Clinical trial NCT02848651
Conditions: Non-Small Cell Lung Cancer
Sponsor: Genentech, Inc.
Start date: 2016-09-23; Completion date: 2019-05-14
Enrollment: 153 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a Phase II, open-label, prospective, multicenter study designed to evaluate the efficacy and safety of single-agent atezolizumab as a first-line therapy in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC). In addition, the primary biomarker objective was to measure blood tumor mutational burden (bTMB) and evaluate whether it can predict for improved clinical outcome with atezolizumab.

Detailed description:

Arms: arm 1: Participants received 1200 milligrams (mg) of atezolizumab administered by intravenous infusion every 21 days until disease progression, loss of clinical benefit, or unacceptable toxicity (up to a total of 2 years of atezolizumab treatment).
Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Atezolizumab 1200 mg was administered by intravenous infusion on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit, or unacceptable toxicity (up to a total of 2 years of atezolizumab treatment).

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A PHASE II SINGLE-ARM STUDY OF ATEZOLIZUMAB 
MONOTHERAPY IN LOCALLY ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER: CLINICAL EVALUATION OF 
NOVEL BLOOD-BASED DIAGNOSTICS 
NCT Number: 
NCT02848651 
Document Date: 
Protocol Version 5: 29- April-2019 
 
 


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The information contained in this document, especially any unpublished data, is the property of 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
Protocol ML39237, Version 5
PROTOCOL
TITLE:
A PHASE II SINGLE-ARM STUDY OF 
ATEZOLIZUMAB MONOTHERAPY IN LOCALLY 
ADVANCED OR METASTATIC NONSMALL CELL 
LUNG CANCER: CLINICAL EVALUATION OF 
NOVEL BLOOD-BASED DIAGNOSTICS
PROTOCOL NUMBER:
ML39237
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, Pharm.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  29 April 2016
DATES AMENDED
Version 2:  16 February 2017
Version 3:  05 December 2017
Version 4:  28 March 2018
Version 5:  See electronic date stamp below
 
29-Apr-2019 16:53:34
Title
Approver's Name
Date and Time (UTC)


Atezolizumab—Genentech, Inc.
2/Protocol ML39237, Version 5
PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
The protocol has been amended to allow patients who remain on the study and elect to 
rollover into the optional long-term follow-up (LTFU) portion of the study to be followed 
for survival data, and patients who continue to receive study drug will also be monitored 
for safety events.  Patients on study drug will continue therapy until they have received a 
total of 2 years of atezolizumab treatment (32 cycles).  Thereafter patients will continue 
to be contacted for overall survival follow-up every 3 months for the first year, then every 
6 months thereafter for up to 5 years from enrollment of the first patient into the study, 
until the last patient dies, withdraws consent, or is lost to follow-up, whichever occurs 
first.
The following additional changes have been made:

Section 1.2 has been updated with the most current FDA-approved atezolizumab
prescribing information.

Section 2 (Table 3) has been updated to remove independent review facility (IRF)
assessments from study endpoints.

In Section 3.1 language regarding using public resources to obtain survival data and 
details on the handling of that data was removed.  Also, language was added that 
allows patients to receive up to a total of 2 years of atezolizumab treatment
(32 cycles).

In Section 3.2 it was clarified that collection of LTFU for patients is optional.  Also, 
language was added to define the length of the LTFU.

In Section 4.5.9, language regarding using public resources to obtain survival data 
and details on the handling of that data was removed.  Also the LTFU email address 
was removed.

In Section 5.3.1, adverse event reporting for patients who receive atezolizumab and 
continue in the LFTU portion of the study has been added. All adverse events 
should be reported until 30 days after the last dose of atezolizumab during this 
period of the study.  Additionally, serious adverse events and non-serious adverse 
events of special interest will be reported until 90 days after the last dose of 
atezolizumab for these patients.

In Section 6, language was added to clarify that the overall survival analysis will be 
updated once the LTFU data is available, and will be summarized in a separate 
report.

In Section 6.4.2 and 6.6.2, language regarding IRF assessments have been 
removed.

Appendix 1 was renamed to Appendix 1a (Schedule of Activities) and footnote “e” 
was revised to refer to Appendix 1b for assessments related to the LTFU.

Appendix 1b was created to outline the assessments related to the LTFU.


