemci-
tabine:  
Day 8  
( 1 day)g 
 
Days 
after 
Final 
Dose 
or 
Last 
Visit 
Every
Months 
 aa 
x 
  
 
 
 
 
 
 
 
Urinalysis bb 
x 
 
x w, bb 
 
 
 
x bb 
 
 
Blood for serum, plasma and 
PBMC preparationcc 
  
 
Refer to Appendix 2 
 
 
Refer to Appendix 2 
 
 
At Cycle1 Day1 or as soon as possible after enrollment, during the conduct of the 
clinical study 
x ee 
 
 
 
 
 
 
Tumor biopsy at the time of 
disease progression/recurrence  
 
 
x ff, gg 
 
 
 
x gg 
xgg 
 
Tumor response and disease 
status FU assessments  
x hh 
 
x i 
 
 
 
x jj 
x jj 
 x jj 
Concomitant medications kk 
x  
 
x 
x 
x 
x 
x 
x 
 

Appendix 1: Schedule of Activities 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
145/Protocol GO42501, Version 5 
m Tumor tissue and lymph node tissue obtained from surgical resection is required for pathological response analysis.  
 
  Refer to Section 4.5.7 for 
tissue sample requirements. 
n The initial infusion of atezolizumab or tiragolumab will be delivered over
 minutes.  Subsequent infusions will be delivered over 
 
 minutes if the previous infusion was tolerated without infusion-associated adverse events, or
 minutes if the patient 
experienced an infusion-associated adverse event with the previous infusion. 
o Patients enrolled to Cohort A (PD-L1 high) will receive adjuvant treatment with Atezo  Tira Q3W for 16 cycles, or platinum based 
chemotherapy for 4 cycles, and will be scheduled for disease FU assessments.  Patients enrolled to Cohort B will receive adjuvant 
treatment with Atezo  Tira Q3W for 16 cycles and will be scheduled for disease FU assessments as well.  If PORT is required, Cycle 5 will 
begin after PORT is completed.  See Section 4.5.4 for guidance regarding PORT.  
p PRO assessments (
 
) are required to be completed by the patient at the investigational site at the start of the clinic visit before discussion of the 
patient's health state, lab results or health record, before administration of study treatment, and/or prior to any other study assessment(s) 
that could bias patients’ responses to ensure that the validity of the instrument is not compromised and that data quality meets regulatory 
requirements.  Study personnel should review all questionnaires for completeness before the patient leaves the investigational site.  During 
the neoadjuvant treatment phase, PRO assessments will be administered on Day 1 of each cycle only.  PRO assessments will be collected 
at the pre-surgery visit and post-surgery visit.  During the adjuvant treatment phase, PRO assessments will be administered on Day 1 of 
Cycle 5 and Day 1 of every other cycle thereafter.  For patients who are unable to come to the clinic due to government restrictions or 
safety considerations and continuing to receive treatment, PROs may be completed via a telephone call; source documentation sufficient to 
pass an audit should be obtained which includes, among other information, that the questionnaires were administered via telephone 
because of government restrictions or safety considerations.  
q Includes respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.  For the first infusion, vital signs should be 
measured within 60 minutes prior to the infusion and every 15 ( 5) minutes during the infusion and at 30 ( 10) minutes after the infusion.  
For subsequent infusions, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms 
occurred during the previous infusion, during the infusion and at 30 ( 10) minutes after the infusion. 
r Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.   
s Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints. 

Appendix 1: Schedule of Activities 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
146/Protocol GO42501, Version 5 
t Pulmonary function tests (PFTs) must have been performed within 6 months of planned resection and repeated at screening (only if 
clinically indicated), and should include lung volumes, spirometry, and a diffusion capacity.  PFTs must be repeated at screening if 
performed before 6 months of planned resection or have never been performed.  Abnormal PFTs may be further evaluated with 
quantitative ventilation/perfusion scanning or cardiopulmonary exercise testing.  Repeat PFTs should be performed at the pre-surgery visit 
after completion of neoadjuvant treatment, if clinically indicated, or as part of local institutional pre-surgery workup.  PFT values must meet 
criteria outlined in Section 4.1.1  
u ECG recordings will be obtained during screening and as clinically indicated at other timepoints.  Patients should be resting in a supine 
position for at least 10 minutes prior to ECG recording. 
v Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).  Hematology labs should also be performed prior to administration of gemcitabine on 
Day 8. 
w If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
x Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered SOC for the region), sodium, potassium, 
magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, and LDH.  
Chemistry panel assessments should also be performed prior to administration of gemcitabine on Day 8. 
y All women of childbearing potential will have a serum pregnancy test at screening, within 14 days prior to initiation of study treatment.  After 
screening, urine pregnancy tests will be performed at every cycle in the neoadjuvant phase, during every cycle in the adjuvant treatment 
phase and at the treatment discontinuation visit.  After the treatment discontinuation visit, a urine pregnancy test will be performed at either 
6 months after the final dose of chemotherapies, 90 days after the final dose of tiragolumab, or 5 months after the final dose of 
atezolizumab, whichever is later.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
z TSH, free T3 (or total T3 at sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and 4 for both cohorts 
in the neoadjuvant phase and Cycles 5, 9, 13, 17, and 20 only for patients receiving Atezo  Tira in the adjuvant phase. 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
152/Protocol GO42501, Version 5 
Appendix 3  
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.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
nonmeasurable 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"). 
 
