Clinical trial NCT02927301
Conditions: Non-Small Cell Lung Cancer
Sponsor: Genentech, Inc.
Start date: 2017-04-20; Completion date: 2023-09-05
Enrollment: 181 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was designed to evaluate the safety and efficacy of neoadjuvant and adjuvant atezolizumab in participants with resectable Non-Small Cell Lung Cancer (NSCLC). Neoadjuvant therapy consisted of two 21-day cycles with atezolizumab. Following surgery, adjuvant therapy consisted of up to 12 months of atezolizumab in participants who demonstrate clinical benefit with neoadjuvant therapy. All participants who undergo surgery entered a surveillance period, which consisted of standardized blood sample collection and Chest CT Scans, for up to 2 years. All participants were monitored for disease recurrence and survival for up to 3 years after last dose of study drug.

Detailed description:

Arms: arm 1: Participants received two cycles of atezolizumab as neoadjuvant therapy prior to surgery. Participants who demonstrated clinical benefit were eligible to receive up to 12 months of atezolizumab.
Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
Intervention descriptions: intervention 1: Atezolizumab was given as 1200 milligrams (mg) via intravenous (IV) infusion on Day 1 of each 21-day cycle.

Protocol documents:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
Atezolizumab—Genentech, Inc.
1/Protocol ML39236, Version 7 
PROTOCOL
TITLE:
A PHASE II, OPEN-LABEL, MULTICENTER, 
SINGLE-ARM STUDY TO INVESTIGATE THE EFFICACY 
AND SAFETY OF ATEZOLIZUMAB AS NEOADJUVANT 
AND ADJUVANT THERAPY IN PATIENTS WITH STAGE 
IB, II, IIIA OR SELECTED IIIB RESECTABLE AND 
UNTREATED NON-SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
ML39236
VERSION NUMBER:
7
EUDRACT NUMBER:
Not applicable
IND NUMBER:
117296
NCT NUMBER:
NCT02927301
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, PA-C, MMSc
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  11 May 2016
DATES AMENDED:
Version 2:  21 September 2016
Version 3:  30 August 2017
Version 4:  08 November 2018
Version 5:  22 July 2019
Version 6: 11 February 2021
Version 7: See electronic date stamp below
 
Approver's Name
Title
Date and Time (UTC)
15-Feb-2022 19:44:00


Atezolizumab—Genentech, Inc.
2/Protocol ML39236, Version 7 
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
The protocol has been amended to update the risks associated with the use of 
atezolizumab as per the Atezolizumab Investigator’s Brochure v18.  In addition, the 
protocol was updated to align text with the company’s most recent model document.  
Sections throughout the protocol have been updated accordingly and include the 
following:

The atezolizumab risk language was updated throughout to align with the 
Atezolizumab Investigator’s Brochure v18 (Appendix 9).
–
Throughout the protocol, the term “immune-related hepatitis” was changed to 
“immune-mediated hepatitis.

The following revisions were made to align text with the most recent internal model 
document:
–
A COVID-19 benefit-risk assessment was added as per a company policy 
enacted since version 6 of this protocol (Section 1.3).
–
Requirements for Medical Monitor approval of Investigator decisions 
concerning the handling of study treatment or other procedures were removed, 
and text was added indicating that Investigators may discuss situations with 
Medical Monitor for guidance (Sections 3.1.4 and 4.4.1; Appendices 1 and 2).  
–
In the permitted therapies, the vaccinations (e.g., influenza, COVID-19) allowed 
were modified, and megestrol acetate (appetite stimulant) was added.  In 
addition, the phrase “for adrenocortical insufficiency” was removed from the 
mineralocorticoid therapy (Section 4.4.1).
–
In the prohibited therapies, the text concerning live attenuated vaccines has 
been revised (Section 4.4.3).
–
Standard text concerning COVID-19 screening before and during study 
participation as well as text concerning the association between COVID-19 and 
cytokine-release syndrome (CRS) were added per a company policy enacted 
since version 6 of this protocol (Section 5.1).
–
Text concerning systemic immune activation was removed as this information 
is covered in Appendix 9 (Section 5.1.1).
–
The text concerning treatment interruptions was revised to include additional 
information concerning the acceptable length of treatment interruptions 
(Section 5.1.2.1).
–
A sentence was added to clarify how cases of late-onset cytokine reaction 
syndrome (CRS) are to be reported in the case report forms (Section 5.3.5.1).
–
The name of the reporting form, “Serious Adverse Event/Adverse Event of 
Special Interest Reporting” form, was changed to “Clinical Trial Adverse 
Event/Special Situations” form (Sections 5.4.2.1, 5.4.2.2, and 5.6).


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–
Language was added concerning collecting and reporting infant health 
information, if permitted by the site and both parents, of infants from a 
pregnancy occurring during the study or within 5 months after the final dose of 
atezolizumab (Sections 5.4.3.1 and 5.5.1).
–
The phrase “and review” was added to source data verification (i.e., “source 
data verification and review”) (Section 7.3).
–
In the final sentence concerning compliance, “and applicable local, regional, 
and nation laws” was added (Section 8.1). 
–
The term “a Child’s Informed Assent Form” was revised to “an Assent Form” 
(Section 8.2.).
–
Additional references were added to support newly added text (Section 10).
–
Minor updates were made to the Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1) language (Appendix 6).
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—Genentech, Inc.
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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 23
1.1
Background on Non-Small Cell Lung Cancer ........................ 23
1.2
Background on Atezolizumab................................................ 23
1.2.1
Summary of Nonclinical Studies............................................ 24
1.2.2
Clinical Experience with Atezolizumab .................................. 25
1.2.2.1
Clinical Safety........................................................................ 25
1.2.2.2
Clinical Activity....................................................................... 29
1.2.2.3
Clinical Pharmacokinetics and Immunogenicity..................... 31
1.3
Study Rationale and Benefit-Risk Assessment...................... 31
2.
OBJECTIVES AND ENDPOINTS ............................................................... 35
3.
STUDY DESIGN......................................................................................... 36
3.1
Description of the Study......................................................... 36
3.1.1
Overview of Study Design ..................................................... 36
3.1.2
Neoadjuvant Atezolizumab Therapy Phase........................... 41
3.1.3
Surveillance........................................................................... 42
3.1.4
Adjuvant Atezolizumab Therapy Phase................................. 43
3.1.5
Data Review .......................................................................... 43
3.2
End of Study and Length of Study......................................... 44
3.3
Rationale for Study Design.................................................... 44
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 44
3.3.2
Rationale for Patient Population ............................................ 45
3.3.3
Rationale for Biomarker Assessments................................... 45
4.
MATERIALS AND METHODS .................................................................... 47
4.1
Patients.................................................................................. 47
4.1.1
Inclusion Criteria.................................................................... 47
4.1.2
Exclusion Criteria................................................................... 49
4.2
Method of Treatment Assignment and Blinding..................... 51
4.3
Study Treatment.................................................................... 51


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4.3.1
Formulation, Packaging, and Handling.................................. 52
4.3.2
Dosage, Administration, and Compliance.............................. 52
4.3.3
Investigational Medicinal Product Accountability ................... 54
4.3.4
Post-Trial Access to Atezolizumab ........................................ 54
4.4
Concomitant Therapy ............................................................ 54
4.4.1
Permitted Therapy................................................................. 54
4.4.2
Cautionary Therapy ............................................................... 56
4.4.3
Prohibited Therapy ................................................................ 56
4.5
Study Assessments ............................................................... 56
4.5.1
Informed Consent Forms and Screening Log........................ 56
4.5.2
Prescreening Tumor Biopsy .................................................. 57
4.5.3
Medical History and Demographic Data ................................ 57
4.5.4
Physical Examinations........................................................... 58
4.5.5
Vital Signs.............................................................................. 58
4.5.6
Tumor and Response Evaluations......................................... 58
4.5.7
Other Disease-Specific Assessments.................................... 60
4.5.8
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 60
4.5.8.1
Tissue Sample Prioritization .................................................. 64
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 65
4.6.1
Patient Discontinuation.......................................................... 65
4.6.2
Atezolizumab Treatment Discontinuation .............................. 65
4.6.3
Study and Site Discontinuation.............................................. 66
5.
ASSESSMENT OF SAFETY....................................................................... 66
5.1
Safety Plan ............................................................................ 66
5.1.1
Risks Associated with Atezolizumab ..................................... 67
5.1.2
Management of Patients Who Experience 
Specific Adverse Events........................................................ 67
5.1.2.1
Atezolizumab Dose Modification and Treatment 
Interruption ............................................................................ 67
5.2
Safety Parameters and Definitions ........................................ 68
5.2.1
Adverse Events ..................................................................... 68


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5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 69
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 69
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 70
5.3.1
Adverse Event Reporting Period ........................................... 70
5.3.2
Eliciting Adverse Event Information....................................... 72
5.3.3
Assessment of Severity of Adverse Events ........................... 72
5.3.4
Assessment of Causality of Adverse Events ......................... 73
5.3.5
Procedures for Recording Adverse Events............................ 73
5.3.5.1
Infusion-Related Reactions.................................................... 74
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 74
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 74
5.3.5.4
Persistent or Recurrent Adverse Events................................ 75
5.3.5.5
Abnormal Laboratory Values ................................................. 75
5.3.5.6
Abnormal Vital Sign Values ................................................... 76
5.3.5.7
Abnormal Liver Function Tests.............................................. 76
5.3.5.8
Deaths ................................................................................... 77
5.3.5.9
Preexisting Medical Conditions.............................................. 77
5.3.5.10
Lack of Efficacy or Worsening of Non-Small Cell 
Lung Cancer.......................................................................... 77
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 78
5.3.5.12
Adverse Events Associated with an Accidental 
Overdose or Medication Error in Drug 
Administration........................................................................ 78
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 79
5.4.1
Emergency Medical Contacts................................................ 80
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 80
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 80
5.4.2.2
Events That Occur after Study Drug Initiation........................ 80
5.4.3
Reporting Requirements for Pregnancies.............................. 81
5.4.3.1
Pregnancies in Female Patients............................................ 81


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5.4.3.2
Abortions ............................................................................... 81
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 82
5.4.4
Reporting Requirements for Special Situations 
and Non-Serious Adverse Events Associated 
with a Special Situation.......................................................... 82
5.5
Follow-Up of Patients after Adverse Events .......................... 82
5.5.1
Investigator Follow-Up........................................................... 82
5.5.2
Sponsor Follow-Up ................................................................ 82
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 82
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 83
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 83
6.1
Determination of Sample Size ............................................... 83
6.2
Summaries of Conduct of Study............................................ 84
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 85
6.4
Efficacy Analyses .................................................................. 85
6.4.1
Primary Efficacy Endpoint...................................................... 85
6.4.2
Secondary Efficacy Endpoints............................................... 85
6.4.3
Exploratory Efficacy Endpoints.............................................. 86
6.5
Safety Analyses..................................................................... 86
6.6
Biomarker Analyses............................................................... 86
6.7
Interim Analyses .................................................................... 87
6.7.1
Planned Interim Analyses...................................................... 87
6.7.1.1
Planned Interim Safety Analysis............................................ 87
6.7.1.2
Planned Interim Efficacy Analysis.......................................... 87
6.7.2
Optional Interim Analyses...................................................... 87
7.
DATA COLLECTION AND MANAGEMENT ............................................... 87
7.1
Data Quality Assurance......................................................... 87
7.2
Electronic Case Report Forms............................................... 88
7.3
Source Data Documentation.................................................. 88


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7.4
Use of Computerized Systems .............................................. 89
7.5
Retention of Records............................................................. 89
8.
ETHICAL CONSIDERATIONS.................................................................... 89
8.1
Compliance with Laws and Regulations ................................ 89
8.2
Informed Consent.................................................................. 90
8.3
Institutional Review Board or Ethics Committee.................... 91
8.4
Confidentiality........................................................................ 91
8.5
Financial Disclosure .............................................................. 92
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 92
9.1
Study Documentation ............................................................ 92
9.2
Protocol Deviations................................................................ 92
9.3
Site Inspections ..................................................................... 92
9.4
Administrative Structure......................................................... 92
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 93
9.6
Protocol Amendments ........................................................... 94
10. REFERENCES ........................................................................................... 95
LIST OF TABLES
Table 1
Adverse Events Reported in 10% of Patients in Study 
PCD4989g .................................................................................. 27
Table 2
Treatment-Related Adverse Events Reported in at Least 10% 
of Patients in Either Treatment Arm in Study GO28753 
(POPLAR)................................................................................... 28
Table 3
Objectives and Corresponding Endpoints................................... 35
Table 4
Proposed Biomarkers for Exploratory Research......................... 63
Table 5
Reporting Requirements After Initiation of Study Drug (by 
Treatment Subgroup).................................................................. 71
Table 6
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 72
Table 7
Causal Attribution Guidance ....................................................... 73
Table 8
Simulated Probabilities of Stopping at the Interim and Final 
analysis for Different Values of Major Pathologic Response....... 84


Atezolizumab—Genentech, Inc.
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LIST OF FIGURES
Figure 1
Study Schema............................................................................. 39
Figure 2
Surveillance Flow Chart with Treatment Subgroups ................... 40
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 98
Appendix 2
Timing of Surveillance Assessments ........................................ 105
Appendix 3
Schedule of Biomarker Samples............................................... 114
Appendix 4
American Joint Committee on Cancer Non-Small Cell Lung 
Cancer Staging, 8th Edition ...................................................... 116
Appendix 5
Pathological Response ............................................................. 118
Appendix 6
Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)........................................................................... 119
Appendix 7
Eastern Cooperative Oncology Group Performance Status...... 129
Appendix 8
Anaphylaxis Precautions........................................................... 130
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 131
Appendix 10
Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor) ......................................................................... 158
Appendix 11
Protocol Version 3 Schedule of Activities.................................. 159


Atezolizumab—Genentech, Inc.
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PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE II, OPEN-LABEL, MULTICENTER, 
SINGLE-ARM STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF ATEZOLIZUMAB AS 
NEOADJUVANT AND ADJUVANT THERAPY IN 
PATIENTS WITH STAGE IB, II, IIIA, OR 
SELECTED IIIB RESECTABLE AND UNTREATED 
NON-SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
ML39236
VERSION NUMBER:
7
EUDRACT NUMBER:
Not applicable
IND NUMBER:
117296
NCT NUMBER:
NCT02927301
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
 PA-C, MMSc
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor.






Atezolizumab—Genentech, Inc.
13/Protocol ML39236, Version 7 
with curative intent will be enrolled to receive two doses of atezolizumab as neoadjuvant 
therapy.  Primary and secondary efficacy analyses, safety analyses, and exploratory biomarker 
analyses will be conducted on this cohort.  
All patients who undergo surgery will enter a Surveillance period and will be monitored for 
disease recurrence using extended chest CT and serial blood samples for biomarker 
assessments for up to 2 years after surgery.  Patients who do not undergo surgery will move to 
Survival Follow-up.
Patients who undergo surgery and receive adjuvant atezolizumab therapy will enter the 
Adjuvant Atezolizumab Therapy Phase.  The Adjuvant Atezolizumab Therapy Phase is 
exploratory and will evaluate atezolizumab adjuvant therapy for up to a maximum of 12 months 
(up to 18 cycles) in patients who demonstrate clinical benefit (evidence of pathologic response 
or absence of radiographic progression) from the Neoadjuvant Atezolizumab Therapy Phase.  
After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without 
radiation) before starting atezolizumab adjuvant therapy.  Any adjuvant treatment (optional SOC 
chemotherapy radiotherapy and/or adjuvant atezolizumab) will be done concomitantly with 
Surveillance.  
For clarity of assessments during the Surveillance phase, patients will be grouped by adjuvant 
treatment: 

Subgroup A:  No Adjuvant Treatment

Subgroup B:  Adjuvant Atezolizumab Treatment

Subgroup C:  SOC Chemotherapy (Radiotherapy) Only

Subgroup D:  SOC Chemotherapy (Radiotherapy) + Adjuvant Atezolizumab Treatment
Neoadjuvant treatment (Neoadjuvant Atezolizumab Therapy Phase) with atezolizumab 1200 mg 
q21d (one cycle 21 days) will be given for a maximum of 2 cycles, and adjuvant treatment 
(Adjuvant Atezolizumab Therapy Phase) with atezolizumab 1200 mg q21d will be given for 
maximum of 12 months. 
Patients could be asked to consent to an optional prescreening tumor biopsy, which will then be 
used for tissue analysis if the patient is eligible to participate in the study based on 
pathologically documented NSCLC and other eligibility criteria.  This prescreening consent form 
also includes optional collection of bronchial brushing samples and lymph nodes (see 
Section 4.5.8 and Appendix 3 for details of sample collection).  
Additionally, patients whose disease progresses or recurs anytime between the neoadjuvant 
phase and end of surveillance period will be asked to consent to an optional tissue biopsy 
(tumor and lymph node, if available) at the time of progression/recurrence.  Images will be 
collected at the time of progression and reviewed.
Patients will be closely monitored for safety and tolerability throughout the study.  Safety 
assessments will include collection and monitoring of adverse events and laboratory 
abnormalities graded per the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory safety assessments will include 
the regular monitoring of hematology and blood chemistry.  Tumor tissue samples, normal lung 
parenchyma, whole blood samples, and optional lymph node samples will be collected for 
biomarker assessments. 
After Surveillance completion, patients will enter the Survival Follow-up period and will be 
followed per SOC, but information on cancer-treatment, recurrence and survival will be collected 
every 6 months for up to 3 years after the patient receives the last dose of atezolizumab on 
study.  Patients who discontinue the study due to adverse events will be followed until resolution 
or stabilization of the adverse event.  
Neoadjuvant Atezolizumab Therapy Phase
During this phase of the study, patients will have their NSCLC assessed by CT scan of the 
chest (with IV contrast), PET/CT, and brain MRI (preferably with gadolinium).  The CT and PET 
CT images will be collected and reviewed for further analyses.  Brain imaging may be omitted 
for patients with clinical Stage IB tumors but should be obtained for patients with clinical Stages 
II, IIIA, and selected IIIB tumors.  If brain MRI is not feasible for technical or patient-related 
reasons (e.g., pacemaker, severe claustrophobia), brain CT scan with IV contrast should be 


Atezolizumab—Genentech, Inc.
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obtained.  Tumor biopsy, whole blood samples, optional lymph node samples, and optional 
bronchial brushings will be obtained before treatment with atezolizumab.  Either archival or 
newly collected sections of tumor biopsy will be formalin-fixed and fresh frozen.  Optional lymph 
nodes will be sectioned for preparation in media and formalin-fixed. 
Pretreatment whole blood will be used for IMMUNOME, and processed for plasma, serum, 
normal control DNA, and peripheral blood mononuclear cells (PBMC) for correlative studies.  
Patients will receive two doses of atezolizumab administered 3 weeks apart before surgical 
resection.  Patients who have radiologic progression prior to the second dose will be 
discontinued from atezolizumab and the patient will not have surgical resection as part of this 
study.
Surgical Resection
Following induction therapy in the Neoadjuvant Atezolizumab Therapy Phase, patients will 
undergo surgical resection of the primary tumor and associated lymph nodes.  
Repeat chest CT scan, PET/CT scan, and MRI of the brain will be obtained prior to surgical 
resection and collected for review.  
Resection may be accomplished via an open or minimally invasive procedure (i.e., thoracotomy, 
sternotomy, clamshell or hemiclamshell incisions; or video assisted thoracic surgery (VATS) or 
robotically assisted VATS.
Pathologic complete resection of the primary tumor (R0) should be performed.  Anatomic 
resection via segmentectomy, lobectomy, bilobectomy or pneumonectomy is strongly preferred 
although wedge resection is acceptable for very small (2 cm or less) tumors located peripherally 
where wedge resection permits a wide margin (at least 1 cm in all directions).
Hilar and mediastinal lymph node dissection or sampling should be performed.  For right sided 
resections, this involves at least lymph nodes from levels 4R, 7, 10R, and 11R.  For left sided 
resections, this involves at least lymph nodes from levels 5/6, 7, 10L, and 11L.  Patients in 
whom a complete resection is not achieved will be discontinued from the study and will be 
replaced.
Pathologic specimens will undergo standard histopathologic and immunohistochemical 
evaluation for lung cancer.  Tumor, normal lung parenchyma, and draining lymph nodes will be 
harvested immediately after resection.  Sections of tumor will be fresh frozen and formalin-fixed 
for correlative studies.  Sections of lymph nodes will be freshly prepared in media and 
formalin-fixed for correlative studies.  Sections of adjacent normal lung tissue will be 
formalin-fixed for correlative studies.  Sections of tumor, adjacent normal lung tissue, and lymph 
node may be freshly dissociated for correlative studies. 
Whole blood samples will be collected at the time of surgical resection for correlative studies.  
The blood will be used for IMMUNOME and processed for PBMC, plasma, and serum for 
correlative studies.
At the postoperative follow-up visit, patients whose tumors have not demonstrated evidence of 
pathologic response or who have radiographic progression will have an end-of-study treatment 
(atezolizumab) visit, after which they will enter Surveillance for 2 years then Survival Follow-up 
for 1 year. 
Whole blood will be collected at postoperative follow-up visit and will be processed for plasma, 
serum, and PBMC for correlative studies.
Surveillance
All patients who undergo surgery will enter the Surveillance Period.  During Surveillance, 
patients will be monitored by extended chest CT scans (including liver and adrenals).  Whole 
blood will be collected for plasma and serum, and PBMCs (at selected timepoints) every 
6 weeks to 3 months for 2 years for correlative studies.  Upon completion of Surveillance, 
patients enter Survival Follow-up.  Patients whose disease progresses or recurs during 
Surveillance will discontinue from Surveillance and enter Survival Follow-up. 
For patients previously enrolled under Protocol Version 3 or earlier:

If the patient re-consents under Protocol Version 4 3 months after the Post-surgery Visit: 
patient will not enter Surveillance and will follow the schedule of activities from Protocol 
Version 3.


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
If the patient re-consents under Protocol Version 4 at any time between Screening and the 
Post-surgery Visit: patient will be offered to enter Surveillance and follow Protocol Version 4 
schedule of activities.

If the patient re-consents under Protocol Version 4 3 months after the Post-surgery Visit: 
patient will be offered to enter Surveillance and follow Protocol Version 4 schedule of 
activities only if post-surgery baseline chest CT scan is available.  If chest CT scan is not 
available, patient will follow the schedule of activities from Protocol Version 3.
Adjuvant Atezolizumab Therapy Phase
Patients whose tumors have evidence of pathologic response or lack of radiographic 
progression will be eligible for the Adjuvant Atezolizumab Therapy Phase, which will occur 
during the Surveillance period.  
During this part of the study, patients will receive adjuvant atezolizumab for up to a maximum of 
12 additional months (up to 18 cycles).  Adjuvant atezolizumab treatment may be started 
directly after surgery or after adjuvant SOC chemotherapy (with or without radiation).  Choice of 
adjuvant SOC chemotherapy will be at the discretion of the treating physician, depending on the 
disease stage, as deemed clinically appropriate.  It is highly recommended that any adjuvant 
treatment be initiated within 120 days after surgery.  Additionally, it is recommended that 
patients who receive SOC Chemotherapy (Radiotherapy) initiate adjuvant atezolizumab within 
60 days of SOC ChemotherapyRadiotherapy (whichever occurs last).  If adjuvant treatment is 
planned to start outside of the recommended window, Investigators may discuss it with the 
Medical Monitor.
Whole blood samples will be collected prior to infusion on adjuvant Cycle 1, Day 1.  Subsequent 
blood samples will be collected during Surveillance and 30 days after the last dose for 
correlative studies.  The blood will be processed for PBMC, plasma, and serum.
Optional bronchial brushings samples may be collected from patients undergoing bronchoscopy 
or EBUS at prescreening or screening and approximately 34 months after starting adjuvant 
atezolizumab treatment (Group D only).
For all patients whose disease progresses or recurs (confirmed by imaging) at any time
between neoadjuvant treatment and surveillance may undergo an optional tissue biopsy (tumor 
and lymph node, if available) for correlative studies, which will require a separate ICF signature.  
A blood sample will also be collected at the time of disease progression/recurrence.
All patients will enter Survival Follow-up, which will cover new anti-cancer treatment, DFS, and 
OS for up to 3 years after the last dose of atezolizumab.
Data Review 
A review committee will be used to review data as specified in the Pathology Review Charter 
and Steering Committee Charter.  This committee will include Genentech study team members, 
study investigators, and may also include external consultants, as needed.
Number of Patients
Approximately 180 patients with NSCLC will be enrolled in this study at approximately 15 study 
centers in the United States.
Target Population
Inclusion Criteria
Neoadjuvant Atezolizumab Therapy Phase
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Able to comply with the study protocol, in the investigator’s judgment

Pathologically documented NSCLC


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Stage IB, II, IIIA, or selected IIIB, including T3N2 or T4 (by size criteria, not by mediastinal 
invasion) NSCLC (based on the 8th edition of the American Joint Committee on Cancer 
[AJCC] Non-Small Cell Lung Cancer Staging system).  Note: Patients may be enrolled 
based on clinical stage, but documentation of nodal involvement by endobronchial 
ultrasound (EBUS) or mediastinoscopy for patients with clinical Stage II and IIIA disease is 
encouraged. 