Atezolizumab—Genentech, Inc.
3/Protocol ML39237, Version 5
Additional minor changes have been made to improve clarity and consistency, and to 
adhere to current protocol template standards.  Substantive new information appears in 
italics.  This amendment represents cumulative changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10
PROTOCOL SYNOPSIS .................................................................................... 11
1.
BACKGROUND .......................................................................................... 22
1.1
Background on NonSmall Cell Lung Cancer ....................... 22
1.1.1
First-Line Treatment for NSCLC without an 
Epidermal Growth Factor Receptor Mutation or 
Anaplastic Lymphoma Kinase Rearrangement...................... 22
1.1.2
Cancer Immunotherapy:  Programmed Death-
Ligand 1/Programmed Death-1 Inhibitors and 
Biomarker Selection .............................................................. 23
1.1.3
Diagnostic Testing for First-Line Treatment of 
NonSmall Cell Lung Cancer ................................................ 25
1.2
Background on Atezolizumab................................................ 25
1.2.1
Summary of Nonclinical Studies............................................ 25
1.2.2
Clinical Experience with Atezolizumab .................................. 26
1.2.2.1
Clinical Safety........................................................................ 27
1.2.2.2
Clinical Activity....................................................................... 30
1.2.3
Clinical Pharmacokinetics and Immunogenicity..................... 31
1.2.4
Rationale for Atezolizumab Dosage ...................................... 32
1.3
Study Rationale and BenefitRisk Assessment..................... 33
2.
OBJECTIVES AND ENDPOINTS ............................................................... 35
3.
STUDY DESIGN......................................................................................... 36
3.1
Description of the Study......................................................... 36
3.2
End of Study and Length of Study......................................... 39
3.3
Rationale for Study Design.................................................... 39
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 39
3.3.2
Rationale for Patient Population ............................................ 40
3.3.3
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment until Loss of Clinical 
Benefit ................................................................................... 41
3.3.4
Rationale for Collection of Blood Specimens......................... 41


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3.3.5
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens ................................................................. 42
3.3.6
Rationale for Biomarker Assessments................................... 42
4.
MATERIALS AND METHODS .................................................................... 43
4.1
Patients.................................................................................. 43
4.1.1
Inclusion Criteria.................................................................... 43
4.1.2
Exclusion Criteria................................................................... 44
4.2
Method of Treatment Assignment and Blinding..................... 48
4.3
Study Treatment.................................................................... 48
4.3.1
Formulation, Packaging, and Handling.................................. 49
4.3.2
Dosage, Administration, and Compliance.............................. 49
4.3.3
Investigational Medicinal Product Accountability ................... 51
4.3.4
Post-Trial Access to Atezolizumab ........................................ 51
4.4
Concomitant Therapy ............................................................ 51
4.4.1
Permitted Therapy................................................................. 51
4.4.2
Cautionary Therapy for Atezolizumab-Treated 
Patients.................................................................................. 52
4.4.3
Prohibited Therapy ................................................................ 53
4.5
Study Assessments ............................................................... 53
4.5.1
Informed Consent Forms and Screening Log........................ 53
4.5.2
Medical History and Demographic Data ................................ 54
4.5.3
Physical Examinations........................................................... 54
4.5.4
Vital Signs.............................................................................. 54
4.5.5
Tumor and Response Evaluations......................................... 54
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 55
4.5.6.1
Samples for Safety Laboratory Tests .................................... 55
4.5.6.2
Biomarker Samples ............................................................... 56
4.5.7
Optional Samples for Research Biosample 
Repository ............................................................................. 58
4.5.7.1
Overview of the Research Biosample Repository.................. 58
4.5.7.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 58
4.5.7.3
Sample Collection.................................................................. 58


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4.5.7.4
Confidentiality........................................................................ 59
4.5.7.5
Consent to Participate in the Research 
Biosample Repository............................................................ 60
4.5.7.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 60
4.5.7.7
Monitoring and Oversight....................................................... 60
4.5.8
On-Study Survival Follow-Up................................................. 61
4.5.9
Optional Long-Term Follow-Up.............................................. 61
4.5.10
ECOG Performance Status ................................................... 61
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 61
4.6.1
Patient Discontinuation.......................................................... 61
4.6.2
Study Treatment Discontinuation........................................... 62
4.6.3
Study and Site Discontinuation.............................................. 62
5.
ASSESSMENT OF SAFETY....................................................................... 63
5.1
Safety Plan ............................................................................ 63
5.1.1
Risks Associated with Atezolizumab ..................................... 63
5.1.2
Management of Patients Who Experience 
Specific Adverse Events........................................................ 64
5.2
Safety Parameters and Definitions ........................................ 65
5.2.1
Adverse Events ..................................................................... 65
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 65
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 66
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 67
5.3.1
Adverse Event Reporting Period ........................................... 67
5.3.2
Eliciting Adverse Event Information....................................... 68
5.3.3
Assessment of Severity of Adverse Events ........................... 68
5.3.4
Assessment of Causality of Adverse Events ......................... 69
5.3.5
Procedures for Recording Adverse Events............................ 70
5.3.5.1
Infusion-Related Reactions.................................................... 70
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 70


