Conditions: Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 438
Healthy volunteers: no

Brief summary:
This study will evaluate the pharmacokinetics, safety, and efficacy of atezolizumab subcutaneous (SC) compared with atezolizumab intravenous (IV) in participants with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) who have not been exposed to cancer immunotherapy (CIT) and for whom prior platinum-based therapy has failed. The study is comprised of two parts, as follows: A dose-finding part (Part 1, Phase Ib) will aim to identify the dose of atezolizumab SC to be tested in Part 2. A dose-confirmation part (Part 2, Phase III, randomized) will aim to confirm that the dose moved forward from Part 1 yields drug exposure that is comparable to that of atezolizumab IV.

Detailed description:

Arms:
arm 1: Atezolizumab arm 2: Atezolizumab+recombinant human hyaluronidase (rHuPH20), followed by Atezolizumab arm 3: Atezolizumab+rHuPH20, followed by Atezolizumab arm 4: Atezolizumab+rHuPH20, followed by Atezolizumab arm 5: Atezolizumab + rHuPH20

Interventions: intervention 1: Atezolizumab intervention 2: rHuPH20
Intervention descriptions: intervention 1: Atezolizumab will be administered as per the schedule specified in arm or cohort. intervention 2: rHuPH20 will be administered as per the scheduled specified in the cohort for Part 1.

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol BP40657, Version 7  
PROTOCOL 
TITLE: 
A RANDOMIZED, MULTICENTER, PHASE Ib/III 
STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, EFFICACY, AND SAFETY 
OF ATEZOLIZUMAB SUBCUTANEOUS 
COMPARED WITH ATEZOLIZUMAB 
INTRAVENOUS IN PATIENTS WITH PREVIOUSLY 
TREATED LOCALLY ADVANCED OR 
METASTATIC NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BP40657 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2018-002328-18 
IND NUMBER: 
pre-IND 140100 
NCT NUMBER 
NCT03735121 
TEST PRODUCT: 
Atezolizumab (RO5541267/F06, RO5541267/F03, 
RO5541267/F01, RO5221651) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic signature and date stamp on the final 
page of this document. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol BP40657, Version 7  
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
7 
See electronic stamp on the final page of 
this document 
6 
25 February 2022 
5 
10 February 2021 
4 
28 August 2020 
3 
30 March 2020 
2 
1 June 2019 
1 
5 August 2018 
 
 


Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol BP40657, Version 7  
PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
Protocol BP40657 (IMscin001) has been amended primarily to align with the 
Atezolizumab Investigator’s Brochure, Version 19.  Changes to the protocol, along with a 
rationale for each change, are summarized below: 
• 
The medical term “Wegener granulomatosis” has been replaced by the term 
“granulomatosis with polyangiitis” to align with the updated preferred term in 
MedDRA (Section 4.1.2.1 and Appendix 8). 
• 
The list of identified risks for atezolizumab has been revised to include pericardial 
disorders (Section 5.1.1 and Appendix 10). 
• 
The list of identified risks for atezolizumab has been revised to include myelitis and 
facial paresis (Section 5.1.1 and Appendix 10). 
• 
Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an 
identified risk associated with atezolizumab and language has been revised 
accordingly (Section 5.1.1). 
• 
The list of adverse events of special interest has been revised to include myelitis 
and facial paresis (Section 5.2.3). 
• 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section CPT A1-4 
Data Protection / Legacy 8.4 Confidentiality. 
• 
Appendix 8 has been revised to indicate that caution should be used when 
considering atezolizumab for patients who have previously experienced a pericardial 
disorder while receiving another immunostimulatory anti-cancer agent. 
• 
Appendix 8 has been revised to include autoimmune myelitis. 
• 
The adverse event management guidelines have been updated to align with the 
Addendum 1 and the Addendum 2 to the Atezolizumab Investigator’s Brochure, 
Version 19 (Appendix 10). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol BP40657, Version 7  
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND .......................................................................................... 27 
1.1 
Background on Non−Small Cell Lung Cancer ....................... 27 
1.2 
Treatment for Non–Small Cell Lung Cancer .......................... 28 
1.2.1 
First-Line Non–Small Cell Lung Cancer ................................ 28 
1.2.2 
Previously Treated Non–Small Cell Lung Cancer .................. 30 
1.3 
Background on Atezolizumab ................................................ 30 
1.3.1 
Nonclinical Studies with Subcutaneously Injected 
Atezolizumab ......................................................................... 31 
1.4 
Background on Recombinant Human 
Hyaluronidase (rHuPH20) ...................................................... 32 
1.5 
Study Rationale and Benefit-Risk Assessment ...................... 33 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 36 
2.1 
Objectives and Endpoints for Part 1 ...................................... 36 
2.1.1 
Pharmacokinetic Objectives for Part 1 ................................... 36 
2.1.2 
Safety Objective for Part 1 ..................................................... 37 
2.1.3 
Immunogenicity Objective for Part 1 ...................................... 37 
2.2 
Objectives and Endpoints for Part 2 ...................................... 37 
2.2.1 
Pharmacokinetic Objectives for Part 2 ................................... 37 
2.2.2 
Safety Objectives for Part 2 ................................................... 38 
2.2.3 
Efficacy Objectives for Part 2 ................................................. 38 
2.2.4 
Immunogenicity Objectives for Part 2 .................................... 38 
2.2.5 
Biomarker Objective for Part 2 ............................................... 39 
2.2.6 
Health Care Professional−Reported Experience 
Utility Objective for Part 2 ...................................................... 39 
3. 
STUDY DESIGN ......................................................................................... 39 
3.1 
Description of the Study......................................................... 39 
3.1.1 
Overview of Study Design ..................................................... 39 
3.1.1.1 
Part 1:  Dose Finding ............................................................. 40 
3.1.1.2 
Part 2:  Dose Confirmation .................................................... 43 


 
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3.1.2 
Treatment with Atezolizumab and Disease 
Progression according to RECIST v1.1 ................................. 45 
3.1.3 
Monitoring Committees .......................................................... 46 
3.1.3.1 
Internal Monitoring Committee ............................................... 46 
3.1.3.2 
Joint Monitoring Committee ................................................... 46 
3.2 
End of Study and Length of Study ......................................... 46 
3.3 
Rationale for Study Design .................................................... 46 
3.3.1 
Rationale for Atezolizumab Dose, Administration 
Site, and Schedule for Part 2 ................................................. 46 
3.3.2 
Rationale for Patient Population and Control Arm ................. 47 
3.3.3 
Rationale for Restricting the Number of Patients 
with a Sensitizing EGFR Mutation ......................................... 48 
3.3.4 
Rationale for Co-Primary Pharmacokinetic 
Endpoints (Cycle 1 Ctrough and AUC0–21 d) ....................... 48 
3.3.5 
Rationale for Clinical Outcome Assessments ........................ 49 
4. 
MATERIALS AND METHODS .................................................................... 49 
4.1 
Patients .................................................................................. 49 
4.1.1 
Inclusion Criteria .................................................................... 50 
4.1.1.1 
General Inclusion Criteria Applicable to Both 
Parts 1 and 2 (All Patients) .................................................... 50 
4.1.1.2 
Additional Inclusion Criteria Applicable to 
Part 1 Only ............................................................................. 53 
4.1.1.3 
Additional Inclusion Criteria Applicable to 
Part 2 Only ............................................................................. 53 
4.1.2 
Exclusion Criteria ................................................................... 54 
4.1.2.1 
General Exclusion Criteria Applicable to Both 
Parts 1 and 2 (All Patients) .................................................... 54 
4.1.2.2 
Additional Exclusion Criteria Applicable to 
Part 1 Only ............................................................................. 57 
4.1.2.3 
Additional Exclusion Criteria Applicable to 
Part 2 Only ............................................................................. 57 
4.2 
Method of Treatment Assignment and Blinding ..................... 58 
4.3 
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 58 
4.3.1 
Study Treatment Formulation and Packaging ........................ 58 
4.3.1.1 
Atezolizumab SC for Co-Mix .................................................. 58 


 
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4.3.1.2 
rHuPH20 ................................................................................ 58 
4.3.1.3 
Atezolizumab SC ................................................................... 59 
4.3.1.4 
Atezolizumab IV ..................................................................... 59 
4.3.2 
Study Treatment Dosage, Administration, and 
Compliance ............................................................................ 59 
4.3.2.1 
Atezolizumab SC for Co-Mix with rHuPH20 or 
Atezolizumab SC ................................................................... 59 
4.3.2.2 
Atezolizumab IV ..................................................................... 60 
4.3.3 
Investigational Medicinal Product Accountability ................... 61 
4.3.4 
Continued Access to Investigational Medicinal 
Products ................................................................................ 62 
4.4 
Concomitant Therapy ............................................................ 62 
4.4.1 
Permitted Therapy ................................................................. 63 
4.4.2 
Cautionary Therapy for Atezolizumab-Treated 
Patients .................................................................................. 64 
4.4.2.1 
Corticosteroids, Immunosuppressive 
Medications, and TNF-α Inhibitors ......................................... 64 
4.4.2.2 
Herbal Therapies ................................................................... 64 
4.4.3 
Prohibited Therapy ................................................................ 64 
4.5 
Study Assessments ............................................................... 65 
4.5.1 
Informed Consent Forms and Screening Log ........................ 65 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 65 
4.5.3 
Physical Examinations ........................................................... 65 
4.5.4 
Vital Signs .............................................................................. 66 
4.5.5 
Tumor and Response Evaluations ......................................... 66 
4.5.5.1 
Screening Assessments ........................................................ 66 
4.5.5.2 
Assessments during Treatment ............................................. 66 
4.5.6 
Digital Photography Images ................................................... 67 
4.5.7 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 68 
4.5.7.1 
Local Laboratories ................................................................. 68 
4.5.7.2 
Central Laboratories .............................................................. 69 
4.5.7.3 
Central Laboratories, Applicable to Part 2 Only ..................... 69 


 
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7/Protocol BP40657, Version 7 
4.5.7.4 
Applicable to All Laboratory, Biomarker, and 
Other Biological Samples ...................................................... 70 
4.5.8 
Cardiac Assessments ............................................................ 71 
4.5.8.1 
Assessments of Patient- and Health Care 
Professional−Reported Experience ....................................... 72 
4.5.8.2 
Data Collection Methods for Assessments of 
Patient- and Health Care Professional-Reported 
Experience ............................................................................. 72 
4.5.8.3 
Description of Instruments for Assessments of 
Patient- and Health Care Professional−Reported 
Experience ............................................................................. 73 
4.6 
Treatment, Patient, Study, and Site 
Discontinuation ...................................................................... 74 
4.6.1 
Study Treatment Discontinuation ........................................... 74 
4.6.2 
Patient Discontinuation from Study ........................................ 75 
4.6.3 
Study Discontinuation ............................................................ 76 
4.6.4 
Site Discontinuation ............................................................... 76 
5. 
ASSESSMENT OF SAFETY ....................................................................... 76 
5.1 
Safety Plan ............................................................................ 76 
5.1.1 
Risks Associated with Atezolizumab ..................................... 77 
5.1.2 
Risks Associated with rHuPH20 ............................................ 77 
5.2 
Safety Parameters and Definitions ........................................ 78 
5.2.1 
Adverse Events ..................................................................... 78 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 78 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 79 
5.2.4 
Selected Adverse Events ....................................................... 80 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 80 
5.3.1 
Adverse Event Reporting Period ........................................... 81 
5.3.2 
Eliciting Adverse Event Information ....................................... 81 
5.3.3 
Assessment of Severity of Adverse Events ........................... 81 
5.3.4 
Assessment of Causality of Adverse Events ......................... 82 
5.3.5 
Procedures for Recording Adverse Events ............................ 83 


 
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8/Protocol BP40657, Version 7 
5.3.5.1 
Infusion-Related Reactions, Injection-Related 
Reactions, and Cytokine-Release Syndrome ........................ 83 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 84 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 84 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 85 
5.3.5.5 
Abnormal Laboratory Values ................................................. 85 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 86 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 86 
5.3.5.8 
Deaths ................................................................................... 87 
5.3.5.9 
Preexisting Medical Conditions .............................................. 87 
5.3.5.10 
Lack of Efficacy or Worsening of NSCLC .............................. 87 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 88 
5.3.5.12 
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error ................................................ 88 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 89 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 90 
5.4.1 
Emergency Medical Contacts ................................................ 90 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................... 91 
5.4.2.1 
Events That Occur prior to Study Treatment 
Initiation ................................................................................. 91 
5.4.2.2 
Events That Occur after Study Treatment 
Initiation ................................................................................. 91 
5.4.3 
Reporting Requirements for Pregnancies .............................. 91 
5.4.3.1 
Pregnancies in Female Patients ............................................ 91 
5.4.3.2 
Abortions ............................................................................... 92 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 92 
5.5 
Follow-Up of Patients after Adverse Events .......................... 92 
5.5.1 
Investigator Follow-Up ........................................................... 92 
5.5.2 
Sponsor Follow-Up ................................................................ 93 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 93 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol BP40657, Version 7 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 93 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 94 
6.1 
Analysis Timing ..................................................................... 94 
6.2 
Analysis Populations ............................................................. 94 
6.2.1 
Part 1:  Dose Finding ............................................................. 94 
6.2.2 
Part 2:  Dose Confirmation .................................................... 95 
6.2.3 
Immunogenicity Analyses ...................................................... 95 
6.3 
Statistical Hypothesis and Planned Sample Size .................. 95 
6.3.1 
Part 1:  Dose Finding ............................................................. 95 
6.3.2 
Part 2:  Dose Confirmation .................................................... 96 
6.4 
Summaries of Conduct of Study ............................................ 98 
6.5 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 98 
6.5.1 
Part 1:  Dose Finding ............................................................. 98 
6.5.2 
Part 2:  Dose Confirmation .................................................... 98 
6.6 
Analyses of Primary Endpoint ................................................ 99 
6.6.1 
Part 1:  Dose Finding ............................................................. 99 
6.6.2 
Part 2:  Dose Confirmation .................................................... 99 
6.7 
Secondary and Exploratory Pharmacokinetic 
Analyses .............................................................................. 101 
6.7.1 
Part 1:  Dose Finding ........................................................... 101 
6.7.2 
Part 2:  Dose Confirmation .................................................. 102 
6.8 
Efficacy Analyses ................................................................ 102 
6.8.1 
Objective Response Rate .................................................... 102 
6.8.2 
Progression-Free Survival ................................................... 103 
6.8.3 
Overall Survival ................................................................... 103 
6.8.4 
Duration of Response .......................................................... 104 
6.9 
Safety Analyses ................................................................... 104 
6.9.1 
Part 1:  Dose Finding ........................................................... 104 
6.9.2 
Part 2:  Dose Confirmation .................................................. 105 
6.10 
Subgroup Analyses ............................................................. 105 
6.11 
Immunogenicity Analyses .................................................... 105 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol BP40657, Version 7 
6.12 
Biomarker Analyses ............................................................. 106 
6.13 
Patient- and Health Care Professional−Reported 
Experience Analyses ........................................................... 106 
6.14 
Interim Analysis ................................................................... 106 
6.15 
China Subpopulation Analyses ............................................ 107 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 107 
7.1 
Data Quality Assurance ....................................................... 107 
7.2 
Electronic Case Report Forms ............................................. 108 
7.3 
Source Data Documentation ................................................ 108 
7.4 
Use of Computerized Systems ............................................ 108 
7.5 
Retention of Records ........................................................... 109 
8. 
ETHICAL CONSIDERATIONS .................................................................. 109 
8.1 
Compliance with Laws and Regulations .............................. 109 
8.2 
Informed Consent ................................................................ 109 
8.3 
Institutional Review Board or Ethics Committee .................. 110 
8.4 
Confidentiality ...................................................................... 111 
8.5 
Financial Disclosure ............................................................ 112 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 112 
9.1 
Study Documentation .......................................................... 112 
9.2 
Protocol Deviations .............................................................. 112 
9.3 
Management of Study Quality ............................................. 112 
9.4 
Site Inspections ................................................................... 113 
9.5 
Administrative Structure....................................................... 113 
9.6 
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 113 
9.7 
Protocol Amendments ......................................................... 114 
10. REFERENCES ......................................................................................... 115 
 
 
LIST OF TABLES 
Table 1 
Study Definitions ......................................................................... 36 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol BP40657, Version 7 
Table 2 
Administration of First and Subsequent Atezolizumab SC 
Co-Mix and Atezolizumab SC Injections ..................................... 60 
Table 3 
Administration of First and Subsequent Atezolizumab IV 
Infusions...................................................................................... 61 
Table 4 
Tumor Tissue Sample Requirements .......................................... 70 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 82 
Table 6 
Causal Attribution Guidance ....................................................... 83 
Table 7 
Statistical Power of Test of Non-Inferiority of Ctrough and 
AUC0–21 d ..................................................................................... 98 
Table 8 
95% Confidence Interval for ORR in Atezolizumab SC Group .. 102 
 
 
LIST OF FIGURES 
Figure 1 
Part 1: Overview of the Dose Finding Study Design ................... 43 
Figure 2 
Part 2:  Overview of the Dose Confirmation Study Design .......... 45 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities: Part 1 ................................................... 121 
Appendix 2 
 Schedule of Activities: Part 2 ................................................... 126 
Appendix 3 
 Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 1, Cohort 1 ......................................................................... 132 
Appendix 4 
Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 2, SC Arm .......................................................................... 135 
Appendix 5 
Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 2, IV Arm ........................................................................... 136 
Appendix 6 
 PK and ADA Sampling Instructions for Investigators ............... 137 
Appendix 7 
 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 138 
Appendix 8 
 Preexisting Autoimmune Diseases and Immune Deficiencies . 147 
Appendix 9 
 Anaphylaxis Precautions .......................................................... 149 
Appendix 10 
 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 150 
Appendix 11 
 European Organisation for Research and Treatment of 
Cancer (EORTC) IL57 Questionnaire ....................................... 184 
Appendix 12 
 Cancer Therapy Satisfaction Questionnaire (CTSQ) ............... 185 
Appendix 13 
 Health Care Professional Subcutaneous Perspective 
Questionnaire ............................................................................ 187 
Appendix 14 
 Health Care Professional SC versus IV Perspective 
Questionnaire ............................................................................ 189 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
12/Protocol BP40657, Version 7 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, MULTICENTER, PHASE Ib/III 
STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, EFFICACY, AND SAFETY 
OF ATEZOLIZUMAB SUBCUTANEOUS 
COMPARED WITH ATEZOLIZUMAB 
INTRAVENOUS IN PATIENTS WITH PREVIOUSLY 
TREATED LOCALLY ADVANCED OR METASTATIC 
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: BP40657 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2018-002328-18 
IND NUMBER: 
pre-IND 140100 
NCT NUMBER 
NCT03735121 
TEST PRODUCT: 
Atezolizumab (RO5541267/F06, RO5541267/F03, 
RO5541267/F01, RO5221651) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.  
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
13/Protocol BP40657, Version 7 
PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, PHASE Ib/III STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, EFFICACY, AND 
SAFETY OF ATEZOLIZUMAB SUBCUTANEOUS COMPARED 
WITH ATEZOLIZUMAB INTRAVENOUS IN PATIENTS WITH 
PREVIOUSLY TREATED LOCALLY ADVANCED OR METASTATIC
NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER: 
BP40657 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2018-002328-18 
IND NUMBER: 
pre-IND 140100 
NCT NUMBER: 
NCT03735121 
TEST PRODUCT: 
Atezolizumab (RO5541267/F06, RO5541267/F03, RO5541267/F01, 
RO5221651) 
PHASE: 
Phase Ib/III 
INDICATION: 
Non−small cell lung cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics, safety, and efficacy of atezolizumab SC 
compared with atezolizumab IV in patients with locally advanced or metastatic non−small 
cell lung cancer (NSCLC) who have not been exposed to cancer immunotherapy (CIT) 
(i.e., "CIT-naive") and for whom prior platinum-based therapy has failed.  The study is 
comprised of two parts, as follows: 
• 
Part 1 (Phase Ib, dose finding) will aim to identify the dose of atezolizumab SC that yields 
drug exposure that is comparable to that of atezolizumab IV 
• 
Part 2 (Phase III, randomized, dose confirmation) will aim to demonstrate the non-inferiority 
of observed drug exposure following treatment with atezolizumab SC at the identified dose 
compared with drug exposure following treatment with atezolizumab IV  
OBJECTIVES AND ENDPOINTS FOR PART 1 
Pharmacokinetic Objectives for Part 1 
The primary pharmacokinetic (PK) objective for Part 1 is to determine the dose of atezolizumab 
SC that is predicted to yield drug exposure that is comparable to that of atezolizumab IV on the 
basis of the following endpoint: 
• 
Serum atezolizumab trough concentration (Ctrough) at Cycle 1 (i.e., predose Cycle 2) 
The secondary PK objective for Part 1 is to characterize the PK profile of atezolizumab SC on 
the basis of the following endpoint: 
• 
Serum atezolizumab concentration at specified timepoints during SC administration 
The exploratory PK objective for Part 1 is to characterize the PK profile of rHuPH20 on the 
basis of the following endpoint: 
• 
Plasma rHuPH20 concentration at specified timepoints during SC administration 


 
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14/Protocol BP40657, Version 7 
Safety Objective for Part 1 
A secondary objective for Part 1 is to evaluate the safety of atezolizumab SC on the basis of 
the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 
(CTCAE v5.0) 
• 
Incidence and severity of targeted vital signs 
• 
Incidence and severity of clinical laboratory abnormalities 
Immunogenicity Objective for Part 1 
The exploratory immunogenicity objective for Part 1 is to evaluate the immune response to 
atezolizumab SC and rHuPH20 on the basis of the following endpoints: 
• 
Incidence of anti-drug antibodies (ADAs) to atezolizumab after SC administration relative to 
the prevalence of ADAs at baseline 
• 
Incidence of ADAs to rHuPH20 after SC administration relative to the prevalence of ADAs 
at baseline 
OBJECTIVES AND ENDPOINTS FOR PART 2 
Pharmacokinetic Objectives for Part 2 
The primary PK objective for Part 2 is to demonstrate non-inferiority of exposure to 
atezolizumab SC compared with atezolizumab IV on the basis of the following co-primary 
endpoints: 
• 
Observed serum Ctrough at Cycle 1 (predose Cycle 2) 
• 
Model-predicted area under the concentration-time curve (AUC) from 0 to 21 days 
(AUC0-21 d) at Cycle 1  
A secondary PK objective for Part 2 is to evaluate exposure following administration of 
atezolizumab SC compared with atezolizumab IV on the basis of the following endpoints, as 
appropriate and as data allow:  
• 
Model-predicted Ctrough at Cycle 1 (Ctrough Cycle 1), model-predicted Ctrough at steady state 
(Ctrough,ss), and model-predicted AUC at steady state (AUCss) 
The exploratory PK objective for Part 2 is to evaluate potential relationships between 
atezolizumab exposure and efficacy and safety. 
Safety Objectives for Part 2 
A secondary objective for Part 2 is to evaluate the safety of atezolizumab SC compared with 
atezolizumab IV on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to NCI 
CTCAE v5.0 
• 
Overall patient-reported adverse event burden over time, as assessed by the patient global 
impression of cancer treatment side effects burden item from the European Organisation 
for Research and Treatment of Cancer (EORTC) IL57 
Efficacy Objectives for Part 2 
A secondary objective for Part 2 is to evaluate the efficacy of atezolizumab SC on the basis of 
the following endpoints: 
• 
Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR), as determined by the investigator according to 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
• 
Progression-free survival (PFS), defined as the time from study entry to the first occurrence 
of disease progression or death from any cause (whichever occurs first), as determined by 
the investigator according to RECIST v1.1 
• 
Overall survival (OS), defined as the time from study entry to death from any cause 


 
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• 
Duration of response (DOR), defined as the time from first occurrence of a documented 
objective response to disease progression or death from any cause (whichever occurs 
first), as determined by the investigator according to RECIST v1.1 
An additional secondary objective for Part 2 is to evaluate patient experience with atezolizumab 
SC compared with atezolizumab IV, on the basis of the following endpoints: 
• 
Functioning and global health status over time, as assessed by the physical functioning, 
role functioning, and global health status/quality of life scales of the EORTC IL57 
• 
Overall satisfaction with treatment, as assessed by the modified satisfaction with therapy 
(SWT) scale of the Cancer Therapy Satisfaction Questionnaire (CTSQ) 
Immunogenicity Objectives for Part 2 
A secondary objective for Part 2 is to evaluate the incidence of ADAs to the tested molecules 
on the basis of the following endpoint: 
• 
Incidence of ADAs to atezolizumab after SC administration or IV administration relative to 
the prevalence of ADAs at baseline 
• 
Incidence of ADAs to rHuPH20 after SC administration relative to the prevalence of ADAs 
at baseline 
The exploratory immunogenicity objective for Part 2 is to evaluate potential effects of ADAs on 
the basis of the following endpoint: 
• 
Relationship between post-baseline ADA status and PK, safety, or efficacy endpoints 
Biomarker Objective for Part 2 
The exploratory biomarker objective for Part 2 is to evaluate biomarkers that may be predictive 
of response to atezolizumab (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), are 
associated with acquired resistance to atezolizumab, can provide evidence of atezolizumab 
activity (i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding 
of disease biology. They will be evaluated on the basis of the following endpoint: 
• 
Relationship between biomarkers in tumor tissue and efficacy, or other biomarker endpoints 
Health Care Professional-Reported Experience Utility Objective for Part 2 
The secondary utility objective for Part 2 is to evaluate health care professional (HCP)-reported 
experience with administration of atezolizumab SC and atezolizumab IV, on the basis of the 
following endpoints: 
• 
Convenience, potential time savings, and overall satisfaction with atezolizumab SC 
compared with atezolizumab IV, as assessed by the HCP SC versus IV Perspective 
Questionnaire  
• 
Convenience, ease of administration, and overall satisfaction with atezolizumab SC, as 
assessed by the HCP Subcutaneous Perspective Questionnaire 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a two-part, open-label, multicenter Phase Ib/III study in patients with locally advanced or 
metastatic NSCLC who are CIT-naive and for whom prior platinum therapy has failed.  The two 
parts of the study are as follows: 
Part 1 of the study will consist of three single-arm cohorts and will determine the dose of 
atezolizumab SC that yields comparable exposure to atezolizumab IV on the basis of serum 
Ctrough at Cycle 1 (predose Cycle 2).  Atezolizumab SC co-mix will be used for Cohort 1 of 
Part 1.  A ready-to-use formulation of atezolizumab with rHuPH20 (atezolizumab SC) may be 
used for Cohorts 2 and 3 of Part 1, subject to review and approval from relevant Health 
Authorities and Sponsor decision. 
Part 2 of the study will consist of a two-arm, randomized, multicenter study of atezolizumab SC 
compared with atezolizumab IV.  The aim of Part 2 is to demonstrate non-inferiority of PK 
exposure of the SC formulation versus the IV formulation based on the co-primary endpoints, 
Cycle 1 observed serum Ctrough (predose Cycle 2) and model-predicted AUC from 0 to 21 days 


 
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(AUC0–21 d).  The ready-to-use SC formulation of atezolizumab co-formulated with rHuPH20 
(atezolizumab SC) will be used in Part 2. 
Safety will be monitored throughout the study by the Sponsor Internal Monitoring Committee 
(IMC) for Part 1 and by a Joint Monitoring Committee (JMC) for Part 2. 
Part 1:  Dose Finding 
Part 1 will be composed of three cohorts:  Cohorts 1 and 2 will consist of approximately 
12 evaluable patients each and Cohort 3 will consist of approximately 20−30 evaluable patients.  
Patients will receive one (Cohort 1) or more (Cohorts 2 and 3) administrations of atezolizumab 
SC co-mix or atezolizumab SC (see below for details) followed by treatment with atezolizumab 
IV 1200 mg every 3 weeks (Q3W), as indicated, for subsequent cycles until disease 
progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of consent. 
The following cohorts are planned: 
• 
Cohort 1: Patients will receive 1800 mg atezolizumab SC co-mix for one cycle (21 days), 
followed by 1200 mg atezolizumab IV Q3W for subsequent cycles. 
• 
Cohort 2: Patients will receive 1200 mg atezolizumab SC co-mix or atezolizumab SC every 
2 weeks (14 days) for 3 cycles, followed by 1200 mg atezolizumab IV Q3W for subsequent 
cycles. 
• 
Cohort 3:  Patients will receive 1800 mg atezolizumab SC co-mix or atezolizumab SC 
Q3W (21 days) for 3 cycles, followed by 1200 mg atezolizumab IV Q3W for subsequent 
cycles. 
In Cohorts 1 and 2, all SC injections will be administered in the thigh.  In Cohort 3, the first 
subcutaneous dose of atezolizumab will be administered in the lower part of the abdomen and 
the following 2 doses will be administered in the thigh. 
The doses specified for Cohorts 2 and 3 are projected doses.  The actual doses will depend on 
the results from Cohort 1.  Additional dose-finding cohorts may be opened if the doses from 
planned cohorts result in atezolizumab exposure outside of the expected exposure obtained 
with atezolizumab IV or if the variability in Ctrough is too high to determine a dose for Part 2 of the 
study. 
All patients must report any symptoms and adverse events immediately to the investigator, 
particularly during the first 72 hours after the first injection.  Enrollment of the first 6 patients in 
Cohort 1 will be staggered in order to closely monitor the safety and tolerability resulting from 
the first atezolizumab SC co-mix administration.  This will allow for a 72-hour interval during 
which safety will be assessed by the investigator and communicated to the Sponsor.  Safety of 
the first 72 hours in these patients will be evaluated by the Sponsor before enrollment of the 
next patient.  For Cohorts 2 and 3, enrollment of only the second patient will be dependent on 
the outcome of the safety assessment of the 72 hours from the first patient.  Further enrollment 
in Cohorts 2 and 3 will be completed without staggering. 
Data from all cohorts will be analyzed to determine the optimal atezolizumab SC dose to be 
tested in Part 2. 
Patients will be followed until 90 days after the final dose of study treatment, initiation of new 
systemic anti-cancer therapy, withdrawal from the study, or study termination by the Sponsor, 
whichever occurs first. 
Part 1 will be conducted at up to approximately 20 sites globally. 
Part 2:  Dose Confirmation 
Part 2 will be initiated once a dose has been identified based on the cumulative data collected 
from Part 1.  In Part 2, patients will be randomized in a 2:1 ratio to receive monotherapy with 
either 1875 mg of atezolizumab SC Q3W or 1200 mg of atezolizumab IV Q3W, respectively, 
starting on Day 1 of each 21-day cycle.   
Part 2 of this study will initially randomize approximately 327 patients across approximately 
150 sites in a global enrollment phase.   
To ensure a patient population representative of standard clinical practice, the Sponsor will 
periodically evaluate the prevalence of EGFR mutation and limit the number of patients with 
EGFR-positive mutation to a maximum of approximately 10% of all randomized patients if 
required.  The Sponsor may also monitor other biomarkers such as PD-L1 expression levels 


 
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and, if considered appropriate, carry out actions to ensure a balanced distribution in the study 
population. 
A structured evaluation of safety data will be conducted after the first 24 patients (approximately 
16 patients in the atezolizumab SC arm and another 8 patients in the atezolizumab IV arm) 
have completed at least one cycle to ensure that the safety of atezolizumab SC (provided as 
a ready-to-use mixture of atezolizumab and rHuPH20) is comparable to that of the 
atezolizumab SC co-mix formulation administered in Part 1.  A blinded sample-size re-
estimation will be conducted once approximately 210−250 patients have been randomized. 
Atezolizumab SC Cycle 1 observed serum Ctrough (predose Cycle 2) and model-predicted area 
under the concentration-time curve (AUC) from 0 to 21 days (AUC0–21 d) at Cycle 1 will be 
measured and compared with atezolizumab IV Cycle 1 Ctrough and model-predicted AUC0-21 d, 
respectively, to confirm non-inferiority between atezolizumab SC and atezolizumab IV 
(co-primary PK endpoints).  Efficacy and safety information will be collected on a regular basis 
to assess secondary efficacy and safety endpoints.  
Patients will receive atezolizumab SC or atezolizumab IV, as indicated, until disease 
progression, loss of clinical benefit, or unacceptable toxicity.  Crossover is not allowed. 
NUMBER OF PATIENTS 
A total of approximately 60 patients with locally advanced or metastatic NSCLC will be enrolled 
in Part 1 of the study.  Part 2 of the study is expected to randomize approximately 327 patients 
during the global enrollment phase of this study.  
TARGET POPULATION 
Inclusion Criteria 
General inclusion criteria applicable to both Parts 1 and 2 are described.  Additional inclusion 
criteria applicable to either Part 1 or Part 2 are also described. 
General Inclusion Criteria Applicable to Both Parts 1 and 2 (All Patients) 
All patients must meet all the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol, in the investigator's judgment 
• 
Measurable disease as defined by RECIST v1.1 
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease. 
• 
Eastern Cooperative Oncology Group Performance Status of 0 or 1 
• 
Life expectancy ≥ 12 weeks 
• 
Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment: 
– 
ANC ≥ 1.5 × 109/L (1500/µL) without granulocyte colony-stimulating factor support  
– 
Lymphocyte count ≥ 0.5 × 109/L (500/µL) 
– 
Platelet count ≥ 100 × 109/L (100,000/µL) (without transfusion)  
– 
Hemoglobin ≥ 90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
– 
AST, ALT, and ALP ≤ 2.5 × upper limit of normal (ULN), with the following exceptions: 
Patients with documented liver metastases:  AST and ALT ≤ 5 × ULN 
Patients with documented liver or bone metastases:  ALP ≤ 5 × ULN 
– 
Total bilirubin ≤ 1.5 × ULN with the following exception: 
Patients with known Gilbert disease:  total bilirubin level ≤ 3 × ULN 
– 
Serum creatinine ≤ 1.5 × ULN  