Measurable disease, as defined by RECIST v1.1 

NSCLC must have a solid or subsolid appearance on CT scan and cannot have a purely 
ground glass opacity (GGO) appearance.  For subsolid lesions, the tumor size (i.e., clinical 
T stage) should be measured based on the solid component only, exclusive of the GGO 
component

Evaluated by the operating attending surgeon prior to study enrollment to verify that the 
primary tumor and any involved lymph nodes are technically completely resectable

Adequate pulmonary function to be eligible for surgical resection with curative intent 
–
Pulmonary function tests (PFTs) must have been performed within 6 months of planned 
resection and repeated at screening and should include lung volumes, spirometry, and 
a diffusion capacity.  Abnormal PFTs may be further evaluated with quantitative 
ventilation/perfusion scanning or cardiopulmonary exercise testing.  Postoperative 
percent predicted forced expiratory volume in 1 second (FEV1) and diffusion capacity 
must be 40% and/or maximal oxygen consumption (VO2 max) should be 
10 mL/kg/min.

Adequate cardiac function to be eligible for surgical resection with curative intent 
–
If clinically indicated, patients with underlying ischemic or valvular heart disease should 
be evaluated preoperatively by a cardiologist.

Availability of at least 2 cores of a pre-treatment formalin-fixed, paraffin-embedded (FFPE) 
biopsy and at least 1 core of fresh frozen biopsy of the primary tumor (archival sample) or 
willing to undergo an additional core needle biopsy (CNB; preferred method) or EBUS, or 
bronchoscopy (acceptable alternative) to provide newly collected samples. 
–
For core biopsies, needle sizes of 1618 gauge are preferred.  If a 19 gauge or smaller 
needle is used, consider adding another pass. In addition, to ensure a quality tissue 
sample, a rapid on-site evaluation (ROSE) methodology is highly recommended to 
evaluate the adequacy of the sample. 
–
If sample is collected during EBUS, at least 3 passes are requested (1922 gauge 
needle can be used)

ECOG Performance Status of 0 or 1 

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to the first dose of atezolizumab:
–
ANC 1500/L
–
Platelet count 100,000/L
–
Hemoglobin 9.0 g/dL; patients may be transfused to meet this criterion.
–
AST and ALT 2.5 upper limit of normal (ULN)
–
Serum bilirubin 1.5 ULN
–
Serum creatinine 3.0 mg/dL

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% per year 
during the treatment period and for at least 5 months after the last dose of atezolizumab.  
Women must refrain from donating eggs during this same period.
–
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).


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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.
Adjuvant Atezolizumab Therapy Phase

ECOG Performance Status of 0 or 1

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained per SOC prior to the starting adjuvant atezolizumab in the Adjuvant Atezolizumab 
Therapy Phase:
–
ANC 1500/L
–
Platelet count 100,000/L
–
Hemoglobin 9.0 g/dL; patients may be transfused to meet this criterion
–
AST and ALT 2.5 ULN
–
Serum bilirubin 1.5 ULN
–
Serum creatinine 3.0 mg/dL
Exclusion Criteria
Neoadjuvant Atezolizumab Therapy Phase
Patients who meet any of the following criteria will be excluded from study entry:

NSCLC that is clinically T4 by virtue of mediastinal organ invasion or Stage IIIB by virtue of 
N3 disease

Any prior therapy for lung cancer, including chemotherapy, hormonal therapy, or 
radiotherapy, within 3 years

Patients with prior lung cancer that have been in remission for 3 years

Prior treatment with anti-PD-1 or anti-PD-L1 therapies or pathway-targeting agents

Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation

Major surgical procedure within 28 days prior to Cycle 1, Day 1

Malignancies other than the disease under study within 3 years prior to Cycle 1, Day 1, with 
the exception of patients with a negligible risk of metastasis or death and with expected 
curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or 
squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, 
or ductal carcinoma in situ treated surgically with curative intent) or undergoing active 
surveillance per SOC management (e.g., Rai Stage 0 chronic lymphocytic leukemia, 
prostate cancer with Gleason score 6, and prostate-specific antigen (PSA 10 ng/mL, etc.)

Treatment with systemic immunosuppressive medications (e.g., prednisone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor 
[anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1


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Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea or premedication for contrast dye 
allergy) are eligible.
–
The use of inhaled corticosteroids for chronic obstructive pulmonary disease (COPD) 
and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or 
adrenocortical insufficiency is allowed.

History or risk of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid 
disease, vasculitis, or glomerulonephritis
–
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible.
–
Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible.
–
Patients with eczema, psoriasis, or lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible 
provided they meet the following conditions:
Rash must cover 10% of body surface area (BSA)
Disease is well controlled at baseline and only requiring low potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 
0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
No acute exacerbations of underlying condition within the last 12 months (requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, high potency or oral steroids)

History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or 
evidence of active pneumonitis on screening chest CT scan

Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, 
cirrhosis, fatty liver, and inherited liver disease

History of HIV infection

Active hepatitis B (chronic or acute) defined as having a positive hepatitis B surface antigen 
(HBsAg) test at screening
–
Patients with past or resolved hepatitis B infection (defined as having a negative HBsAg 
test and a positive total hepatitis B core antibody (HBcAb) test eligible.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test and 
a positive HCV RNA test at screening

Active tuberculosis

Administration of a live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks before 
Cycle 1, Day 1 or at any time during the study
–
Influenza vaccination should be given during influenza season only 
(approximately October to March).  

Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited 
to hospitalization for complications of infection, bacteremia, or severe pneumonia

Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
–
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or COPD) are eligible.

Treatment with an investigational agent for any condition within 4 weeks prior to Cycle 1, 
Day 1 (or within five half-lives of the investigational product, whichever is longer)

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Pregnant or lactating, or intending to become pregnant during the study


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Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of atezolizumab.
Adjuvant Atezolizumab Therapy Phase

Progressive or recurrent disease as documented by CT (per RECIST v1.1 criteria) at the 
end of SOC adjuvant therapy
–
Patients with radiographic progression and no evidence of pathologic response of the 
study during the neoadjuvant phase are not eligible for the Adjuvant Atezolizumab 
Therapy Phase.
End of Study
The end of this study is defined as the date when the last data point required for survival 
follow-up is received from the last patient.  This is expected to occur approximately 3 years after 
the last patient receives the last dose of adjuvant atezolizumab.
The Neoadjuvant Atezolizumab Therapy Phase will end when the last data point required for 
primary efficacy analysis (i.e., pathology evaluation at time of surgery) is obtained.  This is 
expected to occur approximately 30 days after the last patient’s surgery.  
The Surveillance period will end 2 years after the post-surgery visit.
After completing neoadjuvant or adjuvant treatment with atezolizumab, patients will be followed 
for survival for up to 3 years.  For patients that undergo surgery and enter Surveillance, time in 
surveillance will overlap with time in survival follow-up.  
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is atezolizumab.
The dose of atezolizumab in this study will be 1200 mg administered by IV infusion q21d (one 
cycle 21 days). 
In the Neoadjuvant Atezolizumab Therapy Phase, neoadjuvant treatment with atezolizumab 
1200 mg will be given q21d (2 days) for a maximum of 2 cycles.  In the Adjuvant Atezolizumab 
Therapy Phase, adjuvant treatment with atezolizumab 1200 mg will be given q21d (3 days) for 
maximum of 12 months.
Administration of atezolizumab will be performed on an outpatient basis in a setting with 
emergency medical facilities and staff who are trained to monitor for and respond to medical 
emergencies.  
Premedication may be administered for any atezolizumab infusions after Cycle 1.
The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first infusion is 
tolerated without infusion-associated adverse events, the second infusion may be delivered 
over 30 (10) minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may 
be delivered over 30 (10) minutes.  If the patient had an infusion-related reaction during 
previous infusion, the subsequent infusion must be administered over 60 (15) minutes.  
For the first infusion, the patient’s vital signs should be measured within 60 minutes before the 
infusion and during and after the infusion, if clinically indicated.  For subsequent infusions, vital 
signs will be collected within 60 minutes before the infusion and at the end of the infusion, as 
clinically indicated.
Patients may need to remain in the clinic post-infusion for monitoring of side effects, if needed.
Patients will be informed about the possibility of delayed post-infusion symptoms and instructed 
to contact their study physician if they develop such symptoms.
Guidelines for the management of infusion-related reactions are provided in the protocol.


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Statistical Methods
Efficacy Analyses
The primary and secondary efficacy analyses will include all enrolled patients who have 
received at least one dose of the study drug and who do not have EGFR or ALK mutant tumors 
(efficacy population).  
Primary Efficacy Endpoint
The effectiveness of the atezolizumab will be assessed by major pathologic response rate in the 
efficacy population, excluding patients who have not received surgery after neoadjuvant 
treatment with atezolizumab.  A statistical test of a single proportion of major pathologic 
response rate will be tested against the alternative that the rate is 15%.  If the null hypothesis is 
rejected then this is evidence that the response rate exceeds 5% when atezolizumab is given 
before resection.  The one-sided 95% confidence interval (CI) for major pathologic response will 
be reported.
Determination of Sample Size
The primary objective of this study is to determine the major pathologic response rate.  If there 
is evidence that the major pathologic response rate is at least 15% then there will be further 
consideration for the testing of atezolizumab in neoadjuvant lung cancer.  This is a single-arm 
study, and all patients will be treated with atezolizumab.  The primary endpoint is assessed by a 
statistical test of a single proportion of responders against the simple alternative of 5% response.  
This design provides 95% statistical power to detect a difference of 10% (15% vs. 5%) at a 
significance level of 0.05 (1-sided test, variance of the test statistic calculated under the 
alternative hypothesis).  To achieve this, approximately 180 patients will be enrolled in this 
study.  At the final analysis (after 180 patients are enrolled), if there are at least 17 patients who 
respond then the statistical test rejects the null hypothesis of a 5% response rate in favor of a 
higher response rate.
This study includes one interim analysis to assess futility after 90 patients are assessed.  The 
non-binding futility interim boundary satisfies conditional power of 0.30.  Thus, the probability 
that the statistical test at the final analysis will be significant at the specified power and test level 
is at least 0.30, conditional on the data available at the time of the interim analysis.  At the 
interim analysis, if there are seven or fewer responders out of 90 patients then the conditional 
power of the study drops below 0.30, and enrollment into the study may be terminated. 
Differential response by PD-L1 status (positive vs. negative) will also be assessed.  While the 
composition of PD-L1 status in this patient population is not known, the study will aim to include 
at least 60 PD-L1-positive patients.  With 60 patients, the one-sided 95% CI excludes 20% if the 
major pathologic response rate is 30% (18 responders out of 60 patients).  Final enrollment 
numbers may be expanded accordingly.
Interim Analyses
The interim analyses described below will be performed.  The study will continue during the 
interim analyses.
Planned Interim Safety Analysis
There is not yet extensive data on the safety of thoracic surgical resections after treatment with 
checkpoint inhibitors.  Therefore, after the first 30 patients who complete protocol-specified 
atezolizumab treatment and have undergone the planned surgical resection of their tumor, the 
patient cohort will be evaluated for tolerability and safety of the neoadjuvant regimen.  If, at the 
time of the safety interim analysis, three or more patients have experienced Grade 5 adverse 
events related to protocol treatment, then the study will be discontinued.
Planned Interim Efficacy Analysis 
The study includes one interim analysis to assess futility after 90 patients are assessed.  The 
non-binding futility interim boundary satisfies conditional power at a cut-off of 0.30.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
BSA
body surface area
CNB
core needle biopsy
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
DFS
disease-free survival
DLT
dose-limiting toxicity
EBUS
endobronchial ultrasound
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
U.S. Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FFPE
formalin-fixed, paraffin-embedded
GGO
ground glass opacity
HLH
hemophagocytic lymphohistiocytosis
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
ICH
International Conference on Harmonisation
IF
immunofluorescence
IFN
interferon
IHC
immunohistochemistry
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
ITT
intent-to-treat
IRB
Institutional Review Board


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Abbreviation
Definition
IV
Intravenous
IxRS
interactive voice/web response system
K-M
Kaplan-Meier
MAS
macrophage activation syndrome
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
next-generation sequencing
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PET
positron emission tomography
PFS
progression-free survival
PFT
pulmonary function test
PK
pharmacokinetic
PR
partial response
q21d
every 21 days
q3w
every 3 weeks
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RT-PCR
reverse transcriptase polymerase chain reaction
SARS-Cov-2
severe acute respiratory syndrome coronavirus 2
SD
stable disease
SITC
Society for Immunotherapy for Cancer
SOC
standard of care
TKI
tyrosine kinase inhibitor
TNF
tumor necrosis factor
UBC
urothelial bladder cancer
UC
urothelial cancer
ULN
upper limit of normal
VATS
video assisted thoracic surgery
VO2
maximal oxygen consumption
WES
whole-exome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON NON-SMALL CELL LUNG CANCER
Lung cancer is the leading cause of cancer death worldwide. In the United States about 
200,000 cases are diagnosed each year with approximately 150,000 deaths occurring 
and a progressive increase in mortality with age (Siegel et al. 2015). Non-small cell lung 
cancer (NSCLC) accounts for approximately 85% of all lung cancers and is divided into 
squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtypes.  The 
majority of patients present with advanced metastatic disease that cannot be cured with 
current therapies.  A minority of patients (about 25%) present with localized disease that 
is sometimes (about 50%) cured by surgical resection.  Of those not cured by surgical 
resection, the majority recur in distant sites that could not be detected prior to surgical 
resection. For these Stage IBIIIA patients, the addition of systemic chemotherapy 
before or after surgery improved 5-year survival rates by about 5% (Pignon et al. 2008).  
Chemotherapy before surgery (neoadjuvant) results in slightly higher response rates 
compared to chemotherapy for advanced stages but there are essentially no complete 
responses (CRs).  Recently, immunotherapy with antibodies that bind to checkpoint 
inhibitors such as programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1)
have been shown to produce long lasting responses in some patients with advanced 
NSCLC who were refractory to standard chemotherapy (Rizvi et al. 2015).  
Subsequent randomized clinical trials showed that these antibodies produce superior 
survival compared to docetaxel chemotherapy in patients who progressed after systemic 
platinum doublet chemotherapy (Borghaei et al. 2015; Brahmer et al. 2015; 
Fehrenbacher et al. 2016).  The clinical benefits were greater in patients with high PD-L1
expression although survival was similar to docetaxel even in patients lacking PD-L1
expression. Early studies with these antibodies in the first line therapy setting showed 
even better results especially in patients with high PD-L1 expression (Gettinger 2015; 
Garon et al. 2015). Because PD-L1 expression is a continuous variable and not a 
perfect predictive biomarker, many investigators are exploring other potential biomarkers 
of predictive therapeutic benefit.  The number of mutations determined by whole-exome 
sequencing (WES) has been shown to perform as another potential predictive biomarker 
(Rizvi et al. 2015). The expression of many other genes and proteins is being explored,
but this is complicated by the lack of tissue and a limited understanding of its association 
with objective response rates (ORR) and survival. 
1.2
BACKGROUND ON ATEZOLIZUMAB
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1. PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is sustained in 
states of chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008). Binding of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of 


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T cells.  B7.1 is a molecule expressed on antigen-presenting cells and activated T cells.  
PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate 
downregulation of immune responses, including inhibition of T-cell activation and 
cytokine production (Butte et al. 2007; Yang et al. 2011).
Overexpression of PD-L1 on tumor cells and the tumor microenvironment has been 
reported to impede anti-tumor immunity, resulting in immune evasion (Blank and 
Mackensen 2007).  Therefore, interruption of the PD-L1/PD-1 pathway represents an 
attractive strategy to reinvigorate tumor-specific T-cell immunity.
Atezolizumab (Tecentriq, formerly MPDL3280A) is a humanized IgG1 monoclonal 
antibody consisting of two heavy chains (448 amino acids) and two light chains 
(214 amino acids), and is produced in Chinese hamster ovary cells.  Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid substitution at 
position 298 on the heavy chain, which results in a non-glycosylated antibody that has 
minimal binding to Fc receptors and prevents Fc-effector function at expected 
concentrations in humans.  Atezolizumab targets human PD-L1 and inhibits its 
interaction with its receptors, PD-1 and B7.1 (CD80, B7-1).  Both of these interactions 
are reported to provide inhibitory signals to T cells.  Direct targeting of PD-L1 leaves the 
PD-L2-PD-1 interaction intact, potentially avoiding effects on immune homoeostasis.
Atezolizumab (Tecentriq) is approved for the treatment 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 atezolizumab for details on 
nonclinical and clinical studies.
1.2.1
Summary of Nonclinical Studies
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab.
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid in
projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 


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with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical studies in patients.
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.
1.2.2
Clinical Experience with Atezolizumab
Atezolizumab clinical data are available from multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  
Single agent safety and efficacy data in patients with lung cancer are presented below 
from the following studies:

Study PCD4989g:  A Phase Ia, multicenter, first-in-human, open label, dose 
escalation study evaluating the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of 
biologic activity of atezolizumab administered as a single agent by IV infusion given 
every 3 weeks (q3w) to patients with locally advanced or metastatic solid 
malignancies or hematologic malignancies.

Study GO28753 (POPLAR):  A randomized, Phase II, open-label study assessing 
the clinical benefit of atezolizumab as a single agent versus docetaxel in 
PD-L1-unselected patients with locally advanced or metastatic NSCLC that has 
progressed during or following treatment with a platinum-containing regimen.

Study GO28754 (BIRCH):  A Phase II, multicenter, single-arm study assessing the 
clinical benefit of atezolizumab as a single agent in PD-L1-selected patients with 
locally advanced or metastatic NSCLC

Study GO28915 (OAK):  A randomized, Phase III, open-label study assessing the 
clinical benefit of atezolizumab as a single agent versus docetaxel in 
PD-L1-unselected patients with locally advanced or metastatic NSCLC that has 
progressed during or following treatment with a platinum-containing regimen.
1.2.2.1
Clinical Safety
Single-Agent Clinical Safety in Patients with Non-Small Cell Lung Cancer in 
Study PCD4989g
Study PCD4989g is a Phase Ia dose escalation and expansion study, in which 
atezolizumab is being used as a single agent in patients with locally advanced or 
metastatic solid tumors or hematologic malignancies, and provides significant data (with
629 safety-evaluable patients across all cancer types as of the data cutoff date of 15
December 2015) for the safety profile of atezolizumab as monotherapy.
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined.
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications, including small-cell lung cancer, NSCLC, urothelial bladder cancer 


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


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Table 1
Adverse Events Reported in 10% of Patients in Study PCD4989g
Preferred Term
All Grades
n (%)
Any adverse event (10% incidence)
592 (94.1%)
Fatigue
248 (39.4%)
Nausea
175 (27.8%)
Decreased appetite
166 (26.4%)
Diarrhea
141 (22.4%)
Constipation
136 (21.6%)
Dyspnea
135 (21.5%)
Pyrexia
134 (21.3%)
Cough
127 (20.2%)
Vomiting
124 (19.7%)
Anemia
121 (19.2%)
Back Pain
111 (17.6%)
Headache
104 (16.5%)
Asthenia
101 (16.1%)
Arthralgia
95 (15.1%)
Pruritus
89 (14.1%)
Rash
82 (13.0%)
Abdominal pain
77 (12.2%)
Edema peripheral 
72 (11.4%)
Urinary tract infection
67 (10.7%)
Insomnia
66 (10.5%)
Dizziness
63 (10.0%)
Single-Agent Clinical Safety in Patients with Non-Small Cell Lung Cancer in 
Study GO28753 (POPLAR)
As of the 1 December 2015 data cutoff date, 142 patients with NSCLC were treated with 
atezolizumab as a fixed dose of 1200 mg IV q3w and 135 patients were treated with 
docetaxel 75 mg/m2 IV q3w in Study GO28753.  The frequency of patients with any 
reported adverse event regardless of attribution was 96% in both arms.  Fewer patients 
in the atezolizumab arm (41%) experienced Grade 34 adverse events compared with 
the docetaxel arm (53%).  For Grade 34 adverse events that were assessed as 
treatment-related, the difference was greater between the two arms (12% vs. 39%, 
respectively).  The most common atezolizumab-related Grade 3 adverse events were 
pneumonia (2%) and increased aspartate aminotransferase (2%).  No


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atezolizumab-related Grade 4 events have been reported.  Treatment-related adverse 
events reported in at least 10% of patients in either treatment arm are listed in Table 2.
Table 2
Treatment-Related Adverse Events Reported in at Least 10% of 
Patients in Either Treatment Arm in Study GO28753 (POPLAR)
MedDRA Preferred Term
Atezolizumab
(n142)
No. (%)
Docetaxel
(n135)
No. (%)
Fatigue
55 (38.7%) 
54 (40.0%)
Decreased appetite
49 (34.5%) 
28 (20.7%)
Nausea
32 (22.5%) 
45 (33.3%)
Cough
40 (28.2%)
33 (24.4%)
Dyspnoea
39 (27.5%)
27 (20.0%)
Constipation
31 (21.8%)
32 (23.7%)
Diarrhoea
25 (17.6%) 
38 (28.1%)
Alopecia
3 (2.1%) 
52 (38.5%)
Anaemia
25 (17.6%)
27 (20.0%)
Pyrexia
24 (16.9%)
16 (11.9%)
Vomiting
20 (14.1%)
18 (13.3%)
Asthenia
15 (10.6%)
22 (16.3%)
Arthralgia
22 (15.5%)
12 (8.9%)
Insomnia
22 (15.5%)
11 (8.1%)
Rash
16 (11.3%)
16 (11.9%)
Back pain
16 (11.3%)
11 (8.1%)
Myalgia
9 (6.3%)
18 (13.3%)
Musculoskeletal pain
19 (13.4%)
7 (5.2%)
Weight decreased
16 (11.3%)
9 (6.7%)
Haemoptysis
15 (10.6%)
8 (5.9%)
Pneumonia
17 (12.0%)
4 (3.0%)
Neuropathy peripheral
3 (2.1%) 
16 (11.9%)
Neutropenia
2 (1.4%) 
17 (12.6%)
Single-Agent Clinical Safety in Patients with Non-Small Cell Lung Cancer in 
Study GO28754 (BIRCH)
As of the 1 December 2015 data cutoff date, 659 patients with NSCLC have been 
treated with atezolizumab as a fixed dose of 1200 mg IV q3w.  In Study GO28754, 
93.8% patients experienced at least one adverse event, 65% of patients experienced 
one treatment-related adverse event, and 12% of patients experienced
Grade 3 treatment-related adverse event.  