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5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 71
5.3.5.4
Persistent or Recurrent Adverse Events................................ 71
5.3.5.5
Abnormal Laboratory Values ................................................. 72
5.3.5.6
Abnormal Vital Sign Values ................................................... 72
5.3.5.7
Abnormal Liver Function Tests.............................................. 73
5.3.5.8
Deaths ................................................................................... 73
5.3.5.9
Preexisting Medical Conditions.............................................. 74
5.3.5.10
Lack of Efficacy or Worsening of NSCLC .............................. 74
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 74
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 75
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 75
5.4.1
Emergency Medical Contacts................................................ 76
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 76
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 76
5.4.2.2
Events That Occur after Study Drug Initiation........................ 76
5.4.3
Reporting Requirements for Pregnancies.............................. 77
5.4.3.1
Pregnancies in Female Patients............................................ 77
5.4.3.2
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 77
5.4.4
Reporting Requirements for Cases of 
Atezolizumab Accidental Overdose or 
Medication Error.................................................................. 77
5.5
Follow-Up of Patients after Adverse Events .......................... 78
5.5.1
Investigator Follow-Up........................................................... 78
5.5.2
Sponsor Follow-Up ................................................................ 79
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 79
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 79


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 80
6.1
Determination of Sample Size ............................................... 80
6.2
Summaries of Conduct of Study............................................ 80
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 81
6.4
Efficacy Analyses .................................................................. 81
6.4.1
Primary Efficacy Endpoint...................................................... 81
6.4.2
Secondary Efficacy Endpoints............................................... 81
6.4.3
Exploratory Efficacy Endpoints.............................................. 82
6.5
Safety Analyses..................................................................... 82
6.6
Biomarker Analyses............................................................... 82
6.6.1
Primary Biomarker Analyses ................................................. 82
6.6.2
Secondary Biomarker Analyses............................................. 82
6.6.3
Exploratory Biomarker Analyses............................................ 83
6.7
Interim Analyses .................................................................... 83
6.7.1
Planned Interim Analysis ....................................................... 83
6.7.2
Optional Interim Analyses...................................................... 83
7.
DATA COLLECTION AND MANAGEMENT ............................................... 83
7.1
Data Quality Assurance......................................................... 83
7.2
Electronic Case Report Forms............................................... 84
7.3
Source Data Documentation.................................................. 84
7.4
Use of Computerized Systems .............................................. 85
7.5
Retention of Records............................................................. 85
8.
ETHICAL CONSIDERATIONS.................................................................... 85
8.1
Compliance with Laws and Regulations ................................ 85
8.2
Informed Consent.................................................................. 86
8.3
Institutional Review Board or Ethics Committee.................... 87
8.4
Confidentiality........................................................................ 87
8.5
Financial Disclosure .............................................................. 88
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 88
9.1
Study Documentation ............................................................ 88
9.2
Protocol Deviations................................................................ 88


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9.3 
Site Inspections ..................................................................... 88 
9.4 
Administrative Structure ......................................................... 88 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 89 
9.6 
Protocol Amendments ........................................................... 90 
10.  REFERENCES ........................................................................................... 91 
LIST OF TABLES 
Table 1 
Adverse Events Reported in  10% of Patients in Study 
PCD4989g .................................................................................. 28 
Table 2 
  Treatment-Related Adverse Events Reported in at Least 10% 
of Patients in Either Treatment Arm in Study GO28753 
(POPLAR) ................................................................................... 29 
Table 3 
Objectives and Corresponding Endpoints ................................... 35 
Table 4 
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 50 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 69 
Table 6 
Causal Attribution Guidance ....................................................... 70 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 37 
 