 
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– 
Serum albumin ≥ 25 g/L (2.5 g/dL) 
– 
For patients not receiving therapeutic anticoagulation:  INR or aPTT ≤ 1.5 × ULN 
• 
Negative HIV test at screening 
• 
Negative hepatitis B surface antigen (HBsAg) test at screening 
• 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening 
The HBV DNA test will be performed only for patients who have a positive total 
HBcAb test. 
• 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
• 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, 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 5 months after the final dose of 
atezolizumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
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 acceptable methods of contraception. 
• 
Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute 
toxicities from previous therapy, excluding alopecia 
For peripheral neuropathy, improvement to Grade ≤ 2 is acceptable. 
• 
Intact normal skin without potentially obscuring tattoos, pigmentation, or lesions in the area 
for intended injection 
• 
Histologically or cytologically documented NSCLC that is currently locally advanced or 
metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or 
recurrent) NSCLC (per the Union Internationale contre le Cancer/American Joint 
Committee on Cancer staging system, 8th edition) 
Pathological characterization may be from tumor specimens collected at a time when 
the NSCLC was at an earlier stage but must be sufficient to define patients as having 
either squamous or non-squamous histology. 
• 
Disease progression during or following treatment with a platinum-containing regimen for 
locally advanced, unresectable/inoperable or metastatic NSCLC or disease recurrence 
within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen or 
combined modality (e.g., chemoradiation) regimen with curative intent  
Patients may have received one additional cytotoxic chemotherapy regimen provided 
no interval disease progression has occurred.  Chemotherapy regimens will be 
counted based on interval disease progression and not the number of agents or 
switches in agents (e.g., a first-line therapy that consists of several cycles of a 
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a new chemotherapy agent without interval disease progression will all be considered 
one chemotherapy regimen). 
Adjuvant/neoadjuvant chemotherapy or chemoradiation counts as a prior 
chemotherapy regimen if < 6 months have elapsed between the last dose and the date 
of recurrence.  Combined treatment with chemotherapy and radiation constitutes 
a single regimen; surgery is not considered a regimen. 
Patients with advanced lung cancer and a sensitizing EGFR mutation will additionally 
be required to have experienced disease progression (during or after treatment) or 
intolerance with one or more EGFR TKIs appropriate for the treatment of 
EGFR-mutant NSCLC as outlined below: 
– 
Patients who have progressed on or were intolerant to first-line osimertinib or other 
third generation EGFR TKIs are eligible. 
– 
Patients who have progressed on or were intolerant to first- or second-generation 
EGFR TKIs (for example: erlotinib, gefitinib, afatinib, dacomitinib) and who have no 
evidence of the EGFR T790M mutation in the tumor tissue after TKI therapy are 
eligible.  Patients whose T790M mutational status is unknown are also eligible if 
this is in accordance to local standard practice. 
– 
Patients who have progressed on or were intolerant to first- or second-generation 
EGFR TKIs and who have evidence of the EGFR T790M mutation in the tumor 
tissue after TKI therapy must also have progressed on, were intolerant to, or lack 
access to third-generation TKIs such as osimertinib or others. 
Patients with a previously detected ALK fusion oncogene must additionally have 
experienced disease progression (during or after treatment) or intolerance to treatment 
with one or more ALK inhibitors (e.g., alectinib, crizotinib, brigatinib, ceritinib, lorlatinib, 
or others) appropriate for the treatment of NSCLC in patients having an ALK fusion 
oncogene. 
The last dose of prior systemic anti-cancer therapy must have been 
administered  ≥ 21 days prior to enrollment/randomization, with the exception being 
TKIs approved for treatment of NSCLC have to be discontinued  ≥ 7 days prior to 
Cycle 1, Day 1.  The baseline scan must be obtained after discontinuation of prior TKIs 
(washout not required prior to obtaining the scan).  
The last dose of treatment with any investigational agent or participation in another 
interventional study must have ended  ≥ 28 days prior to enrollment/randomization. 
Anti-cancer agents used for pleurodesis are not counted as a line of therapy. 
Prior radiation therapy is allowed provided the patient has recovered from any toxic 
effects thereof. 
Additional Inclusion Criteria Applicable to Part 1 Only 
Patients in Part 1 must also meet the following additional criteria for study entry: 
• 
A body mass index (BMI) between 18 and 32 kg/m2 inclusive 
Additional Inclusion Criteria Applicable to Part 2 Only  
Patients in Part 2 must also meet the following additional criteria for study entry: 
• 
For patients whose tumor may harbor a sensitizing EGFR mutation, known EGFR test 
results at the time of randomization 
Patients who may harbor a sensitizing EGFR mutation are defined as having 
non-squamous histology (including those with a mixed histology that includes any 
non-squamous component), and without any other known driver mutation (e.g., KRAS 
status wild-type/unknown, BRAF status wild-type/unknown, or ALK fusion oncogene 
negative/unknown).   
EGFR tests may be assessed locally or submitted for central laboratory testing.  If 
available, EGFR status assessed locally should be performed on tissue samples using 
a validated health authority−approved test that detects mutations in exons 18−21.  
Patients recruited in China are required to be tested centrally, even if local results are 
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If patients are recruited in China or if no local results are available, tissue is required 
for central testing as promptly as possible and always prior to randomization  
Patients with a sensitizing EGFR mutation will be excluded once approximately 10% of 
the total target sample size has been reached.   
• 
Availability of a pre−study treatment representative formalin-fixed paraffin-embedded 
(FFPE) tumor specimen in paraffin block (preferred) or at least six slides containing 
unstained, freshly cut, serial sections from an FFPE tumor specimen for exploratory 
biomarker analysis (e.g., PD-L1) 
For patients recruited in China, availability of nine slides (including six for exploratory 
biomarker testing) containing unstained, freshly cut, serial sections from a pre−study 
treatment representative formalin-fixed paraffin embedded (FFPE) tumor specimen. 
For both patients recruited in China and ex-China, if fewer slides are available at 
baseline, additional slides may be requested in case of testing failure. 
 
Exclusion Criteria 
General exclusion criteria applicable to both Parts 1 and 2 are described.  Additional exclusion 
criteria applicable to either Part 1 or Part 2 are also described. 
General Exclusion Criteria Applicable to Both Parts 1 and 2 (All Patients) 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusions 
Patients who meet any of the following cancer-specific criteria will be excluded from study 
entry: 
• 
Symptomatic, untreated, or actively progressing CNS metastases  
Asymptomatic patients with treated CNS lesions are eligible provided that all of the 
following criteria are met:  
– 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
– 
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 
– 
The patient has not undergone stereotactic radiotherapy within 7 days prior to 
initiation of study treatment, whole-brain radiotherapy within 14 days prior to 
initiation of study treatment, or neurosurgical resection within 28 days prior to 
initiation of study treatment. 
– 
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease.  Anticonvulsant therapy at a stable dose is permitted. 
– 
Metastases are limited to the cerebellum or the supratentorial region (i.e., no 
metastases to the midbrain, pons, medulla, or spinal cord). 
– 
There is no evidence of interim progression between completion of CNS-directed 
therapy and initiation of study treatment. 
Note:  Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases.  Following 
treatment, these patients may then be eligible without the need for an additional brain 
scan prior to enrollment, if all other criteria are met. 
• 
Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for ≥ 2 weeks prior to enrollment 
• 
History of leptomeningeal disease 
• 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
• 
Uncontrolled tumor-related pain 
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Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should have recovered from the effects of radiation.  There is no 
required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
• 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL, or corrected serum calcium > ULN) 
• 
History of malignancy other than NSCLC within 5 years prior to screening, with the 
exception of those with a negligible risk of metastasis or death and treated with expected 
curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or 
squamous cell skin cancer, localized prostate cancer treated with curative intent, or ductal 
carcinoma in situ treated surgically with curative intent) 
General Medical Exclusions 
Patients who meet any of the following general medical criteria will be excluded from study 
entry: 
• 
Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or 
within 5 months after the final dose of atezolizumab 
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment. 
• 
History of severe anaphylactic reactions to chimeric or humanized antibodies or fusion 
proteins 
• 
Known hypersensitivity to Chinese hamster ovary cell products or any component of the 
atezolizumab formulation 
• 
Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met: 
– 
Rash must cover < 10% of body surface area. 
– 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
– 
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the 
previous 12 months. 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Active tuberculosis 


 
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• 
Current treatment with anti-viral therapy for HBV 
• 
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 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
• 
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to initiation of study 
treatment, unstable arrhythmias, or unstable angina 
Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded.  
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized 
in the opinion of the treating physician, in consultation with a cardiologist if appropriate. 
• 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the course of the 
study  
• 
Prior allogeneic stem cell or solid organ transplantation 
• 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab 
• 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, or that may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications 
Exclusion Criteria Related to Medications 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies including 
anti-TIGIT, anti−PD-1, and anti−PD-L1 therapeutic antibodies  
Patients who have had prior anti−CTLA-4 treatment may be enrolled, provided the 
following requirements are met:  
– 
Last dose of anti−CTLA-4 at least 6 weeks prior to enrollment  
– 
No history of severe immune-mediated adverse effects from anti−CTLA-4 
(National Cancer Institute Common Terminology Criteria for Adverse Events [NCI 
CTCAE] Grade 3 or 4) 
• 
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior 
to initiation of study treatment  
Prior treatment with cancer vaccines is allowed.  
• 
Treatment with systemic immunosuppressive medication (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti−TNF-α agents) within 2 weeks prior to enrollment 
Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), 
systemic immunosuppressant medications may be enrolled in the study.  
The use of corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients 
with orthostatic hypotension, and low-dose supplemental corticosteroids for 
adrenocortical insufficiency is allowed. 
• 
Known allergy or hypersensitivity to hyaluronidase, bee or vespid venom, or any other 
ingredient in the formulation of rHuPH20  
Additional Exclusion Criteria Applicable to Part 1 Only 


 
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Patients in Part 1 who meet the following additional criterion will be excluded from study entry: 
• 
Pathology (e.g., lower extremity edema, cellulitis, lymphatic disorder or prior surgery, 
preexisting pain syndrome, previous lymph node dissection, etc.) that could interfere with 
any protocol-specified outcome assessment (e.g., PK) 
Additional Exclusion Criteria Applicable to Part 2 Only 
Patients in Part 2 who meet any of the following additional criteria will be excluded from study 
entry: 
• 
Tested tumor PD-L1 expression status with an intention to treat the patient if positive.  This 
implies that: 
– 
Patients who had access to PD-1 or PD-L1 first line therapies and were tested for PD-L1 
expression status are not eligible, irrespective of the test result 
– 
Patients who had no access to PD-1 or PD-L1 first line therapies but were tested 
anyway as part of a testing routine despite lack of access are eligible, irrespective of the 
test result 
 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or 
when the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later.  The end of the study is expected to occur approximately 
33 months after the last patient is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
LENGTH OF STUDY 
The total duration of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 5.3 years. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
The investigational medicinal products (IMPs) for this study are atezolizumab SC for co-mix, 
atezolizumab SC, atezolizumab IV, and rHuPH20; IMPs will be supplied by the Sponsor. 
Atezolizumab SC for co-mix will be manually mixed with rHuPH20 at a concentration of 
2000 U/mL. 
Atezolizumab SC will be co-formulated with rHuPH20 in the atezolizumab SC formulation at 
a concentration of 2000 U/mL. 
In Part 1 of the study, patients will receive one (Cohort 1) or three (Cohorts 2 and 3) 
administrations of atezolizumab SC co-mix or atezolizumab SC.  After treatment with 
atezolizumab co-mix or atezolizumab SC is concluded, patients will receive atezolizumab 
1200mg IV Q3W for subsequent cycles until disease progression, loss of clinical benefit, 
unacceptable toxicity, or withdrawal of consent.   
In Part 2, patients will be randomized in a 2:1 ratio to receive monotherapy with either 1875 mg 
of atezolizumab SC Q3W or 1200 mg of atezolizumab IV Q3W, respectively, starting on Day 1 
of each 21-day cycle.  The dose level of atezolizumab SC proposed to be tested in this phase 
will be derived from the results obtained in Part 1 of the study.  Patients will receive 
atezolizumab SC or atezolizumab IV until disease progression, loss of clinical benefit, or 
unacceptable toxicity.  
STATISTICAL METHODS 
PRIMARY ANALYSIS 
PK analyses of Part 1 will be performed on data from all PK-evaluable patients enrolled in 
Part 1.  A PK-evaluable patient is defined as one who has received at least one dose of 
atezolizumab (atezolizumab SC co-mix, atezolizumab SC, or atezolizumab IV) and has at least 
one evaluable postdose PK sample, and who does not have protocol deviations that could 
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Specific criteria for exclusion from the primary analysis will be defined prior to the analysis and 
documented in the Statistical Analysis Plan. 
The Part 1 safety analysis population is defined as all patients who received at least one dose 
of atezolizumab (atezolizumab SC co-mix, atezolizumab SC, or atezolizumab IV). 
In Part 2, the primary analysis will be performed in the per protocol PK analysis population.  
This population will include patients in the atezolizumab SC and atezolizumab IV treatment 
arms who do not have protocol deviations that could affect PK results.  
DETERMINATION OF SAMPLE SIZE 
The sample size for Part 1 was determined by using simulation methods.  Cohorts 1 and 2 are 
planned to enroll approximately 12 eligible patients each and Cohort 3 is planned to enroll 
approximately 20−30 eligible patients for a total of approximately 60 patients in Part 1.  Based 
on the known PK profile of atezolizumab IV, such a sample size should allow estimation of the 
PK parameters with sufficient precision. 
A total of 327 patients are planned to be randomized in Part 2 of the study.  This sample size 
will provide sufficient power for the statistical hypothesis test for the primary endpoint, based on 
the following assumptions: 
• 
2:1 randomization ratio 
• 
True GMR ≥ 0.95 for Cycle 1 Ctrough 
• 
True GMR ≥ 0.95 for Cycle 1 AUC0–21 d 
• 
One-sided significance level 0.05 
• 
Coefficient of variation (CV%) of geometric mean Ctrough in Cycle 1 is < 55%; this value is 
based on the results observed after atezolizumab SC co-mix administration in Part 1 of the 
study (clinical cutoff date 10 March 2020)  
• 
CV% of geometric mean Cycle 1 AUC0–21 d is < 45%; this value is based on the results 
observed after atezolizumab SC co-mix administration in Part 1 of the study (CCOD 10 
March 2020) 
• 
Positive correlation between Cycle 1 AUC0–21 d  and Cycle 1 Ctrough > 0.8; this value is based 
on the results observed after atezolizumab SC co-mix administration in Part 1 of the study 
(CCOD 10 March 2020) 
 
The total number of patients to be enrolled in Part 2 of the study may be increased or 
decreased, after taking into account the actually observed PK variability during the blinded 
sample-size re-estimation (once approximately 210−250 patients have been randomized).  For 
example, for a coefficient of variation of 70% for Cycle 1 Ctrough, the number of patients enrolled 
in Part 2 would be increased to 477 in order to ensure sufficient power for the non-inferiority 
test. 
SAFETY ANALYSES  
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms, and adverse event severity will be graded according to NCI 
CTCAE v5.0.  Laboratory toxicities will be defined based on local laboratory normal ranges and 
NCI CTCAE, v5.0. 
INTERIM ANALYSES  
No formal interim statistical analysis is planned in the study.  
During Part 1, PK data will be analyzed on an ongoing basis. In addition, data will be reviewed 
by an Internal Monitoring Committee (IMC) at regular intervals.  All required analyses will be 
performed by the study team and provided to the IMC.  Any outcomes of these safety reviews 
that affect study conduct will be communicated in a timely manner to the investigators for 
notification of the IRBs/ECs.  
During Part 2, a JMC will be set up to evaluate PK and safety data on an ongoing basis.  All 
analyses for this review will be prepared by the study team, who will maintain the blind of 
treatment allocation. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody, also known as an anti-therapeutic 
antibody 
AUC 
area under the concentration−time curve 
CCOD 
clinical cutoff date 
CIT 
cancer immunotherapy 
Cmax 
maximum serum concentration observed 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRS 
cytokine-release syndrome 
CT 
computed tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
CTSQ 
Cancer Therapy Satisfaction Questionnaire 
CV 
coefficient of variation 
DOR 
duration of response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ER 
exposure-response 
FAS 
Full Analysis Set 
FFPE 
formalin-fixed paraffin-embedded 
GMR 
geometric mean ratio 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCP 
health care professional 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
ICH 
International Council for Harmonisation 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 


 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
FAS 
Full Analysis Set (population) 
IxRS 
interactive voice or web-based response system 
JMC 
Joint Monitoring Committee 
Ln 
natural logarithm 
LVEF 
left ventricular ejection fraction 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
pharmacokinetic 
popPK 
population PK 
PR 
partial response 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rHuPH20 
recombinant human hyaluronidase 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SmPC 
Summary of Product Characteristics 
SWT 
Satisfaction with Cancer Therapy (scale) 
T3 
triiodothyronine 
T4 
thyroxine 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum serum concentration 
TPS 
tumor proportion score 
UCC 
urothelial cell carcinoma 
ULN 
upper limit of normal 
 
 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON NON−SMALL CELL LUNG CANCER 
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most 
common cancer in both men and women and accounts for 12%−14% of all new cancer 
cases in the United States.  In 2019 in the United States, it was estimated that there 
were 228,150 new cases of lung cancer (116,440 in men and 111,710 in women) and 
142,670 lung cancer deaths (American Cancer Society 2019).  Similar data from Europe 
estimate that in 2018 there were 387,900 lung cancer deaths (267,300 in men and 
120,600 in women) (Ferlay et al. 2019). 
In China in 2015, there were approximately 733,300 new cases of lung cancer and 
610,200 lung cancer deaths (Chen et al. 2016). 
Non−small cell lung cancer (NSCLC) is the predominant subtype of lung cancer, 
accounting for approximately 85% of all cases (Howlader et al. 2015).  NSCLC can be 
divided into two major histologic types:  adenocarcinoma and squamous cell carcinoma 
(Travis et al. 2011).  Adenocarcinoma histology accounts for more than half of all 
NSCLC, while squamous cell histology accounts for approximately 25% of NSCLC 
(Langer et al. 2010).  The remaining cases of NSCLC are represented by large cell 
carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated 
histology. 
Despite recent advances in the treatment options for patients with metastatic NSCLC, 
the majority of patients will ultimately relapse and die from their disease:  5-year survival 
rates are still disappointingly low (Detterbeck et al. 2017).  Continued research into new 
drugs and combination therapies is therefore required to expand the clinical benefit to 
a broader patient population and to improve outcomes in NSCLC.  Poor prognostic 
factors for survival in patients with NSCLC include advanced stage of disease at the time 
of initial diagnosis, distant metastases, poor performance status, and a history of 
unintentional weight loss.  Notably, more than half of the patients with NSCLC are 
diagnosed with distant disease. 
Genetic changes that have prognostic and/or predictive significance in NSCLC include 
mutations in the EGFR gene and rearrangement in the ALK gene.  The rates of these 
mutations differ between squamous cell carcinoma and adenocarcinoma.  For example, 
EGFR mutations have been reported in 10%−40% of patients with adenocarcinoma 
NSCLC but are infrequently observed in squamous NSCLC (Herbst et al. 2008).  
Rearrangement in the ALK gene is very rare in the squamous histology but observed in 
approximately 7% of patients with adenocarcinoma (Herbst et al. 2008; Langer et al. 
2010). 


 
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1.2 
TREATMENT FOR NON–SMALL CELL LUNG CANCER 
1.2.1 
First-Line Non–Small Cell Lung Cancer 
The discovery of treatable oncogenic alterations has led to the recommendation that 
molecular testing should be included as a standard approach to further classify 
NSCLC.  Genotype-directed therapy has the potential to dramatically improve the 
balance of benefit and toxicity for selected patients with NSCLC characterized by 
alterations of driver oncogenes, including sensitizing EGFR mutations and ALK 
rearrangements.  However, these mutations are more prevalent in adenocarcinoma 
NSCLC and are very rare in squamous NSCLC.   
For patients with a targetable oncogenic driver mutation, randomized Phase III studies 
have demonstrated clinical efficacy and manageable toxicity of EGFR and ALK inhibitors 
versus chemotherapy (Fan et al, 2018; Ayati et al. 2020). 
Patients with previously untreated NSCLC that does not harbor a targetable oncogenic 
driver mutation have been typically treated with platinum-based chemotherapy.  The 
standard-of-care chemotherapy in the first-line setting often involves either cisplatin or 
carboplatin and a taxane or pemetrexed, with or without bevacizumab for non-squamous 
NSCLC, and cisplatin or carboplatin and gemcitabine for squamous NSCLC.  However, 
the benefit conferred by platinum-based doublets appeared to have reached a plateau in 
objective response rate (ORR; approximately 15%−22%) and median survival (7 to 
10 months).  The addition of bevacizumab to carboplatin and paclitaxel in the treatment 
of non-squamous NSCLC resulted in an increase in response rate from 15% to 35% and 
an increase in median overall survival (OS) from 10 to 12 months.  
Immune checkpoint inhibitors, including PD-L1/PD-1−blocking antibodies, have emerged 
as a new therapeutic option for the first-line treatment of metastatic NSCLC (Xia et al, 
2019).  In the randomized Phase III study GO29436 (IMpower150), OS and 
progression-free survival (PFS) were significantly prolonged with atezolizumab, 
bevacizumab, paclitaxel, and carboplatin relative to bevacizumab, paclitaxel, and 
carboplatin in patients with advanced non-squamous NSCLC without an activating 
EGFR mutation or ALK gene rearrangement independent of the PD-L1 expression level 
(Socinski et al. 2018).  The randomized Phase III study GO29537 (IMpower130) found 
that the addition of atezolizumab to carboplatin plus nab-paclitaxel significantly improved 
overall and progression-free survival in first-line treatment of Stage IV non-squamous 
NSCLC with no ALK or EGFR mutations.  A benefit in OS and PFS in the atezolizumab 
group was observed, regardless of PD-L1 expression (West et al. 2019).  In the 
KEYNOTE-189 study, OS and PFS were also significantly improved with 
pembrolizumab, pemetrexed, and carboplatin relative to pemetrexed and carboplatin in 
patients with advanced non-squamous NSCLC (Gandhi et al. 2018; Gadgeel et al. 
2019).  In the CHECKMATE-9LA study, nivolumab, given in combination with ipilimumab 
and two cycles of chemotherapy, demonstrated superior efficacy when compared to 
chemotherapy-only (Reck et al, 2020).  


 
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Results from these studies have led to the approval in the United States and other 
countries of atezolizumab, nivolumab in combination with ipilimumab and 
pembrolizumab, with the corresponding chemotherapy regimens, as first-line therapy for 
patients with advanced non-squamous NSCLC without an activating EGFR mutation or 
ALK gene rearrangement.   
Chemotherapy-based regimens are associated with substantial toxicities and are 
generally poorly tolerated by elderly patients and by patients with poor performance 
status.  Therefore, novel therapies that deliver an improved therapeutic index are 
needed for NSCLC.  Pursuing personalized cancer immunotherapy (CIT), several 
Phase III trials have been conducted to investigate chemotherapy-free regimens 
involving anti−PD-L1/PD-1 inhibitors versus standard cytotoxic chemotherapy in 
treatment-naive patients with PD-L1−positive NSCLC.   
The KEYNOTE-024 study demonstrated significant improvement in survival with 
pembrolizumab monotherapy over standard platinum-based doublets in advanced 
NSCLC with high PD−L1 expression (tumor proportion score [TPS] ≥ 50% (Reck et al. 
2016; Reck et al. 2019).   
In the KEYNOTE-042 study in which patients with a TPS ≥ 1% were enrolled, survival 
outcomes of pembrolizumab compared with chemotherapy doublets in the two primary 
patient populations with a TPS ≥ 50% and a TPS ≥ 1% were statistically significant and 
clinically meaningful in favor of pembrolizumab.  However, patients in a prespecified 
exploratory subgroup with TPS 1%−49% appeared to have similar OS in the two arms 
(Mok et al. 2019).  Based on results from these studies, pembrolizumab is approved for 
first-line treatment in patients with metastatic NSCLC without an activating EGFR 
mutation or ALK gene rearrangement, in the United States in patients whose tumors 
express PD-L1 (TPS ≥ 1%) and in the European Union in patients whose tumors 
express high PD-L1 (TPS ≥ 50%). 
At the time of the interim OS analysis (clinical cutoff date, 10 September 2018) in 
Study GO29431 (IMpower110), of atezolizumab monotherapy compared with 
platinum-based doublet chemotherapy as first-line treatment of metastatic NSCLC that 
expresses high PD-L1, atezolizumab monotherapy showed a statistically significant and 
clinically meaningful improvement in OS compared with chemotherapy in patients with 
high PD-L1 expression (TC3/IC3-WT).  Because the OS statistical testing boundary was 
not crossed in the TC2/3 or IC2/3-WT or TC1/2/3 or IC1/2/3-WT subgroups at this 
interim analysis, the study will continue to the OS final analysis for these subgroups 
(Spigel et al. 2019). 
In conclusion, immune checkpoint inhibitor treatment in combination with and without 
chemotherapy is becoming standard of care in the treatment of patients with first-line 
NSCLC.  However, patient access to immunotherapies in the first-line setting can vary 
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1.2.2 
Previously Treated Non–Small Cell Lung Cancer 
The choice of agent in the second-line setting depends on a number of factors, including 
prior treatment regimens, tumor histology, comorbidities, toxicity from previous 
treatments, toxicity profile for a given agent, smoking history, and patient preference.  
Overall, the benefit profile of second-line therapies has been disadvantaged both by 
limited survival benefit and significant toxicities such as myelosuppression and 
neuropathy (docetaxel) and diarrhea (pemetrexed) (Stinchcombe and Socinski 2008). 
With the approval of immune checkpoint inhibitors as first-line treatment of patients with 
advanced NSCLC, the treatment algorithm for this patient population is changing.  
Monotherapy with immune checkpoint inhibitors (e.g., nivolumab [PD-1 inhibitor], 
pembrolizumab [PD-1 inhibitor], and atezolizumab [PD-L1 inhibitor]) have been 
approved for patients with metastatic NSCLC who experience disease progression 
during or following platinum-containing chemotherapy.  Pembrolizumab is approved for 
patients whose tumors express PD-L1 (TPS ≥ 1%), whereas PD-L1 expression is not 
a requirement for patients receiving treatment with nivolumab or atezolizumab.  For 
pembrolizumab, the median OS was 10.4 months for patients treated at 2 mg/kg every 
3 weeks (Q3W) and 12.7 months for patients treated at 10 mg/kg Q3W (squamous and 
non-squamous histology combined) versus 8.5 months in the control arm (Keytruda 
U.S. Package Insert; Keytruda Summary of Product Characteristics [SmPC]).  For 
nivolumab, the median OS was 9.2 months versus 6 months in the control arm for 
patients with squamous histology and 12.2 months versus 9.4 months in the control arm 
for patients with non-squamous histology (Opdivo U.S. Package Insert; Opdivo SmPC).   
Atezolizumab IV monotherapy is approved for the treatment of patients with locally 
advanced or metastatic NSCLC after prior chemotherapy.  This approval is based on 
results from the Phase III study GO28915 (OAK) demonstrating a statistically significant 
and clinically meaningful survival improvement with atezolizumab IV in monotherapy 
versus chemotherapy (docetaxel) in patients with locally advanced or metastatic NSCLC 
who received prior chemotherapy (HR = 0.73; 95% CI: 0.62 to 0.87; p = 0.0003; median 
OS 13.8 vs. 9.6 months) (Rittmeyer et al. 2017). 
In addition to immune checkpoint inhibitors and platinum-based chemotherapy, 
docetaxel and pemetrexed are approved for patients with metastatic NSCLC who 
experience disease progression during or following prior chemotherapy.  Docetaxel was 
associated with an estimated median OS of 6−10 months (Stinchcombe and Socinski 
2008; Ramlau et al. 2012).  Pemetrexed had a higher impact on PFS and OS compared 
with docetaxel in patients with non-squamous histologies, thus limiting its approval to 
patients with these histologies (Scagliotti et al. 2009). 
1.3 
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), 


 
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both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and patients with 
cancer and is being investigated as a potential therapy in a wide variety of solid tumors 
and hematological malignancies.  Atezolizumab is being studied as a single agent in the 
advanced cancer and adjuvant therapy settings, as well as in combination with 
chemotherapy, targeted therapy, and other cancer immunotherapies. 
Atezolizumab IV, as single agent and/or in combination, is approved for the treatment of 
urothelial carcinoma, non−small cell lung cancer, small-cell lung cancer, triple-negative 
breast cancer, hepatocellular carcinoma, and melanoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies with atezolizumab IV. 
1.3.1 
Nonclinical Studies with Subcutaneously Injected 
Atezolizumab 
The nonclinical safety of subcutaneously injected atezolizumab has been studied in 
a Good Laboratory Practice repeat-dose study in cynomolgus monkeys to evaluate the 
toxicity and toxicokinetics following weekly administration for 8 weeks (nine total doses) 
and to assess the reversibility or persistence of any effects after a 12-week, 
treatment-free recovery period.  Weekly SC administration of atezolizumab was well 
tolerated at dose levels up to 50 mg/kg.  All animals survived to scheduled necropsy or 
disposition.  Atezolizumab administration had no effects on clinical observations, body 
weight, food consumption, respiratory rate, heart rate, body temperature, blood 
pressure, electrocardiograms, pulse oximetry, physical, neurologic, ophthalmologic, 
or cardiovascular examinations, clinical pathology (hematology, serum chemistry, 
coagulation, or urinalysis), immunologic endpoints (immunophenotyping via 
flow cytometry, serum cytokines, anti-nuclear antibodies, or anti-dsDNA antibodies), 
organ weights, or macroscopic pathology. 
At terminal necropsy, microscopic lesions that were considered related to atezolizumab 
administration included arteritis/periarteritis in various tissues in 1 of 6 animals in the 
15 mg/kg SC dose groups and in 2 of 6 animals in the 50 mg/kg SC dose group.  
Generally, affected vessels were located within the interstitium of parenchymal organs 
(heart, kidney, liver, pancreas, and epididymis) or within the submucosa or muscularis of 
tubular organs, such as the gastrointestinal and female reproductive tracts.  These 
observations were characterized primarily by increased thickening of the tunica 
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accompanying mixed inflammatory cell infiltrate.  Similar microscopic arterial findings 
occur spontaneously in cynomolgus monkeys to the same extent (generally subclinical in 
severity, similar in tissue distribution) (Beach et al. 1974; Chamanza et al. 2006); 
however, this finding is considered atezolizumab-related as it occurred only in test 
article−treated groups, appears to be dose-related in incidence (high- and mid-dose 
groups), and occurred at a higher incidence than historical controls at this test facility 
(historical incidence of approximately 1%).  Arteritis/periarteritis was not present at the 
recovery necropsy timepoint, indicating either resolution during the recovery period or 
lack of occurrence in the recovery cohorts due to the relatively low incidence within 
affected dose levels.  In addition, minimal, focal to multifocal, and often perivascular 
mononuclear cell infiltrates were noted in the SC tissue at the injection sites for 3 of 
6 animals and 6 of 6 animals in the 15 and 50 mg/kg SC dose groups, respectively; 
these findings were also considered related to atezolizumab administration.  This 
injection site change was not present at recovery necropsy, suggesting reversibility.  
The minimal injection-site findings are consistent with SC administration of heterologous 
protein and resolved during the recovery period; therefore, they were not considered 
adverse. 
Linear dose-dependent systemic exposures were observed up to Day 7 in all dosed 
groups.  The mean concentration-time profiles for males and females show that 
exposure to atezolizumab generally increased with the increase in dose level and no sex 
differences greater than 2-fold were observed in mean maximum serum concentration 
(Cmax) or exposure values, with the exception of the 5 mg/kg dose level (Roche Study 
13-3278 Clinical Study Report, available on request) that was likely confounded by the 
presence of anti-drug antibodies (ADAs).  Overall, the serum concentration−time profiles 
of all dose groups exhibited apparent biphasic disposition in which a rapid initial 
distribution phase was followed by a slower elimination phase.  Bioavailability of 
atezolizumab following SC administration of 15 mg/kg or 50 mg/kg was estimated to be 
54.3% and 51.8%, respectively. 
1.4 
BACKGROUND ON RECOMBINANT HUMAN HYALURONIDASE 
(rHuPH20) 
The feasibility and patient acceptability of SC administration of any drug are dependent 
on the volume of drug that must be administered.  The recombinant human 
hyaluronidase enzyme (rHuPH20) (Hylenex) is a hyaluronidase for human injection that 
has been developed by Halozyme Therapeutics, Inc., and is approved in the European 
Union and United States as a permeation enhancer to improve dispersion and 
absorption of SC formulations, enabling larger volumes to be administered without 
reduced tolerability and with improved patient acceptability.  Hyaluronidase transiently 
hydrolyses hyaluronan, a component of the SC matrix, leading to reduced viscosity of 
the extracellular matrix of the hypodermis and, thus, to an improved delivery of 
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a recombinant human molecule, has a higher purity and is associated with improved 
tolerability compared with the animal-derived enzyme (Hylenex U.S. Package Insert). 
The safety and efficacy of hyaluronidase products have been widely established.  The 
most significant safety risk identified is hypersensitivity/allergenicity, which is thought to 
be related to the lack of purity of the animal-derived preparations.  The rHuPH20 to be 
used in the current study is produced from a second generation of the Hylenex process 
that has improved yield and purity.  The concentration of rHuPH20 is guided by data 
from a mini-pig study in which trastuzumab was administered subcutaneously.  In the 
presence of either 2000 or 6000 U/mL of rHuPH20, there was a more rapid absorption of 
subcutaneously administered trastuzumab from rHuPH20-containing formulations, while 
the effect on the absorption rate of trastuzumab was comparable with both rHuPH20 
concentrations.  Therefore, the lower rHuPH20 concentration of 2000 U/mL was 
selected.  
The highest total rHuPH20 dose administered in a clinical study was 96,000 U (rHuPH20 
Investigator’s Brochure).  This Phase I study investigated the SC injection of 
adalimumab with different rHuPH20 concentrations in healthy volunteers using different 
volumes of injection (2, 8, and 16 mL).  All injections were well tolerated with no serious 
adverse events reported.  Common injection-site reactions observed were erythema, 
ecchymosis, pain, and induration.  All injection-site reactions, such as erythema, pain, 
and induration, were mild (98%) or moderate (2%).  
To date, four monoclonal antibodies co-formulated with rHuPH20, are approved for SC 
therapy in oncology in the United States and three in the European Union (Phesgo 
U.S. Package Insert, Darzalex U.S. Package Insert, Darzalex SmPC, Herceptin U.S. 
Package Insert; Herceptin SmPC; Rituxan U.S. Package Insert; MabThera SmPC).   
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Atezolizumab is available as a concentrated solution for IV infusion.  Atezolizumab IV is 
infused over a period of 60 (± 15) minutes.  Subsequent infusions are delivered in 
30 (±10) minutes if the previous infusion was tolerated without infusion-related reaction 
or 60 (± 15) minutes if the patient experienced an infusion-related reaction with the 
previous infusion.  For many patients, the atezolizumab IV infusion time may be a taxing 
experience and disadvantage of the current therapeutic approach.  For other patients, 
such as those with difficult venous access or poor renal or cardiac function, the need for 
IV infusions may constitute a major challenge.  Furthermore, increasing usage of 
intravenously administered monoclonal antibodies combined with or without 
chemotherapy has placed a strain on medical centers with respect to time and resources 
required to prepare and administer the IV infusions that are currently commercially 
available.  The change to the SC route of administration for monoclonal antibodies such 
as trastuzumab and rituximab has demonstrated a reduction in treatment burden for 
patients, with improved time and resource utilization at the treatment facility (Pivot et al. 
2013; Rummel et al. 2015; De Cock et al. 2016).  Furthermore, available data for 


 
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subcutaneously administered monoclonal antibodies (daratumumab [Darzalex], 
trastuzumab [Herceptin], rituximab [MabThera/Rituxan], and trastuzumab plus 
pertuzumab [Phesgo]) consistently demonstrate that subcutaneous formulations are well 
tolerated and anti-tumor activity remains the same regardless of administration route 
(Ismael et al. 2012; Davies et al. 2014; Assouline et al. 2015). 
In view of the above aspects, a new formulation of atezolizumab for SC injection is being 
developed (atezolizumab SC).  Atezolizumab SC is a ready-to-use formulation of 
atezolizumab co-formulated with rHuPH20, a human recombinant hyaluronidase, 
developed to improve dispersion of large volumes of drugs (i.e., it functions as a 
permeation enhancer).  Atezolizumab SC will be administered with a target delivery time 
under 10 minutes (depending on bioavailability results). 
Results as of the clinical cutoff date (CCOD) of 10 March 2020 from Part 1 of this study 
(BP40657), with safety of Cycle 1 where all 67 patients received atezolizumab SC 
administration, demonstrated that although the percentage of patients with adverse 
events were 69.2% (9 of 13 patients) in Cohort 1, 53.3% (8 of15 patients) in Cohort 2, 
and 61.5% (24 of 39 patients) in Cohort 3, most adverse events were Grade 1 or 2 in 
maximum severity.  No adverse events in Cycle 1 led to discontinuation of atezolizumab 
SC.  The safety profile of atezolizumab SC was consistent with the known risks of 
atezolizumab IV.  No new safety concerns were identified, and no clinically significant 
difference in safety profiles among the cohorts was observed. 
Based on these considerations, it is expected that SC administration of atezolizumab will 
result in reduced treatment burden, increased patient satisfaction, and improved 
cost-effectiveness, while maintaining similar efficacy and safety to the IV formulation of 
the same product. 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent clinical 
data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy.  