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
153/Protocol GO42501, Version 5 
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 
nonmeasurable 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. 
 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
154/Protocol GO42501, Version 5 
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 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 nontarget disease or new 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
155/Protocol GO42501, Version 5 
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 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
156/Protocol GO42501, Version 5 
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 
nonmeasurable), 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 nontarget 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). 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
157/Protocol GO42501, Version 5 
 
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 
 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
158/Protocol GO42501, Version 5 
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. 
Patients with Non-Measurable Disease Only 
For patients with non-measurable disease only, the same general concepts apply as 
noted above.  However, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-measurable disease cannot be easily quantified (by definition, if all 
lesions are truly non-measurable), a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from "trace" to "large" or an increase in lymphangitic 
disease from localized to widespread.  If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
159/Protocol GO42501, Version 5 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient's baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, 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. 
 

Appendix 3: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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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. 
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 4  
AJCC/UICC Non-Small Cell Lung Cancer Staging, 8th Edition 
American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer 
(UICC) nonsmall cell lung cancer (NSCLC) Staging, 8th edition. 
 
 
 
 

Appendix 4: AJCC/UICC Non Small Cell Lung Cancer Staging, 8th Edition 
  
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Appendix 9  
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 or 
patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 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 9 Preexisting Autoimmune Diseases and Immune Deficiencies 
  
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Autoimmune Diseases and Immune Deficiencies 

 
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Appendix 10  
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 11  
Guidelines for Management of Adverse Events Associated with 
Chemotherapy 
This appendix provides guidelines for the management of patients who experience 
adverse events associated with platinum-based chemotherapy (see Table 1Table 12).  
Appendix 12 describes risks associated with atezolizumab and tiragolumab and provides 
guidelines for management of patients who experience atezolizumab- and 
tiragolumab-associated infusion-related reactions (IRRs) and immune-mediated adverse 
events (e.g., pulmonary, hepatic, gastrointestinal, endocrine, ocular, myocarditis, 
pancreatic, dermatologic, neurologic, meningoencephalitis, renal, myositis, and 
hemophagocytic lymphohistiocytosis). 
DOSE MODIFICATIONS 
Dose modifications for cisplatin, carboplatin, pemetrexed, paclitaxel, and gemcitabine 
are permitted for toxicity according to the prescribing information and local standard of 
care. When a treatment cycle is delayed or interrupted because of toxicity resulting from 
any component of the regimen, all study drugs should generally be withheld and 
resumed together to remain synchronized.  
 
  
 
 
 
 
CISPLATIN DOSE MODIFICATION AND MANAGEMENT OF SPECIFIC 
ADVERSE EVENTS 
Treatment with cisplatin should be discontinued if a patient experiences any hematologic 
or non-hematologic Grade 3 or 4 toxicity after two dose reductions or if treatment is 
delayed for more than 63 days due to toxicities. 
Hematologic Toxicity 
At the start of each cycle, the ANC must be  1500/L and the platelet count must 
be  100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time 
for recovery.  Growth factors may be used in accordance with American Society of 
Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) 
guidelines (Smith et al. 2015; NCCN 2020).  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 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
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Table 1 
Cisplatin Dose Modification for Hematologic Toxicities 
Toxicity a 
Cisplatin Dose 
ANC  500 cells/L and platelets  50,000/L 
75% of previous dose 
Platelets  50,000/L, regardless of ANC 
75% of previous dose 
Platelets  50,000/L with Grade  2 bleeding, regardless of ANC 
50% of previous dose 
ANC  1000/L plus fever of  38.5°C 
75% of previous dose 
a Nadir of prior cycle. 
 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity. 
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment then can be resumed. 
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines. 
Non-Hematologic Toxicity 
If a patient develops a non-hematologic toxicity (see Table 2), cisplatin should be 
withheld for up to 63 days until resolution to equal or less than the patient’s baseline (or 
Grade  1 if patient did not have that toxicity at baseline).  Treatment should be resumed 
according to the guidelines in Table 2.  
Diarrhea should be controlled with adequate anti-diarrhea medication.  Nausea and/or 
vomiting should be controlled with adequate anti-emetics. 
Table 2 
Cisplatin Dose Modification for Non-Hematologic Toxicities 
(Excluding Neurotoxicity) 
Toxicity 
Cisplatin Dose 
Any diarrhea requiring hospitalization (irrespective of 
grade) or Grade 3 or 4 diarrhea that occurs on adequate 
anti-diarrhea medication 
75% of previous dose 
Grade 3 or 4 nausea/vomiting a 
75% of previous dose 
Any other Grade 3 or 4 toxicity 
75% of previous dose 
a Despite the use of anti-emetics. 
 