 
LIST OF APPENDICES 
Appendix 1a 
Schedule of Activities .................................................................. 94 
Appendix 1b 
Optional Long-Term Follow-Up Schedule of Assessments ................. 99 
Appendix 2 
Schedule of Biomarker Samples ............................................... 100 
Appendix 3 
IASLC Lung Cancer Staging Project Proposed for the Eighth 
Edition of the American Joint Committee on Cancer 
NonSmall Cell Lung Cancer Staging System1 ........................ 101 
Appendix 4 
Response Evaluation Criteria in Solid Tumors (RECIST):  
Excerpt from Original Publication .............................................. 103 
Appendix 5 
Anaphylaxis Precautions ........................................................... 115 
Appendix 6 
Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 116 
Appendix 7 
Preexisting Autoimmune Diseases ........................................... 117 
Appendix 8 
Management of Atezolizumab-Specific Adverse Events ........... 118 


Atezolizumab—Genentech, Inc.
10/Protocol ML39237, Version 5
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II SINGLE-ARM STUDY OF 
ATEZOLIZUMAB MONOTHERAPY IN LOCALLY 
ADVANCED OR METASTATIC NONSMALL CELL 
LUNG CANCER:  CLINICAL EVALUATION OF 
NOVEL BLOOD-BASED DIAGNOSTICS
PROTOCOL NUMBER:
ML39237
VERSION NUMBER:
5
EUDRACT NUMBER:
Not applicable
IND NUMBER:
117296
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, Pharm.D.
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 ML39237, Version 5
Patients for whom approved therapies exist must provide written consent to acknowledge 
deferring these treatment options in favor of continuing study drug at the time of initial 
progression.
Screening tests and evaluations will be performed within 28 days prior to treatment initiation.
Blood samples will be collected at screening, baseline, during therapy, and at first evidence of 
radiographic disease progression or loss of clinical benefit.  Data from the latter blood draws will 
be used to explore whether the radiographic findings are consistent with changes in bTMB as 
measured by the blood-based assays and to explore possible mutational mechanisms of 
resistance.  Additional blood samples may be taken at each scan as defined in the schedule of 
activities.
Tissue biopsies (tissue blocks preferred) may be submitted at any time during the study, with 
biopsies from diagnosis (archival or fresh) and at progression preferred.  For patients who 
provide tissue samples, next generation sequencing (NGS) may be performed by Foundation 
Medicine.  If performed by Foundation Medicine, the investigator can obtain results from these 
analyses in the form of an NGS report, which is available upon request directly from Foundation 
Medicine.  The investigator may share and discuss the results with the patient, unless the 
patient chooses otherwise.  The Foundation Medicine NGS assay, FoundationOne, has not 
been cleared or approved by health authorities.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment decisions. Results may 
not be available for samples that do not meet testing criteria.  Patients who are unable to 
undergo biopsy sample collection but otherwise meet the eligibility criteria may still be enrolled 
to receive atezolizumab.
All patients will undergo tumor assessment at baseline and every 6 weeks (7 days) thereafter 
regardless of dose delays for the first 12 months following Cycle 1, Day 1.  After 12 months, 
tumor assessment will be required every 9 weeks (7 days); tumor assessments will continue 
until disease progression per RECIST v1.1 or loss of clinical benefit, consent withdrawal, study 
discontinuation, study completion or death, whichever occurs first.  Patients who discontinue 
treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled 
tumor assessments until disease progression, withdrawal of consent, study discontinuation, 
study completion (i.e., end of study), or death, whichever occurs first.  In the absence of disease 
progression, tumor assessments should continue regardless of whether patients start a new 
anti-cancer therapy, unless consent is withdrawn.
All patients will be followed for survival and anti-cancer therapy while in the study and will be 
given the option of participating in a long-term follow-up which will include collection of long-
term survival data beyond the end of the study. The optional long-term follow-up will begin 
following the end of the study.  Patients must provide additional consent to participate in this 
optional long-term follow-up. Patients on study drug will continue therapy until they have 
received a total of 2 years of atezolizumab treatment (32 cycles).  Thereafter, patients will 
continue overall survival follow-up every 3 months for the first year, then every 6 months 
thereafter, for up to 5 years from enrollment of the first patient into the study, until the last 
patient dies, withdraws consent, or is lost to follow-up, whichever occurs first.
Safety will be assessed on the basis of vital sign measurements, ECOG performance status 
scores, physical examination findings, clinical laboratory test results, and the frequency, severity, 
and relationship to atezolizumab of adverse events. 
When a patient discontinues study drug, regardless of the reason for discontinuation, the patient 
will be asked to return to the clinic within 30 days after the last dose for a study drug 
discontinuation visit.  Patients who discontinue will not be replaced.
Number of Patients
There will be approximately 150 patients with Stage IIIBIVB, locally advanced or metastatic, 
epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)negative NSCLC 
who are immunotherapy-naive enrolled at approximately 25-30 study sites in the United States. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form


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
Age 18 years

ECOG performance status of 0 or 1

Histologically or cytologically confirmed Stage IIIBIVB NSCLC (based on the IASLC Lung 
Cancer Staging Project proposed for the eighth edition of the AJCC NSCLC staging system)
–
Patients with histologically or cytologically confirmed Stage IIIB-IV NSCLC based on the 
seventh edition of the AJCC NSCLC staging system are also eligible for study entry.