 
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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)-γ (Merad and Martin 2020).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving atezolizumab.  At this time, there 
is insufficient evidence for causal association between atezolizumab and an increased 
risk of severe outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for SARS-CoV-2−related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and SARS-CoV-2 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 SARS-CoV-2 vaccination 
(Society for Immunotherapy of Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, SARS-CoV-2 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 SARS-CoV-2 vaccination in patients 
who are receiving cancer immunotherapy (SITC 2020).  For patients enrolling in this 
study and receiving atezolizumab treatment, a decision to administer the vaccine to a 
patient should be made on an individual basis by the investigator in consultation with the 
patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
SARS-CoV-2 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.   
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering SARS-CoV-2 vaccines.  When 
administered, SARS-CoV-2 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the SARS-CoV-2 vaccine is considered a 
concomitant medication and should be documented as such (see Section 4.4.1). 


 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacokinetics, safety, and efficacy of atezolizumab SC 
compared with atezolizumab IV in patients with locally advanced or metastatic NSCLC 
who have not been exposed to cancer immunotherapy (CIT) (i.e., "CIT-naive") and for 
whom prior platinum-based therapy has failed.  The study is comprised of two parts, as 
follows: 
• 
Part 1 (Phase Ib, dose finding) will aim to identify the dose of atezolizumab SC that 
yields drug exposure that is comparable to that of atezolizumab IV 
• 
Part 2 (Phase III, randomized, dose confirmation) will aim to demonstrate the 
non-inferiority of observed drug exposure following treatment with atezolizumab SC 
at the identified dose compared with drug exposure following treatment with 
atezolizumab IV  
 
Specific objectives for each part of the study and corresponding endpoints are outlined 
in Sections 2.1 and 2.2. 
Definitions used in this study are outlined in the following table: 
Table 1 
Study Definitions 
Atezolizumab 
Atezolizumab monoclonal antibody as a molecule, irrespective of its 
formulation 
Atezolizumab SC co-mix 
SC formulation of atezolizumab for co-mix with rHuPH20, manually 
mixed at the local pharmacy 
Atezolizumab SC 
Ready-to-use SC formulation of atezolizumab co-formulated with 
rHuPH20 
Atezolizumab IV 
Currently approved formulation of atezolizumab for IV infusion in its 
1200 mg vial configuration 
Study treatment 
Combination of treatments assigned to patients as part of this study 
(i.e., in Part 1, atezolizumab SC co-mix or atezolizumab SC; in 
Part 2, atezolizumab SC or atezolizumab IV 
IV =  intravenous; SC = subcutaneous. 
 
2.1 
OBJECTIVES AND ENDPOINTS FOR PART 1 
2.1.1 
Pharmacokinetic Objectives for Part 1 
The primary pharmacokinetic (PK) objective for Part 1 is to determine the dose of 
atezolizumab SC that is predicted to yield drug exposure that is comparable to that of 
atezolizumab IV on the basis of the following endpoint: 
• 
Serum atezolizumab trough concentration (Ctrough) at Cycle 1 (i.e., predose Cycle 2) 
 


 
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The secondary PK objective for Part 1 is to characterize the PK profile of atezolizumab 
SC on the basis of the following endpoint: 
• 
Serum atezolizumab concentration at specified timepoints during SC administration 
 
The exploratory PK objective for Part 1 is to characterize the PK profile of rHuPH20 on 
the basis of the following endpoint: 
• 
Plasma rHuPH20 concentration at specified timepoints during SC administration 
 
2.1.2 
Safety Objective for Part 1 
A secondary objective for Part 1 is to evaluate the safety of atezolizumab SC on the 
basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, 
Version 5.0 (CTCAE v5.0) 
• 
Incidence and severity of targeted vital signs 
• 
Incidence and severity of clinical laboratory abnormalities 
 
2.1.3 
Immunogenicity Objective for Part 1 
The exploratory immunogenicity objective for Part 1 is to evaluate the immune response 
to atezolizumab SC and rHuPH20 on the basis of the following endpoints: 
• 
Incidence of ADAs to atezolizumab after SC administration relative to the 
prevalence of ADAs at baseline 
• 
Incidence of ADAs to rHuPH20 after SC administration relative to the prevalence of 
ADAs at baseline 
 
2.2 
OBJECTIVES AND ENDPOINTS FOR PART 2 
2.2.1 
Pharmacokinetic Objectives for Part 2 
The primary PK objective for Part 2 is to demonstrate non-inferiority of exposure 
to atezolizumab SC compared with atezolizumab IV on the basis of the following 
co-primary endpoints: 
• 
Observed serum Ctrough at Cycle 1 (predose Cycle 2) 
• 
Model-predicted area under the concentration-time curve (AUC) from 0 to 21 days 
(AUC0–21 d) at Cycle 1  
 
A secondary PK objective for Part 2 is to evaluate exposure following administration of 
atezolizumab SC compared with atezolizumab IV on the basis of the following endpoints, 
as appropriate and as data allow:  
• 
Model-predicted Ctrough at Cycle 1 (Ctrough Cycle 1), model-predicted Ctrough at steady 
state (Ctrough,ss), and model-predicted AUC at steady state (AUCss) 
 
The exploratory PK objective for Part 2 is to evaluate potential relationships between 
atezolizumab exposure and efficacy and safety.  


 
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2.2.2 
Safety Objectives for Part 2 
A secondary objective for Part 2 is to evaluate the safety of atezolizumab SC compared 
with atezolizumab IV on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to NCI 
CTCAE v5.0 
• 
Overall patient-reported adverse event burden over time, as assessed by the patient 
global impression of cancer treatment side effects burden item from the European 
Organisation for Research and Treatment of Cancer (EORTC) IL57  
 
2.2.3 
Efficacy Objectives for Part 2 
A secondary objective for Part 2 is to evaluate the efficacy of atezolizumab SC on the 
basis of the following endpoints: 
• 
ORR, defined as the proportion of patients with a complete response (CR) or partial 
response (PR), as determined by the investigator according to Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
• 
PFS, defined as the time from study entry to the first occurrence of disease 
progression or death from any cause (whichever occurs first), as determined by the 
investigator according to RECIST v1.1 
• 
OS, defined as the time from study entry to death from any cause 
• 
Duration of response (DOR), defined as the time from first occurrence of 
a documented objective response to disease progression or death from any cause 
(whichever occurs first), as determined by the investigator according to 
RECIST v1.1 
 
An additional secondary objective for Part 2 is to evaluate patient experience with 
atezolizumab SC compared with atezolizumab IV, on the basis of the following 
endpoints: 
• 
Functioning and global health status over time, as assessed by the physical 
functioning, role functioning, and global health status/quality of life scales of the 
EORTC IL57 
• 
Overall satisfaction with treatment, as assessed by the modified satisfaction with 
therapy (SWT) scale of the Cancer Therapy Satisfaction Questionnaire (CTSQ) 
 
2.2.4 
Immunogenicity Objectives for Part 2 
A secondary objective for Part 2 is to evaluate the incidence of ADAs to the tested 
molecules on the basis of the following endpoint: 
• 
Incidence of ADAs to atezolizumab after SC administration or IV administration 
relative to the prevalence of ADAs at baseline 
• 
Incidence of ADAs to rHuPH20 after SC administration relative to the prevalence of 
ADAs at baseline 
 


 
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The exploratory immunogenicity objective for Part 2 is to evaluate potential effects of 
ADAs on the basis of the following endpoint: 
• 
Relationship between post-baseline ADA status and PK, safety, or efficacy 
endpoints 
 
2.2.5 
Biomarker Objective for Part 2 
The exploratory biomarker objective for Part 2 is to evaluate biomarkers that may be 
predictive of response to atezolizumab (i.e., predictive biomarkers), are early surrogates 
of efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to atezolizumab, 
can provide evidence of atezolizumab activity (i.e., pharmacodynamic biomarkers), or 
can increase the knowledge and understanding of disease biology.  They will be 
evaluated on the basis of the following endpoint: 
• 
Relationship between biomarkers in tumor tissue (listed in Section 4.5.7) and 
efficacy, or other biomarker endpoints  
 
Refer to Section 4.5.7 for details on biomarkers and samples required for exploratory 
biomarker analysis. 
2.2.6 
Health Care Professional−Reported Experience Utility 
Objective for Part 2 
The secondary utility objective for Part 2 is to evaluate health care professional 
(HCP)-reported experience with administration of atezolizumab SC and atezolizumab IV, 
on the basis of the following endpoints: 
• 
Convenience, potential time savings, and overall satisfaction with atezolizumab SC 
compared with atezolizumab IV, as assessed by the HCP SC versus IV Perspective 
Questionnaire  
• 
Convenience, ease of administration, and overall satisfaction with atezolizumab SC, 
as assessed by the HCP Subcutaneous Perspective Questionnaire 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a two-part, open-label, multicenter Phase Ib/III study in patients with locally 
advanced or metastatic NSCLC who are CIT-naive and for whom prior platinum therapy 
has failed.  The two parts of the study are as follows: 
• 
Part 1 of the study will consist of three single-arm cohorts and will determine the 
dose of atezolizumab SC that yields comparable exposure to atezolizumab IV on 
the basis of serum Ctrough at Cycle 1 (predose Cycle 2).  Atezolizumab SC co-mix will 
be used for Cohort 1 of Part 1.  A ready-to-use formulation of atezolizumab with 
rHuPH20 (atezolizumab SC) may be used for Cohorts 2 and 3 of Part 1, subject to 
review and approval from relevant Health Authorities and Sponsor decision. 


 
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• 
Part 2 of the study will consist of a two-arm, randomized, multicenter study of 
atezolizumab SC compared with atezolizumab IV.  The aim of Part 2 is to 
demonstrate non-inferiority of PK exposure of the SC formulation versus the IV 
formulation based on the co-primary endpoints, Cycle 1 observed serum Ctrough 
(predose Cycle 2) and model-predicted AUC0–21 d.  The ready-to-use SC formulation 
of atezolizumab co-formulated with rHuPH20 (atezolizumab SC) will be used in 
Part 2. 
 
The study designs of Part 1 and Part 2 are is shown in Figure 1 and Figure 2, 
respectively.  The schedule of activities for Part 1 is provided in Appendix 1 and for 
Part 2 in Appendix 2.  The PK, immunogenicity, and biomarker sampling schedules are 
presented in Appendix 3 for Part 1 and Appendix 4 and Appendix 5 for Part 2. 
After providing informed consent, patients will undergo screening procedures as outlined 
in the schedules of activities.  Patients who do not initially meet all eligibility criteria for 
participation in this study may qualify for two re-screening opportunities (for a total of 
three screenings per patient) at the investigator’s discretion, provided all initial and 
subsequent screening assessments are performed within 56 days prior to Day 1.  
Re-screened patients must meet all eligibility criteria and re-sign the Informed Consent 
Form prior to re-screening. 
A patient may be enrolled only once in this trial.  As a general rule, patients enrolled into 
the study will not be replaced (see Section 4.6.1 for further details). 
Safety will be monitored throughout the study by the Sponsor Internal Monitoring 
Committee (IMC) for Part 1 (see Section 3.1.3.1) and by a Joint Monitoring Committee 
(JMC) for Part 2 (see Section 3.1.3.2). 
3.1.1.1 
Part 1:  Dose Finding 
Part 1 will be composed of three cohorts:  Cohorts 1 and 2 will consist of approximately 
12 evaluable patients each and Cohort 3 will consist of approximately 20−30 evaluable 
patients. 
Patients will receive one (Cohort 1) or more (Cohorts 2 and 3) administrations of 
atezolizumab SC co-mix or atezolizumab SC (see below for details) followed by 
treatment with atezolizumab IV 1200 mg Q3W, as indicated, for subsequent cycles until 
disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of 
consent (see Section 3.1.2 for details). 
The following cohorts are planned: 
• 
Cohort 1:  Patients will receive 1800 mg atezolizumab SC co-mix for one cycle 
(21 days), followed by 1200 mg atezolizumab IV Q3W for subsequent cycles. 
• 
Cohort 2:  Patients will receive 1200 mg atezolizumab SC co-mix or atezolizumab 
SC Q2W (14 days) for 3 cycles, followed by 1200 mg atezolizumab IV Q3W for 
subsequent cycles. 


 
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• 
Cohort 3:  Patients will receive 1800 mg atezolizumab SC co-mix or atezolizumab 
SC Q3W (21 days) for 3 cycles, followed by 1200 mg atezolizumab IV Q3W for 
subsequent cycles. 
 
In Cohorts 1 and 2, all SC injections will be administered in the thigh.  In Cohort 3, the 
first subcutaneous dose of atezolizumab will be administered in the lower part of the 
abdomen and the following 2 doses will be administered in the thigh. 
The doses specified for Cohorts 2 and 3 are projected doses.  The actual doses will 
depend on the results from Cohort 1.  Additional dose-finding cohorts may be opened if 
the doses from planned cohorts result in atezolizumab exposure outside of the expected 
exposure obtained with atezolizumab IV or if the variability in Ctrough is too high to 
determine a dose for Part 2 of the study. 
Dose Selection 
Atezolizumab SC will be developed with the aim of selecting a dose that results in 
a serum Ctrough that is comparable to that with atezolizumab 1200 mg IV Q3W.  As 
atezolizumab has not been administered using the SC formulation in a clinical trial, the 
dose ranges for the SC formulation have been selected assuming a bioavailability of 
70% based on prior clinical experience with other monoclonal antibodies administered 
using rHuPH20.  Therefore, the 1800 mg atezolizumab SC co-mix is calculated to have 
serum Ctrough comparable to 1200 mg atezolizumab IV Q3W.  Doses for Cohorts 2 and 3 
may be adjusted based on the Cohort 1 results.  These cohorts will be enrolled after 
evaluation and completion of Cohort 1.  Based on the ongoing evaluation of 
bioavailability data, it may be necessary to adjust the dose within the same cohort.  
In the event the 1800 mg atezolizumab SC co-mix dose results in atezolizumab 
exposure consistent with the 1200 mg atezolizumab IV dose, it is expected that 1200 mg 
atezolizumab SC co-mix or atezolizumab SC Q2W will result in atezolizumab serum 
Ctrough comparable to 840 mg atezolizumab IV Q2W.  However, if the PK characteristics 
of atezolizumab SC remain uncertain, dosing regimens for Cohorts 2 and 3 may be 
modified to achieve comparable exposure to that observed with 1200 mg IV. 
Safety Monitoring for the Different Cohorts 
All patients must report any symptoms and adverse events immediately to the 
investigator, particularly during the first 72 hours after the first injection.  Enrollment of 
the first 6 patients in Cohort 1 will be staggered in order to closely monitor the safety and 
tolerability resulting from the first atezolizumab SC co-mix administration.  This will allow 
for a 72-hour interval during which safety will be assessed by the investigator and 
communicated to the Sponsor.  Safety of the first 72 hours in these patients will be 
evaluated by the Sponsor before enrollment of the next patient.  For Cohorts 2 and 3, 
enrollment of only the second patient will be dependent on the outcome of the safety 
assessment of the 72 hours from the first patient.  Further enrollment in Cohorts 2 and 3 
will be completed without staggering. 


 
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Gating Criteria and Treatment in Cohorts 2 and 3  
Following assessment of PK and safety data for Cohort 1 provided the investigated dose 
has shown to be safe and tolerated (if PK properties have shown to be similar to PK 
properties for atezolizumab IV in Cohort 1), Cohorts 2 and 3 may be opened at the same 
time.  On the basis of Sponsor decision (see Section 3.1.3.1) and cohort enrollment 
initiation requirements, Cohorts 2 and 3 will enroll independently, which may lead to 
enrollment overlap of Cohorts 2 and 3. 
In Cohorts 2 and 3, patients will receive 3 cycles of atezolizumab SC co-mix or 
atezolizumab SC before switching to atezolizumab IV.  This will allow further 
assessment of safety, as well as an early assessment of the immunogenicity of 
atezolizumab following multiple SC doses.  For Cohort 2 only and upon consultation with 
the Medical Monitor, additional atezolizumab SC co-mix or atezolizumab SC cycles may 
be administered if this is deemed to be in the patients' best interest.  
Data from all cohorts will be analyzed to determine the optimal atezolizumab SC dose to 
be tested in Part 2. 
Patients will be followed until 90 days after the final dose of study treatment, initiation of 
new systemic anti-cancer therapy, withdrawal from the study, or study termination by the 
Sponsor, whichever occurs first. 
Part 1 will be conducted at up to approximately 20 sites globally. 
Figure 1 presents an overview of the Part 1 dose finding design.  Schedules of activities 
for Part 1 are provided in Appendix 1 and Appendix 3. 


 
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Figure 1 Part 1: Overview of the Dose Finding Study Design 
 
Atezo = atezolizumab; NSCLC = non−small cell lung cancer; PD = progressive disease; 
Q2W = every 2 weeks; Q3W = every 3 weeks.  
a Single dose of atezolizumab SC co-mix (in the thigh).  
b Three cycles of atezolizumab SC co-mix or atezolizumab SC Q2W (in the thigh). 
c Three cycles of atezolizumab SC co-mix or atezolizumab SC Q3W (first injection in the 
abdomen and subsequent two injections in the thigh). 
 
3.1.1.2 
Part 2:  Dose Confirmation 
Part 2 will be initiated once a dose has been identified based on the cumulative data 
collected from Part 1 (see Section 3.3.1).  In Part 2, patients will be randomized in a 2:1 
ratio to receive monotherapy with either 1875 mg of atezolizumab SC Q3W or 1200 mg 
of atezolizumab IV Q3W, respectively, starting on Day 1 of each 21-day cycle.   
Part 2 of this study will initially randomize approximately 327 patients across 
approximately 150 sites in a global enrollment phase.   
To ensure a patient population representative of standard clinical practice, the Sponsor 
will periodically evaluate the prevalence of EGFR mutation and limit the number of 
patients with EGFR-positive mutation to a maximum of approximately 10% of all 
randomized patients if required.  The Sponsor may also monitor other biomarkers such 
as PD-L1 expression levels and, if considered appropriate, carry out actions to ensure 
a balanced distribution in the study population. 
A structured evaluation of safety data will be conducted after the first 24 patients 
(approximately 16 patients in the atezolizumab SC arm and another 8 patients in the 
atezolizumab IV arm) have completed at least one cycle to ensure that the safety of 
atezolizumab SC (provided as a ready-to-use mixture of atezolizumab and rHuPH20) is 
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The totality of available safety data will be used for the assessment.  At the time of the 
structured evaluation of safety data, the available Cycle 1 Ctrough data will be reviewed for 
these 24 patients.  This data review will be performed in a blinded fashion and will 
provide a check that the Cycle 1 Ctrough with the atezolizumab SC formulation is similar to 
the Cycle 1 Ctrough measured after administration of the atezolizumab co-mix formulation.  
Randomization will not be interrupted, and patients will continue being treated.  
A blinded sample-size re-estimation will be conducted once approximately 
210−250 patients have been randomized.  A blinded estimation of the total coefficient 
of variation percent (CV%) from all available Cycle 1 Ctrough and AUC data will be 
compared with the CV% used in the calculation of sample size.  Depending on the 
observed, blinded CV%, the Sponsor may decide to increase or decrease the number of 
patients to be randomized (see Section 6.3.2). 
Atezolizumab SC Cycle 1 observed serum Ctrough (predose Cycle 2) and model-predicted 
AUC0–21 d will be measured and compared with atezolizumab IV Cycle 1 Ctrough and 
model-predicted AUC0-21 d, respectively, to confirm non-inferiority between atezolizumab 
SC and atezolizumab IV (co-primary PK endpoints).  Model-predicted Ctrough,Cycle 1, 
Ctrough,ss, and AUCss will be evaluated and compared between atezolizumab SC and 
atezolizumab IV (for more details, refer to Section 6).  Efficacy and safety information will 
be collected on a regular basis to assess secondary efficacy and safety endpoints.  
Patients will receive atezolizumab SC or atezolizumab IV, as indicated, until disease 
progression, loss of clinical benefit, or unacceptable toxicity (see Section 3.1.2 for 
details).  Crossover is not allowed. 
For Part 2, patients will undergo tumor assessments at baseline, every 6 weeks for the 
first 36 weeks following treatment initiation, and every 9 weeks thereafter, regardless of 
treatment delays, until radiographic disease progression per RECIST v1.1 or (for 
patients who continue atezolizumab after radiographic disease progression) loss of 
clinical benefit as determined by the investigator.  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue treatment for reasons other 
than disease progression or loss of clinical benefit, even if they start new anti-cancer 
therapy.  Follow-up data capture, including survival status and subsequent anti-cancer 
therapies, will continue for each patient until death, loss of follow-up, withdrawal of 
consent, or study termination by Sponsor, whichever occurs first.  
Safety assessments will include the incidence, nature, and severity of adverse events 
and laboratory abnormalities graded per the NCI CTCAE v5.0.  Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry.  
Serum samples will be collected to monitor atezolizumab pharmacokinetics and to detect 
the presence of antibodies to atezolizumab.  Patient-reported outcome (PRO) 
assessments will also be performed at regular intervals as detailed in the schedule of 
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3.1.3 
Monitoring Committees 
3.1.3.1 
Internal Monitoring Committee 
An IMC will be established for Part 1 of the study and will be composed of Sponsor 
members who are independent from the study team.  The IMC will share responsibility 
with the study team for the monitoring of patient safety.   
The IMC will meet on a regular basis over the course of the Part 1 of the study as 
specified in the IMC charter.  The IMC may also meet on an unscheduled basis should 
any unexpected safety concerns arise.  Further details on the composition, roles, and 
responsibilities of the IMC are documented in the IMC charter. 
3.1.3.2 
Joint Monitoring Committee 
A JMC will be convened to evaluate safety data during Part 2 of the study.  The JMC will 
be composed of internal and external members; further details on the composition, roles 
and responsibilities, and meeting schedule of the JMC are documented 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 (LPLV) occurs 
or when the last data point required for statistical analysis or safety follow-up is received 
from the last patient, whichever occurs later.  The end of the study is expected to occur 
approximately 33 months after the last patient is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total duration of the study, from screening of the first patient to the end of the study, 
is expected to be approximately 5.3 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Atezolizumab Dose, Administration Site, and 
Schedule for Part 2 
Refer to Section 3.1.1.1 for a rationale of the dose and schedule selection in Part 1 of 
the study.  PK, ADA, and safety results from Part 1 of the study have provided the 
rationale for dose, administration site, and schedule selection for atezolizumab SC for 
Part 2.  These results are summarized below.  
In Part 1, atezolizumab SC co-mix, given at a dose of 1800 mg Q3W in the thigh, 
provided similar observed Cycle 1 Ctrough and AUC0−21 d values as atezolizumab given at 
a dose of 1200 mg IV Q3W in Phase III study GO28915 (OAK) (observed Cycle 1 Ctrough 
[CV %]:  121.1 µg/mL [42.8%] and 76.0 µg/mL [53.9%], respectively; Cycle 1 AUC0−21 d:  
3868 µg*day/mL [38.6%] (observed) and 2978 µg*day/mL [26.1%] [model-predicted], 
respectively). 


 
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Atezolizumab PK data after both SC and IV administrations from Part 1 were modeled 
using a population PK (popPK) approach.  A higher bioavailability was estimated for 
administration in the thigh (82.9%) compared with in the abdomen (71.1%), with an 
inter-individual variability of 124%.  Using the popPK model, simulations of the proposed 
Phase III study in Part 2 indicated that an SC dose of 1800 mg Q3W given in the thigh 
had a high probability of providing comparable PK exposures to atezolizumab IV 
1200 mg Q3W, in terms of Cycle 1 and steady state Ctrough and AUC0−21 d.  
The observed treatment-emergent ADA incidence for atezolizumab SC co-mix is within 
the range of ADA incidence rates observed across multiple Phase II and III studies with 
atezolizumab IV.  Overall, the distributions of Cycle 1 Ctrough values for ADA-positive and 
ADA-negative patients largely overlap each other for the three cohorts in Part 1.  Thus, 
no impact of ADA status on PK exposure was observed.  All atezolizumab Ctrough levels, 
regardless of ADA status, were above the target concentration of 6 µg/mL.  
Overall, atezolizumab administered subcutaneously was well tolerated and exhibited 
a safety profile consistent with the known risks of atezolizumab IV monotherapy.  No 
new or significant safety concerns were identified.  No clinically significant difference of 
safety profile for different dose regimens (1800 mg Q3W vs. 1200 mg Q2W) was 
observed.  Comparison between Cohort 1 and Cohort 3 of Cycle 1 (SC only) adverse 
events did not show a meaningful difference of safety profile between dosing in the thigh 
and dosing in the abdomen. 
The dose of 1800 mg corresponds to an atezolizumab SC volume of 14.4 mL.  To 
improve dosing precision with the use of a 20 mL syringe, 15 mL of atezolizumab SC, 
corresponding to a dose of 1875 mg, will be administered in Part 2.  The predicted 
exposures after the administration of an SC dose of 1875 mg are comparable to those 
observed after the administration of an 1800 mg dose, and as such, the safety profile is 
expected to be similar. 
Based on the PK and safety results of Part 1, and to allow more precise dosing, the dose 
of 1875 mg Q3W administered in the thigh has been selected for atezolizumab SC for 
a randomized comparison of PK, efficacy, and safety with atezolizumab IV 1200 mg 
Q3W in Part 2.  
3.3.2 
Rationale for Patient Population and Control Arm 
This study is to be conducted in patients with locally advanced or metastatic NSCLC 
who are "CIT- naive" and for whom first-line platinum-based therapy has failed.  
Atezolizumab IV is currently approved as a monotherapy in this setting based on the 
results of the Phase III study GO28915 (OAK) (Tecentriq U.S. Package Insert).  Study 
GO28915 demonstrated that atezolizumab IV in monotherapy provides a survival 
improvement as compared with chemotherapy (docetaxel) in previously treated patients 
with advanced NSCLC (HR = 0.73; 95% CI: 0.62, 0.87; p = 0.0003; median OS 13 vs. 
9.6 months).  In addition to being a regimen with which atezolizumab has demonstrated 


 
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to be efficacious and its safety well-characterized, this monotherapy regimen also 
provides the possibility to assess the safety, efficacy, and immunogenicity of 
atezolizumab without the confounding effects of chemotherapy. 
3.3.3 
Rationale for Restricting the Number of Patients with a 
Sensitizing EGFR Mutation 
Data in the second-line NSCLC setting suggest that PD-1/PDL1 inhibition is less 
effective, irrespective of PDL-1 expression, in patients with EGFR mutations compared 
with patients without EGFR mutations (Cavanna et al. 2019).  The preferred course of 
treatment for patients with a sensitizing EGFR mutation is to target the acquired 
resistance and continue therapy under an alternative inhibitor (Jiang et al, 2018).  
Consequently, limiting the number of patients with a sensitizing EGFR mutation will 
ensure that the results obtained in this study are representative of current clinical 
practice. 
3.3.4 
Rationale for Co-Primary Pharmacokinetic Endpoints (Cycle 1 
Ctrough and AUC0–21 d)   
The development program and use of co-primary PK endpoints, Cycle 1 observed serum 
Ctrough (predose Cycle 2) and model-predicted AUC0–21 d, are based on a PK-bridging 
approach according to which the lowest exposure (Ctrough) and the overall drug exposure 
in a given dosing interval (AUC0–21 d) in a SC formulation that is at least as high as IV 
Ctrough and AUC0–21 d is expected to result in a comparable degree of target-site saturation 
and therefore the same degree of efficacy, regardless of the route of administration.  
Cycle 1 exposure metrics were selected to mitigate response-dependent decreases of 
clearance over time, as is recommended for checkpoint inhibitors (Liu et al. 2017). 
Previous experiments based on the PK bridging approach have already shown 
anti-tumor activity is not impaired by a change in administration route (Shpilberg and 
Jackisch 2013; Jackisch et al. 2015).  Similarly, in Study BP40657, demonstration of PK 
non-inferiority between the SC and IV formulations in terms of Cycle 1 Ctrough and 
AUC0−21 d will be obtained if the lower bound of the 90% CI for the geometric mean ratio 
(GMR) is ≥ 0.8, with 0.8 being the lower bound of the range recommended for 
bioequivalence. 
A comprehensive assessment of available atezolizumab IV monotherapy PK and 
exposure-response (ER) analyses for UCC and NSCLC has been conducted on the 
basis of eight clinical studies (Roche Report 1087176; Pooled Exposure-Response 
Analysis of Single-Agent Atezolizumab in Patients with UCC and NSCLC from 
PCD4989g, IMvigor211, and OAK Studies; available on request).  The population PK 
model based on Phase I data (Study PCD4989g) was externally validated by four Phase 
II studies (GO28753 [POPLAR], GO28754 [BIRCH], GO28625 [FIR], and GO29293 
[IMvigor210]) and three Phase III studies (GO28915 [OAK], GO29294 [IMvigor211], and 
GO29436 [IMpower150]). 