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Single-Agent Clinical Safety in Patients with Non-Small Cell Lung Cancer in 
Study GO28915 (OAK)
As of the July 2016 data cutoff date, 609 patients with NSCLC were treated with 
atezolizumab as a fixed dose of 1200 mg IV q3w and 578 patients were treated with 
docetaxel 75 mg/m2 IV q3w in Study GO28915.  Fewer patients in the atezolizumab arm 
(37%) experienced Grade 34 adverse events compared with the docetaxel arm (54%).  
For Grade 34 adverse events that were assessed as treatment-related, the difference 
was greater between the two arms (15% vs. 43%, respectively).  Rates of 
immune-mediated adverse events were low in patients treated with 
atezolizumab pneumonitis (1%), hepatitis (0.3%), and colitis (0.3%).  Adverse 
event-related discontinuation rates were 8% with atezolizumab arm vs. 19% for 
docetaxel arm.
For additional information, refer to the Atezolizumab Investigator’s Brochure.
Single-Agent Clinical Safety in Patients Undergoing Surgery
Based on the mechanism of action and known safety profile of atezolizumab, no major 
complications (pre or post-surgery) are anticipated. The most commonly reported 
immune-mediated events with atezolizumab are dermatologic reactions and laboratory 
abnormalities (changes in liver function tests and thyroid function tests). Given the 
protocol design, short timeframe from atezolizumab administration to surgery, and the 
known longer time to onset of such events, these events are considered unlikely in the 
Neoadjuvant Atezolizumab Therapy Phase of this study (see Section 1.3).
1.2.2.2
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1)-based responses, have been observed in patients with different tumor 
types (including NSCLC, RCC, melanoma, gastric cancer, UBC, colorectal cancer, head 
and neck cancer, breast cancer, and sarcoma) treated with atezolizumab in 
Study PCD4989g.
Refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in all
patients treated to date, regardless of tumor type.
Single-agent data from Studies PCD4989g and GO28754 (BIRCH), and data from the 
randomized Study GO28753 (POPLAR) in patients with advanced NSCLC are 
summarized below.
Single-Agent Clinical Activity in Patients with Non-Small Cell Lung Cancer
in Study PCD4989g
As of the 02 December 2014 cutoff date, 88 patients with NSCLC in Study PCD4989g 
who received their first dose of atezolizumab by 21 October 2013 were evaluable for 
efficacy.  The median age was 60.5 years; the group represented a heavily pre-treated 
patient population.  RECIST responses (confirmed) were observed in 20 of 88 (22.7%) 
patients, inclusive of squamous and non-squamous histologies and across all treatment 


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cohorts (treatment dose levels: 1 to 20 mg/kg).  A total of 8 of the 20 responding 
patients have continued to respond at the time of the clinical data cutoff.
Single-Agent Clinical Activity in Patients with Non-Small Cell Lung Cancer 
in Study GO28753 (POPLAR)
In Study GO28753 (POPLAR), demographic characteristics were comparable between 
the atezolizumab and docetaxel treatment arms in the intent-to-treat (ITT) population.  
The median age was 62 years in both treatment arms, and the majority of patients had 
one prior therapy (65% for atezolizumab and 67% for docetaxel), non-squamous 
histology (66% for atezolizumab and 66% for docetaxel), and Eastern Cooperative 
Oncology Group (ECOG) performance status of 1 (68% for atezolizumab and 68% for 
docetaxel).  More females were enrolled in the docetaxel arm (35% vs. 47%).
At the primary analysis on 8 May 2015, there were 287 efficacy-evaluable patients (ITT 
population), 143 in the docetaxel arm and 144 in the atezolizumab arm. Median OS was 
12.6 months for atezolizumab compared with 9.7 months for docetaxel (HR of 0.73; 95% 
CI:  0.53, 0.99).  Increasing improvement in OS was associated with increasing PD-L1 
expression.  Survival was similar to docetaxel in patients lacking PD-L1 expression and 
improved with atezolizumab in both responders and non-responders.  Progression-free 
survival (PFS) and ORR were similar between the two treatment arms in the ITT 
population (Fehrenbacher et al. 2016).
Single-Agent Clinical Activity in Patients with Non-Small Cell Lung Cancer
in Study GO28754 (BIRCH)
In the BIRCH study, 659 PD-L1-selected patients with advanced NSCLC were treated 
with atezolizumab; 139 patients were naïve to prior chemotherapy (Cohort 1) and 
520 patients had received at least one prior platinum-based chemotherapy regimen 
(Cohorts 2 and 3).  ORR was 19% in Cohort 1 and 17% in the other two cohorts.  The 
majority of responses were ongoing and duration of response and OS data were not 
mature (Besse et al. 2015). 
Single-Agent Clinical Activity in Patients with Non-Small Cell Lung Cancer 
in Study GO28915 (OAK)
In the OAK study, demographic characteristics were comparable between the 
atezolizumab and docetaxel treatment arms in the ITT population.  The majority of 
patients had one prior therapy (75% in both arms), non-squamous histology (74% in 
both arms), history of tobacco use (80% for atezolizumab and 83% for docetaxel), and 
ECOG Performance Status of 1 (64% for atezolizumab and 62% for docetaxel).  
At the primary analysis, there were 850 efficacy-evaluable patients (ITT population):  
425 in the docetaxel arm and 425 in the atezolizumab arm. Median OS in the ITT 
population was 13.8 months for atezolizumab compared with 9.6 months for docetaxel
(HR of 0.73; 95% CI: 0.62, 0.87, p0.0003).  OS benefit was seen regardless of PD-L1 
expression (HR of 0.75 in 1% PD-L1 expression population; 0.41 in 50% tumor cell or 


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10% immune cell expression population) and was consistent across subgroups, 
including histology (HR of 0.73 for both), in patients with asymptomatic central nervous 
system metastases (HR of 0.54) and never smokers (HR of 0.71). PFS and ORR were 
similar between the two treatment arms in the ITT population (Rittmeyer et al. 2017).
1.2.2.3
Clinical Pharmacokinetics and Immunogenicity
On the basis of available preliminary PK data (0.0320 mg/kg), atezolizumab appeared 
to show linear pharmacokinetics at doses 1 mg/kg.  For the 1-mg/kg and 20-mg/kg 
dose groups, the mean apparent clearance and the mean volume of distribution under 
steady-state conditions had a range of 3.20 to 4.44 mL/kg and 48.1 to 65.7 mL/kg, 
respectively, which is consistent with the expected profile of an IgG1 antibody in humans.
Development of anti-therapeutic antibodies (ATAs) has been observed in patients in all 
cohorts in Study PCD4989g and was associated with changes in PK (namely, a 
reduction of atezolizumab Cmin to below the PK assay lower limit of quantification), in
some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of 
detectable ATAs has not had a significant impact on pharmacokinetics for doses from 
10 to 20 mg/kg.  Patients dosed at the 10-, 15-, and 20-mg/kg dose levels have 
maintained the expected target trough levels of drug despite the detection of ATAs.  To 
date, no clear relationship between the detection of ATAs and adverse events, infusion 
reactions, or efficacy has been observed.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
It is hypothesized that administration of atezolizumab, an engineered IgG1 monoclonal 
antibody targeting PD-L1, will demonstrate a good safety profile and produce objective 
responses in clinical Stage IB-IIIA NSCLC, especially in tumors which express PD-L1 
prior to resection. PD-L1 expression by tumor and immune cells results in impaired 
anti-tumor immune responses by inhibiting T-cell proliferation, cytokine production, and 
cytotoxic activity. As a result there is significant interest in developing therapeutics to 
block the immunosuppressive effects of PD-L1 and to identify patients who will benefit 
from this treatment strategy. 
While the addition of adjuvant cisplatin based chemotherapy following surgical resection 
of early stage NSCLC has produced significant survival benefits (Pignon et al. 2008), 
rates of local and distant disease relapse leading to death remain unacceptably high. 
Studies show that neoadjuvant chemotherapy has approximately the same benefit as 
adjuvant (Felip et al. 2010).  Thus, it is critical to investigate the use of atezolizumab and 
similar agents in treating early stage resectable disease where one can assess the 
immune environment before and after treatment. It is also critical to develop highly 
predictive biomarkers of benefit and to study the evolution of immune-related markers 
with treatment with atezolizumab.  
There will be two parts to this study:  the first part (Neoadjuvant Atezolizumab Therapy 
Phase) will evaluate the ability of atezolizumab, an engineered IgG1 monoclonal 


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antibody targeting PD-L1, to produce pathologic responses in the neoadjuvant setting in 
patients with early stage NSCLC who have a pretreatment biopsy.  
The subsequent resection of tumors from these patients will allow determination of 
pathologic response rates and potential predictive biomarkers from the pretreatment 
biopsy and evolution of cancer-/immune-related markers associated with response in the 
tumor biopsy specimen after treatment.  
The primary endpoint of the study will be major pathologic response rate (defined as 10% 
of viable tumor cells) determined from the surgical resection (Hellmann et al. 2014).  In 
addition, response rates according to RECIST v1.1 will be determined from chest CT 
scans obtained before and after the atezolizumab therapy and before surgical resection.  
The images will be collected for further analyses.
The Neoadjuvant Atezolizumab Therapy Phase will only include patients with Stage IB, II, 
IIIA, or selected IIIB disease and who are deemed suitable for surgical resection without 
metastatic disease but with sufficient material for initial biopsy to analyze biomarkers.  
Clinical staging of NSCLC is based on computed tomography (CT) of the chest and 
upper abdomen, positron emission tomography (PET) and brain CT or magnetic 
resonance imaging (MRI) to rule out metastatic disease and assess the potential for 
curative-intent resection.  Resection represents the best chance for prolonged survival 
for patients with non-advanced NSCLC. 
After surgical resection, routine clinical surveillance will involve repeated radiographic 
imaging and monitoring of clinical symptoms for disease recurrence.  All patients that 
complete surgical resection, will be monitored for disease recurrence using extended CT 
scans with IV contrast every 6 weeks to 3 months.  Blood samples will be obtained along 
with chest CT scans to explore the association of blood-based biomarkers, such as 
ctDNA positivity with clinical outcome, for up to 2 years.  Early detection of biomarkers 
that predict relapse of disease may help identify personalized treatment options to limit 
disease recurrence for patients in the future.  Blood-based assay approaches, such as 
detection of circulating tumor DNA (ctDNA), may represent an innovative tool to 
complement disease surveillance in NSCLC.
Following resection, the risk for relapse correlates with clinical and pathological stage, 
but the addition of cisplatin based adjuvant chemotherapy improves survival for patients 
with Stage II and IIIA disease (Pignon et al. 2008), and potentially for some Stage IB 
patients with lesions greater than 4 cm (Butts et al. 2010).  
Therefore, this study will also include a second (exploratory) part, the Adjuvant 
Atezolizumab Therapy Phase, which will enroll patients who demonstrated clinical 
benefit (defined as evidence of pathologic response or absence of radiographic 
progression) with neoadjuvant atezolizumab, to receive up to 12 additional months of 
adjuvant atezolizumab. Patients can choose to receive standard-of-care (SOC) adjuvant 


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chemotherapy (with or without radiation) before receiving atezolizumab post-surgical 
resection.  
There are little data to guide the duration of adjuvant immunotherapy in lung cancer.  An 
ongoing Phase III study is evaluating 12 months of atezolizumab treatment after 
cisplatin-based chemotherapy in patients with completely resected Stage IB–IIIA NSCLC 
with high PD-L1 expression.  Another Phase III study is currently recruiting patients with 
unresectable Stage III NSCLC to receive 1 year of consolidation anti-PD-1 therapy after 
definitive chemo-radiation.  Adjuvant immunotherapy has also been explored in other 
solid tumors.  Adjuvant immunotherapy treatment for 1 year with interferon alfa-2b 
prolongs the relapse-free interval and OS of high-risk resected melanoma patients 
(Kirkwood et al. 1996).  One year of adjuvant anti-PD1 therapy is considered standard of 
care for resected melanoma based on the data from the CHECKMATE-238 study 
(Weber at el. 2017).
Follow-up of all patients will allow for exploration of atezolizumab treatment, as well as 
non-protocol specified, post-study cancer treatment, on long term survival outcomes, 
disease-free survival [DFS], overall survival [OS]) and further improve our understanding 
of predictive biomarkers.
Blood samples, tumor biopsies, normal lung parenchyma, lymph node samples, and 
bronchial brushings will also be obtained for secondary and exploratory laboratory 
studies to evaluate potential predictive and prognostic biomarkers and to assess the 
immune response to atezolizumab as detailed in Section 2.
In the setting of the coronavirus 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or 
how systemic cancer therapies, such as chemotherapy, targeted therapy, or 
immunotherapy, impact the incidence or severity of SARS-CoV-2 infection.
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation 
of the host immune response to acute infection, which may result in immunopathology 
or dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (Frebel et al. 2012).  However, there are insufficient and inconsistent 
clinical data to assess if outcome from SARS-CoV-2 infection is altered by cancer 
immunotherapy.
Severe SARS-CoV-2 infection appears to be associated with a cytokine release syndrome 
(CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)-(Merad and Martin 2020).  While it is not known, there may be a 


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potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute severe acute respiratory syndrome corona virus 2 (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 COVID-19 vaccination, and it is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively impact the efficacy and safety of COVID-19 vaccination 
(Society for Immunotherapy for Cancer [SITC] 2020).
Per recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in 
such patients (NCCN 2021).  Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of COVID-19
vaccination in patients who are receiving cancer immunotherapy (SITC 2020).  For 
patients enrolling in this study and receiving atezolizumab treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving atezolizumab treatment to receive 
COVID-19 vaccination include the following:  the risk of SARS-CoV-2 infection and 
potential benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.  
SITC and NCCN recommendations along with institutional guidelines should be used 
by the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4.1).




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Table 3
Objectives and Corresponding Endpoints (cont.)
ctDNAcirculating tumor DNA; DFSdisease-free survival; IFimmunofluorescence; 
IHCimmunohistochemistry; NCI CTCAE v4.0National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 4.0; NGSnext-generation sequencing; NKnatural killer 
(cells); NSCLCnon–small cell lung cancer; MDSCmyeloid-derived suppressor cell;
ORRobjective response rate; OSoverall survival; PD-L1programmed death ligand 1; RECIST
v1.1Response Evaluation Criteria in Solid Tumors, version 1.1; WESwhole exome sequencing.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase II, open-label, single-arm study, designed to evaluate the efficacy of 
atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, IIIA, or selected IIIB
NSCLC scheduled for curative-intent resection by evaluating response to treatment.  In 
addition, the safety of atezolizumab will be evaluated in this treatment setting.  The study 
is also designed to investigate a number of laboratory correlative studies to further 
define the mechanism of anti-tumor activity of atezolizumab and several potential 
predictive biomarkers, which will help identify patients who are more likely to respond to 
treatment, and to aid in the design of future clinical trials.  A strong correlation between 
PD-L1 expression and response to the anti-PD-1/PD-L1 antibodies has been 
demonstrated (Brahmer et al. 2010; Garon et al. 2015; Vansteenkiste et al. 2015), 
indicating that PD-L1 is potentially useful as a predictive biomarker.  Finally, the study 
will also include DFS and OS as exploratory endpoints. 
Approximately 180 patients with NSCLC will be enrolled in this study at approximately 
15 study centers in the United States.  The study will be conducted in two parts, a 
Neoadjuvant Atezolizumab Therapy Phase and an Adjuvant Atezolizumab Therapy 
Phase.  During the Neoadjuvant Atezolizumab Therapy Phase, approximately 
180 patients with pathologically documented Stage IB, II, IIIA, and selected IIIB NSCLC 
and are eligible for surgical resection with curative intent will be enrolled to receive two 
doses of atezolizumab as neoadjuvant therapy.  Primary and secondary efficacy 
analyses, safety analyses, and exploratory biomarker analyses will be conducted on this 
cohort.  
All patients who undergo surgery will enter a Surveillance period and will be monitored 
for disease recurrence using extended chest CT and serial blood samples for biomarker 
assessments for up to 2 years after surgery.  Patients who do not undergo surgery will 
move directly to Survival Follow-up.
Patients who undergo surgery and receive adjuvant atezolizumab therapy will enter the 
Adjuvant Atezolizumab Therapy Phase (see Section 3.1.4).  The Adjuvant Atezolizumab 
Therapy Phase is exploratory and will evaluate atezolizumab adjuvant therapy for up to 
a maximum of 12 months (up to 18 cycles) in patients who demonstrate clinical benefit 


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(evidence of pathologic response or absence of radiographic progression) from the 
Neoadjuvant Atezolizumab Therapy Phase.  After surgical resection, patients may 
receive SOC adjuvant chemotherapy (with or without radiation) before starting 
atezolizumab adjuvant therapy. Any adjuvant treatment (optional SOC 
chemotherapyradiotherapy and/or adjuvant atezolizumab) will be done concomitantly 
with Surveillance.  
For clarity of assessments during the Surveillance period, patients will be grouped by 
adjuvant treatment (See Figure 2 and Appendix 2): 

Subgroup A: No Adjuvant Treatment

Subgroup B: Adjuvant Atezolizumab Treatment

Subgroup C: SOC Chemotherapy (Radiotherapy) Only

Subgroup D: SOC Chemotherapy (Radiotherapy) Adjuvant Atezolizumab 
Treatment
Neoadjuvant treatment (Neoadjuvant Atezolizumab Therapy Phase) with atezolizumab 
1200 mg q21d (one cycle21 days) will be given for a maximum of 2 cycles, and 
adjuvant treatment (Adjuvant Atezolizumab Therapy Phase) with atezolizumab 1200 mg 
q21d will be given for maximum of 12 months.
Patients could be asked to consent to an optional prescreening tumor biopsy, which will 
then be used for tissue analysis if the patient is eligible to participate in the study based 
on pathologically documented NSCLC and other eligibility criteria. This prescreening 
consent form also includes optional collection of bronchial brushing samples and lymph 
node samples (see Section 4.5.8 and Appendix 3 for details of sample collection).
Additionally, patients whose disease progresses or recurs anytime between the 
neoadjuvant phase and end of Surveillance period will be asked to consent to an 
optional tissue biopsy (tumor and lymph node, if available) at the time of 
progression/recurrence. Images will be collected at the time of progression and 
reviewed.
Patients will be closely monitored for safety and tolerability throughout the study.  Safety 
assessments will include collection and monitoring of adverse events and laboratory 
abnormalities graded per the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).  Laboratory safety assessments will 
include the regular monitoring of hematology and blood chemistry.  Tumor tissue 
samples, normal lung parenchyma, whole blood samples, and optional lymph node
samples will be collected for biomarker assessments. 


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After Surveillance completion, patients will enter the Survival Follow-up period and will 
be followed per SOC, but information on off-protocol cancer treatment, recurrence and 
survival will be collected every 6 months for up to 3 years (see Appendix 2) after the 
patient receives the last dose of atezolizumab on study.  Patients who discontinue the 
study due to adverse events will be followed until resolution or stabilization of the 
adverse event.  
A schedule of activities is provided in Appendix 1.  


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Figure 1
Study Schema
CTcomputed tomography; MRImagnetic resonance imaging; PET positron emission tomography; PFT pulmonary function test; 
SOCstandard of care.
a
Refer to Appendix 2.


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Figure 2
Surveillance Flow Chart with Treatment Subgroups
a Total Surveillance period 2 years.  If patient discontinues treatment for any reason, they should remain in Surveillance until they complete 
2 years and then move to Survival Follow-up.


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3.1.2
Neoadjuvant Atezolizumab Therapy Phase
During this phase of the study, patients will have their NSCLC assessed by CT scan of 
the chest (with IV contrast), PET/CT, and brain MRI (preferably with gadolinium).  The 
CT and PET CT images will be collected and reviewed for further analyses.  Brain 
imaging may be omitted for patients with clinical Stage IB tumors but should be obtained 
for patients with clinical Stages II, IIIA, and selected IIIB tumors.  If brain MRI is not 
feasible for technical or patient-related reasons (e.g., pacemaker, severe claustrophobia), 
brain CT scan with IV contrast should be obtained.  Tumor biopsy, whole blood samples, 
optional lymph node samples and optional bronchial brushings will be obtained before 
treatment with atezolizumab.  Either archival or newly collected sections of tumor biopsy 
will be formalin-fixed and fresh frozen (see Section 4.1.1).  Optional lymph nodes will be 
sectioned for preparation in media and formalin-fixed. 
Pretreatment whole blood will be used for IMMUNOME, and processed for plasma, 
serum, normal control DNA, and peripheral blood mononuclear cells (PBMC) for 
correlative studies.    
Patients will receive two doses of atezolizumab administered 3 weeks apart before 
surgical resection.  Patients who have radiologic progression prior to the second dose
will be discontinued from atezolizumab and the patient will not have surgical resection as 
part of this study. 
Surgical Resection
Following induction therapy in the Neoadjuvant Atezolizumab Therapy Phase, patients 
will undergo surgical resection of the primary tumor and associated lymph nodes.  
Repeat chest CT scan, PET/CT scan, and MRI of the brain will be obtained prior to 
surgical resection and collected for review.  
Resection may be accomplished via an open or minimally invasive procedure 
(i.e., thoracotomy, sternotomy, clamshell or hemiclamshell incisions; or video assisted 
thoracic surgery (VATS) or robotically assisted VATS.
Pathologic complete resection of the primary tumor (R0) should be performed. Anatomic 
resection via segmentectomy, lobectomy, bilobectomy or pneumonectomy is strongly 
preferred although wedge resection is acceptable for very small (2 cm or less) tumors 
located peripherally where wedge resection permits a wide margin (at least 1 cm in all 
directions).
Hilar and mediastinal lymph node dissection or sampling should be performed.  For right 
sided resections, this involves at least lymph nodes from levels 4R, 7, 10R, and 11R.  
For left sided resections, this involves at least lymph nodes from levels 5/6, 7, 10L, and 
11L.  Patients in whom a complete resection is not achieved will be discontinued from 
the study and will be replaced.


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Pathologic specimens will undergo standard histopathologic and immunohistochemical 
evaluation for lung cancer.  Tumor, normal lung parenchyma, and draining lymph nodes 
will be harvested immediately after resection.  Sections of tumor will be fresh frozen and 
formalin-fixed for correlative studies (see Appendix 3).  Sections of lymph nodes will be 
freshly prepared in media and formalin-fixed for correlative studies. Sections of adjacent 
normal lung tissue will be formalin-fixed for correlative studies. Sections of tumor, 
adjacent normal lung tissue and lymph node may be freshly dissociated for correlative 
studies.
Whole blood samples will be collected at the time of surgical resection for correlative 
studies. The blood will be used for IMMUNOME and processed for PBMC, plasma, and 
serum for correlative studies.
At the postoperative follow-up visit, patients whose tumors have not demonstrated 
evidence of pathologic response or who have radiographic progression will have an 
endofstudy treatment (atezolizumab) visit, after which they will enter Surveillance for 
2 years then Survival Follow-up for 1 year.
Whole blood will be collected at postoperative follow-up visit and will be processed for 
plasma, serum, and PBMC for correlative studies.
3.1.3
Surveillance
All patients who undergo surgery will enter the Surveillance Period. During Surveillance, 
patients will be monitored by extended chest CT scans (including liver and adrenals).
Whole blood will be collected for plasma and serum, and PBMCs (at selected 
timepoints), every 6 weeks to 3 months for 2 years for correlative studies (see 
Appendix 2 for details). Upon completion of Surveillance, patients enter Survival 
Follow-up. Patients whose disease progresses or recurs during Surveillance will 
discontinue from Surveillance and enter Survival Follow-up.
For patients previously enrolled under Protocol Version 3 or earlier:

If the patient re-consents under Protocol Version 4 3 months after the 
Postsurgery Visit: patient will not enter Surveillance and will follow the schedule of 
activities from Protocol Version 3 (see Appendix 11).