For patients who have received prior neo-adjuvant/adjuvant chemotherapy or 
chemoradiotherapy with curative intent for non-metastatic disease:  a treatment-free interval 
of at least 6 months prior to enrollment.

Patients with any PD-L1 test result by IHC are eligible for the study.

Patients without a PD-L1 test result are eligible for the study.

Measurable disease, as defined by RECIST v1.1, based on protocol-specified tumor 
assessments.
–
Previously irradiated lesions can only be considered measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of measureable disease

Adequate hematologic and end-organ function, defined by the following laboratory test 
results obtained within 14 days prior to the first dose of study drug:
–
ANC 1500 cells/L without granulocyte colony-stimulating factor support
–
Lymphocyte count 500 cells/L
–
Platelet count 100,000 cells/L without transfusion
–
Hemoglobin 9.0 g/dL 
Patients may be transfused to meet this criterion
–
INR or activated partial thromboplastin time (aPTT) 1.5 the upper limit of normal 
(ULN)
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation must have an INR or aPTT within 
therapeutic limits for at least 1 week prior to enrollment.
–
AST, ALT, and alkaline phosphatase 2.5 ULN with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5 ULN
Patients with documented liver or bone metastases:  alkaline phosphatase 5 ULN
–
Serum bilirubin 1.5 ULN
Patients with known Gilbert disease who have a serum bilirubin level 3 ULN may 
be enrolled.
–
Calculated creatinine clearance 30 mL/min

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.
–
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 study 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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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Prior treatment with immunotherapy for any stage NSCLC, including early-stage 
(neoadjuvant or adjuvant) disease. 

Patients with EGFR-sensitizing mutations and ALK rearrangements are excluded from the 
study and should be treated according to standard clinical guidelines.  Refer to National 
Comprehensive Cancer Network (NCCN) guidelines for recommendations on molecular 
testing (NCCN Guidelines 2016).

Active CNS metastases requiring treatment as determined by computed tomography (CT) 
or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments
–
Patients with a history of treated asymptomatic CNS metastases are eligible, provided 
they meet all of the following criteria:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
enrollment
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study
–
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior to 
enrollment, if all other criteria are met.

Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for 2 weeks prior to enrollment

Leptomeningeal disease

Uncontrolled tumor-related pain
–
Patients requiring pain medication must be on a stable regimen at study entry.
–
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment.  Patients 
should be recovered from the effects of radiation.  There is no required minimum 
recovery period.
–
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not currently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
–
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or calcium 
12 mg/dL or corrected serum calcium ULN)
–
Patients who are receiving denosumab prior to enrollment must be willing and eligible to 
discontinue its use and replace it with a bisphosphonate instead while in the study.

Malignancies other than NSCLC within 5 years prior to enrollment, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival 
[OS] 90%) treated with an 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)

Women who are pregnant, lactating, or intending to become pregnant during the study


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–
Women who are not postmenopausal (12 months of nontherapy-induced amenorrhea) 
or surgically sterile must have a negative serum pregnancy test result within 14 days 
prior to initiation of study drug.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis 
–
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid-replacement hormone may be eligible for this study.
–
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible 
for this study.
–
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
Rash must cover <10% of body surface area
Disease is well controlled at baseline and only requiring low-potency topical steroids
No acute exacerbations of underlying condition within the last 12 months requiring 
treatment with either psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral steroids.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan
–
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive HIV test

Active hepatitis B (HBV) infection (chronic or acute), defined as having a positive hepatitis B 
surface antigen (HBsAg) test at screening
–
Patients with past or resolved HBV infection, defined as having a negative HBsAg test 
and a positive total hepatitis B core antibody (HBcAb) test, are eligible for the study.  An 
HBV DNA test must be performed in these patients prior to enrollment.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test and 
a positive HCV RNA test at screening

Active tuberculosis

Severe infections within 4 weeks prior to enrollment, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to enrollment, unstable 
arrhythmias, or unstable angina
–
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or left ventricular ejection fraction <50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate.