 
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In terms of ER for efficacy for both UCC and NSCLC, no clinically meaningful 
atezolizumab ER relationship with ORR or OS was concluded for the approved IV 
1200-mg Q3W dosing regimen.  This suggests that the exposure achieved by the 
approved IV 1200-mg Q3W dosing regimen is in the flat or plateau part of the ER curve.  
Therefore, as long as the atezolizumab SC formulation achieves exposure (Ctrough) and 
AUC0–21 d greater than the target concentration and within the range expected for the 
approved IV 1200-mg Q3W dosing regimen, no detrimental impact on efficacy response 
is expected. 
In terms of atezolizumab ER for safety for both UCC and NSCLC, no clinically 
meaningful ER for atezolizumab for safety was concluded for doses ranging from 
10 mg/kg Q3W to 20 mg/kg Q3W, which includes the 1200-mg IV fixed-dose Q3W 
dosing regimen.  Any new atezolizumab SC formulation that provides Cmax exposure that 
is not greater than what was observed for doses ranging up to 20 mg/kg Q3W (the 
highest dose administered in the first-in-human dose-ranging study PCD4989g) should 
exhibit similar exposure-safety relationships to that observed previously. 
3.3.5 
Rationale for Clinical Outcome Assessments 
It is important that disease and treatment do not compromise patients’ function and 
health-related quality of life, particularly in non-curative settings.  Patient-reported impact 
of their disease and treatment provide important information to complement safety and 
efficacy data and are critical to fully characterize the benefit-risk profile of atezolizumab 
SC.  To this end, patient experience assessments will be administered in Part 2 to inform 
overall treatment burden and treatment satisfaction from the patient’s perspective.  
HCP perspectives on the convenience, overall satisfaction, potential time savings, 
and/or ease of administration with atezolizumab SC and/or atezolizumab IV will also be 
examined in Part 2.  Together with the patient experience assessments, HCP 
experience data will help to provide a more comprehensive characterization of 
atezolizumab SC and atezolizumab IV. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Part 1 of the study will enroll approximately 12 evaluable patients for Cohorts 1 and 2 
each and approximately 20−30 evaluable patients for Cohort 3 (i.e., a total of 
approximately 60 evaluable patients).  For a definition of evaluable patients, see 
Section 6.2. 
Part 2 of the study is expected to randomize approximately 327 patients with locally 
advanced or metastatic NSCLC during the global enrollment phase of this study. 


 
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4.1.1 
Inclusion Criteria 
General inclusion criteria applicable to both Parts 1 and 2 are described.  Additional 
inclusion criteria applicable to either Part 1 or 2 are also described. 
4.1.1.1 
General Inclusion Criteria Applicable to Both Parts 1 and 2 (All 
Patients) 
All patients must meet all the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol, in the investigator's judgment 
• 
Measurable disease as defined by RECIST v1.1 
Previously irradiated lesions can only be considered as measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of disease. 
• 
ECOG Performance Status of 0 or 1 
• 
Life expectancy ≥ 12 weeks 
• 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
– ANC ≥ 1.5 × 109/L (1500/µL) without granulocyte colony-stimulating factor support  
– Lymphocyte count ≥ 0.5 × 109/L (500/µL) 
– Platelet count ≥ 100 × 109/L (100,000/µL) (without transfusion)  
– Hemoglobin ≥ 90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
– AST, ALT, and ALP ≤ 2.5 × upper limit of normal (ULN), with the following 
exceptions: 
Patients with documented liver metastases:  AST and ALT ≤ 5 × ULN 
Patients with documented liver or bone metastases:  ALP ≤ 5 × ULN 
– Total bilirubin ≤ 1.5 × ULN with the following exception: 
Patients with known Gilbert disease:  total bilirubin level ≤ 3 × ULN 
– Serum creatinine ≤ 1.5 × ULN  
– Serum albumin ≥ 25 g/L (2.5 g/dL) 
– For patients not receiving therapeutic anticoagulation:  INR or aPTT ≤ 1.5 × ULN 
• 
Negative HIV test at screening 
• 
Negative hepatitis B surface antigen (HBsAg) test at screening 
• 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening 
The HBV DNA test will be performed only for patients who have a positive total 
HBcAb test. 


 
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• 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV 
antibody test followed by a negative HCV RNA test at screening 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
• 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, 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 5 months after the final 
dose of atezolizumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements. 
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 acceptable methods of contraception. 
• 
Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute 
toxicities from previous therapy, excluding alopecia 
For peripheral neuropathy, improvement to Grade ≤ 2 is acceptable. 
• 
Intact normal skin without potentially obscuring tattoos, pigmentation, or lesions in 
the area for intended injection 
• 
Histologically or cytologically documented NSCLC that is currently locally advanced 
or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, 
or recurrent) NSCLC (per the Union Internationale contre le Cancer/American Joint 
Committee on Cancer staging system, 8th edition) 
Pathological characterization may be from tumor specimens collected at a time 
when the NSCLC was at an earlier stage but must be sufficient to define 
patients as having either squamous or non-squamous histology. 


 
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• 
Disease progression during or following treatment with a platinum-containing 
regimen for locally advanced, unresectable/inoperable, or metastatic NSCLC or 
disease recurrence within 6 months of treatment with a platinum-based 
adjuvant/neoadjuvant regimen or combined modality (e.g., chemoradiation) regimen 
with curative intent  
Patients may have received one additional cytotoxic chemotherapy regimen 
provided no interval disease progression has occurred.  Chemotherapy 
regimens will be counted based on interval disease progression and not the 
number of agents or switches in agents (e.g., a first-line therapy that consists of 
several cycles of a platinum doublet and subsequent maintenance therapy that 
introduces or switches to a new chemotherapy agent without interval disease 
progression will all be considered one chemotherapy regimen). 
Adjuvant/neoadjuvant chemotherapy or chemoradiation counts as a prior 
chemotherapy regimen if < 6 months have elapsed between the last dose and 
the date of recurrence.  Combined treatment with chemotherapy and radiation 
constitutes a single regimen; surgery is not considered a regimen. 
Patients with advanced lung cancer and a sensitizing EGFR mutation will 
additionally be required to have experienced disease progression (during or 
after treatment) or intolerance with one or more EGFR TKIs appropriate for the 
treatment of EGFR-mutant NSCLC as outlined below: 
– 
Patients who have progressed on or were intolerant to first-line osimertinib 
or other third generation EGFR TKIs are eligible. 
– 
Patients who have progressed on or were intolerant to first- or 
second-generation EGFR TKIs (for example: erlotinib, gefitinib, afatinib, 
dacomitinib) and who have no evidence of the EGFR T790M mutation in 
the tumor tissue after TKI therapy are eligible.  Patients whose T790M 
mutational status is unknown are also eligible if this is in accordance to 
local standard practice. 
– 
Patients who have progressed on or were intolerant to first- or 
second-generation EGFR TKIs and who have evidence of the EGFR 
T790M mutation in the tumor tissue after TKI therapy must also have 
progressed on, were intolerant to, or lack access to third-generation TKIs 
such as osimertinib or others. 
Patients with a previously detected ALK fusion oncogene must additionally 
have experienced disease progression (during or after treatment) or intolerance 
to treatment with one or more ALK inhibitors (e.g., alectinib, crizotinib, 
brigatinib, ceritinib, lorlatinib, or others) appropriate for the treatment of NSCLC 
in patients having an ALK fusion oncogene. 
The last dose of prior systemic anti-cancer therapy must have been 
administered ≥ 21 days prior to enrollment/randomization, with the exception 
being TKIs approved for treatment of NSCLC have to be discontinued ≥ 7 days 
prior to Cycle 1, Day 1.  The baseline scan must be obtained after 
discontinuation of prior TKIs (washout not required prior to obtaining the scan).  


 
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The last dose of treatment with any investigational agent or participation in 
another interventional study must have ended ≥ 28 days prior to 
enrollment/randomization. 
Anti-cancer agents used for pleurodesis are not counted as a line of therapy. 
Prior radiation therapy is allowed provided the patient has recovered from any 
toxic effects thereof. 
 
4.1.1.2 
Additional Inclusion Criteria Applicable to Part 1 Only 
Patients in Part 1 must also meet the following additional criteria for study entry: 
• 
A body mass index (BMI) between 18 and 32 kg/m2 inclusive 
 
4.1.1.3 
Additional Inclusion Criteria Applicable to Part 2 Only 
Patients in Part 2 must also meet the following additional criteria for study entry: 
• 
For patients whose tumor may harbor a sensitizing EGFR mutation, known EGFR 
test results at the time of randomization 
Patients who may harbor a sensitizing EGFR mutation are defined as having 
non-squamous histology (including those with a mixed histology that includes 
any non-squamous component), and without any other known driver mutation 
(e.g., KRAS status wild-type/unknown, BRAF status wild-type unknown, or ALK 
fusion oncogene negative/unknown).   
EGFR tests may be assessed locally or submitted for central laboratory testing.  
If available, EGFR status assessed locally should be performed on tissue 
samples using a validated health authority−approved test that detects mutations 
in exons 18−21.  Patients recruited in China are required to be tested centrally, 
even if local results are available. 
If patients are recruited in China or if no local results are available, tissue is 
required for central testing as promptly as possible and always prior to 
randomization (see below and in Section 4.5.7.3). 
Patients with a sensitizing EGFR mutation will be excluded once approximately 
10% of the total target sample size has been reached.   
• 
Availability of a pre−study treatment representative formalin-fixed 
paraffin-embedded (FFPE) tumor specimen in paraffin block (preferred) or at least 
six slides containing unstained, freshly cut, serial sections from an FFPE tumor 
specimen for exploratory biomarker analysis (e.g., PD-L1) (see Section 4.5.7.3 for 
further details) 
For patients recruited in China, availability of nine slides (including six for 
exploratory biomarker testing) containing unstained, freshly cut, serial sections 
from a pre−study treatment representative formalin-fixed paraffin embedded 
(FFPE) tumor specimen. 
For both patients recruited in China and ex-China, if fewer slides are available at 
baseline, additional slides may be requested in case of testing failure (see Section 
4.5.7.3 and the laboratory manual for further details). 


 
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4.1.2 
Exclusion Criteria 
General exclusion criteria applicable to both Parts 1 and 2 are described.  Additional 
exclusion criteria applicable to either Part 1 or 2 are also described. 
4.1.2.1 
General Exclusion Criteria Applicable to Both Parts 1 and 2 (All 
Patients) 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusions  
Patients who meet any of the following cancer-specific criteria will be excluded from 
study entry: 
• 
Symptomatic, untreated, or actively progressing CNS metastases  
Asymptomatic patients with treated CNS lesions are eligible provided that all of 
the following criteria are met:  
– 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
– 
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage. 
– 
The patient has not undergone stereotactic radiotherapy within 7 days 
prior to initiation of study treatment, whole-brain radiotherapy within 
14 days prior to initiation of study treatment, or neurosurgical resection 
within 28 days prior to initiation of study treatment. 
– 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.  Anticonvulsant therapy at a stable dose is permitted. 
– 
Metastases are limited to the cerebellum or the supratentorial region 
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord). 
– 
There is no evidence of interim progression between completion of 
CNS-directed therapy and initiation of study treatment. 
Note:  Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases.  Following 
treatment, these patients may then be eligible without the need for an additional 
brain scan prior to enrollment, if all other criteria are met. 
• 
Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for ≥ 2 weeks prior to enrollment 
• 
History of leptomeningeal disease 
• 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 


 
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• 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should have recovered from the effects of radiation.  
There is no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment. 
• 
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, 
calcium > 12 mg/dL, or corrected serum calcium > ULN) 
• 
History of malignancy other than NSCLC within 5 years prior to screening, with the 
exception of those with a negligible risk of metastasis or death and treated with 
expected curative outcome (such as adequately treated carcinoma in situ of the 
cervix, basal or squamous cell skin cancer, localized prostate cancer treated with 
curative intent, or ductal carcinoma in situ treated surgically with curative intent) 
 
General Medical Exclusions 
Patients who meet any of the following general medical criteria will be excluded from 
study entry: 
• 
Pregnancy or breastfeeding, or intention of becoming pregnant during study 
treatment or within 5 months after the final dose of atezolizumab 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
• 
History of severe anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
• 
Known hypersensitivity to Chinese hamster ovary cell products or any component of 
the atezolizumab formulation 
• 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to (for a comprehensive list, see Appendix 8), myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis 
with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, 
with the following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 


 
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– 
Rash must cover < 10% of body surface area. 
– 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
– 
There is no occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the previous 12 months. 
• 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
Active tuberculosis 
• 
Current treatment with anti-viral therapy for HBV 
• 
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 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
• 
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to initiation 
of study treatment, unstable arrhythmias, or unstable angina 
Patients with a known left ventricular ejection fraction (LVEF) < 40% will be 
excluded.  
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or LVEF < 50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation 
with a cardiologist if appropriate. 
• 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation 
of study treatment, or anticipation of need for a major surgical procedure during the 
course of the study  
• 
Prior allogeneic stem cell or solid organ transplantation 
• 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment 
or within 5 months after the final dose of atezolizumab 
• 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, or that may 
affect the interpretation of the results, or may render the patient at high risk from 
treatment complications 


 
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Exclusion Criteria Related to Medications 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies 
including anti-TIGIT, anti−PD-1, and anti−PD-L1 therapeutic antibodies  
Patients who have had prior anti−CTLA-4 treatment may be enrolled, provided 
the following requirements are met:  
– 
Last dose of anti−CTLA-4 at least 6 weeks prior to enrollment  
– 
No history of severe immune-mediated adverse effects from anti-CTLA-4 
(National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI CTCAE] Grade 3 or 4) 
• 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug 
(whichever is longer) prior to initiation of study treatment  
 
Prior treatment with cancer vaccines is allowed.  
• 
Treatment with systemic immunosuppressive medication (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti−TNF-α agents) within 2 weeks prior to enrollment 
Patients who have received acute, low-dose (≤ 10 mg oral prednisone or 
equivalent), systemic immunosuppressant medications may be enrolled in the 
study.  
The use of corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension, and low-dose supplemental 
corticosteroids for adrenocortical insufficiency is allowed. 
• 
Known allergy or hypersensitivity to hyaluronidase, bee or vespid venom, or any 
other ingredient in the formulation of rHuPH20  
 
4.1.2.2 
Additional Exclusion Criteria Applicable to Part 1 Only 
Patients in Part 1 who meet the following additional criterion will be excluded from study 
entry: 
• 
Pathology (e.g., lower extremity edema, cellulitis, lymphatic disorder or prior 
surgery, preexisting pain syndrome, previous lymph node dissection, etc.) that could 
interfere with any protocol-specified outcome assessment (e.g., PK) 
 
4.1.2.3 
Additional Exclusion Criteria Applicable to Part 2 Only 
Patients in Part 2 who meet any of the following additional criteria will be excluded from 
study entry: 
• 
Tested tumor PD-L1 expression status with an intention to treat the patient if 
positive.  This implies that: 
– 
Patients who had access to PD-1 or PD-L1 first line therapies and were tested 
for PD-L1 expression status are not eligible, irrespective of the test result 


 
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– 
Patients who had no access to PD-1 or PD-L1 first line therapies but were 
tested anyway as part of a testing routine despite lack of access are eligible, 
irrespective of the test result 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an open-label study.  
Patients should receive their first dose of study drug on the day of enrollment for Part 1 
or on the day of randomization for Part 2, if possible.  If this is not possible, the first dose 
should occur within 5 days after enrollment/randomization. 
Patients in Part 2 will be randomly assigned to one of two treatment arms:  atezolizumab 
SC or atezolizumab IV.  Randomization will occur in a 2:1 ratio using a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm. 
Although Part 2 is open-label, Sponsor’s standard operating procedures for blinding and 
unblinding will be followed (see Section 3.1.1.1 regarding blinded analyses). 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab SC for 
co-mix, atezolizumab SC, atezolizumab IV, and rHuPH20.  IMPs will be supplied by the 
Sponsor. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Atezolizumab SC for Co-Mix 
Atezolizumab SC for co-mix will be provided as a sterile liquid at a concentration of 
125 mg/mL.  The vial is designed to deliver 20.0 mL (2500 mg) of atezolizumab solution 
(i.e., a nominal fill of 20.0 mL atezolizumab in 20-mL vials).   
For information on the formulation of atezolizumab SC for co-mix, see the Atezolizumab 
Investigator's Brochure. 
4.3.1.2 
rHuPH20 
rHuPH20 to be manually mixed with atezolizumab SC for co-mix will be provided as 
a sterile liquid at a concentration of 110 K U/mL.  The vial contains 0.5 mL (55,000 U) of 
rHuPH20 solution. 
For information on the formulation of rHuPH20, see the rHuPH20 Investigator's 
Brochure. 


 
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4.3.1.3 
Atezolizumab SC 
Atezolizumab SC will be provided as a sterile liquid at a concentration of 125 mg/mL.  
rHuPH20 will be co-formulated with atezolizumab in the atezolizumab SC formulation at 
a concentration of 2000 U/mL. 
For information on the formulation of atezolizumab SC, see the pharmacy manual.  
4.3.1.4 
Atezolizumab IV 
The atezolizumab IV drug product will be provided as a sterile liquid in a single-use, 
20-mL glass vial that contains approximately 20.0 mL (1200 mg) of atezolizumab 
solution (i.e., a nominal fill of 20.0 mL atezolizumab in 20-mL vials).   
For more detailed information on the formulation of atezolizumab, see the Atezolizumab 
Investigator’s Brochure.  
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
No dose modification for atezolizumab is allowed. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (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. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Appendix 10. 
4.3.2.1 
Atezolizumab SC for Co-Mix with rHuPH20 or Atezolizumab SC 
In order to generate atezolizumab SC co-mix, atezolizumab SC for co-mix will be mixed 
with rHuPH20 at a concentration of 2000 U/mL.  For more details regarding this 
procedure, refer to the version of the pharmacy manual corresponding to the protocol 
version to which the patient was last consented. 
The drug product will be administered subcutaneously by a health care professional in 
the anterior thigh region or, for the first dose in Cohort 3 of Part 1 only, in the lower part 
of the abdomen.  Depending on the Part 1 cohort, patients will receive one or several 
doses of atezolizumab SC co-mix or atezolizumab SC via the SC route.  Atezolizumab 
SC co-mix and atezolizumab SC injections will be administered per the instructions 
outlined in Table 2.  In Part 2 of the study, atezolizumab SC will be provided as 
a ready-to-use mixture of atezolizumab and rHuPH20 at a concentration of 2000 U/mL. 


 
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When applicable the injection site should be alternated between the left and right thigh.  
New injections should be given at least 2.5 cm from the old site and never into areas 
where the skin is red, bruised, tender, or hard.  If administered in the abdomen, injection 
should be given in either of the two lower quadrants around the umbilicus; it should not 
be administered above the umbilicus.  In all cases (abdomen or thigh), start and stop 
times of the SC injection should be captured. 
No premedication will be allowed for the first dose of atezolizumab SC co-mix or 
atezolizumab SC.  Premedication may be administered for Cycles ≥ 2 at the discretion of 
the treating physician.  Injection sites will be digitally photographed after a SC injection if 
a severe adverse reaction at the injection site is observed. 
In case a patient develops unacceptable toxicity to the SC injection of atezolizumab, 
treatment with IV infusion may continue.  In case a patient develops toxicity that is linked 
to the treatment with atezolizumab irrespective of the form of administration (SC or IV), 
further continuation of treatment is not recommended.  Refer to Appendix 10 for further 
guidance on atezolizumab toxicity management.  
Administration of atezolizumab SC co-mix or atezolizumab SC 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 9.  Atezolizumab SC co-mix and atezolizumab SC injections 
will be administered per the instructions outlined in Table 2. 
Table 2 
Administration of First and Subsequent Atezolizumab SC Co-Mix 
and Atezolizumab SC Injections 
First and Subsequent SC Injections 
• 
No premedication is permitted prior to the first SC injection. 
• 
For subsequent SC injections, if the patient experienced an injection-related 
reaction with any previous injection, premedication with antihistamines, 
antipyretics, and/or analgesics may be administered at the discretion of the 
investigator. 
• 
Vital signs (pulse rate, respiratory rate, blood pressure, and temperature) 
should be measured within 60 minutes prior to the injection. 
• 
Vital signs should be measured at 30 (± 10) minutes after the injection (and 
before any PK sample scheduled to be drawn at the same time) and as 
clinically indicated. 
• 
Patients should be informed about the possibility of delayed post-injection 
symptoms and instructed to contact their study physician if they develop such 
symptoms 
PK = pharmacokinetic. 
 
4.3.2.2 
Atezolizumab IV 
Administration of atezolizumab IV will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 


 
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manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 9.  
Atezolizumab IV infusions will be administered per the instructions outlined in Table 3. 
Table 3 
Administration of First and Subsequent Atezolizumab IV 
Infusions 
First Infusion 
Subsequent Infusions 
• 
No premedication is permitted prior to the 
atezolizumab infusion. 
• 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
• 
Atezolizumab should be infused over 
60 (± 15) minutes. 
• 
If clinically indicated, vital signs should be 
measured every 15 (± 5) minutes during the 
infusion 
• 
Vital signs should be measured at 
30 (± 10) minutes after the infusion and 
before any PK sample scheduled to be 
drawn at the same time. 
• 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
• 
If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
• 
Vital signs should be measured within 
60 minutes prior to the infusion. 
• 
Atezolizumab should be infused over 
30 (± 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (± 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
• 
If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be measured during the infusion. 
• 
Vital signs should be measured at 
30 (± 10) minutes after the infusion and 
before any PK sample scheduled to be 
drawn at the same time. 
PK = pharmacokinetic. 
 
Guidelines for medical management of infusion-related reactions and injection-related 
reactions are provided in Appendix 10. 
No dose modification for atezolizumab is allowed. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (atezolizumab SC for co-mix, rHuPH20, 
atezolizumab IV, and atezolizumab SC) will be provided by the Sponsor where required 
by local health authority regulations.  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. 


 
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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 (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the Atezolizumab Investigator's Brochure or 
rHuPH20 Investigator’s Brochure for information on IMP handling, including preparation 
and storage, and accountability. 
4.3.4 
Continued Access to Investigational Medicinal Products 
Currently, the Sponsor does not have any plans to provide Roche IMPs (atezolizumab 
SC, atezolizumab SC for co-mix, rHuPH20, and atezolizumab IV) or any other study 
treatments or interventions to patients who have completed the study.  The Sponsor may 
evaluate whether to continue providing IMPs 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 
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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: 
• 
Oral contraceptives 
• 
Hormone-replacement therapy 
• 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
• 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section 4.4.3) 
• 
Megestrol acetate administered as an appetite stimulant  
• 
Mineralocorticoids (e.g., fludrocortisone) 
• 
Corticosteroids (≤ 10 mg oral prednisone or equivalent) administered for chronic 
obstructive pulmonary disease or asthma 
• 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
• 
Palliative radiotherapy (e.g., treatment of known bony metastases) provided it does 
not interfere with the assessment of tumor target lesions (e.g., the lesion being 
irradiated is not the only site of disease, as that would render the patient not 
evaluable for response by tumor assessments according to RECIST v1.1) 
It is not a requirement to withhold atezolizumab during palliative radiotherapy. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab administration only, at the discretion of the 
investigator. 
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 Section 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 β2-adrenergic agonists; see Appendix 9). 


 
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4.4.2 
Cautionary Therapy for Atezolizumab-Treated Patients 
4.4.2.1 
Corticosteroids, Immunosuppressive Medications, and TNF-α 
Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and TNF-α inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-α inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-α inhibitors may be 
administered at the discretion of the 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 therapy (refer to Appendix 10 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: 
• 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authority−approved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment, until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and local therapy under certain circumstances (see 
Section 4.4.1 for details). 
• 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
• 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during atezolizumab treatment, and for 5 months after 
the final dose of atezolizumab. 
• 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab. 
 


 
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4.5 
STUDY ASSESSMENTS  
The schedules of activities to be performed during the study are provided in Appendix 1 
and Appendix 3 (Part 1) and Appendix 2, Appendix 4, and Appendix 5 (Part 2).  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. 
Patients who are willing to participate in the study and have given written informed 
consent will undergo a thorough screening medical examination (including a physical 
examination, baseline tumor scan, vital signs, and laboratory tests) within 28 days prior 
to drug administration.  Laboratory tests will be performed within 14 days prior to drug 
administration.  
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, Concomitant Medication, and Demographic 
Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
will be recorded at screening.  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 
Physical Examinations 
A complete physical examination 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 
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Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
Height and weight will be recorded at screening and weight only at Day 1 of each cycle, 
or whenever the investigator considers there is a substantial change from baseline.  
Results will be recorded on the eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.   
Vital signs should be measured within 60 minutes prior to and 30 (± 10) minutes after 
each atezolizumab infusion/injection and as clinically indicated.  In addition, vital signs 
should be measured at other specified timepoints as outlined in the schedules of 
activities (see Appendix 1 and Appendix 2) and Section 4.3.2. 
4.5.5 
Tumor and Response Evaluations 
4.5.5.1 
Screening Assessments 
The screening assessment must include CT scans (with oral and/or IV contrast) or 
magnetic resonance imaging (MRI) scans of the chest, abdomen, pelvis, and head.  
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), a 
non-contrast CT scan of the chest may be performed, and MRI scans of the abdomen, 
pelvis, and head should be performed.  A CT scan with contrast or MRI scan of the head 
must be performed at screening to evaluate CNS metastasis in all patients (MRI scan 
must be performed if CT scan is contraindicated).  An MRI scan of the head is required 
to confirm or refute the diagnosis of CNS metastases at baseline in the event of an 
equivocal CT scan.  Bone scans and CT scans of the neck should also be performed if 
clinically indicated.  At the investigator's discretion, other methods of assessment of 
measurable disease as per RECIST v1.1 may be used. 
4.5.5.2 
Assessments during Treatment 
For Part 1, patients will be monitored as per local practice and no protocol-specific scans 
will be mandated during treatment.  Note that the following tumor assessments apply 
only to Part 2. 
For Part 2, tumor assessments should occur every 6 weeks (± 3 business days) for the 
first 36 weeks following treatment initiation, and every 9 weeks (± 7 days) thereafter, 
regardless of treatment delays, until radiographic disease progression per RECIST v1.1 
or (for patients who continue atezolizumab after radiographic disease progression) loss 
of clinical benefit as determined by the investigator (see Section 3.1.2).  Thus, tumor 
assessments are to continue according to schedule in patients who discontinue 


 
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treatment for reasons other than disease progression or loss of clinical benefit, even if 
they start new anti-cancer therapy.  At the investigator's discretion, tumor assessments 
may be repeated at any time if progressive disease is suspected. 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for 
a full-contrast diagnostic CT scan. 
All measurable and evaluable lesions identified at baseline should be re-assessed at 
each subsequent tumor evaluation.  The same radiographic procedures used to assess 
disease sites at screening should be used for subsequent tumor assessments (e.g., the 
same contrast protocol for CT scans).  Tumor assessments must be continued after 
disease progression per RECIST v1.1 for patients who receive treatment beyond 
progression (or further if patient is thought to be deriving benefit from the investigator; 
see Section 3.1.2).  This includes continued measurement of target lesions, evaluation 
of non-target lesions (including monitoring for further worsening of any non-target lesions 
that have shown unequivocal progression), and evaluation of any newly identified 
lesions (including measurements, if lesions are measurable; see Appendix 7) at all 
subsequent assessments). 
Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 7) prior to treatment administration at each cycle.  
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits. 
Patients who discontinue study drug for reasons other than disease progression 
(e.g., toxicity) should continue to undergo scheduled tumor assessments at the same 
frequency as would have been followed if the patient had remained on study drug until 
death, disease progression, loss of clinical benefit, withdrawal of consent, or until the 
study closes, whichever occurs first.  Patients who start a new anti-cancer therapy in the 
absence of disease progression should be followed according to the protocol schedule 
until disease progression, death, withdrawal of consent, or study termination by Sponsor, 
whichever occurs first. 
4.5.6 
Digital Photography Images 
In case of severe injection-site reactions, unscheduled photographs will be taken.  
Photographs should include a label showing the subject’s identification number and 
initials, date and time of calendar date, and a centimeter ruler to provide scale.  Efforts 
will be made to standardize the photography with regard to parameters such as angle, 
light, distance from body and settings. 


 
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4.5.7 
Laboratory, Biomarker, and Other Biological Samples 
4.5.7.1 
Local Laboratories 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
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 standard of care for the region), sodium, potassium, magnesium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total bilirubin, alkaline phosphatase, ALT, AST, and lactate dehydrogenase 
(LDH) 
• 
Coagulation:  INR and aPTT 
• 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (T3) 
(or total T3 for sites where free T3 is not performed), and free thyroxine (also known 
as T4) 
• 
HIV serology 
• 
HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA 
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection. 
• 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection. 
• 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine (or serum, if urine is not feasible) pregnancy tests will be 
performed at specified timepoints as detailed in the schedules of activities 
(Appendix 1 and Appendix 2).  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
• 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted  
 


 
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4.5.7.2 
Central Laboratories 
The following samples will be sent to one or more central laboratories or to the Sponsor 
or a designee for analysis (see Appendix 6 for instructions on PK and ADA sampling 
procedures): 
• 
Serum samples will be assayed for atezolizumab concentrations with use of 
a validated assay 
• 
Plasma samples will be assayed for hyaluronidase (rHuPH20) concentration with 
use of a validated assay (during Part 1 only). 
• 
Serum samples will be assayed for the presence of ADAs to atezolizumab with use 
of validated immunoassays.  
• 
Plasma samples will be assayed for the presence of ADAs to hyaluronidase 
(rHuPH20) with use of validated immunoassays. 
• 
C-reactive protein 
 
4.5.7.3 
Central Laboratories, Applicable to Part 2 Only 
The following samples for Part 2 will be sent to one or more central laboratories or to the 
Sponsor or designee for analysis: 
• 
Archival or newly collected tumor tissue sample obtained at baseline for exploratory 
research on biomarkers (e.g., PD-L1, as well as ALK and/or EGFR status if 
required. 
A representative FFPE tumor specimen in a paraffin block (preferred) or at least six 
slides containing unstained, freshly cut, serial sections from an FFPE tumor 
specimen must be submitted along with an associated pathology report.  For 
patients recruited in China, see additional details below. 
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Samples collected via resection, core-needle biopsy (at least cores, embedded in 
a single paraffin block), or excisional, incisional, punch, or forceps biopsy are 
acceptable.  Fine-needle aspiration (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or smears), brushing, cell pellets from 
pleural effusion, and lavage samples are not acceptable.  Tumor tissue from bone 
metastases that have been decalcified is not acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable for required 
testing, a pre−study treatment tumor biopsy is required.  A pre−study treatment 
tumor biopsy may also be performed if a patient's archival tissue test results do not 
meet eligibility criteria.  Note that in all cases, if tissue does not meet the required 
quality, additional material may be requested.   
If a patient is recruited in China or if no local EGFR results are available, all tissue 
must be submitted prior to randomization and as early as possible during screening 
to avoid compromising the duration of the screening period.  When local EGFR 
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tumor tissue (archival or freshly obtained) sample may be submitted within 4 weeks 
after randomization.  All material should be sent in a single shipment. 
In all cases, it is preferred that additional slides for EGFR and ALK are serial 
sections with those used for PD-L1 testing.  Note that samples that are not serial 
sections with PD-L1 slides (e.g., from different blocks) will have different sample 
requirements.  See the laboratory manual for details on tumor sample requirements.  
The numbers of required samples are outlined in Table 4 below. 
 
Table 4 
Tumor Tissue Sample Requirements 
Testing Performed 
Ex-China 
China a  
PD-L1 
1 block or ≥ 6 slides 
NA 
PD-L1 + EGFR b 
1 block or ≥ 7 slides 
7 slides 
PD-L1 + ALK c 
1 block or ≥ 8 slides 
NA 
PD-L1 + EGFR b + ALK c 
1 block or ≥ 9 slides 
9 slides 
EGFR a 
NA 
3 slides 
NA = not applicable. 
a Patients recruited in China require slides for central EGFR testing and exploratory biomarker 
testing, if permitted by local regulation.  Exploratory biomarker testing includes PD-L1 and 
ALK (the latter requires slides only if not locally available).  Central testing of EGFR is 
required for enrollment. 
b For patients recruited ex-China, EGFR testing is required if no local assessment is available 
and the patient could have an EGFR mutation (i.e., non-squamous histology or lack of other 
driver mutation, please refer to section 4.1.1.3 for more details). 
c ALK testing is required if no local assessment is available and the patient could have an ALK 
mutation (i.e., non-squamous histology or lack of other driver mutation). 
 
With the exception of patients recruited in China, exploratory biomarker research may 
include, but will not be limited to, analysis of genes or gene signatures associated with 
tumor immunobiology, PD-L1, EGFR, ALK, lymphocyte subpopulations, T-cell receptor 
repertoire, or cytokines associated with T-cell activation.  Research may involve 
extraction of DNA, cell-free DNA, or RNA; analysis of mutations, single nucleotide 
polymorphisms, and other genomic variants.  
For patients recruited in China, exploratory biomarker research may include PD-L1, 
EGFR, and ALK (the latter only if central testing is required).    
4.5.7.4 
Applicable to All Laboratory, Biomarker, and Other Biological 
Samples 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 


 
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Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions: 
• 
Plasma and serum samples collected for PK or immunogenicity analysis may be 
needed for additional immunogenicity characterization and for PK or immunogenicity 
assay development and validation; therefore, these samples will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed. 
• 
Tumor tissue samples collected for biomarker research will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed. 
• 
For enrolled patients for whom a block has been sent, remaining archival tissue 
blocks will be returned to the site upon request or 18 months after final closure of 
the study database, whichever occurs first.   
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.8 
Cardiac Assessments 
Triplicate electrocardiogram (ECG) recordings will be obtained at specified timepoints, 
as outlined in the schedules of activities (see Appendix 1 and Appendix 2).  ECGs 
acquired on different days should be as closely time-matched as feasible.  Three 
interpretable ECG recordings (e.g., without artifacts) must be obtained at each timepoint.  
The average of the three readings will be used to determine ECG intervals (e.g., PR, 
QRS, QT).  Single ECG recordings may be obtained at unscheduled timepoints as 
indicated.  All ECG recordings must be performed using a standard high-quality, 
high-fidelity digital electrocardiograph machine equipped with computer-based interval 
measurements.  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.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws).  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.  Digital 
recordings will be stored at site.  Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF. 