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Nephrotoxicity 
Creatinine clearance (CrCl) must be  60 mL/min prior to the start of any cycle.  If there 
is a decrease in CrCl between cycles, but the CrCl is still above 60 mL/min at the time of 
the next cycle, the treating physician should use his or her clinical judgment regarding 
continuing cisplatin, dose reduction, or delaying the cycle.  If a patient’s CrCl value has 
not returned to 60 mL/min within 63 days following the last cisplatin administration, the 
patient must be discontinued from cisplatin. 
Neurotoxicity 
In the event of neurotoxicity, the recommended dose adjustment for cisplatin 
is documented in Table 3.  For a Grade 3 or 4 neurotoxicity, cisplatin should be resumed 
at 50% of the previous dose upon improvement or discontinued immediately (based on 
investigator’s clinical judgment). 
Table 3 
Cisplatin Dose Modification for Associated Neurotoxicity 
Toxicity 
Cisplatin Dose 
Grade 1 neurotoxicity 
100% of previous dose 
Grade 2 neurotoxicity 
75% of previous dose 
Grade 3 or 4 neurotoxicity 
50% of previous dose or 
permanent discontinuation 
 
If the patient develops ototoxicity, subsequent doses of cisplatin should not be given until 
an audiometric analysis indicates that auditory acuity is within normal limits 
(http://www.drugs.com/pro/platinol.html).  Refer to Table 3 for dose modification. 
CARBOPLATIN DOSE MODIFICATION AND MANAGEMENT OF SPECIFIC 
ADVERSE EVENTS 
Treatment with carboplatin 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. 
Additional guidance has been provided regarding recommended dose reductions, holds, 
and discontinuations of study treatment for toxicities and/or to comply with the 
prescribing information (see Section 4.3.2). 
Hematologic Toxicity 
At the start of each cycle, the ANC must be  1500/L, and the platelet count must 
be  100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time 
for recovery.  Growth factors may be used in accordance with ASCO and NCCN 
guidelines (Smith et al. 2015; NCCN 2020).  Upon recovery, dose adjustments at the 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
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start of a subsequent cycle will be made on the basis of the lowest platelet and 
neutrophil values from the previous cycle (see Table 4). 
Table 4 
Carboplatin Dose Modification for Hematologic Toxicities 
Toxicity a 
Carboplatin Dose  
ANC  500 cells/L and platelets  50,000/L 
75% of previous dose 
Platelets  50,000/L, regardless of ANC 
75% of previous dose 
Platelets  50,000/L with Grade  2 bleeding, regardless of ANC 
50% of previous dose 
ANC  1000/L plus fever of  38.5°C 
75% of previous dose 
a Nadir prior cycle. 
 
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose. 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity. 
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment will then be resumed. 
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines. 
Non-Hematologic Toxicity 
For a non-hematologic toxicity (see Table 5), 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 patient did not have that toxicity at baseline).  Dose reductions at the start of the 
subsequent cycle will be made on the basis of non-hematologic toxicities from the dose 
administered in the preceding cycle.  Table 5 provides the relevant dose adjustments for 
non-hematologic toxicities. 
 
 

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Table 5 
Carboplatin Dose Modification on the Basis of Non-Hematologic 
Toxicities in the Preceding Cycle 
Toxicity 
Adjusted Carboplatin Dose as % of 
Previous Dose a 
Diarrhea 
Grade 3 or 4 b 
75% 
Nausea/vomiting 
Grade 3 or 4 c 
75% 
Neurotoxicity 
Grade 2  
75% 
 
Grade 3 or 4 
50% or permanent discontinuation 
Transaminase elevation 
Grade 3 
75% 
 
Grade 4 
Discontinue 
Other 
Grade 3 or 4 
75% 
AUC  area under the concentrationtime curve. 
a If deemed appropriate by the treating physician, adjust carboplatin dose to the 
specified percentage of the previous AUC. 
b Grade 3 or 4 diarrhea that occurs on adequate anti-diarrhea medication or 
any grade of diarrhea requiring hospitalization. 
c Despite the use of anti-emetics. 
 