Major surgical procedure other than for diagnosis within 28 days prior to enrollment or 
anticipation of need for a major surgical procedure during the course of the study

Prior allogeneic bone marrow transplantation or solid organ transplant


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
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, antiPD-1, 
and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including but not limited to interferons 
or interleukin 2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to 
enrollment

Any approved anti-cancer therapy or hormonal therapy within 3 weeks prior to initiation of 
study drug; the following exceptions are allowed:
–
Hormone-replacement therapy or oral contraceptives
–
Tyrosine kinase inhibitors (TKIs) approved for treatment of NSCLC discontinued 7 days 
prior to enrollment; the baseline scan must be obtained after discontinuation of prior 
TKIs.

Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 28 days prior to enrollment

Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to enrollment
–
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.

Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study or for 
5 months after the last dose of atezolizumab
–
Influenza vaccination should be given during influenza season only (approximately 
October to March).  
–
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 
weeks prior to Cycle 1, Day 1, at any time during the study, or for 5 months after the last 
dose of atezolizumab.

Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks 
prior to enrollment
–
Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after 
discussion with and approval by the Medical Monitor.
–
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
End of Study
The end of this study is defined as the date after which all enrolled patients who remain alive 
have been followed for at least 18 months from study-drug initiation.  Thereafter, patients who 
discontinue study drug will be followed for optional long-term survival.
Patients who remain on study drug will continue therapy until they have received a total of 
2 years of atezolizumab treatment (32 cycles), and will be followed for safety.  Survival data 
will be collected during the optional long-term follow up period every 3 months for the first 
year, then every 6 months thereafter, for up to 5 years from enrollment of the first patient 
into the study until the last patient dies, withdraws consent, or is lost to follow-up, 
whichever occurs first.
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 3 years.  In addition, the Sponsor may decide to terminate the 
study at any time.


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Investigational Medicinal Products
The investigational medicinal product for this study is atezolizumab.
Test Product (Investigational Drug)
Patients will receive 1200 mg of atezolizumab (equivalent to an average body weightbased 
dose of 15 mg/kg) administered by IV infusion every 21 (3) days.  Administration of 
atezolizumab will be performed in a setting with emergency medical facilities and staff who are 
trained to monitor for and respond to medical emergencies.
Non-Investigational Medicinal Products
Premedication with antihistamines may be administered for any atezolizumab infusions after 
Cycle 1.  Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  In general, investigators should manage a 
patient’s care with supportive therapies as clinically indicated per local standards.  
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab.  Therefore, in situations where systemic corticosteroids 
or TNF-inhibitors would be routinely administered, alternatives, including antihistamines, 
should be considered first by the treating physician.  If the alternatives are not feasible, systemic 
corticosteroids and TNF-inhibitors may be administered at the discretion of the treating 
physician except in the case of patients for whom CT scans with contrast are contraindicated 
(i.e., patients with contrast allergy or impaired renal clearance).
Systemic corticosteroids are recommended, with caution at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with atezolizumab 
therapy.  
Statistical Methods
Primary Efficacy Analyses
The efficacy analysis population will be based on all patients who have received at least one 
dose of study drug.  The primary efficacy endpoint of this study is investigator-assessed 
objective response rate (ORR), defined as the proportion of patients whose confirmed best 
overall response is either a partial response (PR) or complete response (CR) per RECIST v1.1.  
For this analysis, patients not meeting these criteria, including patients without at least one post-
baseline response assessment, will be considered non-responders.  An estimate of the ORR 
from all patients who received study drug and the 95% confidence interval (CI) will be calculated 
by using the Blaker method.  
Primary Biomarker Analyses
Biomarker analysis population will be based on all patients who have received at least one dose 
of study drug and have baseline biomarker assessment.  Kaplan-Meier (K-M) curves and a log-
rank test will be used to evaluate the differences in investigator-assessed PFS between 
mutation positive versus negative groups at various cutoff points.  Tests will be two-sided at a 
significance level of 0.10.
Determination of Sample Size  
The sample size for this study is based on the primary efficacy objective and primary biomarker 
objective.  Based on 150 patients, the maximum half width of the 2-sided 95% CI of the 
estimated ORR will be within 8%.  Additionally, based on 120 biomarker-evaluable patients (80% 
of the study population), with a minimum follow-up of 6 months during the primary analysis, and 
with 28 patients in the smaller biomarker positive or negative group (19% of the study 
population), the study primary biomarker analysis will have 89% and 79% power to detect PFS 
difference if the hazard ratios of PFS between the biomarker positive vs. negative group is 0.50 
or 0.55, respectively.  The above-mentioned power is for a 2-sided test with a significance level 
of 0.1, assuming a median PFS of 4 months for the subgroup with a shorter median PFS.
Interim Analyses
One interim analysis is planned 6 months after approximately one-half of the patients have 
been enrolled.  The purpose of the interim analysis is to provide preliminary results in evaluating 
the biomarker cutoff and to perform a futility analysis.  No conclusions or study 
alterations/terminations are to be made based on the biomarker interim analysis results.  No 
type-1 error adjustments will be made for the interim analysis.  