 
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In Part 2, patients with a known history of pericardial effusions or with evidence of 
pericardial effusion on screening chest CT must have an LVEF assessment prior to the 
administration of study drugs as specified in the schedule of activities (Appendix 2).  
LVEF can be assessed using echocardiogram (ECHO) as the preferred method.  The 
same method must be used for baseline and subsequent LVEF measurements in each 
patient.  New York Heart Association Class II Congestive Heart Failure or greater must 
be confirmed by a cardiologist. 
4.5.8.1 
Assessments of Patient- and Health Care 
Professional−Reported Experience 
PRO instruments will be completed to assess the treatment benefit and more fully 
characterize the safety profile of atezolizumab SC versus atezolizumab IV in Part 2.  
In addition, PRO instruments will enable the capture of each patient's direct experience 
with atezolizumab.  The HCP-reported experience instruments will be completed to 
assess the convenience, potential time savings, ease of administration, and overall 
satisfaction regarding administration of atezolizumab SC and atezolizumab IV. 
PRO data will be collected using ten selected items from the EORTC Item Library 
(EORTC IL57) and the modified satisfaction with therapy (SWT) scale from the CTSQ.  
HCP-reported experience data will be collected using the HCP SC versus IV Perspective 
Questionnaire and the HCP Subcutaneous Perspective Questionnaire.   
4.5.8.2 
Data Collection Methods for Assessments of Patient- and 
Health Care Professional-Reported Experience 
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study (see Appendix 2).  At the clinic, instruments will be administered before the patient 
receives any information on disease status, prior to the performance of non-PRO 
assessments or any study assessments that may bias patient responses, and prior to 
the administration of study treatment, unless otherwise specified. 
Paper-based PRO instruments, translated into the local language as appropriate, will be 
provided by the Sponsor to enable the instruments to be administered at each specified 
timepoint.  Patients may be exempted from completing PRO instruments that are not 
available in their native language. 
During clinic visits, PRO instruments should be administered as outlined below: 
• 
Patients' health status should not be discussed prior to administration of the 
instruments. 
• 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
• 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 5 minutes at most specified visits and 10 minutes at the Cycle 3 visit (or at the 
treatment discontinuation visit if study treatment is discontinued prior to the Cycle 3 
visit). 


 
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• 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
• 
Site staff should not interpret or explain questions but may read questions verbatim 
upon request. 
• 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
• 
Site staff should review all completed instruments and should ask the patient to 
rectify any response that is not clearly marked in the appropriate location.  If 
a response is missing, site staff should ask the patient to complete the item or 
confirm that the item was intentionally left blank. 
• 
Site staff must enter the responses from the instruments into the eCRF 
 
The HCP Perspective Questionnaires will be completed at the clinic by the HCP(s) who 
administer study treatment (e.g., nurse, physician).  The HCP Subcutaneous 
Perspective Questionnaire will be completed after administration of at least three doses 
of atezolizumab SC across all patients in Part 2 (see Appendix 2).  The HCP SC versus 
IV Perspective Questionnaire will be completed after administration of at least three 
doses of atezolizumab SC and at least three doses of atezolizumab IV across all 
patients in Part 2 (see Appendix 2).  The instruments will be provided by the Sponsor.  
HCPs must complete the official version of the instruments, as provided by the Sponsor.  
The instruments must not be copied from the protocol. 
The data from the HCP Perspective Questionnaires will be entered in a Vendor 
database and the data transferred to the Sponsor. 
4.5.8.3 
Description of Instruments for Assessments of Patient- and 
Health Care Professional−Reported Experience 
EORTC IL57 
The EORTC IL57 consists of three scales and a single item from the EORTC Item 
Library, for a total of 10 items (Aaronson et al. 1993; Kulis et al. 2018).  The EORTC 
IL57 physical functioning scale includes five items evaluating the extent to which patients 
have trouble doing strenuous activities; taking long walks; taking short walks; needing to 
stay in bed or a chair; and needing help with eating, dressing, bathing, or using the toilet.  
The EORTC IL57 role functioning scale includes two items evaluating the extent to 
which patients are limited in doing their work and pursuing their leisure activities in the 
previous week.  The EORTC IL57 global health status/quality of life (GHS/QoL) scale 
includes two items evaluating patients’ overall health and quality of life in the previous 
week.  The EORTC global impression of cancer treatment side effects burden item asks 
patients to rate how much they are bothered by treatment side effects.  A similarly 
worded item has been shown to be a valid and useful summary measure of overall 
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adverse event reporting (Pearman et al. 2018).  The item is rated on a 4-point Likert 
scale that ranges from “not at all” to “very much” and has a recall period of one week.  
The ten items in the EORTC IL57 (see Appendix 11) take approximately 5 minutes to 
complete.  
Cancer Therapy Satisfaction Questionnaire 
The CTSQ is a validated 16-item questionnaire measuring three domains related to 
patients’ satisfaction with cancer therapy:  expectations of therapy, feelings about side 
effects, and satisfaction with therapy (Abetz et al. 2005; Trask et al. 2008; Cheung et al. 
2016).  This study will utilize the modified SWT scale, which consists of seven items that 
are rated on a 5-point scale, with 1 representing the worst response and 5 representing 
the best response, except in the case of one reverse-scored item (see Appendix 12).  
The SWT scale takes approximately 5 minutes to complete. 
Health Care Professional Perspective Questionnaires 
The HCP Subcutaneous Perspective Questionnaire consists of five items evaluating the 
convenience, ease of administration and overall satisfaction with atezolizumab SC, as 
well as reasons for HCP-reported satisfaction or dissatisfaction (see Appendix 13).  The 
HCP SC versus IV Perspective Questionnaire consists of five items evaluating the 
convenience, potential time savings, and overall satisfaction with atezolizumab SC and 
atezolizumab IV, as well as reasons for HCP-reported satisfaction (see Appendix 14). 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
At any point in time and without reason, patients can withdraw their consent to 
discontinue treatment from the study. 
Patients must permanently discontinue study treatment (atezolizumab SC co-mix, 
atezolizumab IV, or atezolizumab SC) if they experience any of the following: 
• 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient's potential response to therapy and severity of the event 
• 
Any medical condition that may jeopardize the patient's safety if he or she continues 
study treatment 
• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• 
Use of another non-protocol anti-cancer therapy 
• 
Pregnancy 
• 
Loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 3.1.2 for details) 
 


 
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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  In Part 1 of the study, patients who discontinue study treatment 
prematurely may be replaced if they are not considered evaluable (see Section 6.2.1).  
In Part 2 of the study, patients who discontinue study treatment prematurely will not be 
replaced, with the exception of patients who withdraw prior to receiving the first dose. 
Patients will return to the clinic for a treatment discontinuation visit ≤ 30 days after the 
final dose of study treatment.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.  After treatment 
discontinuation, adverse events will continue to be recorded as outlined in the schedules 
of activities (see Appendix 1 and Appendix 2). 
In Part 2, patients who discontinue study treatment for any reason other than 
progressive disease or loss of clinical benefit are required to continue undergoing tumor 
response assessments as outlined in the schedule of activities (see Appendix 2).  After 
treatment discontinuation, information on survival follow-up and new anti-cancer therapy 
will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 2−3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study). 
4.6.2 
Patient Discontinuation from 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 withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
• 
Changes that result in failure to meet eligibility criteria (i.e., pregnancy) 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.   
If a patient requests to be withdrawn from the study, this request must be documented in 
the source documents and signed by the investigator.   
Patients who withdraw from Part 1 of the study may be replaced if they are not 
considered evaluable (see Section 6.2.1).  In Part 2, patients who withdraw may be 
replaced if withdrawal occurs before the first dose.  The decision to replace a withdrawn 
subject will be made at the discretion of the Sponsor depending on the overall number of 


 
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premature withdrawals.  In Part 2, no patient prematurely discontinued from the study, 
for any reason, after receiving at least a single dose of treatment, will 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 
• 
Development of atezolizumab SC formulation is discontinued 
• 
Following advice from the JMC or Health Authorities 
 
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 clinical experience with 
atezolizumab, and rHuPH20 in completed and ongoing studies.  The anticipated 
important safety risks are outlined below in Sections 5.1.1 and 5.1.2). 


 
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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 will be performed in 
a monitored setting in which there is immediate access to trained personnel and 
adequate equipment and medicine to manage potentially serious reactions.  Guidelines 
for managing patients who experience anticipated adverse events, including criteria for 
treatment interruption or discontinuation, are provided in Appendix 10.  Refer to 
Sections 5.2−5.7 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-γ (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. 
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, myositis, nephritis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis (HLH), including 
macrophage activation syndrome (MAS).  Refer to Appendix 10 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 rHuPH20 
rHuPH20 is administered with atezolizumab.  For more details regarding the safety 
profile of rHuPH20, refer to the rHuPH20 Investigator’s Brochure.  Refer to Appendix 10 
for adverse management guidelines for rHuPH20 administered with atezolizumab. 


 
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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 
in patients treated with atezolizumab are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of study treatment is suspected. 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
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• 
Hepatitis, including AST or ALT > 10 × ULN 
• 
Systemic lupus erythematosus 
• 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, hemophagocytic lymphohistiocytosis, and macrophage activation 
syndrome 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade ≥ 2 cardiac disorders 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
• 
Myelitis 
• 
Facial paresis 
 
5.2.4 
Selected Adverse Events  
Injection-Site Reactions 
With SC administration, local reactions at site of injection (erythema, pruritus, edema, 
rash, and pain) may occur.  In case of severe injection-site reactions, unscheduled 
photographs will be taken.  Photographs should include a label showing the subject’s 
identification number and initials, date and time of calendar date, and a centimeter ruler 
to provide scale.  Efforts will be made to standardize the photography with regard to 
parameters such as angle, light, distance from body, and settings. 
See Section 5.3.5.1 instructions on reporting injection-related reactions and 
infusion related reactions.  
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6.   
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   


 
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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the final dose of study treatment 
or until initiation of new systemic anti-cancer therapy, whichever occurs first. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 5 
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. 
 
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 5): 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable) 
• 
Known association of the event with study treatment or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment–related factors that are known to be associated with the 
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Table 6 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions, Injection-Related Reactions, and 
Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of infusion-related 
reactions/injection-related reactions and CRS.  While infusion-related 
reactions/injection-related reactions 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 or injection should be captured 
on the Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction", 
“injection-related reaction”, or "cytokine-release syndrome").  If possible, 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 


 
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and symptoms of an infusion-related reaction/injection-related reaction should be 
recorded on the dedicated Infusion-Related Reaction and Injection-Related Reaction 
eCRF. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms of an of an infusion-related 
reaction/injection-related reaction also recorded separately on the dedicated 
Infusion-Related Reaction or Injection-Related Reaction eCRF. 
In recognition of the challenges in clinically distinguishing between these two events, 
consolidated guidelines for medical management of infusion-related 
reactions/injection-related reactions and CRS are provided in Appendix 10. 
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  
 
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. 


 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with 
a descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which  ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
In Part 2 of the study, duration of survival is a secondary efficacy endpoint.  Deaths that 
occur during the protocol-specified adverse event reporting period (see Section 5.3.1) 
that are attributed by the investigator solely to progression of NSCLC should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other 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). In Part 1, an IMC will monitor the frequency of deaths 
from all causes.  In Part 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 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of NSCLC 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 criteria.  In rare cases, the determination of 


 
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clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
Hospitalization due solely to progression of the underlying cancer 
 
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 
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 


 
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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 SC co-mix, atezolizumab SC, atezolizumab 
IV, and rHuPH20, adverse events associated with special situations should be recorded 
as described below for each situation: 
• 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with atezolizumab SC co-mix, atezolizumab 
SC, atezolizumab IV, and rHuPH20, regardless of whether they result in an adverse 
event, should be recorded on the Adverse Event eCRF and reported to the Sponsor 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 the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor.  Sites are not 
expected to review the PRO data for adverse events. 


 
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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) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites  
Medical Monitor: 
, M.D. 
(Primary) 
Telephone No.: 
Mobile Telephone No.: 
 
Medical Monitor: 
, M.D. (Secondary) 
Telephone No.: 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 


 
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7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
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 and adverse events of special 
interest will be reported until 90 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the 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 or 
within 5 months after the last dose of atezolizumab.  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 


 
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events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.   
5.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).   
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 


 
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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 
In both Part 1 and Part 2, 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. 
In Part 2, after the end of the reporting period for serious adverse events and adverse 
events of special interest (defined as 90 days after the final dose of study treatment or 
until initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.   
If a non-serious-related adverse event becomes serious after the reporting period, this 
should be reported as per the serious adverse event reporting process. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Atezolizumab Investigator's Brochure  
• 
rHuPH20 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. 


 
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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The global population will include all patients randomized during the global enrollment 
phase of Part 2 (including patients randomized at qualified sites in China during that 
phase), whereas the China subpopulation will include all patients randomized at qualified 
sites.  Separate analyses may be performed for the China subpopulation (see 
Section 6.15 for information on the China subpopulation analyses). 
6.1 
ANALYSIS TIMING 
The data in Part 1 of the study will be analyzed on an ongoing basis in order to inform 
the dose selection for subsequent cohorts, and for Part 2. 
In Part 2, the analysis of the co-primary endpoints, Cycle 1 observed serum Ctrough 
(predose Cycle 2) and model-predicted AUC0–21 d, will be performed when the planned 
number of patients has been randomized and the last required data point has been 
reported.  The cutoff for the primary analysis will therefore be approximately one month 
after randomizing the last patient in Part 2.  Analyses of available data on secondary and 
exploratory endpoints up to this time point will also be presented.  
After that, patients will continue to be followed until the end of the study, approximately 
33 months after randomizing the last patient, or when all patients have discontinued from 
the study, whichever occurs first.  An additional analysis will be performed afterwards to 
evaluate the longer-term efficacy and safety data for atezolizumab SC.  
6.2 
ANALYSIS POPULATIONS  
6.2.1 
Part 1:  Dose Finding 
PK analyses of Part 1 will be performed on data from all PK-evaluable patients enrolled 
in Part 1.  A PK-evaluable patient is defined as one who has received at least one dose 
of atezolizumab (atezolizumab SC co-mix, atezolizumab SC, or atezolizumab IV) and 
has at least one evaluable postdose PK sample and who does not have protocol 
deviations that could affect PK results. 
Specific criteria for exclusion from the primary analysis will be defined prior to the 
analysis and documented in the Statistical Analysis Plan. 
The Part 1 safety analysis population is defined as all patients who received at least one 
dose of atezolizumab (atezolizumab SC co-mix, atezolizumab SC, or atezolizumab IV). 


 
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6.2.2 
Part 2:  Dose Confirmation 
The primary analysis will be performed in the Per Protocol PK analysis population.  This 
population will include patients in the atezolizumab SC and atezolizumab IV treatment 
arms who do not have protocol deviations that could affect PK results. 
Patients will be excluded from the Per Protocol PK analysis population if they 
significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete, where the PK analysis might be 
influenced.   
Reasons for exclusion from the analysis may include, but are not limited to, lack of the 
Cycle 1 Ctrough (predose Cycle 2) PK sample, a Ctrough sample collected outside the 
pre-specified window, administration of a dose amount that significantly deviates from 
the planned dose, a dose delay of more than 7 days, use of an injection site other than 
the thigh, use of expired or quarantined study treatment, or duplicate times of collection 
for the Cycle 1 Ctrough sample.  Excluded cases will be documented, including the reason 
for exclusion.  Specific criteria for exclusion from the primary analysis will be defined 
prior to database closure and documented in the Statistical Analysis Plan. 
Efficacy analyses of OS and PFS will be performed in the Full Analysis Set (FAS), 
defined as all patients who were randomized in Part 2, with patients grouped according 
to their assigned treatment.  ORR and DOR will be assessed in patients in the 
subpopulation of FAS with measurable disease at baseline.  Patients who do not receive 
the intended treatment (i.e., treatment assigned per randomization) will be grouped 
according to their assigned treatment. 
The safety analysis population in Part 2 is defined as all patients who received at least 
one dose of any amount of any component of protocol treatment, with patients grouped 
according to treatment received.  
6.2.3 
Immunogenicity Analyses 
Immunogenicity analyses will be performed on the post-treatment ADA-evaluable 
analysis population, defined as patients who have received at least one dose of protocol 
treatment and have at least one post-treatment ADA result. 
6.3 
STATISTICAL HYPOTHESIS AND PLANNED SAMPLE SIZE 
6.3.1 
Part 1:  Dose Finding 
The primary objective for Part 1 is to determine the dose of atezolizumab that, when 
given subcutaneously, would result in a comparable exposure, in terms of serum Ctrough, 
to atezolizumab IV.  
The sample size for Part 1 was determined by using simulation methods.  Cohorts 1 
and 2 are planned to enroll approximately 12 eligible patients each and Cohort 3 is 
planned to enroll approximately 20−30 eligible patients for a total of approximately 


 
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60 patients in Part 1.  Based on the known PK profile of atezolizumab IV, such a sample 
size should allow estimation of the PK parameters with sufficient precision.  
6.3.2 
Part 2:  Dose Confirmation 
The primary objective of Part 2 is to demonstrate non-inferiority of the PK of 
atezolizumab SC compared with atezolizumab IV on the basis of two co-primary 
endpoints, Cycle 1 observed serum Ctrough (predose Cycle 2) and model-predicted 
AUC0-21 d.  
A statistical hypothesis test will be performed on the GMR of Ctrough following SC 
administration (Ctrough,SC) to Ctrough following IV administration (Ctrough,IV), both values taken 
from data observed in Cycle 1:  Ctrough,SC/Ctrough,IV.  
The null and alternative hypotheses will be as follows: 
• 
H0:  The SC dose is inferior to the IV dose with a non-inferiority margin of 0.8 
(i.e., the GMR Ctrough,SC/Ctrough,IV is less than 0.8), versus 
• 
H1:  The SC dose is non-inferior to the IV dose (i.e., the GMR Ctrough,SC/Ctrough,IV is 
equal or greater than 0.8). 
 
Model-predicted AUC0–21 d in Cycle 1 is the other co-primary endpoint used for the 
primary objective of Part 2.  The model-predicted AUC in Cycle 1 after atezolizumab SC 
administration will be compared with the model-predicted AUC0–21 d in Cycle 1 after IV 
administration. 
A statistical hypothesis test will be performed on the GMR of AUC0–21 d following SC 
administration (AUC0–21 d,SC) to AUC0–21 d following IV administration (AUC0–21 d,IV), both 
values taken from data predicted in Cycle 1:  AUC0–21 d, SC /AUC0–21 d, IV.  
The null and alternative hypotheses will be as follows: 
• 
H0:  The SC dose is inferior to the IV dose with a non-inferiority margin of 0.8 
(i.e., the GMR AUC0–21 d, SC /AUC0–21 d, IV is less than 0.8), versus 
• 
H1:  The SC dose is non-inferior to the IV dose 
(i.e., the GMR AUC0–21 d, SC/AUC0−21 d, IV is equal to or greater than 0.8). 
 
Cycle 1 observed serum Ctrough (predose Cycle 2) and model-predicted AUC0–21 d will be 
tested using the Hochberg procedure (Hochberg and Tamhane 1987; FDA 2017).  In 
Step 1 of this procedure, if the lower bound of the 90% CI for the GMR Ctrough,SC/Ctrough,IV 
and the GMR AUC0–21 d, SC/AUC0–21 d, IV are ≥ 0.8, both null hypotheses will be rejected.  In 
this case it will be concluded that SC administration is non-inferior to IV administration in 
terms of Ctrough and AUC in Cycle 1.  
If in Step 1 the null hypotheses are not rejected, the procedure continues to Step 2.  
In Step 2, if the 95% CI for one GMR (i.e., either Ctrough,SC/Ctrough,IV or 
AUC0–21 d, SC/AUC0−21 d, IV) is ≥ 0.8, the corresponding null hypothesis will be rejected.  In 


 
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this case, it will be concluded that SC administration is non-inferior to IV administration in 
terms of Ctrough or AUC in Cycle 1. 
A total of 327 patients are planned to be randomized in Part 2 of the study.  This sample 
size will provide sufficient power for the statistical hypothesis test for the primary 
endpoint, based on the following assumptions: 
• 
2:1 randomization ratio 
• 
True GMR ≥ 0.95 for Cycle 1 Ctrough 
• 
True GMR ≥ 0.95 for Cycle 1 AUC0–21 d 
• 
One-sided significance level 0.05  
• 
Coefficient of variation (CV%) of geometric mean Ctrough in Cycle 1 is < 55%; this 
value is based on the results observed after atezolizumab SC co-mix administration 
in Part 1 of the study (CCOD 10 March 2020) 
• 
CV% of geometric mean Cycle 1 AUC0–21 d is < 45%; this value is based on the 
results observed after atezolizumab SC co-mix administration in Part 1 of the study 
(CCOD 10 March 2020) 
• 
Positive correlation between Cycle 1 AUC0–21 d  and Cycle 1 Ctrough > 0.8; this value is 
based on the results observed after atezolizumab SC co-mix administration in Part 1 
of the study (CCOD 10 March 2020) 
 
Under these assumptions, a sample size of ≥ 261 PK-evaluable patients in the 
atezolizumab SC and atezolizumab IV arms would provide at least 80% power to 
conclude non-inferiority of Cycle 1 Ctrough,SC and AUC0–21 d, SC with a non-inferiority margin 
of 0.8 for the GMR, or more concisely: Ctrough,SC > 0.8 Ctrough,IV and 
AUC0-21 d, SC > 0.8 AUC0−21 d, IV (see Table 7).  It is expected that up to 20% of randomized 
patients will need to be excluded from the Per Protocol PK population.  The total number 
of 327 patients was chosen in order to ensure the Per Protocol PK population will be 
large enough to meet the primary study objective and to assess comparable safety and 
efficacy data.  
The total number of patients to be enrolled in Part 2 of the study may be increased or 
decreased, after taking into account the actually observed PK variability during the 
blinded sample-size re-estimation (once approximately 210−250 patients have been 
randomized).  For example, for a coefficient of variation of 70% for Cycle 1 Ctrough, the 
number of patients enrolled in Part 2 would be increased to 477 in order to ensure 
sufficient power for the non-inferiority test (see Table 7).   


 
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Table 7 
Statistical Power of Test of Non-Inferiority of Ctrough and AUC0–21 d 
Coefficient of 
Variation for 
Cycle 1 Ctrough 
PK-Evaluable 
Patients 
Probability to reject the null hypothesis 
for both co-primary endpoints 
Estimated Required 
Randomized Patients 
a  
50% 
234 
80% 
293 
55% 
261 
80% 
327 
60% 
297 
80% 
372 
65% 
336 
80% 
420 
70% 
381 
80% 
477 
a Assuming up to 20% not PK-evaluable. 
 
6.4 
SUMMARIES OF CONDUCT OF STUDY 
For both parts of the study, the numbers of patients who enroll or are randomized in the 
study, discontinue from the study, or complete the study will be summarized separately 
for each part.  Reasons for patient discontinuations from the study treatment and from 
the study will be presented in listings and summary tables.  Protocol deviations will be 
evaluated for their potential effects on the interpretation of study results, and reasons for 
exclusion of patients from the analyses will be presented. 
6.5 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Baseline will be defined as the last available assessment prior to study entry.  Study 
entry is defined as either the day of the first dose of study treatment, or, for patients who 
were not dosed, the date they were enrolled into the study according to the IxRS. 
6.5.1 
Part 1:  Dose Finding 
Demographic and baseline disease characteristics will be summarized by treatment 
cohort using descriptive statistics (e.g., means, standard deviations, medians, and 
ranges for continuous variables, and proportions for categorical variables, as 
appropriate).  A demographic listing will also be provided.  
The analyses will be performed in all enrolled patients in Part 1 and for the PK-evaluable 
population.  
6.5.2 
Part 2:  Dose Confirmation 
Demographic and baseline disease characteristics will be summarized using descriptive 
statistics (e.g., means, standard deviations, medians, and ranges for continuous 
variables, and proportions for categorical variables, as appropriate) by treatment arm.  
A demographic listing will also be provided.  These analyses will be performed in the 
FAS and the Per Protocol PK analysis population.  
The safety analyses will be performed in the safety population. 


 
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6.6 
ANALYSES OF PRIMARY ENDPOINT 
6.6.1 
Part 1:  Dose Finding 
Pharmacokinetics of atezolizumab will be characterized following administration of 
atezolizumab SC co-mix or atezolizumab SC.  Modeling of the PK data will be performed 
using a population approach with combined SC and IV data from Part 1 of the study to 
characterize the absorption phase of the SC route of administration.  The existing 
population PK model developed on data from study PCD4989g will be used as a basis.  
Individual exposure metrics (i.e., Ctrough and AUC at Cycle 1) will be derived from the final 
PK model. 
Model-based simulations may be performed to predict Cycle 1 Ctrough (predose Cycle 2) 
in Part 2 of the study to select the atezolizumab SC dose that will yield a mean SC Ctrough 
non-inferior to that following atezolizumab IV administration. 
6.6.2 
Part 2:  Dose Confirmation 
One of the co-primary endpoints is the observed serum Ctrough in Cycle 1. 
The primary analysis of Ctrough will be based on logarithmic values of observed Ctrough in 
Cycle 1 to compensate the known skewness of its distribution.  For natural logarithm 
(Ln) (Ctrough), the statistical hypothesis will be tested using an analysis of covariance 
model  
Ln(Ctrough)ij = µ + τi + εij     (i=SC, IV; j=1, 2, …, ni) 
where µ denotes the overall mean, τi the effect of atezolizumab route of administration i 
(SC or IV), ni the number of patients in arm i (SC or IV), and εij a random error variable 
assumed to be independently and identically normally distributed with mean zero and 
variance σε2. 
The contrast τSC – τIV, its 90% confidence limits, and the variance σε2 will be estimated 
from the model.  An estimate of the treatment effects ratio and the corresponding 90% 
confidence limits for the untransformed variables will be calculated by exponentiation of 
the estimate of contrast τSC – τIV and the 90% confidence limits.  The CV for the 
untransformed primary variable will be estimated using the relationship 
CVε = sqrt(exp(σε2)-1).  
If the lower confidence interval bound of exp(Ln[Ctrough,SC]-Ln[Ctrough,IV])=Ctrough,SC/Ctrough,IV 
is equal or greater than 0.8, then the null hypothesis can be rejected (see Section 6.3.2).  
The estimand for the primary analysis follows a principal stratum strategy based on the 
following attributes: 
• 
Treatment:  atezolizumab IV versus atezolizumab SC, at the determined dose at 
baseline.  All randomized patients are expected to receive the baseline infusion or 
injection.  


 
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• 
Population:  Patients with locally advanced or metastatic patients NSCLC who are 
CIT-naive and for whom prior platinum therapy has failed.  The analysis population 
will consist of the Per Protocol PK analysis population, with patients grouped 
according to their received treatment (see Section 6.2.2). 
• 
Variable:  The Cycle 1 observed serum Ctrough (predose Cycle 2), using the 
measured concentration from the PK sample. 
• 
Intercurrent events, handled as follows: 
Premature discontinuation from treatment:  every effort will be made to ensure 
all randomized patients will receive the treatment at baseline and will have the 
PK sample collected appropriately.  Treatment will start within 5 days of 
randomization.  Withdrawal after randomization, prior to baseline treatment is 
not expected.  In case of such an event, those patients are excluded from the 
analysis population and those patients will not be replaced, as outlined in 
Section 4.6.2. 
Premature discontinuation from study:  Some patients could discontinue the 
study prior to the time point of predose Cycle 2 due to death or other reasons.  
Considering the short interval between randomization and Cycle 2, this situation 
is expected to be exceptional.  Those patients are excluded from the 
population. 
Missing or outside of window PK samples:  Some patients could have a Cycle 1 
Ctrough PK sample missing or outside of the accepted window, due to early 
withdrawal or other reasons.  Every effort will be made to collect PK samples on 
schedule.  Those patients are excluded from the analysis population.  
• 
Summary measure:  GMR and 90% CI of atezolizumab SC versus atezolizumab IV 
of Cycle 1 Ctrough.  The non-interiority would be established if the lower bound of the 
90% CI is ≥ 0.8. 
Supplementary analyses may be conducted to assess any potential impact of 
imbalances in baseline characteristics between treatment arms.  In addition to the 
analysis of observed serum Ctrough values, the same statistical hypothesis test for non-
inferiority will be performed descriptively using Cycle 1 Ctrough values derived from the 
population PK model.  For each patient, individual empirical Bayesian estimates of PK 
parameters will be used to compute the model-predicted Ctrough at Cycle 1.  The aim of 
using predicted Ctrough is to take into account possible deviations from the protocol (i.e., 
sampling schedule or dosing interval) and to reduce noise (i.e., precision of analytical 
measurement).  The Cycle 1 Ctrough values derived from the PK model is a different 
estimand with respect to the observed serum Ctrough; the treatment, population and 
summary measure have the same definition as the primary endpoint.  The intercurrent 
events will be handled using the same strategies as the model-predicted Cycle 1 AUC. 
The model-predicted Cycle 1 AUC0–21 d is a co-primary endpoint and will be analyzed 
using the same method as for the other co-primary endpoint, Cycle 1 observed serum 
Ctrough. 


 
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The estimand for this co-primary analysis follows a principal stratum and treatment 
policy strategy based on the following attributes: 
• 
Treatment:  same as for co-primary endpoint Cycle 1 observed serum Ctrough 
• 
Population:   Patients with locally advanced or metastatic NSCLC who are CIT-naïve 
and for whom prior platinum therapy has failed.  The analysis population for the 
pharmacokinetic analysis set will consist of the population pharmacokinetic analysis 
set, with patients grouped according to their received treatments.  
• 
Variable:  model-predicted Cycle 1 AUC0–21 d, derived from the popPK model.  
• 
Intercurrent events, handled as follows: 
Premature discontinuation from treatment:  same as for the other co-primary 
endpoint  
Premature discontinuation from study:  Some patients could discontinue the 
study following their Cycle 1 dose prior to providing a post-baseline PK blood 
sample or PK blood samples could not be collected.  Considering the short 
interval between the first study drug treatment (Cycle 1) and the first PK blood 
sample (8 ± 2 hours) as well as the numerous PK blood samples collected on 
study, these situations are expected to be exceptional.  Those patients are 
excluded from the analysis population. 
Missing or inaccurate time and date reported for treatment administration or PK 
blood samples:  Some patients could be missing some scheduled PK samples, 
or have PK samples collected outside of the schedule, due to early withdrawal 
or other reasons.  Every effort will be made to ensure that all randomized 
patients will receive the treatment and will have the time and date of dosing and 
PK blood samples reported accurately.  Missing or inaccurate dosing time and 
date can occur during any cycle however, it is very rare.  In case of such an 
event, only such affected samples are excluded and patients are retained as 
long as they have a single reportable dose and corresponding PK sample, 
regardless of the cycle. 
• 
Summary measure:  GMR and 90% CI of atezolizumab SC versus atezolizumab IV 
of Cycle 1 AUC.  The non-interiority would be established if the lower end of the 
90% CI is ≥ 0.8. 
 
The co-primary endpoints will be statistically tested at the same α level (one-sided 
significance level of 0.05) using the Hochberg procedure as described in Section 6.3.2. 
6.7 
SECONDARY AND EXPLORATORY PHARMACOKINETIC 
ANALYSES 
6.7.1 
Part 1:  Dose Finding 
Concentration versus time data will be tabulated and plotted by cohort.  PK parameters 
(e.g., Ctrough, AUC, Cmax, Tmax) will be presented in summary tables with descriptive 
summary statistics by cohort.  Patient listings will be provided.  
Additional PK analyses may be conducted as appropriate. 


 
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6.7.2 
Part 2:  Dose Confirmation 
Model-predicted Cycle 1 (Ctrough only) and steady state Ctrough and AUC will be 
descriptively compared between atezolizumab SC and IV. 
Other PK data will be analyzed using statistical summary measures, listings, and graphs 
as appropriate. 
Exploratory exposure−response analyses may be performed to link atezolizumab 
exposure (e.g., Ctrough, Cmax, and AUC Cycle 1) to safety (Grade 3−5 adverse events, 
adverse events of special interest) and efficacy (ORR and OS) endpoints.  These 
analyses may be reported separately from the CSR. 
6.8 
EFFICACY ANALYSES 
Efficacy analyses will be performed for Part 2 of the study only. 
6.8.1 
Objective Response Rate 
ORR is a secondary endpoint and is defined as the proportion of patients with a PR or 
CR as determined by the investigator according to RECIST v1.1.  
The ORR and 95% confidence intervals according to Pearson-Clopper will be calculated 
and presented by treatment arm.  For the difference in response rates, 95% two-sided 
CIs (Hauck-Andersen) will be calculated. 
The estimand corresponding to this secondary endpoint will be defined in the Statistical 
Analysis Plan. 
The planned sample size in Part 2 is 218 patients in the atezolizumab SC group.  The 
table below summarizes the resulting 95% CI for the ORR, assuming it will be in the 
range of 10%−15%. 
Analyses of ORR will be performed both at the time of the primary analysis of Ctrough and 
at the end of the study.  The latter time point is expected to provide a better estimate 
because of the longer follow-up.  
Table 8 
95% Confidence Interval for ORR in Atezolizumab SC Group 
Number of Responders 
ORR 
95% Confidence Interval 
22 
10.1% 
[6.43 to 14.88] 
29 
13.3% 
[9.09 to 18.54] 
33 
15.1% 
[10.65 to 20.60] 
Table shows the Pearson-Clopper 95% CI for a given observed ORR in 218 patients dosed with 
atezolizumab SC. 
  