Diarrhea should be controlled with adequate anti-diarrhea medication.  Nausea and/or 
vomiting should be controlled with adequate anti-emetics.  For a Grade 3 or 4 
neurotoxicity, carboplatin should be resumed at 50% of the previous dose upon 
improvement, or discontinued immediately (based on investigator’s clinical judgment). 
PEMETREXED DOSE MODIFICATION AND MANAGEMENT OF 
SPECIFIC ADVERSE EVENTS 
The dose modification guidelines are applicable for pemetrexed used as a single agent 
or in combination with cisplatin or carboplatin. 
Treatment with pemetrexed should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or 4 toxicity after two dose reductions or if 
treatment is delayed for more than 63 days due to toxicities (see Table 7). 
Hematologic Toxicity 
At the start of each cycle, the ANC must be  1500/L, and the platelet count must 
be  100,000/L.  Treatment should be delayed for up to 63 days to allow sufficient time 
for recovery.  Growth factors may be used in accordance with ASCO and NCCN 
guidelines (Smith et al. 2015; NCCN 2020).  Upon recovery, dose adjustments at the 
start of a subsequent cycle will be made on the basis of the lowest (nadir) platelet and 
neutrophil values from the previous cycle (see Table 6). 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
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In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose. 
Table 6 
Pemetrexed Dose Modification for Hematologic Toxicities 
Toxicity a 
Pemetrexed Dose  
ANC  500 cells/L and platelets  50,000/L 
75% of previous dose 
Platelets  50,000/L, regardless of ANC 
75% of previous dose 
Platelets  50,000/L with Grade  2 bleeding, regardless of ANC 
50% of previous dose 
a Nadir of prior cycle. 
 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity. 
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment then can be resumed. 
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines. 
Non-Hematologic Toxicity 
At the start of each cycle, the CrCl must be  45 mL/min. For enrollment and dosing 
decisions, CrCl will be estimated using the original, weight-based Cockcroft and Gault 
formula or measured using the appropriate radiolabeled method (51Cr-EDTA or 
Tc99m-DTPA) to determine the glomerular filtration rate (GFR).  The method of CrCl 
assessment used at baseline should be used throughout the study. 
If a patient develops a non-hematologic toxicity (Table 7), pemetrexed should be 
withheld for up to 63 days until resolution to equal or less than the patient’s baseline (or 
Grade 1 or better if patient did not have that toxicity at baseline).  Treatment should be 
resumed according to the guidelines in Table 7.  For a Grade 3 or 4 neurotoxicity, 
pemetrexed should be resumed at 50% of the previous dose upon improvement, or 
discontinued immediately (based on the investigator’s clinical judgment). 
 
 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
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Table 7 
Pemetrexed Dose Modification for Non-Hematologic Toxicities 
Toxicity 
Pemetrexed Dose 
Any diarrhea requiring hospitalization (irrespective of 
grade) or Grade 3 or 4 diarrhea that occurs on 
adequate anti-diarrhea medication 
75% of previous dose 
Neurotoxicity 
 
Grade 2 
75% of previous dose 
Grade 3 or 4 
50% of previous dose or 
permanent discontinuation 
Any other Grade 3 or 4 toxicities 
75% of previous dose 
  
Treatment Delays Caused by Insufficient Folic Acid or Vitamin B12 
Supplementation 
Cycle 1 should not be started until both of the following requirements are met: 
 
The patient has taken folic acid for at least 5 days immediately preceding the first 
dose of pemetrexed, and 
 
The patient has received a vitamin B12 injection (which can be given on Cycle 1, 
Day 1) 
 
Delay subsequent cycles until the patient has taken folic acid for at least 14 of the 
21 days before Day 1 of the subsequent cycle. 
For more details regarding pemetrexed dose modification, see the prescribing 
information for pemetrexed. 
PACLITAXEL DOSE MODIFICATION AND MANAGEMENT OF SPECIFIC 
ADVERSE EVENTS 
The dose modification guidelines are applicable for paclitaxel used as a single agent or 
in combination with carboplatin.  
Dose reductions, holds, and discontinuations for each study drug may be made as 
outlined below.  The investigator may use discretion in modifying or accelerating the 
dose modification guidelines described below, depending on the severity of toxicity and 
an assessment of the benefit versus the risk for the patient, with the goal of maximizing 
patient compliance and access to supportive care. 
Investigators should be vigilant and alert to early and overt signs of 
myelosuppression/infection/febrile neutropenia so that these complications can be 
promptly and appropriately managed.  Patients should be made aware of these signs 
and encouraged to seek medical attention at the earliest opportunity. 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
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Dose modifications of carboplatin and paclitaxel are allowed as described in the 
following sections. 
Hematologic Toxicity 
At the start of each cycle, the ANC must be  1500/L, and the platelet count must 
be  100,000 cells/L.  Treatment may be delayed for up to 63 days from the last dose to 
allow sufficient time for recovery.  Growth factors may be used in lieu of a dose reduction 
for neutropenic fever or Grade 4 neutropenia in accordance with ASCO and NCCN 
guidelines (Smith et al. 2015; NCCN 2020).  Upon recovery, dose adjustments at the 
start of a subsequent cycle will be based on the lowest platelet and neutrophil values 
from the previous cycle (see Table 8 and Table 9). 
Table 8 
Dosing Based on ANC and Febrile Neutropenia—Paclitaxel 
and Carboplatin 
 
Dose of Paclitaxel and Carboplatin 
ANC (Day 1 of Each Cycle) 
 1500/L 
 1500/L 
Febrile neutropenia 
(regardless of duration) 
0 
Paclitaxel 150 mg/m2 
Carboplatin AUC   4.5 mg/mL/min  
AUC  area under the concentrationtime curve. 
 