If the patient re-consents under Protocol Version 4 at any time between Screening
and the Post-surgery Visit: patient will be offered to enter Surveillance and follow 
Protocol Version 4 schedule of activities.

If the patient re-consents under Protocol Version 4 3 months after the 
Postsurgery Visit: patient will be offered to enter Surveillance and follow Protocol 
Version 4 schedule of activities only if post-surgery baseline chest CT scan is 
available. If chest CT scan is not available, patient will follow the schedule of 
activities from Protocol Version 3 (see Appendix 11).


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3.1.4
Adjuvant Atezolizumab Therapy Phase
Patients whose tumors have evidence of pathologic response or lack of radiographic 
progression will be eligible for the Adjuvant Atezolizumab Therapy Phase, which will 
occur during the Surveillance period.  
During this part of the study, patients will receive adjuvant atezolizumab for up to a 
maximum of 12 additional months (up to 18 cycles).  Adjuvant atezolizumab treatment 
may be started directly after surgery or after adjuvant SOC chemotherapy (with or 
without radiation).  Choice of adjuvant SOC chemotherapy will be at the discretion of the 
treating physician, depending on the disease stage, as deemed clinically appropriate.  It 
is highly recommended that any adjuvant treatment be initiated within 120 days after 
surgery.  Additionally, it is recommended that patients who receive SOC Chemotherapy 
(Radiotherapy) initiate adjuvant atezolizumab within 60 days of SOC 
ChemotherapyRadiotherapy (whichever occurs last).  If adjuvant treatment is planned 
to start outside of the recommended window, Investigators may discuss it with the 
Medical Monitor.
Whole blood samples will be collected prior to infusion on adjuvant Cycle 1, Day 1. 
Subsequent blood samples will be collected during Surveillance (see Section 3.1.3) and 
30 days after the last dose for correlative studies.  The blood will be processed for 
PBMC, plasma, and serum.
Optional bronchial brushings samples may be collected from patients undergoing 
bronchoscopy or EBUS at prescreening or screening and approximately 34 months 
after starting adjuvant atezolizumab treatment (Group D only).
For all patients whose disease progresses or recurs (confirmed by imaging) at any time
between neoadjuvant treatment and surveillance may undergo an optional tissue biopsy
(tumor and lymph node, if available) for correlative studies, which will require a separate 
ICF signature (see Section 4.5.1). A blood sample will also be collected at the time of 
disease progression/recurrence.
All patients will enter Survival Follow-up, which will cover new anti-cancer treatment, 
DFS, and OS for up to 3 years after the last dose of atezolizumab (See Appendix 2 for 
details regarding time in Survival Follow-up).
3.1.5
Data Review
A review committee will be used to review data as specified in the Pathology Review 
Charter and Steering Committee Charter.  This committee will include Genentech study 
team members, study investigators, and may also include external consultants, as 
needed.  


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3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last data point required for survival 
follow-up is received from the last patient.  This is expected to occur approximately 
3 years after the last patient receives the last dose of adjuvant atezolizumab.
The Neoadjuvant Atezolizumab Therapy Phase will end when the last data point 
required for primary efficacy analysis (i.e., pathology evaluation at time of surgery) is 
obtained.  This is expected to occur approximately 30 days after the last patient’s 
surgery.  
The Surveillance period will end 2 years after the Post-surgery Visit.
After completing neoadjuvant or adjuvant treatment with atezolizumab, patients will be 
followed for survival for up to 3 years. For patients that undergo surgery and enter 
Surveillance, time in Surveillance will overlap with time in Survival Follow-up (see 
Appendix 2).  
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Atezolizumab Dose and Schedule
The fixed dose of 1200 mg (equivalent to an average body weight-based dose of 
15 mg/kg) was selected on the basis of both nonclinical studies described in 
Section 1.2.1 and available clinical data from Study PCD4989g as described below. 
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors. The 
target trough concentration (Ctrough) was projected to be 6 g/mL on the basis of several 
assumptions, including the following:  1) 95% tumor-receptor saturation is needed for 
efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue 
distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, 
pharmacokinetics, and immunogenicity data. Anti-tumor activity has been observed 
across doses from 1 mg/kg to 20 mg/kg q21d.  The MTD of atezolizumab was not 
reached, and no DLTs have been observed at any dose in Study PCD4989g. Currently 
available PK and ATA data suggest that the 15-mg/kg atezolizumab q3w regimen (or 
fixed-dose equivalent) for Phase II and Phase III studies would be sufficient to both 
maintain Ctrough 6 g/mL and further safeguard against both interpatient variability and 
the potential effect of ATAs that could lead to subtherapeutic levels of atezolizumab 
relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose equivalent).  From 
inspection of available observed Ctrough data, moving further to the 20-mg/kg 


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atezolizumab q3w regimen does not appear to be warranted to maintain targeted Ctrough 
levels relative to the proposed 15-mg/kg atezolizumab q3w level. 
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose or a dose adjusted for weight.  Therefore, a fixed dose 
of 1200 mg has been selected (equivalent to an average body weightbased dose of 
15 mg/kg).  Selection of an every-21-day dosing interval is supported by this preliminary 
PK evaluation.
Refer to the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
3.3.2
Rationale for Patient Population
While the addition of adjuvant cisplatin based chemotherapy following surgical resection 
of early stage NSCLC has produced significant survival benefits (Pignon et al. 2008), 
rates of local and distant disease relapse leading to death remain unacceptably high.  
Studies show that neoadjuvant chemotherapy has approximately the same benefit as 
adjuvant (Felip et al. 2010).  Recently, immunotherapy with antibodies that bind to 
checkpoint inhibitors such as PD-1 and PD-L1 have been shown to produce long lasting 
responses in some patients with advanced NSCLC who were refractory to standard 
chemotherapy (Brahmer et al. 2015).  Therefore this study population was chosen to 
primarily determine the ability of atezolizumab to produce objective responses in patients 
undergoing curative intent surgery for Stage IB-IIIA NSCLC.  This study will also explore 
impact of adjuvant atezolizumab on long term survival outcomes.
3.3.3
Rationale for Biomarker Assessments
It is currently thought atezolizumab functions through preventing suppression of CD8 
cytotoxic T-cell function, but the details of this process as well as the impact of 
atezolizumab on additional immune cell populations is thus far undefined.  Cancer can 
escape the immune system through multiple mechanisms including the manipulation of 
cells with immunosuppressive phenotypes. In addition, it has been shown that elements 
of both the innate and adaptive immune systems have anti-tumor functions. As a result, 
it is necessary to study the global immune modulatory effects of atezolizumab to further 
elucidate its mechanism of action in different patients with lung cancer. 
Furthermore, it has been hypothesized that atezolizumab efficacy shown in 
smoking-associated lung cancer and melanoma is due to the high mutational burden of 
these diseases, leading to the generation of immune stimulating neoantigens.  Recently, 
it has been shown that somatic mutations present within tumor cells are capable of 
eliciting tumor specific T-cell responses (Tran et al. 2014).  The identification of somatic 
mutations in NSCLC producing immune stimulating mutant peptides may help to better 
select patients for treatment with atezolizumab and provide information about potential 
vaccine immunotherapy approaches.  As mentioned previously, the number of mutations 
determined by WES has been shown to perform as another predictive biomarker (Rizvi 


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et al. 2015).  Therefore, WES will be performed with comparison to control normal DNA 
to enable direct determination of mutational load and the spectrum of mutations present 
using tumor tissue and/or blood.  In addition, atezolizumab is proposed to reverse 
exhaustive status of T-cell responses against cancer that was associated with PD-1 
expression (Barber et al. 2006; Dong et al. 2002).  The impact of such mutations on 
treatment with atezolizumab and similar agents is unknown, and their identification could 
help identify patients for treatment.  
Tumor tissue samples will be obtained pre-treatment, at resection and at disease 
progression/recurrence (if available) for, including, but not limited to
immunohistochemistry, immunofluorescence microscopy, next generation sequencing 
(e.g. RNA sequencing, whole exome sequencing, TCR sequencing). Furthermore, 
digital pathology and machine-learning approaches may be applied in this study to 
derive predictive histological signatures or to explore the applicability for digital 
assessment of major pathological response. Adjacent normal lung tissue may be 
obtained at resection to allow comparisons with the tumor immune microenvironment.
Whole blood and lymph nodes will be obtained to analyze, including but not limited to,
changes in the phenotype and function of immune cell subtypes by flow cytometry and 
may be used, but not limited to assess T-cell receptor clonality by NGS, gene expression 
profiling and monitoring of anti-tumor immunity using functional assays.
After surgical resection, routine clinical surveillance involves repeated radiographic 
imaging and monitoring of clinical symptoms for disease recurrence. Blood-based 
biomarkers can help to better understand disease recurrence and improve the 
development of future adjuvant treatment options (Chaudhuri et al. 2017). Blood 
samples obtained during Surveillance will be used for serial ctDNA analysis by NGS and 
may include, but is not limited to, immune profiling by NGS or flow cytometry and 
functional T-cell assays.  
Patients whose disease progresses or recurs anytime between the neoadjuvant phase 
and end of Surveillance will be asked to consent to an optional tissue biopsy (tumor and 
lymph node, if available) at the time of progression or recurrence. The biopsy may be 
used to explore if radiographic findings are consistent with histological presence of tumor 
and/or if the appearance of recurrence was caused by tumor immune infiltration. In 
addition, the tissue may be used for biomarker research to explore mechanisms of 
resistance and recurrence to therapy. This exploratory biomarker analysis will not be 
used for any treatment-related decisions.
See Section 2 for details for secondary and exploratory laboratory analyses. 


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 180 patients with histologically documented Stage IB, II, IIIA, and 
selected IIIB NSCLC and are eligible for surgical resection with curative intent will be 
enrolled in the Neoadjuvant Atezolizumab Therapy Phase of this study.  Approximately 
50 patients who complete neoadjuvant atezolizumab therapy are expected to continue
on to the Adjuvant Atezolizumab Therapy Phase.
4.1.1
Inclusion Criteria
Neoadjuvant Atezolizumab Therapy
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age18 years

Able to comply with the study protocol, in the investigator’s judgment

Pathologically documented NSCLC
–
Stage IB, II, IIIA, or selected IIIB, including T3N2 or T4 (by size criteria, not by 
mediastinal invasion) NSCLC (based on the 8th edition of the American Joint 
Committee on Cancer [AJCC] Non-Small Cell Lung Cancer Staging system; 
see Appendix 4).  Note:  Patients may be enrolled based on clinical stage, but 
documentation of nodal involvement by endobronchial ultrasound (EBUS) or 
mediastinoscopy for patients with clinical Stage II and IIIA disease is 
encouraged. 

Measurable disease, as defined by RECIST v1.1 

NSCLC must have a solid or subsolid appearance on CT scan and cannot have a 
purely ground glass opacity (GGO) appearance.  For subsolid lesions, the tumor 
size (i.e., clinical T stage) should be measured based on the solid component only, 
exclusive of the GGO component

Evaluated by the operating attending surgeon prior to study enrollment to verify that 
the primary tumor and any involved lymph nodes are technically completely 
resectable

Adequate pulmonary function to be eligible for surgical resection with curative intent 
–
Pulmonary function tests (PFTs) must have been performed within 6 months of 
planned resection and repeated at screening and should include lung volumes, 
spirometry, and a diffusion capacity.  Abnormal PFTs may be further evaluated 
with quantitative ventilation/perfusion scanning or cardiopulmonary exercise 
testing.  Postoperative percent predicted forced expiratory volume in 1 second
(FEV1) and diffusion capacity must be 40% and/or maximal oxygen 
consumption (VO2 max) should be 10 mL/kg/min.


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
Adequate cardiac function to be eligible for surgical resection with curative intent 
–
If clinically indicated, patients with underlying ischemic or valvular heart disease
should be evaluated preoperatively by a cardiologist.

Availability of at least 2 cores of a pre-treatment formalin-fixed, paraffin-embedded 
(FFPE) biopsy and at least 1 core of fresh frozen biopsy of the primary tumor
(archival sample) or willing to undergo an additional core needle biopsy (CNB; 
preferred method), EBUS, or bronchoscopy (acceptable alternatives) to provide 
newly collected samples.
–
For core biopsies, needle sizes of 1618 gauge are preferred. If a 19 gauge or 
smaller needle is used, consider adding another pass. In addition, to ensure a 
quality tissue sample, a rapid on site evaluation (ROSE) methodology is highly 
recommended to evaluate the adequacy of the sample. 
–
If sample is collected during EBUS, at least 3 passes are requested 
(1922 gauge needle can be used)

ECOG Performance Status of 0 or 1 (see Appendix 7)

Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 14 days prior to the first dose of atezolizumab:
–
ANC 1500/L
–
Platelet count 100,000/L
–
Hemoglobin 9.0 g/dL; patients may be transfused to meet this criterion.
–
AST and ALT 2.5upper limit of normal (ULN)
–
Serum bilirubin 1.5ULN
–
Serum creatinine 3.0 mg/dL

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% 
per year during the treatment period and for at least 5 months after the last dose of 
atezolizumab.  Women must refrain from donating eggs during this same period.
–
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).

Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, 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.


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Adjuvant Atezolizumab Therapy Phase
Patients must meet the following criteria to be eligible to continue to receive 
atezolizumab adjuvant therapy:

ECOG Performance Status of 0 or 1 (see Appendix 7)

Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained per SOC prior to the starting adjuvant atezolizumab in the Adjuvant 
Atezolizumab Therapy Phase:
–
ANC 1500/L
–
Platelet count 100,000/L
–
Hemoglobin 9.0 g/dL; patients may be transfused to meet this criterion
–
AST and ALT 2.5ULN
–
Serum bilirubin 1.5ULN
–
Serum creatinine 3.0 mg/dL
4.1.2
Exclusion Criteria
Neoadjuvant Atezolizumab Therapy Phase
Patients who meet any of the following criteria will be excluded from study entry:

NSCLC that is clinically T4 by virtue of mediastinal organ invasion or Stage IIIB by 
virtue of N3 disease

Any prior therapy for lung cancer, including chemotherapy, hormonal therapy, or
radiotherapy, within 3 years

Patients with prior lung cancer that have been in remission for 3 years

Prior treatment with anti-PD-1 or anti-PD-L1 therapies or pathway-targeting agents

Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation

Major surgical procedure within 28 days prior to Cycle 1, Day 1

Malignancies other than the disease under study within 3 years prior to Cycle 1, 
Day 1, with the exception of patients with a negligible risk of metastasis or death 
and with expected curative outcome (such as adequately treated carcinoma in situ 
of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated 
surgically with curative intent, or ductal carcinoma in situ treated surgically with 
curative intent) or undergoing active surveillance per SOC management (e.g., Rai 
Stage 0 chronic lymphocytic leukemia, prostate cancer with Gleason score 6, and 
prostate-specific antigen (PSA 10 ng/mL, etc.)

Treatment with systemic immunosuppressive medications (e.g., prednisone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1
–
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea or 
premedication for contrast dye allergy) are eligible.


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–
The use of inhaled corticosteroids for chronic obstructive pulmonary disease 
(COPD) and mineralocorticoids (e.g., fludrocortisone) for patients with 
orthostatic hypotension or adrenocortical insufficiency is allowed.

History or risk of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular
thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis,
Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, 
autoimmune thyroid disease, vasculitis, or glomerulonephritis
–
Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible.
–
Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are 
eligible.
–
Patients with eczema, psoriasis, or lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible provided they meet the following conditions:
Rash must cover 10% of body surface area (BSA)
Disease is well controlled at baseline and only requiring low potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
No acute exacerbations of underlying condition within the last 12 months 
(requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids)

History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan

Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, fatty liver, and inherited liver disease

History of HIV infection

Active hepatitis B (chronic or acute) defined as having a positive hepatitis B surface 
antigen (HBsAg) test at screening
–
Patients with past or resolved hepatitis B infection (defined as having a 
negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test 
eligible.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test and a positive HCV RNA test at screening

Active tuberculosis


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
Administration of a live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks 
before Cycle 1, Day 1 or at any time during the study
–
Influenza vaccination should be given during influenza season only 
(approximately October to March).  

Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia

Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
–
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or COPD) are eligible.

Treatment with an investigational agent for any condition within 4 weeks prior to 
Cycle 1, Day 1 (or within five half-lives of the investigational product, whichever is 
longer)

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Pregnant or lactating, or intending to become pregnant during the study
–
Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of atezolizumab
Adjuvant Atezolizumab Therapy Phase

Progressive or recurrent disease as documented by CT scan (per RECIST v1.1 
criteria) at the end of SOC adjuvant therapy
–
Patients with radiographic progression/recurrence and no evidence of 
pathologic response of the study during the Neoadjuvant Phase are not eligible 
for the Adjuvant Atezolizumab Therapy Phase
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label single-arm study.  Eligible patients will be enrolled to the study to 
receive atezolizumab treatment.  
Patients may be re-screened for enrollment during the screening period, if necessary, at 
the discretion of the investigator.
After written informed consent has been obtained, all required screening test results are 
available, and eligibility has been confirmed, the study site personnel will obtain the 
patient’s unique identification number by registering the patient in an interactive 
voice/web response system (IxRS).
4.3
STUDY TREATMENT
The investigational medicinal product (IMP) for this study is atezolizumab.


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4.3.1
Formulation, Packaging, and Handling
Atezolizumab will be supplied by the Sponsor.  Atezolizumab is provided in a single-use, 
20-cc USP/Ph. Eur. Type 1 glass vial as a colorless-to-slightly-yellow, sterile, 
preservative-free, clear liquid solution intended for IV administration.  The vial is 
designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more 
than the stated volume to enable delivery of the entire 20 mL volume.  The atezolizumab 
drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 
120 mM sucrose, 0.04% polysorbate 20, pH 5.8.
Atezolizumab must be refrigerated at 2C8C (36F46F) upon receipt until use.  
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer. No preservative is used in the atezolizumab drug product; therefore, each 
vial is intended for single use only. Vial contents should not be frozen or shaken and 
should be protected from direct sunlight. 
Atezolizumab will be delivered in 250 mL 0.9% NaCI IV infusion bags with product 
contacting surfaces of polyvinyl chloride (PVC) or polyolefin (PO), and IV infusion lines 
with product contacting surfaces of PVC or polyethylene (PE) and 0.2 m in-line filters 
(filter membrane of polyethersulfone [PES]).  No incompatibilities have been observed 
between atezolizumab and these infusion materials (bags and infusion lines).  
For further details on drug preparation, storage, and administration; see the pharmacy 
manual and the Atezolizumab Investigator’s Brochure.
4.3.2
Dosage, Administration, and Compliance
Dosage
The dose of atezolizumab in this study will be 1200 mg administered by IV infusion q21d
(one cycle21 days). 
In the Neoadjuvant Atezolizumab Therapy Phase, neoadjuvant treatment with 
atezolizumab 1200 mg will be given q21d (2 days) for a maximum of 2 cycles.  In the 
Adjuvant Atezolizumab Therapy Phase, adjuvant treatment with atezolizumab 1200 mg 
will be given q21d (3 days) for maximum of 12 months. 
Administration
Administration of atezolizumab will be performed on an outpatient basis in a setting with 
emergency medical facilities and staff who are trained to monitor for and respond to 
medical emergencies.  
Premedication may be administered for any atezolizumab infusions after Cycle 1 (see 
Section 4.4.1 for details).
The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first 
infusion is tolerated without infusion-associated adverse events, the second infusion 


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may be delivered over 30 (10) minutes.  If the 30-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 30 (10) minutes.  If the patient had an 
infusion-related reaction during previous infusion, the subsequent infusion must be 
administered over 60 (15) minutes.  
For the first infusion, the patient’s vital signs should be measured within 60 minutes 
before the infusion and during and after the infusion, if clinically indicated.  For 
subsequent infusions, vital signs will be collected within 60 minutes before the infusion 
and at the end of the infusion, as clinically indicated. 
Patients may need to remain in the clinic post-infusion for monitoring of side effects, if 
needed.
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.
The management of infusion-related reactions will be according to severity as follows: 

In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related 
event, the infusion rate should be reduced to half the rate being given at the time of 
event onset.  Once the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.  If tolerated, the infusion 
rate may then be increased to the original rate 

In the event that a patient experiences a moderate infusion-related event (NCI 
CTCAE Grade 2) or flushing, fever, or throat pain, the patient should have his or her 
infusion immediately interrupted and should receive aggressive symptomatic 
treatment.  The infusion should be restarted only after the symptoms have 
adequately resolved to baseline grade.  The infusion rate at restart should be half of 
the infusion rate that was in progress at the time of the onset of the infusion-related 
event 

For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), 
the infusion should be stopped immediately, and aggressive resuscitation and 
supportive measures should be initiated.  Patients experiencing severe or 
life-threatening infusion-related events will not receive further infusion and will be 
further managed as clinically indicated until the event resolves 

For anaphylaxis precautions, see Appendix 8.
Dose modifications of atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation are provided in Section 5.1.2.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.


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4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab) will be provided by the 
Sponsor.  The study site will acknowledge receipt of IMPs by returning the appropriate 
documentation form to confirm the shipment condition and content.  Any damaged 
shipments will be replaced. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Atezolizumab
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide atezolizumab or any other study treatments or interventions to patients 
who have completed the study.  The Sponsor may evaluate whether to continue 
providing atezolizumab in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of atezolizumab until the following visit:  1) For 
patients who will receive adjuvant atezolizumab treatment until the adjuvant
atezolizumab completion/ discontinuation visit, or 2) For patients who will not receive 
adjuvant atezolizumab treatment until the Post-surgery Visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF.
4.4.1
Permitted Therapy
In general, investigators should manage a patient’s care with supportive therapies, as 
clinically indicated per standard clinical practice.  
Premedication may be administered for atezolizumab infusions at the discretion of the 
treating physician.  After the first cycle, patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2 receptor antagonist per standard 
practice.  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 


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distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists).  See Appendix 8 for 
anaphylaxis precautions.
Concomitant medications should be avoided with the exception of analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life-threatening 
medical problems.  For immune-related adverse events (IRAEs), patients should be 
carefully monitored for clinically significant systemic IRAEs or organ-specific IRAEs.  
Serological, immunological, and histological data should be used to support the 
diagnosis of immune-mediated toxicity.  Corticosteroid therapy should be initiated if 
considered clinically necessary; use of corticosteroids as pre-medication for patients with 
CT IV contrast allergy is allowed.
The following therapies should continue while patients are in the study:

Oral contraceptives with a failure rate of 1% per year (see Section 4.1.1)

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low-molecular-weight 
heparin or warfarin at a stable dose level)

Vaccinations (such as influenza, COVID-19)
Live, attenuated vaccines are not permitted (see Section 4.4.3).

Megestrol acetate administered as an appetite stimulant

Inhaled or low-dose corticosteroids administered for COPD or asthma

Mineralocorticoids (e.g., fludrocortisone)

Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency
Surgical Resection
Following induction therapy, patients will undergo surgical resection of the primary tumor 
and associated lymph nodes.  Pathologic complete resection of the primary tumor (R0) 
should be performed.  See Section 3.1.3.
Standard-of-Care Chemotherapy (with or without Radiation) after Surgical 
Resection
After surgical resection of their tumor, patients may receive SOC chemotherapy (with or 
without radiation).  Choice of SOC adjuvant therapy will be at the discretion of the 
treating physician, depending on the stage of their disease, as deemed clinically 
appropriate.  (It is highly recommended that any adjuvant treatment be initiated within 
120 days after surgery.  Additionally, it is recommended that patients who receive SOC 
Chemotherapy (Radiotherapy) initiate adjuvant atezolizumab within 60 days of SOC 
ChemotherapyRadiotherapy (whichever occurs last).  If adjuvant treatment is planned 
to start outside of the recommended window, Investigators may discuss it with the 
Medical Monitor).