 
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6.8.2 
Progression-Free Survival 
The duration of PFS is defined as the time from the date of study entry to the date of 
documented disease progression, as determined by the investigator according to 
RECIST v1.1, or death from any cause, whichever is earlier.  
Patients who have not progressed at the time of the analysis will be censored at the last 
available tumor assessment.  Patients without post-baseline tumor assessment will be 
censored on the date of study entry + one day. 
The estimand corresponding to this secondary endpoint will be defined in the Statistical 
Analysis Plan. 
PFS will be analyzed using Kaplan-Meier methodology, including survival plots, median 
duration and corresponding 95% confidence intervals according to the 
Brookmeyer-Crowley method.  The proportion of patients who are PFS event-free at 
6 and 12 months after study entry will be estimated at the final analysis of the study 
when sufficient follow-up data are available.  The corresponding 95% CI will be 
calculated using the standard error derived from Greenwood’s formula.  
Additional sensitivity analyses of PFS may be conducted as appropriate in order to 
investigate the effect of baseline characteristics on the result.  
6.8.3 
Overall Survival 
The duration of OS is defined as the time from the date of study randomization to the 
date of death from any cause.  
Patients without a death record will be censored at the last date they were known to be 
alive.  Patients with no post-baseline information will be censored on the day of study 
entry +1 day. 
The estimand corresponding to this secondary endpoint will be defined in the Statistical 
Analysis Plan. 
OS will be analyzed using Kaplan-Meier methodology, including survival plots, median 
duration and corresponding 95% confidence intervals according to the 
Brookmeyer-Crowley method.  The proportion of patients alive at one and two years will 
be estimated at the final analysis of the study when sufficient follow-up data are 
available.  The corresponding 95% CI will be calculated using the standard error derived 
from Greenwood’s formula. 
Additional sensitivity analyses of OS may be conducted as appropriate in order to 
investigate the effect of baseline characteristics on the result. 


 
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6.8.4 
Duration of Response 
DOR will be assessed in the subpopulation of FAS patients who had measurable 
disease at baseline and who achieved an objective response as determined by the 
investigator according to RECIST v1.1.  DOR is defined as the time interval from the 
date of the first occurrence of a complete or partial response (whichever status is 
recorded first) until the first date that progressive disease or death is documented, 
whichever occurs first.  Patients who have not progressed and who have not died at the 
time of analysis will be censored at the time of last tumor assessment date.  If no tumor 
assessments were performed after the date of the first occurrence of a complete or 
partial response, DOR will be censored at the date of the first occurrence of a complete 
or partial response plus 1 day.   
The estimand corresponding to this secondary endpoint will be defined in the Statistical 
Analysis Plan. 
DOR is based on a non-randomized subset of patients (specifically, patients who 
achieved an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between treatment arms will be made for 
descriptive purposes.  The methodologies detailed for the PFS analysis will be used for 
the DOR analysis.  
6.9 
SAFETY ANALYSES 
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  Laboratory toxicities will be defined based on local 
laboratory normal ranges and NCI CTCAE, v5.0. 
6.9.1 
Part 1:  Dose Finding 
For safety-evaluable patients, data on study drug administration and dose modifications 
will be presented as descriptive summary statistics or listings by cohort and by route of 
administration as appropriate.  All adverse events occurring on or after the first dose of 
study medication will be summarized by treatment cohorts.  Analyses will also be 
performed by NCI CTCAE grade.  In addition, serious adverse events, Grade 5 adverse 
events, Grade 3-4 adverse events, adverse events of special interest, and adverse 
events leading to study drug discontinuation will be presented in summary tables and 
listings.  
Deaths reported during study treatment and during the follow-up period (see 
Section 5.4.2) will be reported by treatment cohort. 
Data on safety laboratory test values and vital signs will be presented by treatment 
cohort and grade, including shift tables and analyses of change from baseline as 
appropriate.  


 
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6.9.2 
Part 2:  Dose Confirmation 
The safety analysis population in Part 2 is defined as all patients who received at least 
one dose of any amount of any component of protocol treatment, with patients grouped 
according to treatment received.  All adverse events, deaths due to adverse events, 
serious adverse events, Grade 3−4 adverse events, adverse events of special interest, 
and adverse events leading to study drug discontinuation that occur on or after the first 
dose of study treatment (i.e., treatment-emergent adverse events) will be summarized by 
mapped term, appropriate thesaurus level, and severity grade.  
A summary and listing of deaths reported during Part 2 of the study (see Sections 5.4.2 
and 5.6) will be provided. 
Data on safety laboratory test values and vital signs will be presented by treatment 
received and grade, including shift tables and analyses of change from baseline as 
appropriate.  
6.10 
SUBGROUP ANALYSES 
In Part 1, there will be no prespecified subgroup analyses.  In Part 2, data on secondary 
endpoints may be analyzed in patient subgroups by, e.g., demographic or baseline 
prognostic characteristics.  These analyses will be performed in an exploratory manner.  
6.11 
IMMUNOGENICITY ANALYSES 
The atezolizumab and rHuPH20 immunogenicity analysis population will consist of all 
patients with at least one ADA assessment.  Patients will be grouped according to 
treatment received. 
The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized for ADA-evaluable patients.  When determining post-baseline 
incidence, patients are considered to be ADA-positive if they are ADA-negative or have 
missing data at baseline but develop an ADA response following study drug exposure 
(treatment–induced ADA response), or if they are ADA-positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Patients are considered to 
be post-treatment ADA-negative if they are ADA-negative or have missing data at 
baseline and all post-baseline samples are negative, or if they are ADA-positive at 
baseline but do not have any post-baseline samples with a titer that is at least 0.60 titer 
unit greater than the titer of the baseline sample (treatment unaffected). 
Demographic and baseline characteristics in ADA-evaluable patients will be summarized 
by treatment arm (as appropriate).  The numbers and proportions of ADA-positive 
patients and ADA-negative patients at baseline (baseline prevalence) and after drug 
administration (post-baseline incidence) will be summarized for both atezolizumab and 
rHuPH20. 


 
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In Part 2, additional analyses may investigate the relationship between atezolizumab 
and rHuPH20 ADA status and safety, efficacy, and PK endpoints via descriptive 
statistics if appropriate. 
6.12 
BIOMARKER ANALYSES 
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.  
6.13 
PATIENT- AND HEALTH CARE PROFESSIONAL−REPORTED 
EXPERIENCE ANALYSES 
Patient- and HCP-reported experience analyses will be performed for Part 2 of the study 
only.  
Descriptive analyses, including summary statistics, will be performed and presented by 
treatment arm for each patient-reported experience measure (item- and scale-level, as 
appropriate).  Item-level analyses will include frequencies and proportions and change 
from baseline at each visit by treatment arm.  Summary statistics (e.g., mean, median, 
minimum, maximum, interquartile range) of scale scores and score changes from 
baseline at each visit will be evaluated by treatment arm. 
For each of the EORTC scales, a prorated scale score will be calculated if 50% or more 
of the constituent items in the scale are completed.  The scale score will be considered 
missing if < 50% of the constituent items were not completed.  A SWT scale score will be 
calculated if five or more items have been completed (out of seven).  The scale score 
will be considered missing if fewer than five items have been completed. 
For the HCP-reported experience data, descriptive summaries for each item will be 
presented by country or region and by other categories as appropriate for all HCPs who 
completed at least one question in a questionnaire. 
6.14 
INTERIM ANALYSIS 
No formal interim statistical analysis is planned in the study.  
During Part 1, PK data will be analyzed on an ongoing basis.  In addition, data will be 
reviewed by an IMC at regular intervals as outlined in Section 3.1.3.1 and the IMC 
charter.  All required analyses will be performed by the study team and provided to the 
IMC.  Any outcomes of these safety reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the IRBs/ECs.  
During Part 2, a JMC will be set up to evaluate PK and safety data on an ongoing basis 
as outlined in Section 3.1.3.2 and the JMC charter.  All analyses for this review will be 
prepared by the study team, who will maintain the blind of treatment allocation.  


 
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A review of PK and safety data from the first 24 patients (approximately 16 patients in 
the atezolizumab SC arm and approximately 8 patients in the atezolizumab IV arm) who 
have completed at least one cycle of treatment will also be conducted 
(see Section 3.1.1.2).  These analyses will be blinded while recruitment into Part 2 
continues. 
Any outcomes of these PK and safety reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of the IRBs/ECs. 
A blinded sample-size re-estimation will be conducted after approximately 
210−250 patients have been randomized.  A blinded estimation of the total CV% from all 
available Cycle 1 Ctrough and Cycle 1 AUC data will be compared with the CV% used in 
the calculation of sample size.  Depending on the total observed CV%, the Sponsor may 
decide to increase or decrease the number of patients randomized. 
6.15 
CHINA SUBPOPULATION ANALYSES 
The China subpopulation will include all patients randomized at qualified sites.  
The analyses for the China subpopulation will be performed in a similar way as done for 
the global population or summarized descriptively as appropriate.  Results from these 
analyses will be summarized in a separate Report.  Further details will be provided in the 
Statistical Analysis Plan.  
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, IxRS data, and any 
other externally generated electronic study 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. 
Data from the PROs will be entered directly in the eCRF and data from the HCPs will be 
entered into a Vendor database and the data transferred to the Sponsor. 


 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in 
a readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
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 


 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
The Sponsor will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form will be provided to each site.  
If applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 


 
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IRB/EC−approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to 
a significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (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 


 
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Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 


 
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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 may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  
In addition, redacted clinical study reports and other summary reports will be provided 
upon request. 
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.  The 


 
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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.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Up to approximately 150 sites globally will participate to enroll approximately 
327 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. 
An IMC and a JMC will be employed to monitor and evaluate patient safety throughout 
the study (see Section 3.1.3). 
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 health care 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 other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  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/ 


 
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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
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). 


 
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10. 
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Appendix 1  
Schedule of Activities: Part 1 
Assessment  
Screening a 
All Cycles 
Treatment Discontinuation b 
Safety 
Follow-Up c 
Days –28 
to –1 
Day 1 (± 3 Days for Cycles > 2) 
≤ 30 Days after Last Dose 
Up to 90 
Days after 
Last Dose 
Signed Informed Consent Form d 
x 
 
 
 
Review of eligibility criteria 
x 
 
 
 
Medical, surgical, and cancer histories, 
including demographic information, EGFR, and 
ALK mutational status e 
x 
 
 
 
HIV, HBV, HCV serology f 
x 
 
 
 
Concomitant medications g 
x 
x 
x 
 
Complete physical examination h 
x 
 
 
 
Limited physical examination i 
 
x 
x 
 
ECOG performance status j 
x 
x 
x 
 
Vital signs k 
x 
x 
x 
 
12-lead electrocardiogram l 
x 
(x) 
(x) 
 
Echocardiogram m 
x 
(x) 
 
 
Weight 
x 
x 
x 
 


Appendix 1: Schedule of Activities for Part 1 (cont.) 
  
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122/Protocol BP40657, Version 7 
Assessment  
Screening a 
All Cycles 
Treatment Discontinuation b 
Safety 
Follow-Up c 
Days –28 
to –1 a 
Day 1 (± 3 Days for Cycles > 2) 
≤ 30 Days after Last Dose 
 Up to 
90 Days 
after Last 
Dose 
Height 
x 
 
 
 
Hematology n 
x 
x  
x 
 
Serum chemistry o 
x 
x 
x 
 
Coagulation panel (aPTT, INR) p 
x 
 
x 
 
C-reactive protein sample (central laboratory) q 
x 
x 
 
 
Urinalysis r 
x 
x 
x 
 
Pregnancy test s 
x 
x 
 
 
TSH, free T3, free T4 
x 
 
x 
 
Serum and plasma samples for PK and ADA 
assessment (central laboratory) t 
 
x 
x 
 
Adverse events c, u 
 
 
Atezolizumab SC co-mix, atezolizumab SC 
injection, or atezolizumab IV infusion v 
 
x 
 
 
Tumor assessment w 
x 
 
 
 
ADA = anti-drug antibody; ALK = anaplastic lymphoma kinase; anti-HBc= antibody against hepatitis B core antigen; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; HBsAG = hepatitis B surface antigen; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IV = intravenous; PD-L1 = programmed death−ligand 1; PK = pharmacokinetic; 
SC = subcutaneous; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. 


Appendix 1: Schedule of Activities for Part 1 (cont.) 
  
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123/Protocol BP40657, Version 7 
Notes:  Assessments in parentheses are optional or as clinically indicated.  Assessments scheduled on the days of study treatment 
injection/infusions should be performed before the injection/infusion unless otherwise noted. 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to study entry (except 
where otherwise specified) may be used for screening assessments rather than repeating such tests.  
b Patients will be asked to return to the clinic not more than 30 days after the last dose of treatment for a treatment discontinuation visit. 
c All adverse events will be reported until 30 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special interest will continue to be reported until 90 days after the final 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  In addition, the Sponsor should be notified 
if the investigator becomes aware of any study treatment–related serious adverse event (see Section 5.6).  
d Written informed consent is required prior to performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur 
before the 28-day screening period.   
e Cancer history includes stage, date of diagnosis, results of EGFR mutation and ALK rearrangement testing (if available), and prior anti-tumor 
treatment.  EGFR and/or ALK may be provided only if already available.  Demographic information includes sex, age, and self-reported 
race/ethnicity.  
f All patients will be tested for HIV prior to inclusion into the study; HIV-positive patients will be excluded from the study.  HBV DNA must be 
collected on or before Cycle 1, Day 1 in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.  
Patients with active hepatitis B (chronic or acute; defined as having a positive HBsAg test result at screening) will be excluded from the study.  
Patients with past or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible only if their HBV DNA test is 
negative.  Patients with HCV will be excluded from the study; patients who test positive for HCV antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
g Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to the screening visit should be documented.  At subsequent visits, changes to current medications or medications 
used since the last documentation of medications will be recorded.  
h Complete physical examinations are defined in Section 4.5.3.  
I Limited physical examinations are defined in Section 4.5.3.  Limited physical examinations may be obtained ≤ 4 days before Day 1 of each cycle. 
j ECOG performance status may be obtained ≤ 4 days before Day 1 of each cycle. 
k Vital signs include pulse rate, respiratory rate, blood pressure, and temperature.  At all administrations, vital signs should be determined within 
60 minutes before and 30 (± 10) minutes after the administration (before any PK sample scheduled to be drawn at the same time) and as 
clinically indicated.  Refer to Section 4.3.2.   
l 
ECG recordings will be obtained during screening and when clinically indicated.  Patients should be resting and in a supine position for at least 
10 minutes prior to each ECG collection. 


Appendix 1: Schedule of Activities for Part 1 (cont.) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
124/Protocol BP40657, Version 7 
m Required in patients with a known history of pericardial effusions or with evidence of pericardial effusion on screening chest CT.  
Echocardiogram is the preferred modality for this assessment.  The same method must be used throughout the study.  Echocardiograms will be 
performed at screening, as clinically indicated or per standard of care thereafter during treatment, and at the treatment discontinuation visit if 
pericardial effusions are not resolved during the study.  Patients who develop new pericardial effusions while in the study must be followed by 
echocardiography.   
n Local laboratory assessments may be obtained ≤ 4 days before Day 1 of each cycle.  Hematology consists of CBC, including RBC count, 
hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), 
and platelet count.  A manual differential can be done if clinically indicated.   
o Local laboratory assessments may be obtained ≤ 4 days before Day 1 of each cycle.  Serum chemistry includes BUN/urea, creatinine, sodium, 
potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, 
and albumin.   
p To be completed ≤ 14 days prior to start of study treatment. 
q C-reactive protein assessment may be obtained ≤ 4 days before Day 1 of each cycle. 
r Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.  To be performed ≤ 4 days before dosing. 
s Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented 
as negative within 14 days prior to Day 1.  A urine (or serum, if urine is not feasible) pregnancy test must be carried out every 2 cycles for 
Cohort 2 and before each cycle for Cohort 3.  If the urine test result is positive, a confirmatory serum test must be done. 
t See Appendix 3 for further details on the sampling schedule and Appendix 6 for further details on the sampling procedure. 
u After informed consent has been obtained but prior to initiation of study drug (screening), only serious adverse events caused by 
a protocol-mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last 
dose of study treatment or until initiation of another non-protocol systemic anti-cancer therapy, whichever occurs first.  Serious adverse events 
and adverse events of special interest will continue to be reported until 90 days after the final dose of study treatment or until initiation of new 
non-protocol systemic anti-cancer therapy, whichever occurs first.  After this period, investigators should report any other serious adverse events 
that are considered to be related to study drug.  The investigator should follow each adverse event until the event has resolved to baseline grade 
or better, the event is assessed as stable by the investigator, the patient is lost to follow up, or the patient withdraws consent.  Every effort should 
be made to follow all serious adverse events considered to be related to study drug or study-related procedures until a final outcome can be 
reported.   
v 
Patients in Cohort 1 will only receive one cycle of atezolizumab SC co-mix.  Patients in Cohorts 2 and 3 will receive 3 cycles.  Patients should 
receive their first dose of study drug on the day of enrollment, if possible.  If this is not possible, the first dose should occur no later than 5 days 
after enrollment.  Atezolizumab treatment may be continued in the absence of meeting discontinuation criteria if the patient is experiencing 
clinical benefit. 


Appendix 1: Schedule of Activities for Part 1 (cont.) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
125/Protocol BP40657, Version 7 
w Tumor assessments performed as standard-of-care prior to obtaining informed consent and within 28 days prior to randomization may be used 
rather than repeating tests as long as they comply with RECIST 1.1 requirements and cover all required body areas (see Section 4.5.5). 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
126/Protocol BP40657, Version 7  
Appendix 2  
Schedule of Activities: Part 2 
Assessment Window (Days) 
Screening a 
All Cycles 
Treatment Discontinuation b 
Follow-Up x, bb 
Days –28 
to –1 
Day 1 (± 3 Days for 
Cycles > 2) 
≤ 30 Days after Last Dose 
Signed Informed Consent Form c 
x 
 
 
 
Review of eligibility criteria 
x 
 
 
 
Medical, surgical, and cancer histories, including 
demographic information, EGFR (and ALK, if 
available) mutational status d 
x 
 
 
 
HIV, HBV, HCV serology e 
x 
 
 
 
Concomitant medications f 
x 
x 
x 
 
Tumor assessment g, h 
x 
x 
Complete physical examination i 
x 
 
 
 
Limited physical examination j 
 
x 
x 
 
ECOG performance status k 
x 
x 
x 
 
Vital signs l 
x 
x 
x 
 
Electrocardiogram m 
x 
(x) 
(x) 
 
Echocardiogram n 
(x) 
(x) 
 
 
Weight 
x  
x 
x 
 


Appendix 2: Schedule of Activities for Part 2 (cont.) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
127/Protocol BP40657, Version 7  
Assessment Window (Days) 
Screening a 
All Cycles 
Treatment Discontinuation b 
Follow-Up x,bb 
Days –28 
to –1 
Day 1 (± 3 Days for 
Cycles > 2) 
≤ 30 Days after Last Dose 
Height 
x 
 
 
 
Hematology o 
x 
x 
x 
 
Serum chemistry p 
x 
x 
x 
 
Coagulation panel (aPTT, INR) q 
x 
 
 
 
C-reactive protein sample (central laboratory) r 
x 
x 
 
 
Urinalysis s 
x 
x 
x 
 
Pregnancy test t 
x 
x 
x 
(x) 
TSH, free T3, free T4 u 
x 
x 
x 
 
Baseline tumor tissue for PD-L1, ALK (if applicable), 
and EGFR (if needed) testing v 
x 
 
 
Serum and plasma samples for PK and ADA 
assessment (central laboratory) w 
 
x 
x 
 
Adverse events x 
 
 
Atezolizumab SC injection or IV infusion y 
 
x 
 
 
Patient-reported experience z  
 
x 
 
HCP-reported experience aa 
 
x 
 
Survival follow-up and anti-cancer treatment x, bb 
 
 
 
x  


Appendix 2: Schedule of Activities for Part 2 (cont.) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
128/Protocol BP40657, Version 7  
ADA = anti-drug antibody; ALK = anaplastic lymphoma kinase; anti-HBc = antibody against hepatitis B core antigen; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; HBsAG = hepatitis B surface antigen; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; PD-L1 = programmed death−ligand 1; PK = pharmacokinetic; 
SC = subcutaneous; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone. 
Notes:  Assessments in parentheses are optional or as clinically indicated.  Assessments scheduled on the days of study treatment 
infusions/ injections should be performed before the infusion/injection unless otherwise noted. 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to start of treatment 
(except where otherwise specified) may be used for screening assessments rather than repeating such tests.  
b Patients will be asked to return to the clinic not more than 30 days after the last dose of treatment for a treatment discontinuation visit. 
c Written informed consent is required prior to performing any study-specific tests or procedures.  Signing of the Informed Consent Form can 
occur before the 28-day screening period.   
d Cancer history includes stage, date of diagnosis, results of EGFR mutation and ALK rearrangement testing (if available), and prior anti-tumor 
treatment.  Local EGFR results must be tested centrally for those patients who may harbor sensitizing EGFR mutations and do not have local 
results and for patients enrolled in China.  Additional tissue will be required for EGFR central testing (see Section 4.5.7.3).  ALK may be 
assessed locally or at a central laboratory.  Additional tissue will be required for central testing for patients who may be carriers of an ALK fusion 
oncogene, if no local results are available (see Section 4.5.7.3).  Demographic information includes sex, age, and self-reported race/ethnicity.  
e All patients will be tested for HIV prior to the inclusion into the study; HIV-positive patients will be excluded from the study.  HBV DNA must be 
collected on or before Cycle 1, Day 1 in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.  
Patients with active hepatitis B (chronic or acute; defined as having a positive HBsAg test result at screening) will be excluded from the study.  
Patients with past or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible only if their HBV DNA test 
is negative.  Patients with HCV will be excluded from the study; patients who test positive for HCV antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
f Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to the screening visit should be documented.  At subsequent visits, changes to current medications or medications 
used since the last documentation of medications will be recorded. 
g Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to start of treatment may be 
used rather than repeating tests.  All measurable and evaluable lesions should be assessed and documented at the screening visit.  The same 
radiographic procedure must be used throughout the study for each patient.  Results must be reviewed by the investigator before dosing at the 
next cycle.  Tumor assessments should continue regardless of whether patients start new anti-cancer therapy in the absence of disease 
progression unless they withdraw consent.  If an optional biopsy is to be performed at approximately the same timepoint of a tumor assessment 
or as a result of the radiographic determination (e.g., response or progression), samples should be acquired after all imaging scans have been 
performed, if at all possible.  Patients who continue treatment beyond radiographic disease progression will be monitored with a follow-up scan 


Appendix 2: Schedule of Activities for Part 2 (cont.) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
129/Protocol BP40657, Version 7  
at the next scheduled tumor assessment when the scan frequency is every 6 weeks.  If the scan frequency is every 9 weeks, the follow-up scan 
must be performed at 6 weeks (± 2 weeks) as an unscheduled tumor assessment, or earlier if clinically indicated.  Investigators may perform 
additional scans or more frequent assessments if clinically indicated. 
h Patients will undergo tumor assessments at baseline, every 6 weeks (approximately every two cycles) ± 3 business days for the first 36 weeks 
following treatment initiation, and every 9 weeks (± 1 week) thereafter, regardless of dose delays, until disease progression per RECIST v1.1 or 
(for patients who continue atezolizumab after radiographic disease progression) loss of clinical benefit as determined by the investigator (see 
Section 3.1.2 for details).  Thus, tumor assessments are to continue according to schedule in patients who discontinue treatment for reasons 
other than disease progression or loss of clinical benefit, even if they start new anti-cancer therapy. 
i Complete physical examinations are defined in Section 4.5.3.  
j Limited physical examinations are defined in Section 4.5.3.  Assessment may be obtained ≤ 4 days before Day 1 of each cycle. 
k ECOG performance status may be obtained ≤ 4 days before Day 1 of each cycle. 
l Vital signs include heart rate, respiratory rate, blood pressure, and temperature.  For all administrations, vital signs should be determined within 
60 minutes before and 30 (± 10) minutes after the administration (before any PK sample scheduled to be drawn at the same time) and as 
clinically indicated.  For IV only and if clinically indicated, vital signs will also be collected during the first administration (every 15 [± 5] minutes).  
During SC administrations or during subsequent IV administrations, vital signs will be collected if clinically indicated.  Refer to Section 4.3.2 for 
more details. 
m Triplicate ECG recordings will be performed during screening and when clinically indicated.  Patients should be resting and in a supine position 
for at least 10 minutes prior to each ECG collection. 
n Required in patients with a known history of pericardial effusions or with evidence of pericardial effusion on screening chest CT.  
Echocardiogram is the preferred modality for this assessment.  The same method must be used throughout the study.  Echocardiograms will be 
performed at screening, as clinically indicated or per standard of care thereafter during treatment, and at the treatment discontinuation visit if 
pericardial effusions are not resolved during the study.  Patients who develop new pericardial effusions while in the study must be followed by 
echocardiography. 
o Local laboratory assessments may be obtained ≤ 4 days before Day 1 of each cycle.  Hematology consists of WBC count, RBC count, 
hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).  
A manual differential can be done if clinically indicated.   
p Local laboratory assessments may be obtained ≤ 4 days before Day 1 of each cycle.  Serum chemistry includes bicarbonate or total carbon 
dioxide (if considered standard of care for the region), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, 
albumin, phosphorus, calcium, total bilirubin, alkaline phosphatase, ALT, AST, and lactate dehydrogenase (LDH).  
q To be completed ≤ 14 days prior to start of study treatment. 
r C-reactive protein may be obtained ≤ 4 days before Day 1 of each cycle.  


Appendix 2: Schedule of Activities for Part 2 (cont.) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol BP40657, Version 7  
s Urinalysis should be performed ≤ 4 days before dosing and consists of specific gravity, pH, glucose, protein, ketones, and blood.  Dipstick 
permitted. 
t Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed 
and documented as negative within 14 days prior to Day 1 of Cycle 1.  A urine (or serum, if urine is not feasible) pregnancy test is required on 
Day 1 of each cycle.  If the urine test result is positive, it needs to be confirmed with a serum test.  In accordance to country-specific health 
authority mandates, pregnancy tests may be required beyond treatment discontinuation, monthly for 5 months after the final dose of 
atezolizumab.  Pregnancy tests after study treatment discontinuation can be performed at home.  If a home urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test and if confirmed, immediately communicated to the treating physician. 
u TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every four cycles 
thereafter (i.e., Cycles 5, 9, 13, etc.).  Assessment may be performed ≤ 4 days before Day 1 of each cycle. 
v Tumor samples requiring EGFR testing must be submitted prior to randomization and as early as possible to avoid compromising duration of the 
screening period.  Patients not requiring EGFR testing for randomization may have their samples submitted within 4 weeks after randomization.  
If archival tissue is unavailable or is determined to be unsuitable for required testing, a pretreatment tumor biopsy is required.  A pretreatment 
tumor biopsy may also be performed if a patient's archival tissue test results do not meet eligibility criteria.  All material should be sent in a single 
shipment.  See Section 4.5.7.3 and the laboratory manual for additional details and tissue sample requirements for central PD-L1, EGFR, and 
ALK testing. 
w See Appendix 4 and Appendix 5 for further details on the sampling schedule and Appendix 6 for further details on the sampling procedure. 
x After informed consent has been obtained but prior to initiation of study drug (screening), only serious adverse events caused by a 
protocol-mandated intervention should be reported.  After initiation of study drug, all adverse events will be reported until 30 days after the last 
dose of study treatment or until initiation of another anti-cancer therapy, whichever occurs first.  Serious adverse events and adverse events of 
special interest will continue to be reported until 90 days after the final dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be 
notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment.  The 
investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or study-related procedures until a final outcome can be reported.   
y Patients should receive their first dose of study drug on the day of randomization, if possible.  If this is not possible, the first dose should occur 
no later than 5 days after enrollment.  Atezolizumab treatment may be continued in the absence of meeting discontinuation criteria if the patient 
is experiencing clinical benefit (see Section 3.1.2). 
z Patient experience data will be collected through use of the European Organisation for Research and Treatment of Cancer (EORTC) IL57 
Questionnaire (see Appendix 11) and the modified Satisfaction with Cancer Therapy (SWT) scale from the Cancer Therapy Satisfaction (CTSQ) 
Questionnaire (see Appendix 12).  The EORTC IL57 questionnaire should be completed at the site by patients on Day 1 of Cycles 1−6, every 


Appendix 2: Schedule of Activities for Part 2 (cont.) 
  
Atezolizumab—F. Hoffmann-La Roche Ltd 
131/Protocol BP40657, Version 7  
even -numbered cycle thereafter (i.e., Cycles 8, 10, etc.) during study treatment, and at the treatment discontinuation visit.  The SWT scale 
should be completed at the site by patients at the Cycle 3 visit, or at the treatment discontinuation visit if study treatment is discontinued prior to 
the Cycle 3 visit.  See additional instructions in Section 4.5.8.2. 
aa Health Care Professional (HCP) experience data will be collected through use of the HCP Subcutaneous Perspective Questionnaire 
(see Appendix 13) and the HCP SC versus IV Perspective Questionnaire (see Appendix 14).  The HCP Subcutaneous Perspective 
Questionnaire should be completed after an HCP has administered at least three doses of atezolizumab SC across all patients in Part 2.  The 
HCP SC versus IV Perspective Questionnaire should be completed after an HCP has administered at least three doses of atezolizumab SC and 
at least three doses of atezolizumab IV across all patients in Part 2.   
bb After treatment discontinuation, information on survival follow-up and new anti-cancer therapy will be collected via telephone calls, patient 
medical records, and/or clinic visits approximately every 2−3 months until death (unless the patient withdraws consent or the Sponsor terminates 
the study).  If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the 
investigator.  If the patient withdraws from the study, the study staff may use a public information source (e.g., county records) to obtain 
information about survival status. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
132/Protocol BP40657, Version 7  
Appendix 3  
Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 1, Cohort 1 
Cycle 
Day 
Time/Maximum 
Window 
PK Sample 
ADA Sample 
Cycle 1 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab  
rHuPH20 
 
8 ± 2 hours 
Atezolizumab 
rHuPH20 
 
 
Day 2 
Between 24 and 
48 hours postdose 
Atezolizumab 
rHuPH20 
 
 
Day 4 
Between 72 and 
96 hours postdose 
Atezolizumab 
rHuPH20 
 
 
Day 8 
Between Day 8 and 
Day 11 
Atezolizumab 
rHuPH20 
 
Cycle 2 
Day 1 b 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Cycles 3, 4, 8, 12, 
and 16 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Cycles 2, 3, 4, 8, 12, 
and 16 
Day 1 
Post-infusion of 
atezolizumab IV c 
Atezolizumab 
 
Treatment 
discontinuation visit 
At visit 
At visit 
Atezolizumab 
rHuPH20 
Atezolizumab  
rHuPH20  
ADA = anti-drug antibody, also called anti-therapeutic antibody; PK = pharmacokinetic; 
rHuPH20 = human hyaluronidase. 
Actual sampling dates and times must be recorded precisely for all samples.  For detailed 
sampling instructions, refer to Appendix 6. 
a Predose sample must be taken on the same day of treatment administration and before 
administration starts.  Exact actual sampling and dosing dates and times will be recorded. 
b This sample is critical and needs to be taken precisely 21 days after the first dose.  Please 
schedule the first dose accordingly. 
c  Post-infusion sample must be taken at 30 (± 10) minutes after the infusion has ended. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
133/Protocol BP40657, Version 7  
Appendix 3 (cont.)  
Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 1, Cohort 2 
Cycle 
Day 
Time/Maximum 
Window 
PK Sample 
ADA Sample 
Cycle 1 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab  
rHuPH20 
 
8 ± 2 hours 
Atezolizumab 
rHuPH20 
 
 
Day 2 
Between 24 and 
48 hours postdose 
Atezolizumab 
rHuPH20 
 
 
Day 4 
Between 72 and 
96 hours postdose 
Atezolizumab 
rHuPH20 
 
 
Day 8 
Between Day 8 and 
Day 11 
Atezolizumab 
rHuPH20 
 
Cycle 2 
Day 1 b 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Cycle 3 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Cycle 4  
Day 1 
Predose a, c 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Post-infusion of 
atezolizumab IV c, d 
Atezolizumab 
 
Cycle 5 
Day 1 
Predose a, c 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Post-infusion of 
atezolizumab IV c, d 
Atezolizumab 
 
Cycles 8, 12, 
and 16 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Treatment 
discontinuation 
visit 
At visit 
At visit 
Atezolizumab 
rHuPH20 
Atezolizumab  
rHuPH20  
ADA = anti-drug antibody, also called anti-therapeutic antibody; PK = pharmacokinetic; 
rHuPH20 = human hyaluronidase. 
Actual sampling dates and times must be recorded precisely for all samples.  For detailed 
sampling instructions, refer to Appendix 6. 
a Predose sample must be taken on the same day of treatment administration and before 
administration starts.  Exact actual sampling and dosing dates and times must be recorded. 
b This sample is critical and needs to be taken precisely 14 days after the first dose, without 
any time window.  Please schedule the first dose accordingly. 
c Samples should be collected as scheduled; however, if collection of this sample is impossible, 
the missing sample must be collected at the Day 1 of the next applicable cycle visit. 
d Post-infusion sample must be taken at 30 (± 10) minutes after the infusion has ended.  
Collection of this sample is not required if the patient continues to be treated with 
atezolizumab SC. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
134/Protocol BP40657, Version 7  
Appendix 3 (cont.)  
Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 1, Cohort 3 
Cycle 
Day 
Time/Maximum 
Window 
PK Sample 
ADA Sample 
Cycles 1 and 2 b 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab  
rHuPH20 
 
8 ± 2 hours 
Atezolizumab 
rHuPH20 
 
 
Day 2 
Between 24 and 
48 hours postdose 
Atezolizumab 
rHuPH20 
 
 
Day 4 
Between 72 and 
96 hours postdose 
Atezolizumab 
rHuPH20 
 
 
Day 8 
Between Day 8 and 
Day 11 
Atezolizumab 
rHuPH20 
 
Cycle 3 b 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Cycle 4 
Day 1 
Predose a, c 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Post-infusion of 
atezolizumab IV c, d 
Atezolizumab 
 
Cycle 5 
Day 1 
Predose a, c 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Post-infusion of 
atezolizumab IV c, d 
Atezolizumab 
 
Cycles 8, 12, 
and 16 
Day 1 
Predose a 
Atezolizumab 
rHuPH20 
Atezolizumab 
rHuPH20 
Treatment 
discontinuation 
visit 
At visit 
At visit 
Atezolizumab 
rHuPH20 
Atezolizumab  
rHuPH20  
ADA= anti-drug antibody, also called anti-therapeutic antibody; PK= pharmacokinetic; 
rHuPH20 = human hyaluronidase. 
Actual sampling dates and times must be recorded precisely for all samples.  For detailed 
sampling instructions, refer to Appendix 6. 
a Predose sample must be taken on the same day of treatment administration and before 
administration starts.  Exact actual sampling and dosing dates and times will be recorded. 
b These samples are critical and needs to be taken precisely 21 days after the first dose, 
without any time window.  Please schedule the first dose accordingly. 
c Samples should be collected as scheduled; however, if collection of this sample is impossible, 
the missing sample must be collected at the Day 1 of the next applicable cycle visit. 
 d  Post-infusion sample must be taken at 30 (± 10) minutes after the infusion has ended.  
Collection of this sample is not required if the patient continues to be treated with 
atezolizumab SC. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol BP40657, Version 7  
Appendix 4 Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 2, SC Arm 
 
Cycle 
Day 
Time/Maximum Window 
PK Sample 
ADA Sample 
Cycle 1 
Day 1 
Predose a 
Atezolizumab 
• Atezolizumab 
• rHuPH20 
8 (± 2) hours after start of 
SC injection 
Atezolizumab 
 
Day 2 
Between 24 and 48 hours 
postdose 
Atezolizumab 
 
Day 4 
Between 72 and 96 hours 
postdose 
Atezolizumab 
 
Day 8 
Between Day 8 and 
Day 11 postdose 
Atezolizumab 
 
Cycle 2 
Day 1  
Predose a, b 
Atezolizumab 
• Atezolizumab 
• rHuPH20 
Cycles 3, 4, 8, 12,  
and 16 
Day 1 
Predose a 
Atezolizumab 
• Atezolizumab 
• rHuPH20 
Treatment 
discontinuation visit 
At visit 
At visit 
Atezolizumab 
• Atezolizumab 
• rHuPH20 
ADA = anti-drug antibody, also called anti-therapeutic antibody; PK = pharmacokinetic; rHuPH20 = human hyaluronidase. 
Actual dosing and sampling dates and times must be recorded precisely for all samples.  For detailed sampling instructions, refer to 
Appendix 6. 
a Predose sample must be taken on the same day of treatment administration and before administration starts. 
b This sample is critical and needs to be taken precisely 21 days after the first dose without any time window.  Please schedule the first dose 
accordingly. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol BP40657, Version 7  
Appendix 5 Schedule of Pharmacokinetic and Immunogenicity Samples: 
Part 2, IV Arm 
 
Cycle 
Day 
Time/Maximum Window 
PK Sample 
ADA Sample 
Cycle 1 
Day 1 
Predose a 
Atezolizumab 
Atezolizumab 
30 (± 10) minutes after 
end of infusion 
Atezolizumab 
 
Cycle 1 
Day 4 
Between 72 and 96 hours 
postdose 
Atezolizumab 
 
Cycle 1 
Day 8 
Between Day 8 and 
Day 11 
Atezolizumab 
 
Cycle 2 
Day 1 
Predose a, b 
Atezolizumab 
Atezolizumab 
30 (± 10) minutes after 
end of infusion 
Atezolizumab 
 
Cycles 3, 4, 8, 12,  
and 16 
Day 1 
Predose a 
Atezolizumab 
Atezolizumab 
Treatment 
discontinuation visit 
At visit 
At visit 
Atezolizumab 
Atezolizumab 
ADA = anti-drug antibody, also called anti-therapeutic antibody; PK = pharmacokinetic. 
Actual dosing and sampling dates and times must be recorded precisely for all samples.  For detailed sampling instructions, refer to 
Appendix 6. 
a Predose sample must be taken on the same day of treatment administration and before administration starts. 
b This sample is critical and needs to be taken precisely 21 days after the first dose without any time window.  Please schedule the first 
dose accordingly. 