Table 9 summarizes dose modifications based on platelet count. 
Table 9 
Dosing Based on Nadir Platelet Count—Paclitaxel 
and Carboplatin 
Nadir of Last Course 
Dose of Paclitaxel and Carboplatin 
Platelets (Day 1 of each cycle) 
 100,000/L 
 100,000/L 
 25,000/L or  50,000/L 
with bleeding or requiring 
transfusion 
0 
Paclitaxel  150 mg/m2 
Carboplatin 
AUC  4.5 mg/mL/min 
AUC  area under the concentrationtime curve. 
 
All dose reductions for the first episode of neutropenic fever or thrombocytopenia 
(platelet count  25,000/L or  50,000/L with bleeding or that requires transfusion) 
are permanent.  If a second episode of neutropenic fever or thrombocytopenia requiring 
dose reduction occurs, another 25% dose reduction of carboplatin and paclitaxel is 
recommended.  Patients who require a third dose reduction will immediately discontinue 
chemotherapy. 
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose. 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
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Treatment should be delayed for up to 3 weeks until the Day 1 ANC is  1500/L, and 
the platelet count is  100,000/L.  However, if the counts have not recovered in 
3 weeks, the patient’s chemotherapy will be dose reduced, withheld until adequate 
neutrophil recovery, or discontinued, according to physician judgment and local standard 
practice.  If chemotherapy is withheld longer than 63 days from the last dose, all 
chemotherapy should be discontinued.  
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity.  
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment schedule will then proceed in the usual 
sequence. 
No dose reductions will be made for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines. 
Gastrointestinal Toxicity 
For Grade 3 or 4 gastrointestinal toxicities, treatment should be delayed until resolution 
to less than or equal to the patient’s baseline value.  Dose reductions at the start of the 
subsequent cycle will be based on gastrointestinal toxicities from the dose administered 
in the preceding cycle.  Table 10 provides the relevant dose adjustments for 
gastrointestinal toxicities. 
Table 10 Carboplatin and Paclitaxel Dose Modification Based on 
Gastrointestinal Toxicities in the Preceding Cycle 
Toxicity 
Adjusted 
Carboplatin Dose 
as % of Previous 
Dose a 
Adjusted Paclitaxel 
Dose as % of 
Previous Dose a 
Diarrhea 
Grade 3 or 4 b 
75 
75 
Oral mucositis/stomatitis 
Grade 3 or 4 
100 
50 
Nausea/vomiting 
Grade 3 or 4  
75 
75 
AUC  area under the concentrationtime curve. 
a If deemed appropriate by the treating physician, adjust carboplatin dose to the specified 
percentage of the previous AUC. 
b And per investigator discretion. 
 

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Nausea and/or vomiting should be controlled with adequate anti-emetic medications.  
If Grade 3 or 4 nausea/vomiting occurs despite the use of anti-emetic medications, the 
dose should be reduced by 25% for the next course.  If tolerated, the dose should be 
increased back to 100% as soon as possible. 
If, on Day 1 of any treatment cycle, the patient has oral mucositis/stomatitis, the 
treatment should be withheld until the oral mucositis/stomatitis is cleared.  If the oral 
mucositis/stomatitis has not cleared in 3 weeks, the patient’s chemotherapy will be 
discontinued.  If acute Grade 3 oral mucositis occurs at any time, 75% of the dose 
should be given when the oral mucositis is completely cleared.  This is a permanent 
dose reduction. 
Hepatic Toxicity (Paclitaxel Only) 
No dose adjustment is required in patients with mild hepatic impairment.  For patients 
who develop hepatic toxicity, paclitaxel dose should be withheld until liver function tests 
(LFTs) resolve to Grade 1 or better prior to subsequent dosing.  If paclitaxel is withheld 
because of hepatic toxicity, carboplatin should also be withheld and administered when 
the paclitaxel is resumed. 
The recommendations for paclitaxel dose reduction based on elevated LFTs are 
provided in Table 11. 
Table 11 Dose Modifications for Paclitaxel for Hepatic Toxicity 
SGOT (AST) 
Levels 
 
Bilirubin Levels 
Paclitaxel Reduction from  
Starting Dose 
 10  ULN 
AND 
 1.25  ULN 
No change 
  10  ULN 
AND 
1.26  2.0  ULN 
25% 
  10  ULN 
AND 
2.01  5.0  ULN 
50% 
  10  ULN 
OR 
  5.0  ULN 
Discontinue paclitaxel a 
ULN  upper limit of normal. 
Note:  Recommendations for paclitaxel dose adjustments are extrapolated from dose 
adjustments for patients with hepatic impairment at baseline. 
a Patients with AST  10  ULN or bilirubin  5.0  ULN were excluded from clinical studies for 
lung cancer. 
 