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4.4.2
Cautionary Therapy
Systemic corticosteroids, immunosuppressive medications, and TNF-inhibitors may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab.  
Therefore, in situations in which systemic corticosteroids, immunosuppressive 
medications, or TNF-inhibitors would be routinely administered, alternatives, including 
antihistamines, should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-inhibitors may be 
administered at the discretion of the investigator.
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy.  Guidelines for management of immune-mediated 
adverse events are described in Section 5.1.
4.4.3
Prohibited Therapy
Use of the following therapies is prohibited during the study and within the timeframe
(neoadjuvant phase, surgery phase, and adjuvant phase) as specified below:

Any non-protocol-specified therapy intended for the treatment of cancer, whether 
health authority-approved or experimental

Immunostimulatory agents, including but not limited to IFN-, IFN-, or IL-2.  These 
agents, in combination with atezolizumab, could potentially increase the risk for 
autoimmune conditions

Live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to initiation of study 
treatment, during atezolizumab treatment, and for 5 months after the final dose of 
atezolizumab

Treatment with systemic immunosuppressive medications (including but not limited 
to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-TNF agents), except as below:
–
Acute, low-dose, systemic immunosuppressant medications (e.g., a one-time 
dose of dexamethasone for nausea)
–
Inhaled corticosteroids for COPD and mineralocorticoids (e.g., fludrocortisone) 
for patients with orthostatic hypotension or adrenocortical insufficiency

Investigational therapy 
4.5
STUDY ASSESSMENTS
Please see Appendix 1 for the schedule of activities to be performed during each part of 
the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms (ICFs) for enrolled 


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patients and for patients who are not subsequently enrolled will be maintained at the 
study site.
For each part of the study, 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.
The following ICFs will be available:
An optional prescreening ICF may be requested for patients undergoing SOC biopsy if 
the patient does not have adequate available archival tumor tissue as required by the 
protocol.  If available, lymph node sample collection is also requested during the 
prescreening tumor biopsy.  For patients undergoing bronchoscopy or EBUS, optional 
(but highly encouraged) bronchial brushings are also included in the prescreening ICF.  
If these procedures are done as part of the prescreen, they may not need to be repeated 
at the time of screening.
A separate ICF will be required for all patients planning to enter the main study, 
regardless of prescreening ICF signature status.
For patients whose disease progresses or recurs: An ICF for an optional tissue biopsy
(tumor and lymph node, if available) is provided with the main ICF. 
4.5.2
Prescreening Tumor Biopsy
A prescreening tumor biopsy could be conducted for patients who do not have an 
adequate tumor specimen, in the opinion of the investigator.  This prescreening biopsy 
will be used to diagnose the patient and for tissue analysis.  This biopsy will not need to 
be repeated at study screening if the sample taken is adequate, as specified in the 
inclusion criteria (see Section 4.1.1). If available, lymph node sample collection is also 
requested during the prescreening tumor biopsy.  For patients undergoing bronchoscopy 
or EBUS, optional (but highly encouraged) bronchial brushings may also be collected at 
this time.
If a patient has an adequate archival tumor biopsy to yield required FFPE and 
fresh-frozen samples, no prescreening biopsy will be needed.  
4.5.3
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including histology, grade, stage, prior cancer therapies and procedures), smoking 
history, asbestos, pleural or pericardial effusion, ascites requiring intervention, exposure, 
HPV infection and HPV subtypes, associated syndromes, Helicobacter pylori infection, 
relevant mutations, and reproductive status (women).  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 


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remedies, nutritional supplements) used by the patient within 7 days prior to screening
will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.4
Physical Examinations
A complete physical examination should be performed at screening and at the 
pre-surgery visit. The examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
4.5.5
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.
In the Neoadjuvant Atezolizumab Therapy Phase, the patient’s vital signs should be 
measured within 60 minutes before the infusion, and during the infusion and after the 
infusion, if clinically indicated.  
Blood oxygen saturation by pulse oximetry will be measured in the Neoadjuvant 
Atezolizumab Therapy Phase as specified in Appendix 1.
In the adjuvant atezolizumab therapy phase, vital signs should be measured as per 
standard clinical practice.
4.5.6
Tumor and Response Evaluations
Neoadjuvant Atezolizumab Therapy Phase
During the Neoadjuvant Atezolizumab Therapy Phase, the patient’s tumor will be staged 
at screening by contrast-enhanced (if patient is not contrast-allergic) helical CT scan of 
the chest, PETCT, and brain MRI, preferably with gadolinium (for Stage II or IIIA 
disease).  If brain MRI is not feasible for technical or patient-related reasons (e.g., 
pacemaker, severe claustrophobia), brain CT scan with IV contrast should be obtained.  
All scans will be repeated prior to surgery to confirm surgical eligibility.  
At the investigator’s discretion, scans may be repeated at any time if progressive 
disease is suspected.


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Radiographic responses will be assessed by the investigator per RECIST v1.1 after two 
cycles of neoadjuvant atezolizumab. 
Pathologic responses will be assessed from surgically resected tumor by the site 
pathologist.
All radiologic digital imaging (including CT and CT/PET scans plus all supporting 
radiologic interpretation or reports) will be submitted for central review.  The timepoints 
are:

Time of biopsy

Pre-surgery

Post-surgery

Or at any time of disease progression
Surveillance
For all patients who enter surveillance, extended Chest CT scans (including liver and 
adrenals) will be performed approximately every 6 weeks to 3 months for up to 2 years
(see Appendix 2); all other non-protocol specified tumor assessments will be performed 
per standard clinical practice.
For patients that receive any adjuvant treatment (Subgroups B, C, and D):  In order to 
align adjuvant treatment with Surveillance assessments, timing of the initial 
post-baseline extended chest CT scan and blood draws will be flexible (see Appendix 2).
For patients in Subgroup D: Extended Chest CT Scan and blood drawn are required at 
C1D1 (5 days) of adjuvant atezolizumab phase.  If C1D1 falls in between surveillance 
visits, an extra extended Chest CT scan needs to be done and subsequent surveillance 
visits will be adjusted accordingly (at every 3 months after adjuvant atezolizumab C1D1).
All radiologic digital imaging (including CT and CT/PET scans plus all supporting 
radiologic interpretation or reports) will be submitted for central review.  The timepoints 
are:

Post-surgery (or new baseline)

Surveillance timepoints

Or at any time of disease progression
Adjuvant Atezolizumab Therapy Phase
For patients who enroll in the Adjuvant Atezolizumab Therapy Phase, extended chest 
CT scans (including liver and adrenals) will be required after SOC adjuvant therapy and 
before initiation of atezolizumab to confirm lack of disease progression/recurrence, then 
for Surveillance, as outlined in Appendix 2; all other non-protocol specified tumor 
assessments will be performed per standard clinical practice.  


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Radiographic responses will be assessed by the investigator per RECIST v1.1 during 
the adjuvant therapy phase (adjuvant atezolizumab, SOC chemotherapy, and/or both).
Follow-Up
After completion of neoadjuvant or adjuvant atezolizumab treatment (whichever occurs 
last), new anti-cancer treatment, recurrence and survival information will be obtained 
and documented approximately every 6 months for up to 3 years.  For patients that 
undergo surgery and enter Surveillance, time in surveillance will overlap with time in 
survival follow-up (see Appendix 2). This information may be obtained at clinic visits or 
by telephone, mail, or email.
4.5.7
Other Disease-Specific Assessments
Neoadjuvant Atezolizumab Therapy Phase: Pathologic responses will be scored by a 
pathologist based on the surgical resection as defined by prior studies (Hellmann et al. 
2014). 
Adjuvant Atezolizumab Therapy Phase: All other non-protocol specified tumor and 
laboratory assessments will be per standard clinical practice. 
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Samples for the following tests will be sent to the study site's local laboratory for analysis:

Hematology:  CBC, including WBC count, RBC count, hemoglobin, hematocrit, 
platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells)

Chemistry panel (serum):  sodium, potassium, chloride, bicarbonate, glucose, BUN 
or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct 
bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH

Coagulation:  international normalized ratio (INR), activated partial thromboplastin 
time (aPTT), prothrombin time (PT)

Viral serology:  HIV, HBsAg, antibodies against HBsAg, hepatitis B core antigen,
and HCV antibody (anti-HCV)
–
HBV DNA is required if a patient has a positive anti-HBc antibody test.

Pregnancy test:  All women of childbearing potential will have a serum pregnancy 
test at screening.

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 

Thyroid function testing (TSH, free T3, free T4)

C-reactive protein (CRP)
Samples listed below for biomarker analyses will be sent to one or several central 
laboratories for storage and/or analysis (see Table 4).  Analyses may include, but are 
not limited to the analysis of DNA, RNA, and proteins using immunohistochemistry, next 
generation sequencing, functional T-cell assays, and flow cytometry.  Additional assays 


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may be performed as technology and science are rapidly evolving.  For sampling 
procedures, sample processing, storage conditions, and shipment instructions, refer to 
the laboratory manual.

Archival or newly collected sample (fresh frozen tumor tissue and FFPE sample) for 
secondary and exploratory biomarker objectives.
–
If archival FFPE and fresh frozen tissue are not available, a new pre-treatment 
CNB (preferred), EBUS, or bronchoscopy (acceptable alternatives) will be 
required.  The new samples will be obtained solely for the purpose of research 
studies (pre-treatment sample).  The number of cores obtained will be 
determined by the radiologist performing the procedure, based on the patient’s 
clinical condition at the time of biopsy, but will ideally include 5 core biopsies 
(minimum of 3 [2 FFPE, and 1 fresh frozen]).  The additional 2 fresh frozen
cores are optional.
–
For core biopsies, needle sizes of 1618 gauge are preferred. If a 19 gauge or 
smaller needle is used please consider adding another pass. In addition, to 
ensure a quality tissue sample, a rapid on site evaluation (ROSE) methodology 
is highly recommended to evaluate the adequacy of the sample. 
–
If sample is collected during EBUS, at least 3 passes are requested (a 
1922 gauge needle can be used)

One representative block of the FFPE specimen and one fresh frozen tumor tissue 
sample collected from surgical resection for secondary and exploratory biomarker 
analyses 

FFPE lymph node obtained at surgical resection and/or obtained pre-treatment, 
optional. FFPE blocks are preferred. If blocks cannot be released, at least 
10 positively charged FFPE slides should be provided. Collection should include 
involved and non-involved lymph nodes, if available.

Optional: Fresh Tumor Tissue from resected specimens obtained at surgery

Optional: Fresh Normal Lung Tissue from resected specimens obtained at surgical 
resection (only if collected together with a fresh tumor tissue samples)

Optional: FFPE normal tumor from resected specimens obtained at surgery.

Optional: Fresh lymph nodes obtained pre-treatment and at surgical resection.  
Collection at surgical resection is only performed, if a pre-treatment sample has 
been collected (pair for flow cytometry) and/or if also a fresh tumor tissue sample 
has been obtained at resection (pair for additional research). Collection can include 
involved and non-involved lymph nodes, if available.

Whole blood samples at selected timepoints and at disease progression for 
exploratory biomarker analyses 

Blood sample for normal control DNA extraction for NGS pre-treatment

Optional:  Bronchial Brushings samples may be collected at screening after 
approximately 34 months of starting adjuvant atezolizumab treatment only for
Immune-related biomarker research that may include, but is not limited to DNA and 


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RNA sequencing.  See lab manual for exact nomenclature and specific areas to be 
sampled during procedure.

Optional: FFPE tumor tissue (and lymph node, if available) biopsy at disease 
progression or recurrence for correlative studies. Tissue collection by CNB is 
preferred, but collection by EBUS, or bronchoscopy are acceptable alternatives.
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 4.


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Table 4
Proposed Biomarkers for Exploratory Research
Sample Type
Proposed Biomarkers a, d
Whole blood DNA

Normal germline control DNA for NGS
Whole blood flow 
cytometry

Cellular IMMUNOME characterization by multicolor flow cytometry
Whole blood PBMC 

Gene expression analysis for cancer/ immune-related genes and 
biomarkers associated with common molecular pathways by NGS or 
RT-PCR

TCR sequencing and functional T-cell assays
Plasma/serum biomarker

Circulating-free DNA by NGS

Serum markers by ELISA or proteomics
Fresh frozen tumor 
tissue 

Cancer/immune-related genes and biomarkers associated with 
common molecular pathways by NGS

Additional tumor- and immune-related analysis that may include 
TCRsequencing 
Fresh lymph nodes b

Cellular IMMUNOME characterization by multicolor flow cytometry

Additional tumor- and immune-related analysis that may include RNA 
sequencing, TCR/BCR-sequencing, CyTOF
Fresh tumor tissue 
(optional)

Tumor- and immune-related analysis that may include RNA 
sequencing, TCR/BCR sequencing, CyTOF
Fresh normal lung tissue 
(optional)

Tumor- and immune-related analysis that may include RNA 
sequencing, TCR/BCR sequencing, CyTOF 
FFPE tumor tissue 

PD-L1 expression

Immune markers

Additional tumor- and immune-related analysis that may include NGS, 
TCR-sequencing and proteomics
FFPE lymph node

Gene expression analysis for cancer-/ immune-related genes and 
biomarkers associated with common molecular pathways by NGS

Additional tumor- and immune-related analysis that may include 
TCRsequencing 
Bronchial brushing 
(optional)c

Tumor- and immune-related biomarker research that may include DNA 
and RNA sequencing
FFPE normal lung 

Additional immune related biomarker research 
FFPEformalin-fixed, paraffin-embedded; NGSnext-generation sequencing; PBMCperipheral 
blood mononuclear cell; PD-L1programmed death ligand 1; TCRT-cell receptor, BCRB-cell 
receptor.
a Proposed analysis may include but is not limited to the following biomarkers or assays
b Lymph node sample at screening is optional, but highly encouraged.  If the patient opts for 
lymph node sample collection at screening, lymph node sample collection will be required at 
time of surgical resection, if available. Residual material may be cryopreserved for additional 
exploratory research.
c Encouraged for patients undergoing EBUS and/or bronchoscopy.  
d All specifics on Biomarker Collections can be found in the Laboratory Manual.


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Residual material will be banked for future analyses related to NSCLC, atezolizumab’s 
mode of action, or to increase understanding of response to atezolizumab and may 
include, but is not limited to, next generation sequencing.
Biological samples will be destroyed a maximum of 15 years after completion of the final 
Clinical Study Report, with the following exception:

Blood samples collected and derivatives thereof will be stored until they are no 
longer needed or until they are exhausted.
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, including data on germline mutations, will be subject 
to the confidentiality standards described below and in Section 8.4. Exploratory 
biomarker data will not be used for making a treatment decision.
4.5.8.1
Tissue Sample Prioritization
Analyses of samples will be prioritized as specified below. See Table 4 for proposed 
analyses.
Pre- and Post-Treatment FFPE Biopsy Samples
1.
Pathology analyses
2.
PD-L1 IHC analysis
3.
Multiplex IF analysis
4.
Additional exploratory analyses
Pre- and Post-Treatment Fresh Frozen Biopsy Samples
1.
RNA and DNA isolation for next generation sequencing
2.
Additional exploratory analyses
Fresh Lymph Node Biopsy (if available)
1.
Cellular IMMUNOME 
2.
Additional exploratory analyses
All other tissue samples (tumor, lymph node, bronchial brushings, adjacent normal lung) 
will be used for additional exploratory analyses. 


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4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance
Every effort should be made to obtain information on patients who withdraw from the 
study but do not withdraw consent.  The primary reason for withdrawal from the study 
should be documented on the appropriate eCRF.  However, patients will not be followed 
for any reason after consent has been withdrawn.  Patients who withdraw from the study 
will not be replaced.
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.
4.6.2
Atezolizumab Treatment Discontinuation
Patients must discontinue neoadjuvant or adjuvant atezolizumab treatment if they 
experience any of the following:

Pregnancy

Radiographic disease progression and/or symptomatic deterioration attributed to 
disease progression as determined by the investigator after integrated assessment 
of radiographic data, biopsy results, and clinical status.  Please note all radiographic 
images related to disease will be collected.

Intolerable toxicity related to atezolizumab, including development of an irAE 
determined by the investigator to be unacceptable given the individual patient’s 
potential response to therapy and severity of the event.  May contact Medical 
Monitor and Sponsor for further guidance.

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues on atezolizumab

Use of another non-protocol-specified anti-cancer therapy
The primary reason for atezolizumab discontinuation should be documented on the 
appropriate eCRF.
If patient prematurely discontinues neo-adjuvant treatment for any reason other than 
progressive disease (after Cycle 1 and before surgery), they may proceed with surgery 
as part of the study and enter surveillance. If patient discontinues treatment for any 


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reason after surgery, they should remain in Surveillance until they complete 2 years and 
then move to Survival Follow-up.  Patients who discontinue atezolizumab prematurely 
will not be replaced.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic UC.  The safety plan for patients in this study is based on clinical experience 
with atezolizumab in completed and ongoing studies.  The anticipated important safety 
risks for atezolizumab are outlined below.  
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 anticipated adverse events, including criteria for dosage modification and 
treatment interruption or discontinuation, are provided below.  In addition, a pre-specified 
interim safety analysis will be conducted to evaluate the safety data during the 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 


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guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a 
patient develops suspected CRS during the study, a differential diagnosis should 
include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or 
radiologic evaluations per investigator judgment.  If a diagnosis of SARS-CoV-2 
infection is confirmed, the disease should be managed as per local or institutional 
guidelines.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions (IRRs) and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis,
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis, myocarditis, nephritis, myositis, and severe cutaneous adverse 
reactions.  Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), 
which are considered to be potential risks for atezolizumab.  
Refer to Appendix 9 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
Management of Patients Who Experience Specific Adverse 
Events 
Guidelines for management of patients who experience specific adverse events 
associated with atezolizumab, including infusion-related reactions and immune-mediated 
events (e.g., myocarditis and pulmonary, hepatic, gastrointestinal, endocrine, ocular, 
pancreatic, dermatologic, neurologic, and renal events), are provided in the Appendix 9.
5.1.2.1
Atezolizumab Dose Modification and Treatment Interruption
Atezolizumab dose modification is not allowed in the Neoadjuvant Atezolizumab Therapy 
Phase.  The following rules apply: 1 ) if atezolizumab is interrupted during infusion due to 
reaction, but resumed, the patient may proceed with all future study-related activities, 
2) if atezolizumab is held (e.g., treatment is delayed) after the first dose due to 
tolerability concerns, the Investigator may choose to discontinue the patient from the 
study if medically indicated, and 3) if the patient receives less than prescribed dose of 
atezolizumab (e.g., if infusion cannot be completed), patient continuation in the study will 
require Medical Monitor approval.  If the patient does not discontinue from study, they 
may proceed as per protocol.  Investigator may contact Medical Monitor for further 
guidance.  If the patient discontinues treatment, they will enter Survival Follow-up, as 
specified in Section 4.6. 


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Atezolizumab dose modification is not allowed during Adjuvant Atezolizumab Therapy 
Phase.  However, atezolizumab may be temporarily suspended in patients experiencing 
toxicity considered to be related to atezolizumab for up to 12 weeks after the last dose if 
they experience toxicity that require a dose to be withheld.  If atezolizumab is withheld 
because of toxicity for 12 weeks after the last dose, then the patient will be 
discontinued from atezolizumab treatment and will be followed for safety and efficacy as 
specified in Section 4.6. If a patient must be tapered off corticosteroids used to treat 
adverse events, atezolizumab may be held for 12 weeks after the last dose until 
corticosteroids are discontinued or reduced to prednisone dose of 10 mg/day (or 
equivalent).
Atezolizumab treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures).  The acceptable length of treatment interruption must be based on an 
assessment of benefitrisk by the investigator 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.
Guidelines for management of specific adverse events associated with atezolizumab are 
provided in the Appendix 9.
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), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline


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
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 atezolizumab treatment or 
concomitant treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of atezolizumab treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [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)
See Appendix 10 for list of adverse events of special interest. 


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in, Sections 5.4, 5.5, and 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, (including the neoadjuvant phase, surgery phase, and adjuvant phase)
whether reported by the patient or noted by study personnel, will be recorded in the 
patient’s medical record and on the Adverse Event eCRF.  
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see
Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 30 days after the 
last dose of atezolizumab (neoadjuvant or adjuvant, whichever occurs last).  Serious 
adverse events and non-serious adverse events of special interest will be reported until 
90 days after the last dose of atezolizumab (neoadjuvant or adjuvant, whichever occurs 
last). For patients participating in the Adjuvant Atezolizumab Therapy Phase, as 
outlined in Section 3.1.4, who will receive and complete SOC chemotherapy prior to
adjuvant atezolizumab, all AE’s will be reported from their first dose of neoadjuvant 
atezolizumab until 30 days after the last dose of adjuvant atezolizumab. Additionally, 
serious adverse events and non-serious adverse events of special interest will be 
reported until 90 days after the last dose of adjuvant atezolizumab for these patients.
During the Surveillance Period, as outlined in Section 3.1.3, if a patient is not receiving 
atezolizumab, only serious adverse events associated with CT scans, blood sample 
collection, and the optional biopsy (collected at the time of disease progression) will be 
collected and reported (see Table 5).


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Table 5
Reporting Requirements After Initiation of Study Drug (by 
Treatment Subgroup)
Subgroup A
Subgroup B
Subgroup C
Subgroup D
Safety 
Reporting 
Requirements
No Adjuvant 
Treatment
Adjuvant 
Atezolizumab 
Treatment
SOC 
Chemotherapy 
(Radiotherapy) 
only
SOC 
Chemotherapy 
(Radiotherapy) 
plus Adjuvant 
Atezolizumab
AEs
From first dose of 
neoadjuvant 
atezolizumab until 
30 days after last 
dose of 
neoadjuvant 
atezolizumab b
From first dose of 
neoadjuvant 
atezolizumab until 
30 days after last 
dose of adjuvant 
atezolizumab a, b
From first dose of 
neoadjuvant 
atezolizumab until 
30 days after last 
dose of 
neoadjuvant 
atezolizumab b
From first dose of 
Neoadjuvant 
atezolizumab until 
30 days after last 
dose of Adjuvant 
atezolizumab a, b
SAEs/AESIs
From first dose of 
neoadjuvant 
atezolizumab until 
90 days after last 
dose of 
neoadjuvant 
atezolizumab b, c
From first dose of 
neoadjuvant 
atezolizumab until 
90 days after last 
dose of adjuvant 
atezolizumab a, b, c
From first dose of 
neoadjuvant 
atezolizumab until 
90 days after last 
dose of 
neoadjuvant 
atezolizumab b, c
From first dose of 
neoadjuvant 
atezolizumab until 
90 days after last 
dose of adjuvant 
atezolizumab a, b, c
AEadverse event; AESIadverse event of special interest; SAEserious adverse event; 
SOCstandard of care.
a No safety reporting interruption between neoadjuvant and adjuvant atezolizumab.
b After informed consent has been obtained but prior to initiation of study drug, adverse events 
should be reported as outlined in Section 5.3.1. During Surveillance, but after patients have 
already completed atezolizumab treatment, AEs should be reported as outlined in 
Section 5.3.1.
c Serious adverse events associated with CT scans, blood sample collection, and the optional 
biopsy (collected at the time of disease progression) will be collected and reported during the 
entire Surveillance period.


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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity. Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 6
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or limiting
self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 5 events must be reported as serious adverse events (see Section 5.4.2 for reporting 
instructions), per the definition of serious adverse event in Section 5.2.2.