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Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct 
additional interim 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.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
aPTT
activated partial thromboplastin time
ATA
anti-therapeutic antibody
BSC
best supportive care
bTMB
blood tumor mutational burden
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
Ctrough
trough concentration
DOR
duration of response
EC
ethics committee
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
U.S. Food and Drug Administration
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
IASLC
International Association for the Study of Lung Cancer
ICH
International Conference on Harmonisation
IgG1
immunoglobulin G subclass 1
IMP
investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
ITT
intent-to-treat
IRB
Institutional Review Board
IV
intravenous
IxRS
interactive voice/Web response system


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Abbreviation
Definition
K-M
Kaplan-Meier
KRAS
Kirsten rat sarcoma
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NaF-PET
sodium fluoride positron emission tomography
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
progressive disease
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
q21d
every 21 days
RBR
Research Biosample Repository
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
TKI
tyrosine kinase inhibitor
TNF
tumor necrosis factor
tTMB
tissue tumor mutational burden
UC
urothelial cancer
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON NONSMALL CELL LUNG CANCER
Lung cancer remains the leading cause of cancer deaths worldwide and is the most 
common cancer in both men and women, accounting for approximately 224,390 of all 
new cases and nearly 160,000 deaths in 2016 in the United States (Miller et al. 2016; 
SEER Stat Fact Sheet 2016). Nonsmall cell lung cancer (NSCLC) is the predominant 
subtype of lung cancer, accounting for approximately 85% of all cases 
(Molina et al. 2008; Howlader et al. 2014).  NSCLC can be divided into two major 
histologic types:  adenocarcinoma and squamous cell carcinoma (Travis et al. 2011).  
Adenocarcinoma histology accounts for more than one-half of all NSCLC, whereas 
squamous cell histology accounts for approximately 25% (Langer et al. 2010) of NSCLC.  
The remaining cases of NSCLC are represented by large cell carcinoma, 
neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated histology.
The overall 5-year survival rate for advanced disease is 2%4%, depending on 
geographic location (Cetin et al. 2011).  Poor prognostic factors for survival in patients 
with NSCLC include advanced stage of disease, poor performance status, a history of 
smoking, and a history of unintentional weight loss at the time of initial diagnosis.  More 
than one-half of the patients with NSCLC are diagnosed with distant metastases, which 
directly contribute to poor survival outcomes.
1.1.1
First-Line Treatment for NSCLC without an Epidermal Growth 
Factor Receptor Mutation or Anaplastic Lymphoma Kinase
Rearrangement 
Genomic profiling of tumors has enabled a deeper understanding of the underlying 
biology and molecular mechanisms of lung cancer. These efforts have revolutionized 
first-line treatment of NSCLC, specifically in patients with actionable driver mutations 
such as epidermal growth factor receptor (EGFR) mutations and gene rearrangements 
in anaplastic lymphoma kinase (ALK) (Tsui et al. 2016). Targeted treatment of these 
“driver” mutations includes the use of tyrosine kinase inhibitors (TKIs) such as erlotinib 
and alectinib, which confer objective response rates (ORRs) upwards of 60%70% 
(Thomas et al. 2015).  Although these treatments have become the mainstay of first-line 
treatment in patients with these molecular subsets, the frequency of these mutations 
(approximately 25%) (Shtivelman et al. 2014), and thus the proportion of patients 
benefiting from such therapy, remains modest.
For patients with locally advanced and metastatic NSCLC not harboring an activating 
EGFR mutation or ALK gene rearrangement, platinum-based doublet chemotherapy 
remains as a first-line therapy and standard of care for NSCLC. A number of clinical 
trials have attempted to identify the optimal doublet for advanced NSCLC.  In 2002, 
results from a Phase III randomized trial comparing four different platinum-based 
doublets were published (Schiller et al, 2002).  In this study of 1155 patients with 
advanced NSCLC, no differences in overall survival (OS) were observed among those 