If paclitaxel is withheld, hepatic values must recover to Grade  1 within 3 weeks or the 
patient’s paclitaxel treatment will be discontinued.  No dose reductions for carboplatin 
will be made for hepatic toxicity. 
The investigator should make all efforts to exclude malignant disease progression as a 
cause of liver enzyme derangement.  All study treatment should be discontinued if the 
disease under investigation has progressed. 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
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Cardiovascular Toxicity (Paclitaxel Only) 
Cardiac rhythm disturbances have occurred infrequently in patients treated with 
paclitaxel in clinical studies; however, most patients were asymptomatic, and cardiac 
monitoring is not required.  Transient asymptomatic bradycardia has been noted in as 
many as 29% of patients.  More significant atrioventricular block has rarely been noted.  
Cardiac events should be managed as follows: 
 
Asymptomatic bradycardia:  no treatment required 
 
Symptomatic arrhythmia during infusion:  Stop paclitaxel infusion, manage 
arrhythmia according to standard practice.  Paclitaxel treatment will be discontinued.  
Chest pain and/or symptomatic hypotension ( 90/60 mmHg or requires fluid 
replacement):  Stop paclitaxel infusion.  Perform an ECG.  Give IV diphenphydramine 
and dexamethasone if hypersensitivity is considered.  Also consider epinephrine or 
bronchodilators if chest pain is not thought to be cardiac.  Paclitaxel treatment will be 
discontinued, and cardiovascular support should be given as appropriate.  If appropriate, 
the advice of a cardiologist should also be sought. 
Neurologic Toxicity (Paclitaxel Only) 
The dose of paclitaxel should be modified as follows for sensory neuropathy. 
Table 12 Paclitaxel Dose Modification for Neurologic Toxicity 
Toxicity 
Paclitaxel Dose Modification 
Grade 0 
None 
Grade 1 
None 
Grade 2 
Withhold treatment until patient recovers to Grade 1 
toxicity, then resume treatment at a 25% reduction. 
Grade 3 or worse 
Withhold treatment until patient recovers to Grade 1 
toxicity, then resume treatment at a 50% reduction. 
 
Dose modifications made for neurotoxicity are permanent.  If recovery to Grade 1 toxicity 
does not occur within 3 weeks, the patient’s paclitaxel treatment will be discontinued. 
Allergic Reaction and Hypersensitivity (Paclitaxel Only) 
Caution:  Patients who had a mild to moderate hypersensitivity reaction have been 
successfully rechallenged, but the administration of prophylactic medication (see below) 
and intensive monitoring of vital signs is recommended. 
 
Mild symptoms:  Complete paclitaxel infusion.  Supervise at bedside.  No treatment 
required. 
 
Moderate symptoms:  Stop paclitaxel infusion.  Give IV diphenhydramine 2550 mg 
and IV dexamethasone 10 mg.  Resume paclitaxel infusion after recovery of 
symptoms at a low rate, 20 mL/hr for 15 minutes, then 40 mL/hr for 15 minutes, then 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
181/Protocol GO42501, Version 5 
if no further symptoms, at full-dose rate until infusion is complete.  If symptoms 
recur, stop paclitaxel infusion.  Paclitaxel treatment will be discontinued. 
 
Severe life-threatening symptoms:  Stop paclitaxel infusion.  Give IV 
diphenhydramine and dexamethasone as above.  Add epinephrine or 
bronchodilators if indicated.  Paclitaxel treatment will be discontinued. 
 
Moderate or severe hypersensitivity reactions should be recorded as an adverse event. 
Other Toxicities 
For any Grade 3 or 4 toxicities not mentioned above, carboplatin or paclitaxel should be 
withheld until the patient recovers completely or to Grade 1 toxicity.  The treatment 
should then be resumed at 75% dose (permanent dose reduction) for Grade 3 toxicities 
and 50% of dose (permanent dose reduction) for Grade 4 toxicities.  If recovery to 
Grade 1 toxicity does not occur within 3 weeks, the patient’s chemotherapy will be 
discontinued.  For Grade 1 and 2 toxicities, no dose reduction should be made. 
For guidelines on the dosing of other study drugs when carboplatin or paclitaxel are 
withheld, see Section 5.1.9. 
GEMCITABINE DOSE MODIFICATIONS, TREATMENT DELAYS OR 
TREATMENT DISCONTINUATION, AND MANAGEMENT OF SPECIFIC 
ADVERSE EVENTS 
The dose modification guidelines for gemcitabine are provided below.  Refer to local 
label for gemcitabine and chemotherapy combination dose modification guidelines.  
Treatment with gemcitabine should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or 4 toxicity after two dose reductions, or if 
treatment is delayed for more than 21 days due to toxicities. 
Hematologic Toxicities 
At the start of each cycle, the ANC must be  1500 cells/L and the platelet count must 
be  100,000 cells/L.  Gemcitabine dose modifications for hematologic toxicity should 
be on the basis of the granulocyte and platelet counts taken on Days 1 and 8 of therapy 
(see Table 13 and Table 14).  Patients receiving gemcitabine should be monitored prior 
to each dose with a full blood count, including differential and platelet counts.  Growth 
factors may be used in accordance with ASCO and NCCN guidelines (Smith et al. 2015; 
NCCN 2020).  Upon recovery, dose adjustments at the start of a subsequent cycle will 
be made on the basis of the lowest (nadir) platelet and neutrophil values from the 
previous cycle (see Table 13). 
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose. 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
182/Protocol GO42501, Version 5 
Table 13 Gemcitabine Dose Modifications or Treatment Delays for 
Hematologic Toxicities on Day 1 
Toxicity a 
Gemcitabine Dose  
ANC > 1000/L and platelets  100,000/L 
100% of previous dose 
ANC 500-999/L OR platelets 50,000-
99,999/L 
75% of previous dose 
ANC  500/L OR platelets <50,000/L 
Hold 
a Nadir of prior cycle. 
 