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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 7):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 7
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug 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 the study drug, 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 the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug 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 the study drug 
(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 the study drug (e.g., cancer diagnosed 2 days after first
dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.


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5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after treatment administration and 
are judged to be related to study treatment infusion (atezolizumab or docetaxel) should 
be captured as a diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  
If possible, avoid ambiguous terms such as "systemic reaction."  Cases of late-onset CRS 
should be reported as "cytokine-release syndrome" on the Adverse Event eCRF.  
Associated signs and symptoms of an IRR should be recorded on the dedicated 
Infusion-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 IRR also recorded separately on the 
dedicated Infusion-Related Reaction eCRF.
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 is a change from baseline and meets any of 
the following criteria:

Is accompanied by clinical symptoms

Results in a change in atezolizumab treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 


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(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it is a change from baseline and meets any of the 
following criteria:

Is accompanied by clinical symptoms

Results in a change in atezolizumab 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 (e.g., 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 
jaundice


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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
All deaths that occur during the protocol-specified adverse event reporting period (see
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of NSCLC.
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").  
If the cause of death later becomes available (e.g., after autopsy), "unexplained death"
should be replaced by the established cause of death.
If the death is attributed to progression of NSCLC, this is the only case when "disease
progression" should be recorded on the Adverse Event eCRF.  
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 Non-Small Cell Lung Cancer
Deterioration that is judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature (i.e., deterioration beyond the expected 
pattern of progression of the underlying disease) should be recorded as an adverse 


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event.  When recording an unanticipated worsening of non-small cell lung cancer on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., "accelerated worsening of non-small 
cell lung cancer").  
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events, unless death is the 
outcome (see Section 5.3.5.8).  These data will be captured as efficacy assessment data 
only.  In most cases, the expected pattern of progression will be based on RECIST v1.1.  
In rare cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression/recurrence, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Accidental Overdose or 
Medication Error in Drug Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  Medication error:  Accidental deviation in the administration of a 


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drug, in some cases, a medication error may be intercepted prior to administration of the 
drug.
An overdose or incorrect administration of atezolizumab treatment is not itself an 
adverse event, but it may result in an adverse event.  All adverse events associated with 
an overdose, incorrect administration or medication error of study drug should be 
recorded 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).
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 drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
For serious adverse events and adverse events of special interest, 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 Institutional Review Board (IRB)/Ethics 
Committee (EC).


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
CRO Medical Monitor contact information:
Medical Monitor:
, M.D. (Primary)
Telephone Nos.:
Email:
Genentech Medical Monitor contact information:
Medical Monitor:
(Secondary), PA-C, MMSc, MBA
Telephone No.:
Email:
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The 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 Drug Initiation
After initiation of study drug, adverse events will be reported until 30 days after the last 
dose of atezolizumab (neoadjuvant or adjuvant, whichever occurs last).  See Table 5 for 
full details.  Serious adverse events and adverse events of special interest will be 
reported until 90 days after the last dose of atezolizumab (neoadjuvant or adjuvant, 
whichever occurs last).  Only serious adverse events associated with CT scans, blood 
sample collection, and optional biopsy at the time of disease progression/recurrence that 
occur after the 90 day reporting window, but during the Surveillance period, will be 
collected and reported (see Table 5). 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 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.  


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Instructions for reporting serious adverse events that occur 90 days after the last dose 
of atezolizumab 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 final 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 drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.
Attempts should be made to collect and report infant health information.  When 
permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant.  If the authorization has been signed, the infant's 
health status at birth should be recorded on the Clinical Trial Pregnancy Reporting 
Form.  In addition, the Sponsor may collect follow-up information on the infant's 
health status at 6 and 12 months after birth.  
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. 


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5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).  Any abortion should be reported in the same 
fashion (as the Sponsor considers abortions to be medically significant).
5.4.4
Reporting Requirements for Special Situations and 
Non-Serious Adverse Events Associated with a Special 
Situation
After initiation of study drug, special situations and adverse events associated with 
special situations will be reported until 90 days after the final dose of study drug.
Investigators should record all case details that can be gathered on the Adverse Event 
eCRF and submit the report via the electronic data capture (EDC) system within 
30 calendar days of awareness. A report will be generated and sent to Roche Safety 
Risk Management by the EDC system. 
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, or the event is assessed as stable by the investigator, or the patient is lost 
to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the adverse event reporting period (defined in Section 5.3.1), 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, 
with follow-up information on the infant collected according to procedures outlined in 
Section 5.4.3.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event or non-serious adverse event of special interest that occurs after the end 


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of the adverse event reporting period (defined as 90 days after the last dose of 
neoadjuvant or adjuvant atezolizumab, whichever occurs last; see Table 5), if the event 
is believed to be related to prior study drug treatment.  These events should be reported 
through use of the Adverse Event eCRF.  However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Atezolizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The objective of this study is to determine if atezolizumab 1200 mg q21d demonstrates 
efficacy in the neoadjuvant setting by producing a major pathologic response rate of at 
least 15%; major pathologic response is defined as 10% of viable tumor cells 
(Hellmann et al. 2014).  Tumors without radiographic response, but which demonstrate a 
major pathologic response (Hellmann et al. 2014) will be counted as a response.
Safety of atezolizumab in this treatment setting will also be assessed. 
Details of the analyses are provided in the Statistical Analysis Plan (SAP).
6.1
DETERMINATION OF SAMPLE SIZE
The primary objective of this study is to determine the major pathologic response rate.  If 
there is evidence that the major pathologic response rate is at least 15% then there will 
be further consideration for the testing of atezolizumab in neoadjuvant lung cancer.  This 
is a single-arm study, and all patients will be treated with atezolizumab.  The primary 
endpoint is assessed by a statistical test of a single proportion of responders against the 


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simple alternative of 5% response.  This design provides 95% statistical power to detect 
a difference of 10% (15% vs. 5%) at a significance level of 0.05 (1-sided test, variance of 
the test statistic calculated under the alternative hypothesis).  To achieve this, 
approximately 180 patients will be enrolled in this study.  At the final analysis (after 
180 patients are enrolled), if there are at least 17 patients who respond then the 
statistical test rejects the null hypothesis of a 5% response rate in favor of a higher 
response rate.  
This study includes one interim analysis to assess futility after 90 patients are assessed.  
The non-binding futility interim boundary satisfies conditional power of 0.30.  Thus, the 
probability that the statistical test at the final analysis will be significant at the specified 
power and test level is at least 0.30, conditional on the data available at the time of the 
interim analysis.  At the interim analysis, if there are seven or fewer responders out of 
90 patients then the conditional power of the study drops below 0.30, and enrollment into 
the study may be terminated. Table 8 summarizes the simulated probabilities of 
stopping at the interim and the final analysis for different values of major pathologic
response.  Note that simulated probabilities not identical to calculated probabilities due 
to the discrete nature of response.
Table 8
Simulated Probabilities of Stopping at the Interim and Final analysis 
for Different Values of Major Pathologic Response
True Major Pathologic
Response Rate
Probability of 
Stopping at Interim
Probability of 
Continuing to Final
Simulated Power
0.05
0.84
0.16
3%
0.10
0.19
0.81
72%
0.15
0.01
0.99
99%
Note:   Simulated probabilities are not identical to calculated probabilities due to the discrete 
nature of response.
Differential response by PD-L1 status (positive vs. negative) will also be assessed.  
While the composition of PD-L1 status in this patient population is not known, the study 
will aim to include at least 60 PD-L1-positive patients.  With 60 patients, the one-sided 
95% CI excludes 20% if the major pathologic response rate is 30% (18 responders out 
of 60 patients).  Final enrollment numbers may be expanded accordingly. 
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic information such as age and race will be tabulated.  Descriptive statistics, 
including means, standard deviations, and ranges for continuous parameters, as well as 
percentages and frequencies for categorical parameters, will be presented.  Adverse 
events, Grade 3/4 adverse events, and serious adverse events will be tabulated.  
6.4
EFFICACY ANALYSES
The primary and secondary efficacy analyses will include all enrolled patients who have 
received at least one dose of the study drug and who do not have EGFR or ALK mutant 
tumors (efficacy population). 
6.4.1
Primary Efficacy Endpoint
The effectiveness of the atezolizumab will be assessed by major pathologic response 
rate in the efficacy population, excluding patients who have not received surgery after 
neoadjuvant treatment with atezolizumab.  A statistical test of a single proportion of 
major pathologic response rate will be tested against the alternative that the rate is 15%.  
If the null hypothesis is rejected then this is evidence that the response rate exceeds 5% 
when atezolizumab is given before resection.  The one-sided 95% confidence interval 
(CI) for major pathologic response will be reported. 
6.4.2
Secondary Efficacy Endpoints
The major pathologic response rates for PDL-1 negative and PDL-1 positive patients in 
the efficacy population will be presented separately.  A comparison of the major 
pathologic rates between the PD-L1 positive and PD-L1 negative groups will be 
performed by calculating the lower bound of a one-sided 80% CI for the difference, 
major pathologic response for PDL-1 positive patientsmajor pathologic response for 
PDL-1 negative patients.
Similar analysis will be performed for the investigator-assessed response rate per 
RECIST v1.1.
Correlation of response will be performed for the following variables:

Mutation load

Neo-antigen score

Gene expression signatures
Forest plot of major pathological response by demographic subgroups and disease 
status subgroups will be provided.
Available biomarker data will be used to assess response by different biomarker defined 
subgroups. Due to the limited sample size, the biomarker data analysis is for the 
exploratory research only


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6.4.3
Exploratory Efficacy Endpoints
Changes in tumor and immune markers from baseline to surgery will be assessed in 
tissue samples. Also, changes in the circulating immuno-phenotype will be assessed.
DFS is defined as the time from the first date of no disease (i.e., date of surgery) to local 
or distant recurrence or death due to any cause, whichever occurs first. DFS will be 
analyzed only for patients who underwent surgery. After surgery, data for patients who 
withdraw from the study without documented disease recurrence or death and for whom 
there is evidence in the eCRF that disease follow-up evaluations were performed will be 
censored at the date of the last assessment when the patient is known to be free from 
disease recurrence (that is, last scan or collection of recurrence information when the 
patient is known to be free from disease recurrence). Patients without post-surgery 
assessments but known to be alive will be censored at the date of surgery plus one day.
Time to event analyses of OS and DFS will be calculated using the Kaplan-Meier 
method for all patients in the efficacy population and for subgroups of responders and 
non-responders and PDL-1 negative and positive.
6.5
SAFETY ANALYSES
The safety analyses will include all enrolled patients who have received at least one 
dose of study drug.
6.6
BIOMARKER ANALYSES
Exploratory biomarker analyses will be performed in order to explore the relationship 
between multiple pathological, immunological, and genomic characteristics of the 
cancers and clinical outcome in these patients.  Biomarker analyses may include, but 
may not be limited to, the analyses described below.  
Pathological Analyses:

A detailed pathological evaluation will be performed on the surgically resected 
samples to obtain data as specified in Section 2.
Immunological Analyses

Immunologic analyses by IHC, IF, and flow cytometry; and as specified in Section 2
Genomic Analyses

WES of DNA from tumor tissue and normal blood DNA, to identify mutations, for 
comparison of individual mutations with treatment response, and for association of 
total mutation burden with treatment response

RNA-Seq analysis of pre-treatment CNB and post-neoadjuvant treatment surgical 
specimens to determine gene expression profile overall and signatures related to 
immune cell components for correlation with response

ctDNA for association with treatment response and other endpoints


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6.7
INTERIM ANALYSES
6.7.1
Planned Interim Analyses
The interim analyses described below will be performed.  The study will continue during 
the interim analyses.
6.7.1.1
Planned Interim Safety Analysis
There is not yet extensive data on the safety of thoracic surgical resections after 
treatment with checkpoint inhibitors.  Therefore, after the first 30 patients who complete 
protocol-specified atezolizumab treatment and have undergone the planned surgical 
resection of their tumor, the patient cohort will be evaluated for tolerability and safety of 
the neoadjuvant regimen.  If, at the time of the safety interim analysis, three or more 
patients have experienced Grade 5 adverse events related to protocol treatment, then 
the study will be discontinued.
6.7.1.2
Planned Interim Efficacy Analysis
The study includes one interim analysis to assess futility after 90 patients are assessed.  
The non-binding futility interim boundary satisfies conditional power at a cut-off of 0.30. 
6.7.2
Optional Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses.  The decision to conduct an optional interim 
analysis, and the timing of the analysis, will be documented in the Sponsor’s trial master 
file prior to the conduct of the interim analysis.  The interim analysis will be performed 
and interpreted by Sponsor study team personnel.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will supply eCRF specifications for this study A contract research 
organization (CRO) will be responsible for the 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 CRO will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.  
The Sponsor will perform oversight of the data management of this study.  The CRO will 
produce an EDC Study Specification document that describes the quality checking to be 
performed on the data. Data will be periodically transferred electronically from the CRO 
to the Sponsor, and the Sponsor’s standard procedures will be used to handle and 
process the electronic transfer of these data.  
Central laboratory data will be sent directly to the Sponsor and/or CRO, using the 
Sponsor’s and/or CRO’s standard procedures to handle and process the electronic 
transfer of these data.


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Imaging data will be sent directly to the Sponsor and/or CRO, using the Sponsor’s 
and/or CRO’s standard procedures.  Please refer to the imaging manual for specific 
instructions.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
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, imaging, 
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.


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To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, medication inventory records, and images, 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 study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the 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 


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European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
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.


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Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).


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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.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by Genentech, Inc. (a member of the Roche 
Group).  Approximately 15 sites in the U.S. will participate in the study, and 
approximately 180 patients will be enrolled. 


Atezolizumab—Genentech, Inc.
93/Protocol ML39236, Version 7 
Enrollment will occur through an interactive voice/web-based response system (IxRS).  
Central laboratory facilities will be used for study assessments throughout the study 
(e.g., PD-L1 testing).  Accredited local laboratories will be used for routine monitoring; 
local laboratory ranges will be collected. 
A Data Review Committee will be the advisory committee, and study status will be 
discussed on an ongoing basis. 
A contract research (CRO) will support coordination and medical monitoring activities.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_informatio
n.pdf
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.


Atezolizumab—Genentech, Inc.
94/Protocol ML39236, Version 7 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Atezolizumab—Genentech, Inc.
95/Protocol ML39236, Version 7 
10.
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atezolizumab as first-line or subsequent therapy for locally advanced or metastatic 
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cisplatin compared with observation in completely resected Stage IB and II 
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Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell 
apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8(8):793800.


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Fehrenbacher L, Spira A, Ballinger M, et al, for the POPLAR Study Group. Atezolizumab 
versus docetaxel for patients with previously treated non-small-cell lung cancer 
(POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 
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Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus 
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Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long-term safety of nivolumab 
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high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group 
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Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled 
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Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients
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14LBA. 
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Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. 
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Atezolizumab—Genentech, Inc.
98/Protocol ML39236, Version 7 
Appendix 1
Schedule of Activities
Assessment
Screening a
Part 1 –
Atezolizumab 
Neoadjuvant 
Treatment
Surgery
Neo-
adjuvant 
Atezo 
Treatment
Completion/
D/C d,
Surveillance
Disease 
Progression
or 
Recurrence g
Survival 
Follow-
up h
All 
Subgroups
For Subgroups B and D only
Pre-
surgery b Surgery
Post-
Surgery/
Surveillance 
Baseline c
Surveillance 
for All 
Treatment 
Subgroups
See 
Appendix 2
Adjuvant 
Atezo
Treatment e,f
Adjuvant 
Atezo 
Treatment c,f
Adjuvant 
Atezo 
Treatment
Completion
/D/C d
(Window [Days])
Day 
42 
to 1
Day 
14 
to 1
C1D1  
(Day 
1 3)
C2D1 
(Day 
22
3) i
Day 36
(3)
Day 40 
(10) j
46 weeks 
after surgery
30 (5) 
days after 
last dose
Every 
6 weeks to 
3 months for 
up to 
2 years k
Adjuvant 
Cycle 1, 
Day 1, 
(5) days
Adjuvant 
Cycle 217, 
Day 1
(5) days i
30 (5) 
days after 
last dose
30 days after 
progression/
recurrence
(5) days l
Up to 
3 years
Informed consent 
(prescreening ICF 
and main ICF) m
x
Prescreening biopsy
See footnote n
Medical history and 
demographic data o
x
Weight
x
x
x
Height
x
Complete physical 
examination p
x
x q
Limited physical 
examination r
x
x
x
x s
x


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
99/Protocol ML39236, Version 7 
Assessment
Screening a
Part 1 –
Atezolizumab 
Neoadjuvant 
Treatment
Surgery
Neo-
adjuvant 
Atezo 
Treatment
Completion/
D/C d,
Surveillance
Disease 
Progression
or 
Recurrence g
Survival 
Follow-
up h
All 
Subgroups
For Subgroups B and D only
Pre-
surgery b Surgery
Post-
Surgery/
Surveillance 
Baseline c
Surveillance 
for All 
Treatment 
Subgroups
See 
Appendix 2
Adjuvant 
Atezo
Treatment e,f
Adjuvant 
Atezo 
Treatment c,f
Adjuvant 
Atezo 
Treatment
Completion
/D/C d
(Window [Days])
Day 
42 
to 1
Day 
14 
to 1
C1D1  
(Day 
1 3)
C2D1 
(Day 
22
3) i
Day 36
(3)
Day 40 
(10) j
46 weeks 
after surgery
30 (5) 
days after 
last dose
Every 
6 weeks to 
3 months for 
up to 
2 years k
Adjuvant 
Cycle 1, 
Day 1, 
(5) days
Adjuvant 
Cycle 217, 
Day 1
(5) days i
30 (5) 
days after 
last dose
30 days after 
progression/
recurrence
(5) days l
Up to 
3 years
ECOG Performance 
Status t
x
x
x t
x t
x
Vital signs u
x
x u
x
x
x
x u
x u
x
Tumor and 
response 
evaluations v
x
x
x w, x
x w
x y, x
x
Pathologic response 
assessment z
x
Pulmonary function 
tests
x aa
x
Hematology bb
x
x
x
x
Chemistry cc
x
x
x
x
Coagulation (aPTT 
and INR)
x
Pregnancy test dd
x


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
100/Protocol ML39236, Version 7 
Assessment
Screening a
Part 1 –
Atezolizumab 
Neoadjuvant 
Treatment
Surgery
Neo-
adjuvant 
Atezo 
Treatment
Completion/
D/C d,
Surveillance
Disease 
Progression
or 
Recurrence g
Survival 
Follow-
up h
All 
Subgroups
For Subgroups B and D only
Pre-
surgery b Surgery
Post-
Surgery/
Surveillance 
Baseline c
Surveillance 
for All 
Treatment 
Subgroups
See 
Appendix 2
Adjuvant 
Atezo
Treatment e,f
Adjuvant 
Atezo 
Treatment c,f
Adjuvant 
Atezo 
Treatment
Completion
/D/C d
(Window [Days])
Day 
42 
to 1
Day 
14 
to 1
C1D1  
(Day 
1 3)
C2D1 
(Day 
22
3) i
Day 36
(3)
Day 40 
(10) j
46 weeks 
after surgery
30 (5) 
days after 
last dose
Every 
6 weeks to 
3 months for 
up to 
2 years k
Adjuvant 
Cycle 1, 
Day 1, 
(5) days
Adjuvant 
Cycle 217, 
Day 1
(5) days i
30 (5) 
days after 
last dose
30 days after 
progression/
recurrence
(5) days l
Up to 
3 years
Urinalysis ee
x
Thyroid function test 
(TSH, free T3, and 
free T4) ff
x
x
x
x
x ff (q3 
cycles)
C-reactive protein
x
Viral serology gg
x
Biomarker samples 
(tissue) hh
xii
x
x jj
Biomarker samples 
(blood-based) hh, kk
x
x
x x
x
x ll
x
x mm
x
x jj
Optional bronchial 
brushing nn
x
x oo
Atezolizumab 
administration pp
x
x
x
x


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
101/Protocol ML39236, Version 7 
Assessment
Screening a
Part 1 –
Atezolizumab 
Neoadjuvant 
Treatment
Surgery
Neo-
adjuvant 
Atezo 
Treatment
Completion/
D/C d,
Surveillance
Disease 
Progression
or 
Recurrence g
Survival 
Follow-
up h
All 
Subgroups
For Subgroups B and D only
Pre-
surgery b Surgery
Post-
Surgery/
Surveillance 
Baseline c
Surveillance 
for All 
Treatment 
Subgroups
See 
Appendix 2
Adjuvant 
Atezo
Treatment e,f
Adjuvant 
Atezo 
Treatment c,f
Adjuvant 
Atezo 
Treatment
Completion
/D/C d
(Window [Days])
Day 
42 
to 1
Day 
14 
to 1
C1D1  
(Day 
1 3)
C2D1 
(Day 
22
3) i
Day 36
(3)
Day 40 
(10) j
46 weeks 
after surgery
30 (5) 
days after 
last dose
Every 
6 weeks to 
3 months for 
up to 
2 years k
Adjuvant 
Cycle 1, 
Day 1, 
(5) days
Adjuvant 
Cycle 217, 
Day 1
(5) days i
30 (5) 
days after 
last dose
30 days after 
progression/
recurrence
(5) days l
Up to 
3 years
Concomitant 
medications qq
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events rr
x
x
x
x
x
x
x
x
x
x
x
x
Survival and 
recurrence follow-
up h
x
atezoatezolizumab; C1D1 Cycle 1, Day 1; C2D1Cycle 2, Day 1; D/Cdiscontinuation; ECGelectrocardiogram; ECOG Eastern Cooperative 
Oncology Group; eCRFelectronic Case Report Form; qevery; SOCstandard of care.
Notes:  All assessments should be performed within the time windows specified for the scheduled visit.  All designated procedures are required at 
each visit, even if visit is outside the recommended time window.  On treatment days, all assessments should be performed prior to dosing, unless 
otherwise specified. 
a
Results of SOC assessments performed prior to obtaining informed consent and within 42 days prior to Day 1 (or within 14 days prior to Day 1 
for laboratory tests) may be used; such assessments do not need to be repeated for screening.
b
Preferably, assessments at this visit should be performed by the surgeon, if feasible.  If not feasible, the assessments may be performed by the 
Medical Oncologist.
c
It is acceptable for visit to occur outside the recommended window; all indicated procedures should be still be performed.