 
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Appendix 6  
PK and ADA Sampling Instructions for Investigators 
Site for PK and ADA for both Atezolizumab and rHuPH20 Sampling 
In any case, precise blood drawing site must be recorded for all samples. 
On days of SC dosing, PK/ADA blood samples should be drawn preferably from the arm.  
If a patient is unable to provide venous access from the arm, the hand or leg may be 
used as alternative back-up sites for PK blood sampling.  If the leg is used to collect 
a PK blood sample, and atezolizumab SC was administered in the thigh, the opposite 
side from where atezolizumab has been most recently administered should be used.  
If atezolizumab was administered in the leg and the same leg where atezolizumab has 
been most recently administered must be used, the area of the injection should be 
avoided.  
For IV dosing, PK/ADA blood samples need to be drawn from the arm not receiving 
atezolizumab infusion.  If a patient is unable to provide venous access of the opposite 
arm from the infusion arm, the hand or leg may be used as alternative back-up sites for 
PK blood sampling.  
Collecting blood for PK samples from central line and/or port should be avoided.  If there 
is no possible way to avoid the central line and/or port, it is better to collect the PK 
sample than to avoid this altogether, but site of collection must be documented.  
PK and ADA Sampling Time Variability Allowed  
Every effort should be made to take PK and ADA samples on the exact day when they 
are scheduled (see Appendix 3, Appendix 4, and Appendix 5) and prior to any infusion 
or injection is given (for predose samples).  Note that predose Cycle 2 sample has no 
time window.  Our recommendation is to plan the first dose accordingly so that these key 
days fall into a day when the patient can attend the clinic. 
In any case, exact actual sampling and dosing dates and times must be recorded for all 
samples. 


 
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Appendix 7  
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 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
• 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval ≤ 5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be ≤ 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
 
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. 


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


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


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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 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
< 10 mm are considered non-pathological and should not be recorded or followed.  All 
lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 


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


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


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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. 
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. 


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


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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 8  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with 
a medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life−threatening 
skin adverse reaction or pericardial disorder while receiving another immunostimulatory 
anti-cancer agent.  The Medical Monitor is available to advise on any uncertainty over 
autoimmune exclusions. 


Appendix 8: Preexisting Autoimmune Diseases and Immune Deficiencies 
  
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Autoimmune Diseases and Immune Deficiencies 
• Acute disseminated 
encephalomyelitis 
• Addison disease 
• Ankylosing spondylitis 
• Antiphospholipid antibody 
syndrome 
• Aplastic anemia 
• Autoimmune hemolytic 
anemia 
• Autoimmune hepatitis 
• Autoimmune 
hypoparathyroidism 
• Autoimmune hypophysitis 
• Autoimmune myelitis 
• Autoimmune myocarditis 
• Autoimmune oophoritis 
• Autoimmune orchitis 
• Autoimmune 
thrombocytopenic purpura 
• Behçet disease 
• Bullous pemphigoid 
• Chronic fatigue syndrome 
• Chronic inflammatory 
demyelinating 
polyneuropathy 
• Churg-Strauss syndrome 
• Crohn disease  
• Dermatomyositis 
• Diabetes mellitus type 1 
• Dysautonomia 
• Epidermolysis bullosa 
acquisita 
• Gestational pemphigoid 
• Giant cell arteritis 
• Goodpasture syndrome 
• Granulomatosis with 
polyangiitis 
• Graves disease 
• Guillain-Barré syndrome 
• Hashimoto disease 
• IgA nephropathy 
• Inflammatory bowel disease 
• Interstitial cystitis 
• Kawasaki disease 
• Lambert-Eaton myasthenia 
syndrome 
• Lupus erythematosus 
• Lyme disease, chronic 
• Meniere syndrome 
• Mooren ulcer 
• Morphea 
• Multiple sclerosis 
• Myasthenia gravis 
 
• Neuromyotonia 
• Opsoclonus myoclonus 
syndrome 
• Optic neuritis 
• Ord thyroiditis 
• Pemphigus 
• Pernicious anemia 
• Polyarteritis nodosa 
• Polyarthritis 
• Polyglandular autoimmune 
syndrome 
• Primary biliary cholangitis 
• Psoriasis 
• Reiter syndrome 
• Rheumatoid arthritis 
• Sarcoidosis 
• Scleroderma 
• Sjögren syndrome 
• Stiff-Person syndrome 
• Takayasu arteritis 
• Ulcerative colitis 
• Vitiligo 
• Vogt-Koyanagi-Harada 
disease 
 


 
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Appendix 9  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
EQUIPMENT NEEDED 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment injection or infusion: 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
• 
Oxygen 
• 
Epinephrine for intramuscular (preferred route), subcutaneous, intravenous, and/or 
endotracheal use 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 injection or 
infusion, the following procedures should be performed: 
1. 
Stop the study treatment injection or infusion (if still ongoing). 
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 


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


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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immune-mediated event.  The decision to re-challenge patients with atezolizumab 
should be based on the investigator’s assessment of the benefits and risks and 
documented by the investigator.  The Medical Monitor is available to advise as 
needed.  
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study. 
TREATMENT INTERRUPTION 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over ≥1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
> 12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for > 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for > 12 weeks if the patient is likely to derive clinical benefit.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefit−risk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.  Atezolizumab treatment may be suspended for reasons 
other than toxicity (e.g., surgical procedures).  The acceptable length of treatment 
interruption must be based on the investigator’s benefit−risk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in Table 1 . 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
• Continue atezolizumab and monitor closely. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
• For Grade 1 pneumonitis, consider withholding atezolizumab. 
Pulmonary 
event, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial 
biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor.  c, d 
• For recurrent events or events with no improvement after 
48−72 hours of corticosteroids, treat as a Grade 3 or 4 event. 
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of 
≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
153/Protocol BP40657, Version 7  
Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis (cont.) 
Pulmonary 
event, Grade 3 
or 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor.  c, d 
• Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
• Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefit−risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re-
challenge patients with atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 
 
HEPATIC EVENTS 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2 . 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
• Continue atezolizumab. 
• Monitor LFTs until values resolve to within normal limits or to 
baseline values. 
Hepatic event, 
Grade 2 
All events: 
• Monitor LFTs more frequently until return to baseline values.  
Events of >  5 days’ duration: 
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor.  c 
LFT = liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of ≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefit−risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefit−risk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.   
 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol BP40657, Version 7  
Table 2 
Management Guidelines for Hepatic Events (cont.) 
Event 
Management 
Hepatic event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor.  c 
• Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury.  
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
LFT = liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of ≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefit−risk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator’s 
benefit−risk assessment and documented by the investigator.  The Medical Monitor is 
available to advise as needed.   
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3 . 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Initiate symptomatic treatment. 
• If strong clinical suspicion for immune-mediated colitis, start 
empiric IV steroids while waiting for definitive diagnosis. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist > 5 days, initiate treatment 
with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone.  If 
the event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of 
≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
157/Protocol BP40657, Version 7  
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
Diarrhea or 
colitis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement.  If event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefit−risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor.  c 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefit−risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.   
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table 4 . 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  Patients should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
Grade 2 
hypothyroidism 
• Consider withholding atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Grade 3 and 4 
hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Refer to an endocrinologist. 
• Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
• Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
• Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hypothyroidism. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of 
≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
Grade 1 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
• Consider patient referral to endocrinologist. 
TSH < 0.1 mU/L: 
• Follow guidelines for Grade 2 hyperthyroidism. 
• Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
• Consider withholding atezolizumab. 
• Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Grade 3 and 4 
hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drugs such as 
methimazole or carbimazole as needed. 
• Refer to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
• Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hyperthyroidism.  c 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefit−risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re-
challenge patients with atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grades 2−4  
• Withhold atezolizumab for up to 12 weeks after event 
onset.  a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor.  c 
Hyperglycemia, 
Grade 1 or 2  
• Continue atezolizumab. 
• Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 
diabetes, treat as per institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefit−risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re-
challenge patients with atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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162/Protocol BP40657, Version 7  
Table 4 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
• Withhold atezolizumab for up to 12 weeks after event 
onset.  a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab.  
b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor.  c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
• Permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefit−risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re-
challenge patients with atezolizumab should be based on the investigator’s benefit−risk 
assessment and documented by the investigator.  The Medical Monitor is available to 
advise as needed.   
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5 . 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
the Medical Monitor.  c 
Ocular event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact Medical 
Monitor.  c 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone.   
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefit−risk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.   
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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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., 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 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6 . 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, 
and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2-4 
 
Immune-mediated 
pericardial disorders, 
Grades 2−4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD or 
pericardiocentesis as appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
 
INFUSION-RELATED REACTIONS/INJECTION-RELATED REACTIONS AND 
CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab co-mix 
or atezolizumab SC.  However, patients who experience an IRR (infusion-related 
reaction for IV formulation/injection-related reaction for SC formulation) or 
cytokine-release syndrome (CRS) with atezolizumab may receive premedication with 
antihistamines, antipyretic medications, and/or analgesics (e.g., acetaminophen) for 
subsequent infusions or injections.  Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
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There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs and CRS are provided in Table 7 . 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-γ (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’s judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 7 
Management Guidelines for Infusion-Related Reactions, 
Injection-Related Reactions, and Cytokine-Release Syndrome 
Event 
Management 
Grade 1a 
Fever b with or without 
constitutional symptoms 
• Immediately interrupt infusion/injection.  c 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion/injectionc at half the rate being given at the time of event 
onset.  
• If the infusionc is tolerated at the reduced rate for 30 minutes, the 
infusionc rate may be increased to the original rate.  If the injection is 
tolerated at the reduced rate, continue until completion. 
• If symptoms recur, discontinue infusion/injectionc of this dose. 
• Administer symptomatic treatment,d including maintenance of IV 
fluids for hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in patients 
with significant symptoms and/or comorbidities, consider managing 
as per Grade 2. 
• For subsequent infusions/injectionsc, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
Grade 2a 
Fever b with 
hypotension not 
requiring vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygene by 
nasal cannula or 
blow-by 
• Immediately interrupt atezolizumab infusion/injectionc. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion/injectionc at half the rate being given at the time of event 
onset. 
• If symptoms recur, discontinue infusion/injectionc of this dose. 
• Administer symptomatic treatment.  c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated and 
manage constitutional symptoms and organ toxicities as per 
institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.  f 
• Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact the Medical 
Monitor. 
• If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered. 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 7 
Management Guidelines for Infusion-Related Reactions, 
Injection-Related Reactions, and Cytokine-Release Syndrome 
(cont.) 
Grade 2a (cont.) 
Fever b with 
hypotension not 
requiring vasopressors 
and/or 
Hypoxia requiring low-
flow oxygene by nasal 
cannula or blow-by 
• For subsequent injections/infusionsc, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact the Medical Monitor. 
Grade 3a 
Fever b with 
hypotension requiring a 
vasopressor (with or 
without vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygene by 
nasal cannula, face 
mask, non-rebreather 
mask, or Venturi-mask 
• Permanently discontinue atezolizumab and contact Medical 
Monitor.  a 
• Administer symptomatic treatment.  d 
• For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
• Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids as 
clinically indicated and manage constitutional symptoms and organ 
toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.  
• Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
Grade 4a 
Fever b with 
hypotension requiring 
multiple vasopressors 
(excluding vasopressin) 
and/or Hypoxia 
requiring oxygen by 
positive pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical ventilation) 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor.  f 
• Administer symptomatic treatment.  d 
• Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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Table 7 
Management Guidelines for Infusion-Related Reactions, 
Injection-Related Reactions, and Cytokine-Release Syndrome 
(cont.) 
Grade 4a (cont.) 
Fever b with 
hypotension requiring 
multiple vasopressors 
(excluding vasopressin) 
and/or  
Hypoxia requiring 
oxygen by positive 
pressure (e.g., CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.  f  For patients who are refractory to 
anti-cytokine therapy, experimental treatmentsg may be considered 
at the discretion of the investigator and in consultation with the 
Medical Monitor. 
• Hospitalize patient until complete resolution of symptoms. 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive 
airway pressure; CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; 
CRS = cytokine-release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; 
eCRF = electronic Case Report Form; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive 
care unit; IRR = infusion-related reaction or injection-related reaction; MAS = macrophage 
activation syndrome; NCCN = National Cancer Comprehensive Network; NCI = National Cancer 
Institute. 
Note:  The management guidelines have been adapted from the NCCN guidelines for the 
management of CAR T-cell−related toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading. 
b Fever is defined as temperature ≥ 38°C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the grade 
is driven by the presence of hypotension and/or hypoxia. 
c For the purposes of this management guideline, “infusion” refers to the IV formulation and 
“injection” refers to the SC formulation. 
d Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
e Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen 
delivered at > 6 L/min. 
f Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  The decision to re-challenge patients with atezolizumab should 
be based on the investigator’s benefit−risk assessment and documented by the investigator.  
The Medical Monitor is available to advise as needed.  For subsequent infusions/injections, 
administer oral premedication with antihistamines, antipyretic medications, and/or analgesics, 
and monitor closely for IRRs and/or CRS.  Premedication with corticosteroids and extending the 
infusion/injection time may also be considered after assessing the benefit−risk ratio. 
g Refer to Riegler et al. (2019). 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8 . 
Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase > 1.5−2.0 × ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., > 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0−5.0 × ULN: 
• Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor.  c 
• For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor.  c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of 
≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed.   


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 8 
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.) 
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 
• Withhold atezolizumab for up to 12 weeks after event 
onset.  a 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better, resume 
atezolizumab.  b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor.  c 
• For recurrent events, permanently discontinue atezolizumab 
and contact the Medical Monitor.  c 
Immune-mediated 
pancreatitis, Grade 4 
• Permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.   
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limiting, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 9 . 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
• Continue atezolizumab. 
• Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
• Continue atezolizumab. 
• Consider patient referral to dermatologist for evaluation and, if indicated, 
biopsy. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical corticosteroids if event 
does not improve.  
• If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day. 
Dermatologic 
event, Grade 3  
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
• Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 1−2 mg/kg/day if event does not improve 
within 48−72 hours. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 
Dermatologic 
event, Grade 4 
• Permanently discontinue atezolizumab and contact Medical Monitor.  c 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 9 
Management Guidelines for Dermatologic Events (cont.) 
Event 
Management 
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis 
• Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic 
epidermal necrolysis. 
• Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation, and, if indicated, 
biopsy. 
• Follow the applicable treatment and management guidelines above. 
• Permanently discontinue atezolizumab for confirmed Stevens-Johnson 
syndrome or toxic epidermal necrolysis. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of 
≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefit−risk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 10 , with specific guidelines for myelitis provided in Table 11 . 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue atezolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2  
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Investigate etiology and refer patients to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume 
atezolizumab.  b 
– 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Medical Monitor.  c 
• For facial paresis: 
– 
If event resolves fully, resume atezolizumab.   b 
– 
If event does not resolve fully while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact the Medical Monitor.  c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor.  c  
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any grade) 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefit−risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as 
needed.   
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 11 Management Guidelines for Immune-Mediate Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the 
Medical Monitor. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 12 . 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 12 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
 
 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13 . 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 13 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine and urine protein, closely 
until values resolve to within normal limits or to baseline values.   
Renal event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset.  a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 
Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor.  c 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on the investigator’s benefit−risk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.   
 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
179/Protocol BP40657, Version 7  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14 . 
Table 14 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
• Continue atezolizumab. 
• Refer patient to rheumatologist or neurologist.  
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a and 
contact the Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
• If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
180/Protocol BP40657, Version 7  
Table 14 Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onseta and 
contact the Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab.  b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor.  c 
• For recurrent events, treat as a Grade 4 event.  Permanently 
discontinue atezolizumab and contact the Medical Monitor.  c 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor.  c 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
181/Protocol BP40657, Version 7  
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for 
the duration of treatment and documented by the investigator.  The Medical Monitor is 
available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge 
patients with atezolizumab should be based on the investigator’s benefit−risk assessment 
and documented by the investigator.  The Medical Monitor is available to advise as needed.   
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).   
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
• 
Fever ≥ 38.5°C 
• 
Splenomegaly 
• 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
– 
Platelet count < 100 × 109/L (100,000/µL) 
– 
ANC < 1.0 × 109/L (1000/µL) 
• 
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L 
(150 mg/dL) 
• 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• 
Low or absent natural killer cell activity 
• 
Ferritin > 500 mg/L (500 ng/mL) 
• 
Soluble IL-2 receptor (soluble CD25) elevated ≥ 2 standard deviations above 
age-adjusted laboratory-specific norms 
 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
182/Protocol BP40657, Version 7  
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
• 
Ferritin > 684 mg/L (684 ng/mL) 
• 
At least two of the following: 
– 
Platelet count ≤ 181 × 109/L (181,000/µL) 
– 
AST ≥ 48 U/L 
– 
Triglycerides > 1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 15 . 
Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. 
• Consider patient referral to hematologist. 
• Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
• Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
• If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
REFERENCES 
Adashek ML, Feldman M. Cytokine-release syndrome resulting from anti−programmed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:502−4. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ 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. 


Appendix 10: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
183/Protocol BP40657, Version 7  
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:625−38. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 29 
October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:355−62. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:481−9. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:323−35. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:2908−14.
















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System identifier: RIM-CLIN-466985
Approval Task
Scientific content approver
07-Feb-2023 17:10:35 GMT+0000

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the 
last page of this document  
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Atezolizumab - F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP40657 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: A RANDOMIZED, MULTICENTER, PHASE Ib/III STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, EFFICACY, AND 
SAFETY OF ATEZOLIZUMAB SUBCUTANEOUS COMPARED 
WITH ATEZOLIZUMAB INTRAVENOUS IN PATIENTS WITH 
PREVIOUSLY TREATED LOCALLY ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER 
STUDY NUMBER: 
BP40657 
STUDY NAME:  
IMscin001 
VERSION NUMBER: 
3 
ROCHE COMPOUND: 
Atezolizumab (RO5541267/F06, RO5541267/F03, 
RO5541267/F01, RO5221651) 
EUDRACT NUMBER: 
2018-002328-18 
IND NUMBER: 
N/A (Non-IND Study) 
NCT NUMBER: 
NCT03735121 
PLAN PREPARED BY: 
 BSc, MSc 


 
Atezolizumab - F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BP40657 
2 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document Version 2, 26 October 2020. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
3 
See electronic date stamp 
on the last page of this 
document. 
Version 6, 25 February 2022 
2 
25 March 2022 
Version 6, 25 February 2022 
1 
10 November 2021 
Version 5, 10 February 2021 


 
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Statistical Analysis Plan BP40657  
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STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
This Statistical Analysis Plan (SAP) for Study BP40657 (IMscin001) has been amended 
to incorporate the following changes. 
 
The name of Population PK analysis set has been changed to PK evaluable set. 
 
Minor updates have been made to the definition of Per Protocol PK population and 
PK evaluable population to improve clarity. 
 
Confirmed duration of response evaluable population has been added to the 
analysis set in Section 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Statistical Analysis Plan BP40657  
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TABLE OF CONTENTS 
1. 
INTRODUCTION .......................................................................................... 8 
1.1 
Objectives and Endpoints Estimands ...................................... 8 
1.2 
Study Design ......................................................................... 14 
1.2.1 
Treatment Assignment and Blinding ...................................... 14 
1.2.2 
Independent Review Facility .................................................. 14 
1.2.3 
Data Monitoring ..................................................................... 15 
2. 
STATISTICAL HYPOTHESES .................................................................... 15 
2.1 
Multiplicity Adjustment ........................................................... 16 
3. 
SAMPLE SIZE DETERMINATION .............................................................. 16 
4. 
ANALYSIS SETS ........................................................................................ 17 
5. 
STATISTICAL ANALYSES ......................................................................... 18 
5.1 
General Consideration ........................................................... 19 
5.2 
Participant Disposition ........................................................... 19 
5.3 
Co-Primary Endpoints Analysis ............................................. 19 
5.3.1 
Definition of Co-Primary Endpoints ........................................ 19 
5.3.2 
Main Analytical Approach for Co-Primary 
Endpoints…… ....................................................................... 21  
5.3.3 
Supplementary Analysis for Co-Primary 
Endpoints… ........................................................................... 22 
5.4 
Secondary Endpoints Analyses ............................................. 22 
5.4.1 
PK Analyses .......................................................................... 22 
5.4.2 
Efficacy Analyses .................................................................. 22 
5.4.2.1 
Objective Response Rate ...................................................... 23 
5.4.2.2 
Progression-Free Survival ..................................................... 23 
5.4.2.3 
Overall Survival ..................................................................... 24 
5.4.2.4 
Duration of Response ............................................................ 25 
5.4.3 
Patient Reported Outcomes .................................................. 26 
5.4.4 
Safety Analysis ...................................................................... 27 
5.4.5 
Immunogenicity Analyses ...................................................... 27 
5.5 
Exploratory Endpoints Analysis ............................................. 28 
5.5.1 
Exploratory PK Analysis ........................................................ 28 


 
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Statistical Analysis Plan BP40657  
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5.5.2 
Exploratory Immunogenicity Analysis .................................... 28 
5.5.3 
Exploratory Biomarker Analysis ............................................. 28 
5.6 
Other Safety Analyses ........................................................... 28 
5.6.1 
Extent of Exposure ................................................................ 28 
5.6.2 
Adverse Events ..................................................................... 29 
5.6.3 
Laboratory Data ..................................................................... 29 
5.6.4 
Vital Signs .............................................................................. 29 
5.7 
Other Analyses ...................................................................... 29 
5.7.1 
Summaries of Conduct of Study ............................................ 29 
5.7.2 
Summaries of Treatment Group Comparability ..................... 30 
5.7.3 
Health Care Professional Reported Experience .................... 30 
5.7.4 
Analyses of Subgroups of Interest ......................................... 30 
5.7.5 
Analyses of China Subpopulation .......................................... 30 
6. 
SUPPORTING DOCUMENTATION ............................................................ 30 
7. 
REFERENCES ........................................................................................... 32 
 
 
LIST OF TABLES 
Table 1 
Study Definitions ........................................................................... 8 
Table 2 
Objectives and Corresponding Endpoints ..................................... 9 
Table 3 
Statistical Power of Test of Non-Inferiority of Ctrough and 
AUC0–21d .................................................................................... 17 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 14 


 
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Statistical Analysis Plan BP40657  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AUC0–21 d 
Area under the concentration-time curve from 0 to 21 days 
CCOD 
Clinical cutoff date 
C-DOR 
Confirmed Duration of response 
CI 
Confidence interval 
CIT 
Cancer immunotherapy 
CSR 
Clinical Study Report 
Ctrough 
Trough plasma concentration 
CTSQ 
Cancer Therapy Satisfaction Questionnaire 
CV 
Co-efficient of variation 
DOR 
Duration of response 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
ER 
Exposure-response 
GMR 
Geometric mean ratio 
HCP 
Health care professional 
HR 
Hazard ratio 
ICE 
Intercurrent event 
ICH 
International Council on Harmonization 
IL57 
Interleukin 57 
IRF 
Independent Review Facility 
IV 
Intravenous 
IxRS 
Interactive voice/web-based response system 
JMC 
Joint monitoring committee 
Ln 
Natural logarithm 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NMPA 
National Medical Products Administration 
ORR 
Objective response rate 
OS 
Overall survival 
PFS 
Progression-free survival 
popPK 
Population pharmacokinetics 
PRO 
Patient-reported outcomes 


 
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Statistical Analysis Plan BP40657  
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Abbreviation or Term 
Description 
PK 
Pharmacokinetic 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SWT 
Satisfaction with therapy 
 
 


 
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Statistical Analysis Plan BP40657  
8 
 
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Part 2 (Dose Confirmation) of Study BP40657 (hereinafter 
IMscin001).  The data in Part 1 of the study was analyzed on an ongoing basis to inform 
and justify the dose selection, site of administration for subsequent cohorts, and for the 
Part 2 dose thus will not be in scope of this SAP.  The analysis for Part 1 was performed 
previously (Data Memo submitted to the FDA for dose justification) and will be reported 
in the CSR.  For detailed background information on the study, refer to Protocol Section 
1.  
1.1 
OBJECTIVES AND ENDPOINTS ESTIMANDS 
This study will evaluate the pharmacokinetics, safety, and efficacy of atezolizumab 
subcutaneous (SC) compared with atezolizumab intravenous (IV) in patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) who have not been 
exposed to cancer immunotherapy (CIT) (i.e., "CIT-naive") and for whom prior 
platinum- based therapy has failed.  The study is comprised of two parts, as follows: 
 
Part 1 (Phase Ib, dose finding) will aim to identify the dose of atezolizumab SC that 
yields drug exposure that is comparable to that of atezolizumab IV 
 
Part 2 (Phase III, randomized, dose confirmation) will aim to demonstrate the 
non-inferiority of observed drug exposure following treatment with atezolizumab SC 
at the identified dose compared with drug exposure following treatment with 
atezolizumab IV  
 
Definitions used in Part 2 of this study are outlined in Table 1. 
Specific objectives for Part 2 of the study and corresponding endpoints are outlined in 
Table 2. 
Table 1 
Study Definitions 
Atezolizumab 
Atezolizumab monoclonal antibody as a molecule, irrespective of its 
formulation 
Atezolizumab SC 
Ready-to-use SC formulation of atezolizumab co-formulated with 
2,000 U/mL rHuPH20 
Atezolizumab IV 
Currently approved formulation of atezolizumab for IV infusion in its 
1200 mg vial configuration 
IV   intravenous; SC  subcutaneous. 
 












 
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Statistical Analysis Plan BP40657  
14 
 
1.2 
STUDY DESIGN 
The study schema for Part 2 is shown in Figure 1. 
Figure 1 Study Schema  
 
LOCB  loss of clinical benefit; NSCLC  non-small cell lung cancer; Q3W  every three weeks; 
R  randomization; CIT  Cancer immunotherapy; IV  intravenous 
Part 2 will be initiated once a dose has been identified based on the cumulative data 
collected from Part 1 (see Section 3.3.1 of the Protocol).  In Part 2, patients will be 
randomized in a 2:1 ratio to receive monotherapy with either 1875 mg of atezolizumab 
SC Q3W or 1200 mg of atezolizumab IV Q3W, respectively, starting on Day 1 of each 
21-day cycle.  
Part 2 of this study will initially enroll approximately 327 participants (later increased to 
~355, see Appendix 1 ) across approximately 150 sites in a global enrollment phase.  
For further details on study design, refer to Protocol Section 3.   
1.2.1 
Treatment Assignment and Blinding 
This is an open-label study.  Patients should receive their first dose of study drug the day 
of randomization for Part 2, if possible.  If this is not possible, the first dose should occur 
within 5 days after randomization. 
Patients in Part 2 will be randomly assigned to one of two treatment arms:  atezolizumab 
SC or atezolizumab IV.  Randomization will occur in a 2:1 ratio using a permuted-block 
randomization method to ensure more patients are assigned to the SC arm.  Although 
Part 2 is open-label, Sponsor’s standard operating procedures for blinding and 
unblinding will be followed.   
To ensure a patient population representative of standard clinical practice, the Sponsor 
will periodically evaluate the prevalence of epidermal growth factor receptor (EGFR) 
mutation and limit the number of patients with EGFR-positive mutation to a maximum of 
approximately 10% of all randomized patients if required.   
1.2.2 
Independent Review Facility 
Not applicable. 


 
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Statistical Analysis Plan BP40657  
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1.2.3 
Data Monitoring 
A Joint Monitoring Committee (JMC) will be convened to evaluate safety data and PK for 
formulation comparability and sample size consideration during Part 2 of the study.  
The JMC will be composed of internal and external members; further details on the 
composition, roles and responsibilities, and meeting schedule of the JMC are 
documented in the JMC charter. 
2. 
STATISTICAL HYPOTHESES 
The primary objective of Part 2 is to demonstrate non-inferiority of the PK of 
atezolizumab SC compared with atezolizumab IV based on two co-primary endpoints, 
Cycle 1 observed serum trough plasma concentration (Ctrough) (predose Cycle 2) 
and model-predicted area under the time-concentration curve from 0 to 21 days 
(AUC0–21 d).  
A statistical hypothesis test will be performed on the GMR of Ctrough following SC 
administration (Ctrough,SC) to Ctrough following IV administration (Ctrough,IV), both values 
taken from data observed in Cycle 1:  Ctrough,SC/Ctrough,IV.  
The null and alternative hypotheses will be as follows: 
 
H0:  The SC dose is inferior to the IV dose with a non-inferiority margin less 
than 0.8 (i.e., the geometric mean ratio (GMR) Ctrough,SC/Ctrough,IV is less than 
0.8), versus 
 
H1:  The SC dose is non-inferior to the IV dose (i.e., the GMR Ctrough,SC/Ctrough,IV 
is equal or greater than 0.8). 
 