Table 14 Gemcitabine Dose Modifications or Treatment Delays for 
Hematologic Toxicities on Day 8 
Absolute Granulocyte Count 
 
Platelet Count 
Percent of 
Gemcitabine Dose 
on Day 1 
> 1500/L 
and 
> 100,000/L 
100 
10001500/L 
or 
75,000100,000/L 
75 
 1000/L 
or 
 75,000/L 
Omit dose 
Note: Omitted Day 8 doses of gemcitabine will not be made up.  Day 8 dose 
adjustment for neutropenia and/or platelets is not a permanent dose reduction. 
 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity. 
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment can then be resumed. 
No dose reductions are recommended for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines. 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
183/Protocol GO42501, Version 5 
Non-Hematologic Toxicities 
In general, for Grade 3 or 4 non-hematologic toxicities, gemcitabine should be withheld 
or the dose reduced by 50%, according to physician judgment. 
Permanent discontinuation should be considered for any of the following events: 
 
Unexplained dyspnea or other evidence of severe pulmonary toxicity 
 
Severe hepatic toxicity 
 
Hemolytic-uremic syndrome 
 
Capillary-leak syndrome 
 
Posterior reversible encephalopathy syndrome 
 
Table 15 provides dose modification guidelines for non-hematologic toxicities. 
Table 15 Gemcitabine Dose Modifications, Treatment Delays, or Treatment 
Discontinuation and Patient Management for Grade 24 
Non-Hematologic Toxicities 
 
Grade 2 
Grade 3 
Grade 4 
First appearance  
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
same dose with 
prophylaxis where 
possible.  
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
75% of original dose 
with prophylaxis where 
possible. 
Discontinue treatment 
unless investigator 
considers it to be in the 
best interest of the patient 
to continue at 50% of 
original dose, once 
toxicity has resolved to 
Grade 1 or better. 
Second 
appearance of 
same toxicity  
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
75% of original dose. 
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
50% of original dose. 
 
Third appearance 
of same toxicity  
Interrupt treatment until 
resolved to Grade 1 or 
better, then continue at 
50% of original dose. 
Discontinue treatment 
permanently. 
 
Fourth 
appearance of 
same toxicity 
Discontinue treatment 
permanently. 
 
 
 

Appendix 11 Guidelines for Management of Adverse Events Associated with Chemotherapy 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
184/Protocol GO42501, Version 5 
REFERENCES 
National Comprehensive Cancer Network. NCCN clinical practice guidelines in 
oncology. Hematopoietic growth factors. 2020 [updated 27 January 2020]. 
Available at: 
https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf  Accessed 
3 August 2020. 
National Comprehensive Cancer Network. NCCN clinical practice guidelines in 
oncology. Antiemesis. 2017 [updated 28 March 2017]. Available at: 
https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf.  Accessed 8 
October 2017. 
Smith TJ, Bohlke K, Lyman GH, et al: Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology clinical practice guideline update. 
J Clin Oncol 2015;33:3199212. 
.

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
185/Protocol GO42501, Version 5 
Appendix 12  
Risks Associated with Atezolizumab and/or Tiragolumab and 
Guidelines for Management of Adverse Events Associated with 
Tiragolumab and/or Atezolizumab 
Toxicities associated or possibly associated with atezolizumab and/or tiragolumab 
treatment should be managed according to standard medical practice.  Additional tests, 
such as autoimmune serology or biopsies, should be used to evaluate for a possible 
immunogenic etiology when clinically indicated. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
and/or tiragolumab may not have an immediate therapeutic effect, and in severe cases, 
immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents.  
Patients and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible 
immune-related adverse events prior to initiating therapy and throughout treatment and 
survival follow-up.  There should be a high level of suspicion that new symptoms are 
treatment related. 
The following are general recommendations for management of any other adverse events 
that may occur and are not specifically listed in the following subsections. 
 
 
 
 
 
 
 
 
 
 
 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
and tiragolumab treatment, with the exception of endocrinopathies that are 
controlled by hormone-replacement therapy. 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
186/Protocol GO42501, Version 5 
 
The investigator should consider the benefit-risk balance for a given patient prior to 
further administration of atezolizumab and tiragolumab.  
 