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
102/Protocol ML39236, Version 7 
d
For the Adjuvant Atezolizumab Therapy Phase, all vital sign measurements and routine laboratory tests and tumor assessments, will be 
performed per SOC except biomarkers assessments and Extended Chest CT scan, which will occur per Surveillance schedule of activities 
(Appendix 2). 
e
Patients who prematurely discontinue neoadjuvant atezolizumab will return to the clinic 30 (5) days after the last dose of atezolizumab 
treatment.  If patients undergo surgery after neoadjuvant atezolizumab discontinuation/completion and will not receive adjuvant atezolizumab, 
the Treatment Discontinuation Visit assessments can be performed at the Post-Surgery Visit (even if it is more than 30 days after the last 
dose). If the patient will receive adjuvant atezolizumab, the Treatment Discontinuation Visit will occur when the patient completes/discontinues 
adjuvant atezolizumab treatment. Patients who do not complete surgery will then be followed for survival.  Patients who complete surgery will 
enter the Surveillance period.  The visit at which progressive disease or recurrence occurs may be used as the Treatment Discontinuation Visit. 
f
Any assessments not marked with an “x” should be performed as per SOC.
g
Disease progression/recurrence must be confirmed by tumor imaging.
h
Patients who prematurely discontinue neoadjuvant atezolizumab and do not undergo surgery will enter Survival Follow-Up for up to 3 years 
after the last dose of neoadjuvant atezolizumab. Patients who undergo surgery will enter the Surveillance period (See Appendix 2) and then
will enter Survival Follow-Up. During Survival Follow-Up, information on recurrence, off-protocol cancer-related treatment and survival will be 
collected every 6 months for up to 3 years Surveillance.  This information may be obtained at clinic visits or by telephone, mail, or email. The 
last Survival Follow-up Visit will serve as the Study Completion Visit.
i
If C2D1 visit is delayed, all subsequent visits will be delayed accordingly.
j
Delay in surgery due to an adverse event is permitted.
k
Window for assessments may be altered to align with adjuvant therapy.  Allowed timeframe for Surveillance assessments is outlined in 
Appendix 2.  Blood sample and extended chest CT from Post-surgery Visit will be a part of Surveillance assessments.
l
Exceptions may be made; Investigators may discuss them with the Medical Monitor.
m
Informed consent must be documented before any prescreening or screening procedure is performed.
n
A prescreening biopsy can be conducted for patients who do not have an adequate archival tumor specimen.  This biopsy will not need to be 
repeated at study screening.  If a patient has an adequate archival tumor specimen, no additional biopsy will be needed.
o
Includes clinically significant diseases, surgeries, cancer history (including histology, stage, prior cancer therapies and procedures), smoking 
history, asbestos, pleural or pericardial effusion, ascites requiring intervention, exposure, HPV infection and HPV subtypes, associated 
syndromes, Helicobacter pylori infection, relevant mutations, and reproductive status (women).  
p
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
q
Complete physical examination only has to be conducted at either the C2D1 visit or the pre-surgery visit, but not at both.
r
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
103/Protocol ML39236, Version 7 
s
Limited examination should be performed per SOC during adjuvant atezolizumab treatment.
t
ECOG Performance Status must be of 0 or 1 at screening and before patients can start adjuvant treatment (see Appendix 7).
u
In the Neoadjuvant Atezolizumab Therapy Phase, measure respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is 
in a seated position, temperature, and oxygen saturation by pulse oximetry.  For both infusions of atezolizumab, measure the patient’s vital 
signs within 60 minutes before the infusion; and during and after the infusion, if clinically indicated.  For the Neoadjuvant Atezolizumab Therapy 
Phase, measure vital signs per SOC.  Record abnormalities observed at screening on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
v
For the Neoadjuvant Atezolizumab Therapy Phase, the patient’s tumor will be staged at screening by contrast-enhanced helical CT scan of the 
chest, PET/CT, and brain MRI, preferably with gadolinium (for Stage II or III disease).  If brain MRI is not feasible for technical or patient-related 
reasons (e.g., pacemaker, severe claustrophobia), brain CT scan with IV contrast should be obtained.  All scans will be repeated prior to 
surgery to confirm surgical eligibility. Radiographic responses will be assessed by the investigator per RECIST v1.1 after the two cycles of 
atezolizumab.  Scans will be repeated and collected at any time if progressive disease is suspected.  For the Adjuvant Atezolizumab Therapy 
Phase, all tumor assessments will be per Surveillance schedule of activities (see Appendix 2).  All imaging will be collected for further analyses.  
See imaging manual for specific instructions.
w
Extended chest CT scan (including liver and adrenals). All other CT Scans will be performed as per SOC.  For additional details on the timing 
of assessments, see Appendix 2.
x
Blood sample and extended chest CT scan from Post-surgery Visit will be a part of Baseline Surveillance assessments.
y
For Group D only: Extended CT chest (including liver and adrenals) needs to be done after completion of SOC adjuvant 
Chemotherapy/Radiotherapy and before initiation of adjuvant atezolizumab to rule out disease progression/recurrence.  If done as part of a 
surveillance visit, it does not need to be repeated.  The other tumor assessments will sync with the surveillance visits (see Appendix 2).
z
For the Neoadjuvant Atezolizumab Therapy Phase, pathologic responses will be scored by a pathologist based on the surgical resection as 
defined by (Hellmann et al. 2014).  
aa
Can be performed within 6 months of planned resection and repeated at screening.
bb
Hematology includes CBC (WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count [neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells]).
cc
Chemistry panel (serum) includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH.  
dd
All women of childbearing potential, including those who have had a tubal ligation, will have a serum pregnancy test at screening. 
ee
Includes specific gravity, pH, glucose, protein, ketones, and blood.
ff
Perform thyroid function tests at baseline, the pre-surgery visit, at post-surgery visit and then approximately every 9 weeks (3 cycles) during 
adjuvant atezolizumab treatment in the Adjuvant Atezolizumab Therapy Phase.
gg
Viral serology includes HIV, Hepatitis B (HBsAg, antibodies against HBsAg, hepatitis B core antigen; HBV DNA is required positive anti-HBc 
antibody test), and HCV antibody (anti-HCV).


Appendix 1
Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
104/Protocol ML39236, Version 7 
hh
See Appendix 3 for detailed schedule.
ii
Tumor tissue may be archival; it does not need to be collected within 42 days of enrollment.
jj
Tissue biopsy (tumor and lymph node, if available); at disease progression/recurrence is optional and requires a separate ICF signature.
Tissue collection by CNB is preferred, however collection by EBUS, or bronchoscopy are acceptable alternatives.
kk
The biomarker blood sample may be collected up to 7 days prior to the visit.  Whole blood sample for biomarker assessments should preferably 
be collected on the day of surgery (prior to surgery and prior to antibiotic administration).  It is acceptable to collect the sample up to 7 days 
prior to surgery (including the day of surgery, and prior to antibiotic administration).  If sample needs to be collected outside of the 
recommended window, please contact the Medical Monitor for guidance and approval.
ll
Plasma, serum and, at selected timepoints, also PBMCs will be collected (see Appendix 2).
mm Biomarker blood samples will be collected approximately at every 6 weeks to 3 months but can be adjusted to synchronize with Surveillance 
visits (See Appendix 2).
nn
Encouraged for patients undergoing EBUS and/or bronchoscopy.  See lab manual for exact nomenclature and specific areas to be sampled 
during procedure.
oo
Should be performed after approximately 34 months of first adjuvant atezolizumab treatment.  
pp
In the Neoadjuvant Atezolizumab Therapy Phase, neoadjuvant treatment with atezolizumab 1200 mg will be given q21d for a maximum of 
2 cycles.  In Adjuvant Atezolizumab Therapy Phase, adjuvant treatment with atezolizumab 1200 mg will be given q21d for maximum of 
12 months (maximum 17 cycles).  Patients may need to remain in the clinic post-infusion for monitoring if needed.  See Section 4.3.2 for 
administration instructions.
qq
Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient from 7 days prior to initiation of atezolizumab treatment until the until the following visit:  1) For patients who will receive 
adjuvant atezolizumab treatment until the Adjuvant Atezolizumab Completion/ Discontinuation Visit (whichever visit will occur last), or 2) For 
patients who will not receive adjuvant atezolizumab treatment until the Post-surgery Visit.
rr
After informed consent has been obtained but prior to initiation of atezolizumab treatment, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  After initiation of atezolizumab treatment, adverse events will be reported until 30 days 
after the last dose of atezolizumab (neoadjuvant or adjuvant, whichever occurs last).  Serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of atezolizumab (neoadjuvant or adjuvant, whichever occurs last; see Section 5.3.1).  
All adverse events associated with CT scans, blood sample collection, and the optional biopsy (collected at the time of disease 
progression/recurrence) that occur after the 90-day reporting window, but during the Surveillance period, will also be collected and reported. 
After the designated reporting period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior atezolizumab 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 and adverse events of special interest considered to be related to 
atezolizumab treatment or trial-related procedures until a final outcome can be reported.


Atezolizumab—Genentech, Inc.
105/Protocol ML39236, Version 7 
Appendix 2
Timing of Surveillance Assessments 
The overall Schema for Surveillance Assessments is provided in Figure 1.
Detailed timing of Surveillance assessments for each adjuvant treatment subgroup can be found in Tables 14, as follows:
Table 1
Group A – No Adjuvant Treatment
Table 2
Group B – Adjuvant Atezolizumab Treatment
Table 3
Group C – SOC Chemotherapy (Radiotherapy) Only
Table 4
Group D– SOC Chemotherapy (Radiotherapy) Adjuvant Atezolizumab Treatment


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
106/Protocol ML39236, Version 7 
Figure 1: Surveillance Assessments Schema
SSurveillance (Visit); PBMCperipheral blood mononuclear cells.
Baseline Extended Chest CT scan and associated blood sample collection should ideally be obtained at the post-surgery visit/surveillance baseline 
(46 weeks after surgery). However, if it is not possible to perform the assessments at the post-surgery visit/surveillance baseline it is also 
acceptable to have them obtained at S1 (approximately 6 weeks after post-surgery visit/surveillance baseline). In this case:

Baseline Chest CT Scan and blood sample collection for PBMC will be obtained at S1

The next scans will be obtained at S3 and then approximately every 3 months up to S9 (if baseline scan is obtained at S1 then S2 scan 
does not need to be obtained)
* Whole blood sample for PBMC needs to be collected at S1 instead of S2 (on the same visit when the scans are performed).  .


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
107/Protocol ML39236, Version 7 
Table 1
Group A – No Adjuvant Treatment
Post-Surgery 
Visit /
Surveillance 
Baseline 
S1 Visit
S2 Visit
Surveillance 
Assessments during 
SOC Chemotherapy
Surveillance Assessments 
during Adjuvant Atezolizumab
Assessments during 
Surveillance Only (S3 to S9)
Time in 
Survival 
Follow-Up a
(4-6 weeks 
after surgery)
6 weeks 
after 
Surveillance 
baseline
(7days)
6 weeks after 
S1 Visit 
(7days)
N/A
N/A
See Below for Timing

Baseline 
extended chest 
CT scan and 
blood sample 
for biomarker 
analysis
Blood 
sample for 
biomarker 
analysis
Extended 
chest CT scan 
and
blood sample 
for biomarker 
analysis
N/A
N/A
Extended chest CT scan 
and blood sample 
collection for biomarker 
analysis
At approximately every 
3 months after S2 for 
2 years (S3 to S9).
1 year
EBUSEndobronchial ultrasound; SOCstandard of care; SSurveillance (visit).
Notes:  If visit is outside of the recommended window, please contact Medical Monitor for guidance and approval; if visit is outside of window, all 
indicated procedures should still be performed.  Patients whose disease progresses or recurs during Surveillance will discontinue from Surveillance 
and enter Survival Follow-up.
a If patient discontinues surveillance for any reason, patient will still be followed up for 3 years after last dose of atezolizumab treatment.


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
108/Protocol ML39236, Version 7 
Table 2
Group B – Adjuvant Atezolizumab Treatment
Post-Surgery 
Visit /  
Surveillance 
Baseline 
Surveillance 1 (S1) 
Visit
S2 Visit
Surveillance 
Assessments during 
SOC Chemotherapy
Surveillance 
Assessments during 
Adjuvant Atezolizumab
Assessments during 
Surveillance Only 
Time in Survival 
Follow-Up a
(46 weeks 
after surgery)
6 weeks after 
Surveillance 
baseline
(7days)
6 weeks after 
S1 Visit 
(7days)
N/A
See footnote b
See footnote d

Baseline 
Extended 
chest CT scan 
and blood 
sample for 
biomarker 
analysis
Blood sample for 
biomarker 
analysis
Extended 
chest CT 
scan and
blood sample 
for biomarker 
analysis
N/A
Extended chest CT 
scan and blood sample 
collection for biomarker 
analysis;
Optional bronchial 
brushings c
Extended chest CT 
scan and blood 
sample collection for 
biomarker analysis
Upon completion 
of surveillance, 
2 years in 
Survival follow-up
(until patients 
completes 
3 years after last 
dose of adjuvant 
atezolizumab)
Ccycle; Dday; EBUSEndobronchial ultrasound; SOCstandard of care; SSurveillance (visit).
Notes:  If visit is outside of the recommended window, please contact Medical Monitor for guidance and approval; if visit is outside of window, all 
indicated procedures should still be performed. Patients whose disease progresses or recurs during Surveillance will discontinue from Surveillance 
and enter Survival Follow-up.
a If patients discontinues surveillance for any reason, patient will still be followed up for 3 years after last dose of atezolizumab treatment.
b Below is guidance on how to synchronize the Surveillance and adjuvant atezolizumab treatment visits, however adjustments can be done as 
needed:
- If C1D1 performed within 6 weeks after Post-Surgery Visit/Surveillance Baseline, assessments can be synchronized with S1. Subsequent 
visits will follow the Surveillance schedule, with S2 approximately 6 weeks after S1 and subsequent visits (S3 to S9) at approximately every 
3 months. Please note subsequent adjuvant cycles can also be adjusted to synchronize with Surveillance visits.


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
109/Protocol ML39236, Version 7 
- If C1D1 is performed between 6 to 12 weeks after Post-Surgery Visit/Surveillance Baseline, C1D1 can be synchronized with S2. 
Subsequent assessments (S3 to S9) should be done approximately at every 3 months and can also be adjusted to synchronize with
adjuvant atezolizumab cycles.
- If first adjuvant atezolizumab cycle is performed 12 weeks after Post-Surgery Visit/Surveillance Baseline, C1D1 can be synchronized with 
S3. Subsequent assessments (S4 to S9) should be done approximately at every 3 months and can also be adjusted to synchronize with
adjuvant atezolizumab cycles.
c Optional Bronchial Brushings: will optionally be performed after approximately 3 to 4 months from the initiation of adjuvant atezolizumab (can be 
adjusted to synchronize with atezolizumab cycle).  Bronchial brushings are highly encouraged for patients undergoing EBUS or bronchoscopy.
See the laboratory manual for exact nomenclature and specific areas to be sampled during procedure
d Upon completion/discontinuation of adjuvant atezolizumab treatment, patients will enter a Surveillance only period.
- Treatment discontinuation visit will be performed 30 (5) days after last dose of adjuvant atezolizumab and a blood sample for biomarker 
assessment will be collected (see Appendix 1).
- Surveillance Only assessments: First assessment (Extended chest CT scan and blood sample for biomarker analysis) will be done 
approximately 3 months after last dose of adjuvant atezolizumab and subsequent assessments approximately at every 3 months until the 
patient completes a total of 2 years in Surveillance (Adjuvant Atezolizumab + Surveillance = 2 years).


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
110/Protocol ML39236, Version 7 
Table 3
Group C – SOC Chemotherapy (Radiotherapy) Only
Post-Surgery 
Visit /
Surveillance 
Baseline 
Surveillance 1 
(S1) Visit
S2 Visit
Surveillance 
Assessments during 
SOC Chemotherapy
Surveillance Assessments 
during Adjuvant 
Atezolizumab
Assessments during 
Surveillance Only 
Time in 
Survival 
Follow-Up a
(46 weeks 
after surgery)
6 weeks 
after 
Surveillance 
baseline
(7days)
6 weeks after 
S1 Visit 
(7days)
See footnote b
N/A
See footnote c

Baseline 
extended 
chest CT 
scan and 
blood sample 
for biomarker 
analysis
Blood 
sample for 
biomarker 
analysis
Extended 
chest CT scan 
and
blood sample 
for biomarker 
analysis
Extended Chest CT 
scan and blood 
sample collection for 
biomarker analysis c
N/A
Extended chest CT scan 
and blood sample 
collection for biomarker 
analysis d
Upon 
completion of 
surveillance, 
until patient 
completes 
3 years after 
last dose of 
neo adjuvant
atezolizumab
Ccycle; Dday; SOCstandard of care; SSurveillance (visit).
Notes:  If visit is outside of the recommended window, please contact Medical Monitor for guidance and approval; all indicated procedures should 
still be performed.  Patients whose disease progresses or recurs during Surveillance will discontinue from Surveillance and enter Survival 
Follow-up.
a
If patient discontinues surveillance for any reason, patient will still be followed up for 3 years after last dose of atezolizumab treatment.
b SOC Adjuvant Chemotherapy/Radiotherapy cycles can be adjusted to synchronize with the Surveillance visits. Below is guidance on how to 
synchronize the visits, but adjustments can be done as needed.
- If C1D1 (chemotherapy) is performed within 6 weeks after Post-Surgery Visit/Surveillance Baseline, it can be synchronized with S1.
Subsequent visits will follow the Surveillance schedule, with S2 approximately 6 weeks after S1, and subsequent visits (S3 to S9) at 
approximately every 3 months. Please note subsequent adjuvant cycles can also be adjusted to synchronize with Surveillance visits.


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
111/Protocol ML39236, Version 7 
- If C1D1 (chemotherapy) is performed between 6 to 12 weeks after Post-Surgery Visit/Surveillance Baseline, C1D1 can be synchronized with 
S2. Subsequent assessments (S3 to S9) should be done approximately at every 3 months and can also be adjusted to synchronize with
adjuvant atezolizumab cycles.
- If C1D1 (chemotherapy) cycle is performed 12 weeks after Post-Surgery Visit/Surveillance Baseline, C1D1 can be synchronized with S3.
Subsequent assessments (S4 to S9) should be done approximately at every 3 months and can also be adjusted to synchronize with
adjuvant atezolizumab cycles.
c Upon completion/discontinuation of SOC Chemotherapy/Radiotherapy, patients will move to Surveillance only period. The first assessment
(Extended chest CT scan and blood sample for biomarker analysis) will be done approximately 3 months after last dose of SOC
Chemotherapy/Radiotherapy and subsequent assessments approximately at every 3 months until the patient completes a total of 2 years in 
Surveillance (SOC Chemotherapy/RadiotherapySurveillance2 years).


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
112/Protocol ML39236, Version 7 
Table 4
Group D– SOC Chemotherapy (Radiotherapy) Adjuvant Atezolizumab Treatment
Post-Surgery Visit /  
Surveillance 
Baseline 
Surveillance 1 
(S1) Visit
S2 Visit
Surveillance 
Assessments during 
SOC Chemotherapy
Surveillance Assessments 
during Adjuvant 
Atezolizumab
Assessments 
during 
Surveillance 
Only 
Time in Survival 
Follow-Up a
(46 weeks after 
surgery)
6 weeks after 
Surveillance 
baseline
(7days)
6 weeks after 
S1 Visit (7days)
See footnote b
See footnote c
See footnote d

Surveillance 
baseline chest CT 
scan and
blood sample
Blood sample 
for biomarker 
analysis
Extended chest CT 
scan and
blood sample for 
biomarker analysis
Chest CT scan and 
blood sample collection 
for biomarker analysis
Extended chest CT scan 
and blood sample 
collection for biomarker 
analysis
Extended 
chest CT scan 
and blood 
sample 
collection for 
biomarker 
analysis
Upon 
completion of 
surveillance, 
until patient 
completes 
3 years after 
last dose of 
neoadjuvant
atezolizumab
Ccycle; Dday; SOCstandard of care; SSurveillance (visit).
Notes:  If a visit is outside of the recommended window, please contact Medical Monitor for guidance and approval; all indicated procedures should 
still be performed.  Patients whose disease progresses or recurs during Surveillance will discontinue from Surveillance and enter Survival 
Follow-up.
a If patients discontinues surveillance for any reason, patient will still be followed up for 3 years after last dose of atezolizumab treatment.
b SOC Adjuvant Chemotherapy/Radiotherapy cycles can be adjusted to synchronize with the Surveillance visits.
Below is guidance on how to synchronize the visits but adjustments can be done as needed.
- If C1D1 (chemotherapy) performed within 6 weeks after Post-Surgery Visit/Surveillance Baseline, it can be synchronized with S1.
Subsequent visits will follow the Surveillance schedule, with S2 approximately 6 weeks after S1 and subsequent visits (S3 to S9) at 
approximately every 3 months. Please note subsequent adjuvant cycles can also be adjusted to synchronize with surveillance visits
- If C1D1 (chemotherapy) is performed between 6 to 12 weeks after Post-Surgery Visit/Surveillance Baseline, C1D1 can be synchronized with 
S2. Subsequent assessments (S3 to S9) should be done approximately at every 3 months and can also be adjusted to synchronize with 
adjuvant atezolizumab cycles.


Appendix 2
Timing of Surveillance Assessments (cont.)
Atezolizumab—Genentech, Inc.
113/Protocol ML39236, Version 7 
- If C1D1 (chemotherapy) cycle is performed 12 weeks after Post-Surgery Visit/Surveillance Baseline, C1D1 can be synchronized with S3.
Subsequent assessments (S4 to S9) should be done approximately at every 3 months and can also be adjusted to synchronize with
adjuvant atezolizumab cycles.
c Upon completion of SOC Chemotherapy/Radiotherapy patients will move to adjuvant atezolizumab treatment for up to 12 months (maximum of 
17 cycles).  Extended CT scan needs to be done after completion of SOC adjuvant Chemotherapy/Radiotherapy and before initiation of adjuvant 
atezolizumab to rule out disease progression/recurrence.  C1D1 (adjuvant atezolizumab) can be initiated within 60 days of last SOC 
Chemotherapy/Radiotherapy.  If adjuvant treatment is planned to start outside of the recommended window, Investigators may discuss it with 
the Medical Monitor).  All atezolizumab adjuvant cycles can be adjusted to synchronize with the surveillance visits.
d Upon completion/discontinuation of adjuvant atezolizumab treatment, patients will move to Surveillance only period. Treatment discontinuation 
visit will be performed 30 (5) days after last dose of adjuvant atezolizumab and blood sample for biomarker assessment will be collected (see 
Appendix 1).  
- Surveillance Only assessments: First assessment (Extended chest CT scan and blood sample for biomarker analysis) will be done 
approximately 3 months after last dose of adjuvant atezolizumab and subsequent assessments approximately at every 3 months until the 
patient completes a total of 2 years in Surveillance (Adjuvant AtezolizumabSurveillance2 years).


Atezolizumab—Genentech, Inc.
114/Protocol ML39236, Version 7 
Appendix 3
Schedule of Biomarker Samples
Visit/Phase
Timepoint/Visit
Sample Type
Screening, 
Day 42 to 1
At visit
FFPE tumor tissue a
Fresh frozen tumor tissue a
Fresh lymph node (if available, highly encouraged) 
Bronchial Brushing (optional)b
FFPE lymph node (optional, highly encouraged)
Atezolizumab 
Neoadjuvant 
Cycle 1, Day 1
Prior to infusion
Whole blood PBMC
Whole blood flow cytometry
Whole blood for serum and plasma biomarkers
Whole blood for DNA
Surgery
Day of surgery (7 to 
1 day[s]) e
Whole blood PBMC
Whole blood flow cytometry 
Whole blood for serum and plasma biomarkers
At time of surgery
Fresh frozen tumor tissue surgical resection
FFPE tumor tissue surgical resection 
Fresh lymph nodes (for IMMUNOME: only if also 
collected at Screening; for dissociation: only if 
collected together with a fresh tumor tissue sample 
at surgery); tumor involved and/or not involved, as 
available 
FFPE normal lung tissue (if available)
FFPE lymph node (tumor involved and/or not 
involved)
Fresh tumor tissue surgical resection (optional)
Fresh normal lung tissue (optional and only if 
collected together with a fresh tumor tissue 
sample)
Post-surgery follow-up 
(30 [7] days after 
surgery)
Whole blood for serum and plasma biomarkers
Surveillance
Every 6 weeks to 
3 months (see 
Appendix 2)
Whole blood PBMC (at S2 and S5 only)
Whole blood for serum and plasma biomarkers


Appendix 3
Schedule of Biomarker Samples (cont.)
Atezolizumab—Genentech, Inc.
115/Protocol ML39236, Version 7 
Visit/Phase
Timepoint/Visit
Sample Type
Atezolizumab Adjuvant 
Cycle 1 Day 1 c (prior to 
infusion)
Whole blood PBMC (if not within2 weeks of S2)
Whole blood for serum and plasma biomarkers (if 
not within 2 weeks of any S visit
Unscheduled (Tumor 
Evaluation and 
Response)
Whole blood for serum and plasma biomarkers
34 months after 
initiation of adjuvant 
atezolizumab therapy
Bronchial Brushings (optional)
Disease Progression or 
Recurrence d
At visit
FFPE tumor biopsy (optional) d
FFPE lymph node (if available) d
Whole blood for serum and plasma biomarkers
Atezolizumab completion/ 
discontinuation visit
At visit
Whole blood for serum and plasma biomarkers
EBUSendobronchial ultrasound; FFPEformalin-fixed, paraffin-embedded; PMBCperipheral blood 
mononuclear cells; SSurveillance (Visit).
a Archival tissue 42 days is acceptable.
b Encouraged for patients undergoing EBUS or bronchoscopy. See lab manual for exact 
nomenclature and specific areas to be sampled during procedure
c Biomarker blood samples will be collected at Cycle 1 of Day 1 and at every tumor and response 
evaluation.
d Patient must sign consent form for optional biopsy at disease progression/recurrence.
e Whole blood sample for biomarker assessments should preferably be collected on the day of surgery 
(prior to surgery and pre-medication for surgery).  However, if it is not possible it is also acceptable to 
collect the sample up to 7 days prior to surgery (including the day of surgery, prior to the procedure). 
If a sample needs to be collected outside of the recommended window, please contact the Medical 
Monitor for guidance and approval.