Model-predicted AUC0–21 d in Cycle 1 is the other co-primary endpoint used for the 
primary objective of Part 2.  The model-predicted AUC in Cycle 1 after atezolizumab SC 
administration will be compared with the model-predicted AUC0–21 d in Cycle 1 after IV 
administration. 
A statistical hypothesis test will be performed on the GMR of AUC0–21 d following SC 
administration (AUC0–21d,SC) to IV administration (AUC0–21 d,IV), both values taken from 
data predicted in Cycle 1:  AUC0–21 d, SC /AUC0–21 d, IV.  
The null and alternative hypotheses will be as follows: 
 
H0:  The SC dose is inferior to the IV dose with a non-inferiority margin less than 0.8 
(i.e., the GMR AUC0–21 d, SC /AUC0–21 d, IV is less than 0.8), versus 
 
H1:  The SC dose is non-inferior to the IV dose (i.e., the GMR AUC0–21 d, 
SC/AUC021 d, IV is equal to or greater than 0.8) 
 


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Statistical Analysis Plan BP40657  
16 
2.1 
MULTIPLICITY ADJUSTMENT 
Cycle 1 observed serum Ctrough (predose Cycle 2) and model-predicted AUC0–21 d will 
be tested using the Hochberg procedure (Hochberg and Tamhane 1987; FDA 2017).  
In step 1 of this procedure, if the lower bounds of the 90% CI for both the GMR 
Ctrough,SC/Ctrough,IV and the GMR AUC0–21 d, SC/AUC0–21 d, IV are ≥ 0.8, both null 
hypotheses will be rejected.  In this case, it will be concluded that SC administration 
is non-inferior to IV administration in terms of Ctrough and AUC in Cycle 1.  
If in Step 1 the null hypotheses are not rejected, the procedure continues to Step 2.  
In Step 2, if the 95% CI for one GMR (i.e., either Ctrough,SC/Ctrough,IV 
or AUC0– 21 d, SC/AUC0−21 d, IV) is ≥ 0.8, the corresponding null hypothesis will be rejected. 
In this case, it will be concluded that SC administration is non-inferior to IV 
administration in terms of Ctrough or AUC in Cycle 1. 
3. 
SAMPLE SIZE DETERMINATION
A total of ~327 patients (later increased to ~355, see Appendix 1) were planned to be 
randomized in Part 2 of the study.  This sample size will provide sufficient power for the 
statistical hypothesis test for the co-primary endpoints, based on the following 
assumptions: 

2:1 randomization ratio

True GMR  0.95 for Cycle 1 Ctrough

True GMR  0.95 for Cycle 1 AUC0–21d

One-sided significance level 0.05

Coefficient of variation (CV%) of geometric mean Ctrough in Cycle 1 is  55%; this
value is based on the results observed after atezolizumab SC co-mix administration
in Part 1 of the study (Clinical cutoff date[CCOD] 10 March 2020)

CV% of geometric mean Cycle 1 AUC0–21d is  45%; this value is based on the
results observed after atezolizumab SC co-mix administration in Part 1 of the study
(CCOD 10 March 2020)

Positive correlation between Cycle 1 AUC0–21d  and Cycle 1 Ctrough  0.8; this value is
based on the results observed after atezolizumab SC co-mix administration in Part 1
of the study (CCOD 10 March 2020)
Under these assumptions, a sample size of  261 pharmacokinetic (PK)-evaluable 
patients in the atezolizumab SC and atezolizumab IV arms would provide at least 80% 
power to conclude non-inferiority of Cycle 1 Ctrough,SC and AUC0–21 d, SC with a 
non- inferiority margin of 0.8 for the GMR, or more concisely: Ctrough,SC  0.8 Ctrough,IV and 
AUC0–21 d, SC  0.8 AUC021 d, IV (see Table 3).   
It is expected that up to 20% of randomized patients will need to be excluded from the 
Per Protocol PK population.  The total number of 327 patients was chosen to ensure the 


 
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Per Protocol PK population will be large enough to meet the primary study objective and 
to assess comparable safety and efficacy data.  
The total number of patients to be enrolled in Part 2 of the study was planned to be 
either increased or decreased, after taking into account the actually observed PK 
variability during the blinded sample-size re-estimation (once approximately 210250 
patients have been randomized).  For example, for a coefficient of variation of 70% for 
Cycle 1 Ctrough, the number of patients enrolled in Part 2 would be increased to 477 in 
order to ensure sufficient power for the non-inferiority test (see Table 3).   
Table 3  Statistical Power of Test of Non-Inferiority of Ctrough and AUC0–21d 
Coefficient of 
Variation for 
Cycle 1 Ctrough 
PK-
Evaluable 
Patients 
Probability to reject the null 
hypothesis for both co-primary 
endpoints 
Estimated Required 
Randomized 
Patients a  
50% 
234 
80% 
293 
55% 
261 
80% 
327 
60% 
297 
80% 
372 
65% 
336 
80% 
420 
70% 
381 
80% 
477 
a Assuming up to 20% not PK-evaluable. 
  
After conducting the blinded estimation of the CV% and of the remaining parameters 
used in the initial sample size as planned, the highest CV% observed was around 55% 
while the rate of not PK-evaluable patients was higher as compared to the initial 
assumption (24% vs 20%).  As a consequence of this change in the initial assumption, a 
larger number of randomized patients was required than initially planned to ensure 80% 
power for both hypotheses test.  Hence, the Sponsor decided to increase the sample 
size to approximately 355. The details of this calculation are summarized in Appendix 1
 
 
 
4. 
ANALYSIS SETS 
The following analysis sets are defined for the analysis of Part 2: 




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been reported.  The cutoff for the primary analysis will therefore be approximately one 
month after randomizing the last patient in Part 2.  Analyses of available data on 
secondary and exploratory endpoints up to this time point will also be presented.  
After that, patients will continue to be followed until the end of the study, approximately 
33 months after randomizing the last patient in the global enrollment phase, or when all 
patients have discontinued from the study, whichever occurs first.  An additional analysis 
will be performed at the end of study to evaluate the longer-term efficacy and safety data 
for atezolizumab SC. 
5.1 
GENERAL CONSIDERATION 
Part 2 primary and secondary PK analyses will be performed on the Per Protocol 
PK- evaluable and/or PK evaluable analysis set, as appropriate, and according to the 
actual treatment received by patients, unless otherwise specified.  All Part 2 efficacy 
analyses will be performed on the Full Analysis Set and according to the treatment 
assigned at randomization by interactive voice/web-based response system (IxRS), 
unless otherwise specified.  All safety analyses will be performed in the safety-evaluable 
population and according to the actual treatment received by patients, unless otherwise 
specified.   
5.2 
PARTICIPANT DISPOSITION 
A detailed study disposition of participants including the number/percentage of 
participants who have completed the study vs. number/percentage of participants who 
have prematurely withdrawn from the study, as well as the primary reasons for 
withdrawal will be summarized overall by treatment arm.  Additionally, a summary table 
of survival follow-up period for participants remaining in the study until the time of final 
overall survival will be provided, for the Full Analysis Set. 
5.3 
CO-PRIMARY ENDPOINTS ANALYSIS 
The primary comparisons of interest are the geometric mean ratios (GMR) and 
confidence intervals of PK parameters for atezolizumab SC versus atezolizumab IV.  
The PK objective for Part 2 is to demonstrate non-inferiority of exposure to atezolizumab 
SC compared with atezolizumab IV based on the following co-primary endpoints: 

Observed serum Ctrough at Cycle 1 (predose Cycle 2)

Model-predicted area under the concentration-time curve (AUC) from 0 to
21 days (AUC0–21 d) at Cycle 1
5.3.1 
Definition of Co-Primary Endpoints 
Following the estimand framework introduced in the ICH-E9 addendum (ICH 2020), the 
estimand for the primary analysis follows a principal stratum strategy based on the 
following attributes:  


 
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Co-Primary Estimand 1: 
o 
Population:  Patients with locally advanced or metastatic NSCLC who are CIT-
naive and for whom prior platinum therapy has failed.  The analysis population will 
consist of the Per Protocol PK population, with patients grouped according to their 
received treatment. 
o 
Variable:  The Cycle 1 observed serum Ctrough (predose Cycle 2), using the 
measured concentration from the PK sample. 
o 
Treatment:  Atezolizumab IV versus atezolizumab SC, at the determined dose at 
baseline.  All randomized patients are expected to receive the baseline infusion or 
injection.  
o 
Intercurrent Events and Handling Strategy: 
▪ 
Premature discontinuation from treatment:  Every effort will be made to 
ensure all randomized patients will receive the treatment at baseline and will 
have the PK sample collected appropriately.  Treatment will start within 5 days 
of randomization.  Withdrawal after randomization, prior to baseline treatment is 
not expected.  In case of such an event, those patients are excluded from the 
analysis population and those patients will not be replaced. 
▪ 
Premature discontinuation from study:  Some patients could discontinue the 
study prior to the time point of predose Cycle 2 due to death or other reasons.  
Considering the short interval between randomization and Cycle 2, this situation 
is expected to be exceptional.  Those patients are excluded from the 
population. 
▪ 
Missing or outside of window PK samples:  Some patients could have a 
Cycle 1 Ctrough PK sample missing or outside of the accepted window, due to 
early withdrawal or other reasons.  Every effort will be made to collect PK 
samples on schedule.  Those patients are excluded from the analysis 
population.  
o 
Summary measure:  Geometric mean ratio (GMR) and 90% CI of atezolizumab SC 
versus atezolizumab IV of Cycle 1 Ctrough.  The non-inferiority would be established if 
the lower bound of the 90% CI is ≥ 0.8. 
 
Co-Primary Estimand 2: 
o 
Population:  Patients with locally advanced or metastatic NSCLC who are CIT-
naive and for whom prior platinum therapy has failed.  The analysis population will 
consist of thePK Evaluable population, with patients grouped according to their 
received treatments.  
o 
Variable:  Model-predicted Cycle 1 AUC0–21 d derived from the popPK model. 
o 
Treatment:  same as for co-primary endpoint Cycle 1 observed serum Ctrough 
o 
Intercurrent Events and Handling Strategy: 
▪ 
Absence of post-treatment PK blood sample:  Some patients could 
discontinue the study following their Cycle 1 dose prior to providing a post-


 
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baseline PK blood sample or PK blood samples could not be collected.  
Considering the short interval between the first study drug treatment (Cycle 1) 
and the first PK blood sample (8+/- 2 hours) as well as the numerous PK blood 
samples collected on study, these situations are expected to be exceptional.  
Those patients are excluded from the analysis population. 
▪ 
Premature discontinuation from treatment:  Every effort will be made to 
ensure all randomized patients will receive the study drug treatment and 
corresponding PK sample collected.  Treatment will start within 5 days of 
randomization.  Withdrawal after randomization, prior to baseline treatment is 
not expected.  In case of such an event, those patients are excluded from the 
analysis population and those patients will not be replaced 
▪ 
Missing or inaccurate time and date reported for treatment administration 
or PK blood samples:  Every effort will be made to ensure all randomized 
patients will receive the treatment and will have the time and date of dosing and 
PK blood samples reported accurately.  Missing or inaccurate dosing time and 
date can occur during any cycle however, it is very rare.  In case of such an 
event, only such affected samples are excluded, and patients are retained as 
long as they have a single reportable dose and corresponding PK sample, 
regardless of the cycle. 
o 
Summary measure:  GMR and 90% CI of atezolizumab SC versus atezolizumab IV 
of Cycle 1 model predicted AUC0-21d.  The non-inferiority would be established if the 
lower bound of the 90% CI is ≥ 0.8. 
5.3.2 
Main Analytical Approach for Co-Primary Endpoints 
The primary analysis of Ctrough will be based on logarithmic values of observed Ctrough in 
Cycle 1 to compensate the known skewness of its distribution.  For natural logarithm 
(Ln) trough plasma concentration (Ctrough), the statistical hypothesis will be tested using 
an analysis of covariance model  
Ln(Ctrough)ij =  + i + ij     (i=SC, IV; j=1, 2, …, ni) 
where µ denotes the overall mean, τi the effect of atezolizumab route of administration i 
(SC or IV), ni the number of patients in arm i (SC or IV), and εij a random error variable 
assumed to be  independently and identically normally distributed with mean zero and 
variance 2. 
The contrast SC – IV, its 90% confidence limits, and the variance 2 will be estimated 
from the model.  An estimate of the treatment effects ratio and the corresponding 90% 
confidence limits for the untransformed variables will be calculated by exponentiation of 
the estimate of contrast SC – IV and the 90% confidence limits.  The CV for the 
untransformed primary variable will be estimated using the relationship 
CV  sqrt(exp(2)-1).  


 
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If the lower confidence interval bound of exp(Ln[Ctrough,SC]-Ln[Ctrough,IV])Ctrough,SC/Ctrough,IV 
is equal or greater than 0.8, then the null hypothesis can be rejected (see Section 2).  
The model-predicted Cycle 1 AUC0–21 d is a co-primary endpoint and will be analyzed 
using the same method as for the other co-primary endpoint, Cycle 1 observed 
serum Ctrough. 
The co-primary endpoints will be statistically tested at the same  level 
(one-sided significance level of 0.05) using the Hochberg procedure as described in 
Section 2.1. 
 
5.3.3 
Supplementary Analysis for Co-Primary Endpoints 
A supplementary sensitivity analysis may be conducted on Cycle 1 Ctrough values derived 
from the popPK model.  The aim of using predicted Ctrough is to take into account possible 
deviations from the protocol (i.e., sampling schedule or dosing interval) and to reduce 
noise (i.e., precision of analytical measurement). 
The Cycle 1 Ctrough values derived from the popPK model is a different estimand with 
respect to the observed serum Ctrough.  The attributes such as treatment and summary 
measure have the same definition as the primary endpoint (Ctrough), while the population 
and intercurrent events will be defined and handled using the same approach and 
strategies specified for the model-predicted Cycle 1 AUC.   
5.4 
SECONDARY ENDPOINTS ANALYSES 
The following secondary endpoints will be analyzed outside of a hypothesis-testing 
framework and according to the methodology provided below. 
5.4.1 
PK Analyses 
For secondary PK and popPK analyses, the PK evaluable population will be used.  
Model- predicted Ctrough at Cycle 1 (Ctrough Cycle 1), model-predicted Ctrough at steady 
state (Ctrough,ss), and model-predicted AUC at steady state (AUCss) will be descriptively 
compared between atezolizumab SC and IV. 
The PK data will be analyzed using statistical summary measures, listings, and graphs 
as appropriate, documented in more detail in a Clinical Pharmacology Analysis Plan 
(2022), and also reported in a standalone PK report.  
5.4.2 
Efficacy Analyses 
The Response-evaluable population will be used for key secondary endpoint analysis of 
objective response rate (ORR) whilst a subset who achieved objective response, will be 
used for duration of response (DOR).  The Full Analysis Set will be used for key 
secondary endpoint analyses such as progression-free survival (PFS) and overall 
survival (OS).  The analysis mentioned below will be performed at the time of primary 


 
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analysis and at the end of the study.  However, efficacy endpoints at the time of primary 
analysis given the nature of the trial and extremely small follow-up time will be immature.  
Therefore, for the primary analysis, secondary endpoints will be descriptively compared 
between atezolizumab SC and IV, followed by more formal analysis in the final report, 
which will include more follow-up time. 
5.4.2.1 
Objective Response Rate 
The analysis population for ORR will be the Response-evaluable population.  Patients 
not meeting the criteria for ORR, including patients without any post baseline tumor 
assessment, will be considered non-responders. 
Following the estimand framework (ICH 2020), the attributes of the estimand for the 
secondary endpoint are defined as follows: 
 
Population:  All randomized patients with measurable disease at baseline included 
in the Response-evaluable population.  
 
Variable:  ORR, defined as the proportion of patients with a CR or PR, as 
determined by the investigator according to RECIST v1.1. 
 
Treatment:  As defined for the primary estimand  
 
Intercurrent events and Handling Strategy: 
o 
Use of any non-protocol anti-cancer treatment (NPT) prior to disease 
progression as detailed in Protocol Section 4.4.3.  
o 
Discontinuation of study treatment prior to disease progression  
o 
ICE Handling Strategy:  Following treatment policy, all the ICE’s will be 
ignored, and tumor assessment data collected after the ICE will be included in 
the ORR analysis. 
 
Population-level summary:  Difference in proportion. 
 
The ORR and 95% confidence intervals according to Clopper-Pearson will be calculated 
and presented by treatment arm.  For the difference in response rates, 95% two-sided 
confidence intervals (Hauck-Anderson) will be calculated.  The above analysis will be 
repeated as apart of sensitivity analysis for confirmed ORR (CR or PR on two 
consecutive occasions   28 days apart, as determined by the investigator according to 
RECIST v1.1.) 
5.4.2.2 
Progression-Free Survival 
Following the estimand framework (ICH 2020), the attributes of the estimand for the 
secondary endpoint are defined as follows: 
 
Population:  All randomized patients with locally advanced or metastatic NSCLC 
who are CIT-naive and for whom prior platinum therapy has failed.   
 
Variable:  PFS, defined as the time from the date of study entry to the date of 
documented disease progression, as determined by the investigator according to 
RECIST v1.1, or death from any cause, whichever is earlier. 


 
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 
Treatment:  As defined for the primary estimand.  
 
Intercurrent events and Handling Strategy: 
o 
Use of any non-protocol anti-cancer treatment (NPT) prior to disease 
progression as detailed in Protocol Section 4.4.3.  
o 
Discontinuation of study treatment prior to disease progression  
o 
ICE Handling Strategy:  Following treatment policy, all the ICE’s will be 
ignored, and observations collected after the ICE will be included in the PFS 
analysis. 
 
Population-level summary:  Median duration and corresponding 95% CI. 
 
If participants have any intercurrent event(s), then the strategies defined above to handle 
the intercurrent events will be implemented.  Otherwise, data for participants without the 
occurrence of disease progression or death as of the clinical cutoff date (CCOD) will be 
censored at the time of the last tumor assessment prior to the CCOD (or at the time of 
randomization plus 1 day if no tumor assessment was performed after the baseline visit).  
PFS will be analyzed using Kaplan-Meier methodology, including survival plots, median 
duration and corresponding 95% confidence intervals according to the 
Brookmeyer- Crowley method (Brookmeyer and Crowley, Biometrics 1982).  
The proportion of patients who are PFS event-free at 6 and 12 months after study entry 
will be estimated at the final analysis of the study when sufficient follow-up data are 
available.  The corresponding 95% CI will be calculated using the standard error derived 
from Greenwood’s formula.  The hazard ratio (HR), and 95% CI for descriptive 
comparison will be estimated using a Cox regression model. 
At the time of final analysis, additional sensitivity analyses of PFS may be conducted as 
appropriate in order to investigate the effect of baseline characteristics imbalances 
(if any) on the result.  
5.4.2.3 
Overall Survival 
Following the estimand framework (ICH 2020), the attributes of the estimand for the 
secondary endpoint are defined as follows: 
 
Population:  All randomized patients with locally advanced or metastatic NSCLC 
who are CIT-naive and for whom prior platinum therapy has failed.   
 
Variable:  OS, defined as the time from randomization to death from any cause 
 
Treatment:  As defined for the primary estimand  
 
Intercurrent events and Handling Strategy: 
o 
Use of any non-protocol anti-cancer treatment (NPT) prior to disease 
progression as detailed in Protocol Section 4.4.3.  
o 
Discontinuation of study treatment prior to disease progression  


 
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o 
ICE Handling Strategy:  Following treatment policy, all the ICE’s will be 
ignored, and observations collected after the ICE will be included in the OS 
analysis. 
 
Population-level summary:  Median duration and corresponding 95% CI. 
 
If participants have any intercurrent events, then the strategies defined above to handle 
the intercurrent events will be implemented.  Otherwise, data for patients who are alive 
at the time of the analysis data cutoff will be censored at the last date they were known 
to be alive.  Data from patients without postbaseline information will be censored at the 
date of randomization plus 1 day.  OS will be analyzed using Kaplan-Meier methodology, 
including survival plots, median duration and corresponding 95% confidence intervals 
according to the Brookmeyer- Crowley method 
(Brookmeyer and Crowley, Biometrics 1982).  The proportion of patients alive at one and 
two years after study entry will be estimated at the final analysis of the study when 
sufficient follow-up data are available.  The corresponding 95% CI will be calculated 
using the standard error derived from Greenwood’s formula.  The hazard ratio (HR), and 
95% CI for descriptive comparison will be estimated using a Cox regression model. 
At the time of final analysis, additional sensitivity analyses of OS may be conducted as 
appropriate in order to investigate the effect of baseline characteristics imbalances 
(if any) on the result.  
5.4.2.4 
Duration of Response  
Analysis of DOR will include only patients who had an objective response.  Patients who 
have not progressed and who have not died at the time of analysis will be censored at 
the time of last tumor assessment date.  If no tumor assessments were performed after 
the date of the first occurrence of a complete or partial response, DOR will be censored 
at the date of the first occurrence of a complete or partial response plus 1 day.   
Following the estimand framework (ICH 2020), the attributes of the estimand for the 
secondary endpoint are defined as follows: 
 
Population:  All patients with a measurable disease at baseline and a post-baseline 
objective response. 
 
Variable:  DOR, defined as the time interval from the date of the first occurrence of 
a complete or partial response (whichever status is recorded first) until the first date 
that progressive disease or death is documented, whichever occurs first.  
 
Treatment:  As defined for the primary estimand  
 
Intercurrent events and Handling Strategy: 
o 
Use of any non-protocol anti-cancer treatment (NPT) prior to disease 
progression as detailed in Protocol Section 4.4.3.  
o 
Discontinuation of study treatment prior to disease progression  


 
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o 
ICE Handling Strategy:  Following treatment policy, all the ICE’s will be 
ignored and observations collected after the ICE will be included in the DOR 
analysis. 
 
Population-level summary:  Median duration and corresponding 95% CI. 
 
DOR is based on a non-randomized subset of patients (specifically, patients who 
achieved an objective response); therefore, formal hypothesis testing will not be 
performed for this endpoint.  Comparisons between treatment arms will be made for 
descriptive purposes.  The methodologies detailed for the PFS analysis will be used for 
the DOR analysis.  The HR and 95% CI for descriptive comparison will be estimated 
using a Cox regression model. 
The above analysis will be repeated for confirmed objective response as defined in 
Section 5.4.2.1, above. 
5.4.3 
Patient Reported Outcomes 
An additional secondary objective for Part 2 is to evaluate patient experience with 
atezolizumab SC compared with atezolizumab IV, based on the following endpoints: 
 
Functioning and global health status over time, as assessed by the physical 
functioning, role functioning, and global health status/quality of life scales of the 
EORTC interleukin 57 (IL57) 
 
Overall satisfaction with treatment, as assessed by the modified satisfaction with 
therapy (SWT) scale of the Cancer Therapy Satisfaction Questionnaire (CTSQ) 
Descriptive analyses, including summary statistics, will be performed, and presented by 
treatment arm for each patient-reported experience measure (item- and scale-level, as 
appropriate).  Item-level analyses will include frequencies and proportions and change 
from baseline at each visit by treatment arm.  Summary statistics (e.g., mean, median, 
minimum, maximum, interquartile range) of scale scores and score changes from 
baseline at each visit will be evaluated by treatment arm. 
For each of the EORTC scales, a prorated scale score will be calculated if 50% or more 
of the constituent items in the scale are completed.  The scale score will be considered 
missing if  50% of the constituent items were not completed.  A SWT scale score will be 
calculated if five or more items have been completed (out of seven).  The scale score 
will be considered missing if fewer than five items have been completed. 
PRO completion, compliance rates, and reasons for missing data will be summarized at 
each time point by treatment arm for each measure in full analysis set.  The compliance 
rate will be based on the total number of patients expected to complete the questionnaire 
at a particular time point. 


 
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5.4.4 
Safety Analysis 
A secondary objective for Part 2 is to evaluate the safety of atezolizumab SC compared 
with atezolizumab IV on the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
NCI CTCAE v5.0 
 
Overall patient-reported adverse event burden over time, as assessed by the patient 
global impression of cancer treatment side effects burden item from the European 
Organization for Research and Treatment of Cancer (EORTC) IL57 
The safety analysis population will consist of all patients who received at least one dose 
of study drug and will be grouped according to actual treatment received. 
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  Laboratory toxicities will be defined based on local 
laboratory normal ranges and NCI CTCAE, v5.0.  
Overall patient-reported adverse event burden over time, as assessed by the patient 
global impression of cancer treatment side effects burden item from the European 
Organization for Research and Treatment of Cancer (EORTC) IL57 will be summarized 
descriptively, as described in Section 5.4.3. 
5.4.5 
Immunogenicity Analyses 
A secondary objective for Part 2 is to evaluate the incidence of anti-drug antibodies 
(ADAs) to the tested molecules on the basis of the following endpoint: 
 
Incidence of ADAs to atezolizumab after SC administration or IV administration 
relative to the prevalence of ADAs at baseline 
 
Incidence of ADAs to rHuPH20 after SC administration relative to the prevalence of 
ADAs at baseline 
 
The atezolizumab and rHuPH20 Post-treatment ADA-evaluable population will consist of 
all patients with at least one post-treatment ADA assessment.  Patients will be grouped 
according to treatment received.  Baseline prevalence will be summarized according to 
treatment received for all Safety-evaluable patients. 
The number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized for ADA-evaluable patients.  When determining post-baseline 
incidence, patients are considered to be ADA-positive if they are ADA-negative or have 
missing data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA-positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Patients are considered to 
be post-treatment ADA-negative if they are ADA-negative or have missing data at 


 
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baseline and all post-baseline samples are negative, or if they are ADA-positive at 
baseline but do not have any post-baseline samples with a titer that is at least 0.60 titer 
unit greater than the titer of the baseline sample (treatment unaffected). 
Demographic and baseline characteristics in ADA-evaluable patients will be summarized 
by treatment arm (as appropriate).   
5.5 
EXPLORATORY ENDPOINTS ANALYSIS 
5.5.1 
Exploratory PK Analysis 
Exploratory exposure response analyses may be performed to link atezolizumab 
exposure (e.g., Ctrough, Cmax, and AUC Cycle 1) to safety and efficacy endpoints.  
These analyses will be reported separately from the clinical study report (CSR). 
5.5.2 
Exploratory Immunogenicity Analysis 
The exploratory immunogenicity objective for Part 2 is to evaluate potential effects of 
ADAs based on the following endpoint: 
 
Relationship between post-baseline ADA status and PK, safety, or efficacy 
endpoints 
 
5.5.3 
Exploratory Biomarker Analysis 
The exploratory biomarker objective for Part 2 is to evaluate biomarkers that may be 
predictive of response to atezolizumab (i.e., predictive biomarkers), are early surrogates 
of efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to atezolizumab, 
can provide evidence of atezolizumab activity (i.e., pharmacodynamic biomarkers), or 
can increase the knowledge and understanding of disease biology.  They will be 
evaluated based on the following endpoint: 
 
Relationship between biomarkers in tumor tissue (listed in the Protocol 
Section 4.5.7) and efficacy, or other biomarker endpoints  
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies, and reported separately from the primary CSR.  
5.6 
OTHER SAFETY ANALYSES 
5.6.1 
Extent of Exposure 
The number of patients who experience a dose delay, dose interruption, dose 
discontinuation, and reasons for the study treatment discontinuation will be summarized 
by treatment arm.  Descriptive statistics will be presented for number of cycles received, 
total cumulative dose, dose intensity, and weeks of exposure. 


 
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5.6.2 
Adverse Events 
Verbatim descriptions of treatment-emergent AEs will be mapped to MedDRA thesaurus 
terms and graded according to the NCI CTCAE v5.0.  All treatment-emergent adverse 
events (events occurring on or after the first study drug treatment up to the data cutoff 
date) will be summarized by mapped term, appropriate thesaurus level, NCI CTCAE 
grade and treatment arm.  In addition, common adverse events serious adverse events, 
severe adverse events (Grade  3), adverse events of special interest, and adverse 
events leading to study drug discontinuation or interruption will be summarized.  Multiple 
occurrences of the same event will be counted once at the maximum severity. 
All deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion or discontinuation and the causes of death 
will be summarized by treatment arm. 
5.6.3 
Laboratory Data 
Clinical laboratory tests will be performed at local laboratories.  Laboratory abnormalities 
will be defined based on local laboratory normal ranges and NCI CTCAE v5.0.  Select 
laboratory abnormalities such as worst toxicity grade and toxicity grade shift from 
baseline will be summarized by treatment arm.  Relevant change from baseline will be 
summarized by treatment arm.  
Patients who meet Hy’s law criteria will be listed and summarized by treatment arm. 
5.6.4 
Vital Signs 
Vital signs (including systolic and diastolic blood pressure, pulse rate, and body 
temperature) and physical measurements (including body weight and height) recorded 
before administration of the study treatment will be listed and summarized with changes 
from baseline.  Vital signs collected at unscheduled visits will be excluded from the 
summary table.  The mean, standard deviation, median, and minimum and maximum 
values will be presented by treatment arm.  A table of clinically significant abnormal 
values by time and by treatment arm will also be presented, as well as, a shift table from 
baseline versus worst post-baseline value will be presented by treatment arm. 
5.7 
OTHER ANALYSES 
5.7.1 
Summaries of Conduct of Study 
The number of patients randomized in part 2 of the study, discontinue from the study, or 
complete the study will be summarized.  Reasons for patient discontinuations from the 
study treatment and from the study will be presented in listings and summary tables.  
Protocol deviations will be evaluated for their potential effects on the interpretation of 
study results, and reasons for exclusion of patients from the analyses will be presented. 


 
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5.7.2 
Summaries of Treatment Group Comparability  
The evaluation of treatment group comparability between the two treatment arms will 
include summaries of demographics and baseline characteristics, medical history, and 
concomitant medications. 
Demographic and baseline characteristics will be summarized using descriptive statistics 
(e.g., means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate).  Summaries will be presented by 
treatment arm. 
Baseline will be defined as the last available assessment prior to study entry.  Study 
entry is defined as the date they were enrolled into the study according to the IxRS. 
5.7.3 
Health Care Professional Reported Experience  
Descriptive summaries for each item in the HCP questionnaire will be presented by 
country or region and by other categories, as appropriate, for all HCPs who completed at 
least one question in a questionnaire. 
5.7.4 
Analyses of Subgroups of Interest 
In Part 2, data on secondary endpoints may be analyzed in patient subgroups by, e.g., 
demographic or baseline prognostic characteristics.  These analyses will be performed 
in an exploratory manner.   
5.7.5 
Analyses of China Subpopulation 
The China subpopulation will include all patients randomized at qualified sites in China.  
Data for the China subpopulation may be analyzed descriptively as appropriate using the 
same statistical methods as described in Section 5.  No formal statistical analysis on the 
co-primary endpoints will be performed for China subpopulation.  Results from these 
analyses may be summarized in a separate Clinical Study Report addendum.   
6. 
SUPPORTING DOCUMENTATION 
For Synopsis, Schedule of assessments, PRO forms, etc. refer to study protocol. 


 
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31 
 
Appendix 1 Re-estimation of Study Sample Size 
A total of 327 patients were initially planned to be randomized in Part 2 of the study.  
This sample size would provide sufficient power for the statistical hypothesis test for the 
co-primary endpoints, based on the assumptions detailed in Section 3 of the SAP. 
The study protocol stated that the total number of patients to be enrolled in Part 2 of the 
study might be increased or decreased after comparing the values assumed for sample 
size calculations (CV for observed Ctrough and model-predicted AUC, correlation between 
both co-primary endpoints and percentage of randomized patients not evaluable for the 
PK co-primary endpoints) with the values actually observed in a blinded sample-size 
re- estimation planned to be conducted after approximately 210250 patients have been 
randomized. 
This blinded estimation of PK parameters was provided by an external vendor when a 
total of 256 patients were randomized, 197 of whom had completed the 1st Cycle and 
had PK data available at the Clinical Cut-Off Date (CCOD) of November 1st, 2021.  
The PK-evaluable population (subset of randomized patients with PK data and no major 
protocol deviation) included 150 patients.  The following blinded summary data was 
shared by external vendor, and was utilized for sample size estimation: 
 
Highest Coefficient of variation (CV%) of geometric mean observed Cycle 1 
Ctrough in any treatment arms:  56.8%;  
 
Highest CV% of geometric mean model-predicted Cycle 1 AUC0–21d in 
any treatment arms: 39.8%;  
 
Positive correlation between Cycle 1 AUC0–21d and Cycle 1 Ctrough: 0.787;  
 
PK-unevaluable rate: 23.9% 
 
Under the same assumptions made in the original sample size calculation and replacing 
the expected CV’s(%) and correlation between PK endpoints with the observed values 
reported above, it was estimated that a total sample size of  270 pharmacokinetic (PK) 
evaluable patients would provide at least 80% power to conclude non-inferiority of 
Cycle 1 observed Ctrough,SC and model-predicted AUC0–21 d, SC with a non-inferiority 
margin of 0.8 for the GMR, or more concisely: Ctrough,SC  0.8 Ctrough,IV and 
AUC0– 21 d, SC  0.8 AUC021 d, IV.   
Further, to account for the increase in PK-unevaluable dropout rate (20% initially 
assumed vs. 23.9% observed (including missing samples)) in the blinded review, the 
minimum sample size needed for this study was increased to 355 patients.  Following 
the process described in Joint Monitoring Committee (JMC) charter 
(The Joint Monitoring Committee Agreement, 14 July 2021) this decision to increase the 
sample size was discussed in the JMC meeting on 09 February 2022 and the JMC 
approval to increase the sample size was documented and archived in TMF.   


 
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7. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982; 38:29-41. 
Clinical Pharmacology Analysis Plan  Clinical Pharmacology Analysis for 
Subcutaneous Atezolizumab in Patients With Previously Treated Locally Advanced 
or Metastatic Non-Small Cell Lung Cancer. February 2022. 
[FDA] U.S. Food and Drug Administration Multiple Endpoints in Clinical Trials, Guidance 
for Industry [resource on the Internet] 2017 [cited: 15 January 2021]. Available 
from: https://www.fda.gov/regulatory-information/search-fda-
guidance- documents/multiple-endpoints-clinical-trials-guidance-industry.  
Hochberg Y, Tamhane AC. Multiple Comparison Procedures. New York: John Wiley & 
Sons, 1987. 
International Council for Harmonisation (ICH). E9 (R1) addendum on estimands and 
sensitivity analysis in clinical trials to the guideline on statistical principles for 
clinical trials. 2020. 
The Joint Monitoring Committee Agreement for Study BP40657, 14 July 2021. 


Signature Page for Study BP40657 (IMscin001) SAP v3 - Published
System identifier: RIM-CLIN-442265
Approval Task
Company Signatory
06-Jun-2022 13:40:29 GMT+0000