 
 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab and tiragolumab in this study. 
TREATMENT INTERRUPTION 
Atezolizumab and tiragolumab treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  
 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
187/Protocol GO42501, Version 5 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in Table 1. 
 
 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
190/Protocol GO42501, Version 5 
HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug(s). 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
 
 
 
 
a 
b 
c 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
191/Protocol GO42501, Version 5 
Table 2 
Management Guidelines for Hepatic Events (cont.)  
a
b
c 
 
  

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
195/Protocol GO42501, Version 5 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

a 
b 
c 
 
 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
200/Protocol GO42501, Version 5 
IMMUNE-MEDIATED CARDIAC EVENTS 
 
 
  Management guidelines for 
cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., 
troponin, B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest 
pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may 
also be a clinical manifestation of myositis or associated with pericarditis (see section on 
immune-mediated pericardial disorders below) and should be managed accordingly.  
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
202/Protocol GO42501, Version 5 
INFUSION-RELATED REACTIONS  
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with tiragolumab and atezolizumab.  These reactions, which are thought 
to be due to release of cytokines and/or other chemical mediators, occur within 24 hours 
of tiragolumab or atezolizumab administration and are generally mild to moderate in 
severity. 
 
 
 
 
 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
203/Protocol GO42501, Version 5 
Table 7 
Management Guidelines for Infusion-Related Reactions 
Event 
Management 
  
 
 
 
 
 
 
 
 
 
 
 
 
IRR  infusion-related reaction. 
 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
204/Protocol GO42501, Version 5 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
205/Protocol GO42501, Version 5 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
206/Protocol GO42501, Version 5 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
207/Protocol GO42501, Version 5 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 9. 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
215/Protocol GO42501, Version 5 
Table 13 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
 
 
 
 
 
 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
nonsteroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
217/Protocol GO42501, Version 5 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 15. 
 
 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
221/Protocol GO42501, Version 5 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
222/Protocol GO42501, Version 5 
 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: Raising awareness among community oncologists. J Oncol 
Pract 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Program 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 

Appendix 12 Guidelines for Management of Adverse Events Associated with Tiragolumab 
and/or Atezolizumab 
  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
223/Protocol GO42501, Version 5 
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 
 

 
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
224/Protocol GO42501, Version 5 
Appendix 13  
Investigational Non-Investigational, and Auxiliary Medicinal 
Product Designations (for Use in European Economic Area) 
Table 1 
Investigational, Authorized Auxiliary Medicinal Product Designations for 
European Economic Area 
Product Name 
IMP/AxMP Designation 
Marketing Authorization 
Status in EEA  
Used within Marketing 
Authorization 
Tiragolumab 
(RO7092284) 
IMP (test product)  
Unauthorized 
Not applicable 
Atezolizumab 
(RO5541267) 
IMP (test product) 
Authorized 
No 
Gemcitabine 
AxMP (background 
treatment) 
Authorized 
Not applicablea 
Paclitaxel 
AxMP (background 
treatment) 
Authorized 
Not applicablea 
Pemetrexed 
AxMP (background 
treatment) 
Authorized 
Not applicablea 
Carboplatin 
AxMP (background 
treatment) 
Authorized 
Not applicablea 
Cisplatin 
AxMP (background 
treatment) 
Authorized 
Not applicablea 
AxMP  auxiliary medicinal product; EEA  European Economic Area; IMP  investigational medicinal 
product 
a The chemotherapies being provided to patients are SOC and listed in treatment guidelines, no 
study objectives related to gaining information on background treatment, there is no comparison 
between the cohorts, and the cohorts have different populations differentiated by PDL1 status. 
 
 

  
Atezolizumab and Tiragolumab—F. Hoffmann-La Roche Ltd 
225/Protocol GO42501, Version 5 
Table 2 
Investigational and Non-Investigational Medicinal Product Designations for 
European Economic Area  
Product Name 
IMP/NIMP Designation 
Marketing Authorization 
Status in EEA 
Used within Marketing 
Authorization 
Tiragolumab 
(RO7092284) 
IMP (test product)  
Unauthorized 
Not applicable 
Atezolizumab 
(RO5541267) 
IMP (test product) 
Authorized 
No 
Gemcitabine 
Non-Roche NIMP 
(background treatment) 
Authorized 
Not applicablea 
Paclitaxel 
Non-Roche NIMP 
(background treatment) 
Authorized 
Not applicablea 
Pemetrexed 
Non-Roche NIMP 
(background treatment) 
Authorized 
Not applicablea 
Carboplatin 
Non-Roche NIMP 
(background treatment) 
Authorized 
Not applicablea 
Cisplatin 
Non-Roche NIMP 
(background treatment) 
Authorized 
Not applicablea 
EEA  European Economic Area; IMP  investigational medicinal product; NIMP  non-
investigational medicinal product  
a The chemotherapies being provided to patients are SOC and listed in treatment guidelines, no 
study objectives related to gaining information on background treatment, there is no comparison 
between the cohorts, and the cohorts have different populations differentiated by PDL1 status. 
 
 

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