Atezolizumab—Genentech, Inc.
116/Protocol ML39236, Version 7 
Appendix 4
American Joint Committee on Cancer Non-Small Cell Lung 
Cancer Staging, 8th Edition


Appendix 4
American Joint Committee on Cancer Non-Small Cell Lung Cancer Staging, 
8th Edition (cont.)
Atezolizumab—Genentech, Inc.
117/Protocol ML39236, Version 7 


Atezolizumab—Genentech, Inc.
118/Protocol ML39236, Version 7 
Appendix 5
Pathological Response
A detailed pathological evaluation will be performed on the surgically resected 
samples to obtain data described below.
Detailed pathological analysis will be performed for the post-treatment biopsies to 
determine the following:
1.
Tumor size (3 measurements)
2.
Tumor diagnosis using the 2015 World Health Organization (WHO) classification
3.
Predominant differentiation of the tumor (well, moderately, or poorly differentiated), 
and for adenocarcinoma histology, the histology subtypes present
4.
Lowest degree of tumor differentiation
5.
Angiolymphatic invasion
6.
Neural invasion
7.
Margin status in mm
8.
Degree of response International Union Against Cancer (UICC) pathological T and 
N stage
9.
Total percentage of areas of necrosis
10. Total percentage of areas of fibrosis
11. Total percentage of viable tumor tissue
12. Total percentage of viable malignant cells
13. Evidence of field effect. 
The pathology review will determine if the percentage of malignant cells after treatment 
is 10%, which is considered a major pathologic response (Hellmann et al. 2014).


Atezolizumab—Genentech, Inc.
119/Protocol ML39236, Version 7 
Appendix 6
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 the addition of 
explanatory text as needed for clarity.1
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as follows.
a.
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of:

10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than
5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
b.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lungs, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
c.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Technetium-99m bone scans, positron emission tomography (PET) scans, and plain 
films are not considered adequate imaging techniques for measuring bone lesions.  
                                           
1
For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
120/Protocol ML39236, Version 7 

However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS
a.
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and not usually more than 4 weeks prior to the beginning of the 
treatment.
b.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will be considered measurable when they are 
superficial and 10 mm in diameter 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, because CT is more sensitive than X-ray, particularly in identifying 


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
121/Protocol ML39236, Version 7 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  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 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness.  MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
IV contrast because of allergy or renal insufficiency, the decision as to whether a 
non-contrast CT or MRI (with or without MRI 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 (with or without MRI IV contrast) will be performed 
should also be based on the tumor type and the anatomic location of the disease 
and should be optimized to allow for comparison with the prior studies if possible.  
Each case should be discussed with the radiologist to determine if substitution of these 
other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward.  Care must be taken in measurement of target lesions on a 
different modality and interpretation of non-target disease or new lesions since the same 
lesion may appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, and Histology.  The utilization 
of these techniques for objective tumor evaluation cannot generally be advised.
TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least one
measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or two 


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
122/Protocol ML39236, Version 7 
organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will be 
recorded as non-measurable lesions (even if the size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs but, additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis 
10 mm are considered non-pathological and should not be recorded or followed.
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
123/Protocol ML39236, Version 7 
RESPONSE CRITERIA
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
–
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
–
In addition to the relative increase of 20%, the sum must also demonstrate an
absolute increase of at least 5 mm.
–
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b.
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met, given that a normal lymph node is defined as having a short 
axis 10 mm.
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but is too small to measure, 
a default value of 5 mm should be assigned and BML (below measurable limit) 
should be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but is too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well and BML should also be ticked.)


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
124/Protocol ML39236, Version 7 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion.
c.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level)

All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
–
The appearance of one or more new lesions is also considered progression.
d.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
125/Protocol ML39236, Version 7 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease; that is, an increase in tumor burden representing an additional 73%
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or an 
increase in lymphangitic disease from localized to widespread or may be described in 
protocols as “sufficient to require a change in therapy.”  If unequivocal progression is 
seen, the patient should be considered to have had overall PD at that point.  Although it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial.
e.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
126/Protocol ML39236, Version 7 
Table 1:  Timepoint Response:  Patients with Target Lesions
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
Table 2:  Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised.
b.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen 
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.


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
127/Protocol ML39236, Version 7 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.
c.
Best Overall Response:  All Timepoints
The best overall response is determined once all data for the patient is known, and is 
interpreted as in Table 3.  Complete or partial responses may be claimed if the criteria 
for each are met at a subsequent time point ≥ 4 weeks later.  
Table 3:  Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
CR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration 
for SD was met; otherwise, PD
PR
NE
SD, provided minimum duration 
for SD was met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent 
scans suggest small lesions were likely still present and in fact the patient had PR, not CR, 
at the first timepoint.  Under these circumstances, the original CR should be changed to PR
and the best response is PR.


Appendix 6 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
(cont.)
Atezolizumab—Genentech, Inc.
128/Protocol ML39236, Version 7 
d.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 13.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.


Atezolizumab—Genentech, Inc.
129/Protocol ML39236, Version 7 
Appendix 7
Eastern Cooperative Oncology Group Performance Status
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead


Atezolizumab—Genentech, Inc.
130/Protocol ML39236, Version 7 
Appendix 8
Anaphylaxis Precautions
EQUIPMENT NEEDED

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for intramuscular (preferred route), subcutaneous, intravenous, or 
endotracheal use in accordance with standard practice

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug administration, the
following procedures should be performed:
1. Stop the study drug administration, if possible.
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.


Atezolizumab—Genentech, Inc.
131/Protocol ML39236, Version 7 
Appendix 9
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 investigator should consider the benefitrisk balance for a given patient prior
to further administration of atezolizumab.  In patients who have met the criteria for 
permanent discontinuation, resumption of atezolizumab may be considered if the patient 
is deriving benefit and has fully recovered from the immune-mediated event.  The
decision to re-challenge patients with atezolizumab should be based on investigator’s 
assessment of benefitrisk and documented by the investigator. The Medical Monitor is 
available to advise, as needed. 
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 1.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
132/Protocol ML39236, Version 7 
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.

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.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, or events with no improvement after 
4872 hours of corticosteroids, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Bronchoscopy or BAL 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.
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 an assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor is
available to advise, as needed.
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; liver function will be 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
133/Protocol ML39236, Version 7 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits or to baseline 
values
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
LFTliver function 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 an 
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
134/Protocol ML39236, Version 7 
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury. 

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function 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 an
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise, as needed.
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
135/Protocol ML39236, Version 7 
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement..

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise, as needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
136/Protocol ML39236, Version 7 
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  Patients should be referred to an endocrinologist 
if an endocrinopathy is suspected.  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 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
137/Protocol ML39236, Version 7 
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH closely.
Symptomatic 
hypothyroidism

Withhold 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.
Asymptomatic 
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 symptomatic hyperthyroidism.

Consider patient referral to endocrinologist.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-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 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 an assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise, as needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
138/Protocol ML39236, Version 7 
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 upon improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 diabetes, 
treat as per institutional guidelines.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

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.
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 an assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
139/Protocol ML39236, Version 7 
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging.
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 an assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
140/Protocol ML39236, Version 7 
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on an assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk
and documented by the investigator (or an appropriate delegate). The Medical Monitor
is available to advise, as needed.
IMMUNE- MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to,


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
141/Protocol ML39236, Version 7 
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 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.
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 24

Permanently discontinue atezolizumab and contact Medical 
Monitor. a

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VAD ventricular assist device.
a 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 investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise, as 
needed.
INFUSION-RELATED REACTIONS AND CYTOKINE RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine release 
syndrome (CRS) with atezolizumab may receive medication with antihistamines, 
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
142/Protocol ML39236, Version 7 
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.
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 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-(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.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
143/Protocol ML39236, Version 7 
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms 

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration.

In case of rapid decline or prolonged CRS (2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2.

For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS.
Grade 2 a
Fever b with 
hypotension not 
requiring 
vasopressors
and/or
Hypoxia requiring 
low-flow oxygen d
by nasal cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional 
practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is,
hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor. e

If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, 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 Medical Monitor.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
144/Protocol ML39236, Version 7 
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Event
Management
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; monitoring in 
the ICU is recommended.  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. e

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.  For patients who are refractory to 
anticytokine therapy, experimental treatments f may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
145/Protocol ML39236, Version 7 
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level positive 
airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive airway pressure; 
CRScytokine-release syndrome; CTCAECommon Terminology Criteria for Adverse Events; 
eCRFelectronic Case Report Form; HLHhemophagocytic lymphohistiocytosis; 
ICUintensive care unit; IRRinfusion-related reaction; MASmacrophage activation 
syndrome; NCCNNational Cancer Comprehensive Network; NCINational Cancer Institute.
Note:  These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus grading for 
CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with 
CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients
with atezolizumab should be based on investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be considered 
after assessing the benefitrisk ratio.
f
Refer to Riegler et al. (2019).
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
146/Protocol ML39236, Version 7 
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0 ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone.
Asymptomatic with amylase and/or lipase 2.05.0 ULN:

Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with corticosteroids
equivalent to 12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate). The Medical Monitor is available to advise, as 
needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
147/Protocol ML39236, Version 7 
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 Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with corticosteroids equivalent to
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
148/Protocol ML39236, Version 7 
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash 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 
Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if indicated, 
biopsy.

Follow the applicable treatment and management guidelines above.

If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, 
permanently discontinue atezolizumab.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
149/Protocol ML39236, Version 7 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk
and documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated
neuropathy, Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-mediated
neuropathy, Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology and refer patient to neurologist.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated
neuropathy, Grade 3 
or 4

Permanently discontinue atezolizumab and contact 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 Medical Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of corticosteroids equivalent to 12 mg/kg/day oral 
or IV prednisone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator 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 


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
150/Protocol ML39236, Version 7 
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 investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  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 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re-challenge patients with 
atezolizumab should be based on investigator's assessment of benefitrisk and documented by 
the investigator (or an appropriate delegate). The Medical Monitor is available to advise, as 
needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
151/Protocol ML39236, Version 7 
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
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 12.
Table 12 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 
Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
152/Protocol ML39236, 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 an 
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with 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 13.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
153/Protocol ML39236, Version 7 
Table 13 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 Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk and
documented by the investigator (or an appropriate delegate). The Medical Monitor is
available to advise, as needed.  


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
154/Protocol ML39236, Version 7 
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Event
Management
Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if patient is 
severely compromised (e.g., cardiac or respiratory symptoms, 
dysphagia, or weakness that severely limits mobility); convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if patient is 
severely compromised (e.g., cardiac or respiratory symptoms, 
dysphagia, or weakness that severely limits mobility); convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator 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 investigator's assessment of benefitrisk and documented 
by the investigator (or an appropriate delegate). The Medical Monitor is available to advise, as 
needed.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
155/Protocol ML39236, Version 7 
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), which are considered to be potential risks for atezolizumab. 
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/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard deviations 
above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
156/Protocol ML39236, Version 7 
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact 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 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019).

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLHhemophagocytic lymphohistiocytosis; MASmacrophage activation syndrome.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.


Appendix 9 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—Genentech, Inc.
157/Protocol ML39236, Version 7 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.


Atezolizumab—Genentech, Inc.
158/Protocol ML39236, Version 7 
Appendix 10
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest (regardless of causality) are required to be reported 
by the investigator to the Sponsor immediately (i.e., no more than 24 hours after learning 
of the event; see Section 5.4.2 for reporting instructions).  Adverse events of special 
interest for this study include the following:

Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, hyperthyroidism, adrenal 
insufficiency, and hypophysitis

Hepatitis, including AST or ALT 10ULN

Systemic lupus erythematosus

Neurologic disorders:  Guillain-Barré Syndrome, myasthenic syndrome or 
myasthenia gravis, and meningioencephalitis

Nephritis

Events suggestive of hypersensitivity, cytokine-release syndrome, influenza-like 
illness, HLH, and MAS

Infusion-related reactions

Cytokine release syndrome, influenza-like illness, systemic inflammatory response 
syndrome (SIRS), systemic immune activation (SIA)

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

Vasculitis

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)


Atezolizumab—Genentech, Inc.
159/Protocol ML39236, Version 7 
Appendix 11
Protocol Version 3 Schedule of Activities
Assessment
Screening a
Part 1 –
Atezolizumab 
Neoadjuvant 
Treatment
Surgery
Part 2 –
Atezolizumab 
Adjuvant 
Treatment
(Medical 
Oncologist) c
Study 
Completion/ 
D/C d
Disease 
Progression or 
Recurrence cc
Follow-
up e
Pre-
surgery b Surgery
Post-
Surgery
(Window [Days])
Day 
42 
to 1
Day 
14 
to 1
C1D1 
(Day 
1 3)
C2D1 
(Day 22
3) f
Day 36
(3)
Day 40 
(10) g
30 (7) 
days 
after 
surgery
Adjuvant 
Cycle Day 1 
(3) days
30 (5) 
days after 
last dose
30 days after 
progression/
recurrence
(5) days dd
Up to 
3 years
Informed consent (prescreening biopsy 
ICF and main ICF) h
x
Prescreening biopsy
See footnote j
Medical history and demographic data i
x
Weight
x
x
Height
x
Complete physical examination k
x
x l
Limited physical examination l
x
x a
x
ECOG Performance Status m
x
x m
x
Vital signs n
x
x n
x
x
x a, n
x
Tumor and response evaluations o
x
x
x a
Pathologic response assessment p
x
Pulmonary function tests
x ff
x
Hematology q
x
x
x
x a


Appendix 11 
Protocol Version 3 Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
160/Protocol ML39236, Version 7 
Assessment
Screening a
Part 1 –
Atezolizumab 
Neoadjuvant 
Treatment
Surgery
Part 2 –
Atezolizumab 
Adjuvant 
Treatment
(Medical 
Oncologist) c
Study 
Completion/ 
D/C d
Disease 
Progression or 
Recurrence cc
Follow-
up e
Pre-
surgery b Surgery
Post-
Surgery
(Window [Days])
Day 
42 
to 1
Day 
14 
to 1
C1D1  
(Day 
1 3)
C2D1 
(Day 22
3) f
Day 36
(3)
Day 40 
(10) g
30 (7) 
days 
after 
surgery
Adjuvant 
Cycle Day 1 
(3) days
30 (5) 
days after 
last dose
30 days after 
progression/
recurrence
(5) days dd
Up to 
3 years
Chemistry r
x
x
x
x a
Coagulation (aPTT and INR)
x
Pregnancy test s
x
Urinalysis t
x
Thyroid function test (TSH, free T3, 
and free T4) u
x
x
x
x (q3 cycles)
C-reactive protein
x
Viral serology v
x
Biomarker samples (tissue) w
x
x
x ee
Biomarker samples (blood-based) w, x
x
x
x
x y
x
x ee
Optional bronchial brushing gg
x
x hh
Study treatment administration z
x
x
x
Concomitant medications aa
x
x
x
x
x
x
x
x
x
x
Adverse events bb
x
x
x
x
x
x
x
x
x
x
Survival and recurrence follow-up e
x
C1D1Cycle 1, Day 1; C2D1Cycle 2, Day 1; D/Cdiscontinuation; ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; 
eCRFelectronic Case Report Form; qevery; SOCstandard of care.
Notes: All assessments should be performed within the time windows specified for the scheduled visit.  On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified.
a Limited examination should be performed per SOC during adjuvant atezolizumab treatment.  Results of SOC tests or examinations 
performed prior to obtaining informed consent and within 42 days prior to Day 1 (or within 14 days prior to Day 1 for laboratory tests) may be 


Appendix 11 
Protocol Version 3 Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
161/Protocol ML39236, Version 7 
used; such tests do not need to be repeated for screening.
b Assessments at this visit may be performed by either the Medical Oncologist or the surgeon.
c For Part 2, all vital sign measurements, routine laboratory tests, and tumor and response assessments will be performed per SOC. 
d Patients who discontinue study treatment or complete the study will return to the clinic 30 (5) days after the last dose of study treatment, 
and then followed for survival.  The visit at which progressive disease occurs may be used as the treatment discontinuation visit. 
e Documentation of disease recurrence, off-protocol cancer-related treatment, and survival will occur every 6 months for up to 3 years after the 
patient receives the last dose of atezolizumab treatment (neoadjuvant or adjuvant, whichever occurs last), or until loss to follow-up, 
withdrawal of consent, or study termination by the Sponsor.  After study treatment discontinuation, patients will be followed per SOC but 
information on recurrence, off-protocol cancer-related treatment, and survival will be collected every 6 months for up to 3 years after the 
patient receives the last dose of atezolizumab neoadjuvant or adjuvant, whichever occurs last.  This information may be obtained at clinic 
visits or by telephone, mail, or email.  The last Survival Follow-up Visit will serve as the Study Completion/Discontinuation Visit.
f
If C2D1 visit is delayed, all subsequent visits will be delayed accordingly.
g Delay in surgery due to an adverse event is permitted.
h Informed consent must be documented before any prescreening or screening procedure is performed.
i
Includes clinically significant diseases, surgeries, cancer history (including histology, stage, prior cancer therapies and procedures), smoking 
history, asbestos, pleural or pericardial effusion, ascites requiring intervention, exposure, HPV infection and HPV subtypes, associated 
syndromes, Helicobacter pylori infection, relevant mutations, and reproductive status (women).  
j
A prescreening biopsy will be conducted for patients who do not have an adequate archival tumor specimen.  This biopsy will not need to be 
repeated at study screening.  If a patient has an adequate archival tumor specimen, no additional biopsy will be needed.
k Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
l
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Complete physical examination only has to 
be conducted at either the C2D1 visit or the pre-surgery visit, but not at both.  Record new or worsened clinically significant abnormalities on 
the Adverse Event eCRF.
m ECOG Performance Status must be of 0 or 1 at screening and before patients can start adjuvant treatment (see Appendix 7).
n In Part 1, measure respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, temperature, and 
oxygen saturation by pulse oximetry.  For both infusions of study treatment, measure the patient’s vital signs within 60 minutes before the 
infusion; and during and after the infusion, if clinically indicated.  For Part 2, measure vital signs per SOC.  Record abnormalities observed at 
screening on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
o For Part 1, the patient’s tumor will be staged at screening by contrast-enhanced (if patient is not contrast-allergic) helical CT scan of the 
chest, PET/CT, and brain MRI, preferably with gadolinium (for Stage II or III disease).  If brain MRI is not feasible for technical or 
patient-related reasons (e.g., pacemaker, severe claustrophobia), brain CT scan with IV contrast should be obtained.  All scans will be 
repeated prior to surgery to confirm surgical eligibility. Radiographic responses will be assessed by the investigator per RECIST v1.1 after the 
two cycles of atezolizumab.  At the investigator’s discretion, scans may be repeated at any time if progressive disease is suspected.  For Part 
2, all tumor assessments will be per SOC.  
p For Part 1, pathologic responses will also be scored by a pathologist based on the surgical resection as defined by prior studies (Hellmann et 
al. 2014).  For Part 2, all tumor and laboratory assessments will be per SOC.  


Appendix 11 
Protocol Version 3 Schedule of Activities (cont.)
Atezolizumab—Genentech, Inc.
162/Protocol ML39236, Version 7 
q Hematology includes CBC (WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count [neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells]).
r
Chemistry panel (serum) includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH.  
s All women of childbearing potential, including those who have had a tubal ligation, will have a serum pregnancy test at screening. 
t
Includes specific gravity, pH, glucose, protein, ketones, and blood.
u Perform thyroid function tests at baseline, the pre-surgery visit, at post-surgery visit and then every 9 weeks (3 cycles) during adjuvant 
atezolizumab treatment in Part 2.
v Viral serology includes HIV, Hepatitis B (HBsAg, antibodies against HBsAg, hepatitis B core antigen; HBV DNA is required positive anti-HBc 
antibody test), and HCV antibody (anti-HCV).
w See Appendix 3 for detailed schedule.
x The biomarker blood sample may be collected up to 7 days prior to the visit.
y Biomarker blood samples will be collected at Cycle 1 of Day 1 and at every tumor and response evaluation. Plasma, serum and, at selected 
timepoints, also PBMCs will be collected (see Appendix 2).
z In Part 1, neoadjuvant treatment with atezolizumab 1200 mg will be given q21d for a maximum of 2 cycles.  In Part 2, adjuvant treatment with 
atezolizumab 1200 mg will be given q21d for maximum of 12 months.  Patients may need to remain in the clinic post-infusion for monitoring if 
needed.  See Section 4.3.2 for administration instructions.  
aa Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 7 days prior to initiation of study treatment until the following visit:  1) For patients who will receive 
adjuvant atezolizumab treatment until the Adjuvant Atezolizumab Completion/ Discontinuation Visit, or 2) For patients who will not receive 
adjuvant atezolizumab treatment until the Post-surgery Visit.
bb 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.  After initiation of atezolizumab, adverse events will be reported until 30 days after the 
last dose of atezolizumab (neoadjuvant or adjuvant, whichever occurs last).  Serious adverse events and adverse events of special interest 
will be reported until 90days after the last dose of atezolizumab (neoadjuvant or adjuvant, whichever occurs last).  After this period, the 
Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior 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 and adverse events of special interest considered to be related to study treatment or trial-related procedures until a 
final outcome can be reported.
cc Disease progression/recurrence must be confirmed by tumor imaging.
dd Exceptions may be made with Medical Monitor approval.
ee Tissue biopsy (tumor and lymph node, if available) and blood sample at disease progression/recurrence are optional and require a separate 
ICF signature.  Tissue collection by core needle biopsy is preferred, however collection by endobronchial ultrasound or bronchoscopy are 
acceptable alternatives.
ff PFT Can be performed within 6 months of planned resection and repeated at screening.
gg Encouraged for patients undergoing EBUS and/or bronchoscopy.  See lab manual for exact nomenclature and specific areas to be sampled 
during procedure
hh Optional bronchial brushing should be performed after approximately 34 months of first adjuvant atezolizumab treatment.  

SAP_003.pdf: 
Official Title: 
A Phase II, Open-Label, Multicenter, Single-Arm Study to Investigate 
the Efficacy and Safety of Atezolizumab as Neoadjuvant and 
Adjuvant Therapy in Patients With Stage IB, II, IIIA or Selected 
IIIB Resectable and Untreated Non-Small Cell Lung Cancer 
NCT Number: 
NCT02927301 
Document Date: 
SAP Version 2: 16 Jun 2020 


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