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receiving cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel or 
carboplatin/paclitaxel.  Each doublet produced response rates of nearly 20% and a 
median survival of approximately 8 months. 
More recently, several randomized Phase III trials have since highlighted the importance 
of tumor histology as an important determinant in treatment decisions.  In a recent 
Phase III non-inferiority trial comparing cisplatin/gemcitabine versus 
cisplatin/pemetrexed in 1725 previously untreated patients, there was no difference in 
OS between the two arms (Scagliotti et al. 2008).  In preplanned subgroup analysis, 
however, patients with adenocarcinoma histology treated with cisplatin/pemetrexed had 
a significant improvement in median OS compared to those treated with 
cisplatin/gemcitabine (12.6 versus 10.9 months).  Conversely, in patients with squamous 
cell histology, cisplatin/gemcitabine produced superior survival compared to 
cisplatin/pemetrexed (median OS 10.8 versus 9.4 months).  Thus, pemetrexed is now 
approved as part of first-line treatment in advanced, non-squamous NSCLC. 
In a separate study, the addition of bevacizumab to carboplatin and paclitaxel resulted in 
an increase in response rate from 15% to 35% and an increase in median OS from 10 to 
12 months (Sandler et al. 2006).
Given the limited survival benefit conferred by cytotoxic chemotherapy, the substantial 
toxicities associated with therapy (such as febrile neutropenia, myelosuppression, 
nausea, alopecia, nephropathy, and neuropathy) and the generally poorly tolerated 
regimens by elderly and poor-performance-status patients, novel therapies that deliver 
an improved therapeutic index are urgently needed for NSCLC.
1.1.2
Cancer Immunotherapy:  Programmed Death-Ligand 
1/Programmed Death-1 Inhibitors and Biomarker Selection
Immune checkpoint inhibitors, which target the programmed death-ligand 1 (PD-L1) and 
programmed death 1 (PD-1) axis, have emerged as a new standard of care for lung 
cancer and other solid tumors.  Such immunotherapy agents harness the patient’s own T 
cells to kill tumor cells and have resulted in encouraging results from Phase II/III clinical 
studies for recurrent 2L+ NSCLC.  However, only a proportion of patients, roughly 
20%30%, have durable long-term benefit (Barlesi et al.2016; Borghaei et al. 2015; 
Brahmer et al. 2015; Vansteenkiste et al. 2015; Herbst et al. 2016).  Additionally, 
subgroup analyses across these trials suggest that patients with activating EGFR 
mutations do not have improved outcomes on immunotherapy compared with treatment 
on standard chemotherapy, suggesting that these patients should receive appropriate 
targeted therapies before being offered immunotherapy.  It remains unknown, however, 
if checkpoint inhibitors have less clinical efficacy compared to standard treatments in 1L 
patients who have EGFR activating mutations.
Pembrolizumab, a PD-1 monoclonal antibody, is now approved by the Food and Drug 
Administration (FDA) for first-line treatment of NSCLC in patients with PD-L1 expression 


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on 50% of tumor cells.  In the Phase III labelenabling trial, PD-L1 expression was 
determined using tissue-based immunohistochemistry (IHC).  Treatment with 
pembrolizumab resulted in an OS hazard ratio (HR) of 0.6 (median OS not reached for 
either treatment arm) and progression-free survival (PFS) HR of 0.5 (median PFS 10.3 
vs. 6.0 months) in favor of pembrolizumab over platinum-based chemotherapy (Reck et 
al. 2016).  These impressive results are changing the current treatment paradigm for 
first-line therapy and have encouraged upfront tissue testing for PD-L1 to identify 
patients with high PD-L1 tumor expression (50% PD-L1, approximately 
30% prevalence). These data also provide further evidence to support the use of 
atezolizumab in a similarly PD-L1 enriched population as in the current clinical trial. 
A separate first-line Phase III trial of nivolumab, another PD-1 monoclonal antibody, 
failed to show a statistically meaningful difference in PFS between nivolumab and 
platinum-based chemotherapy for patients with PD-L1 expression on 5% of tumor 
cells (median PFS 4.2 vs 5.9; HR 1.15; p 0.2511; Socinski et al. 2016).  Overall 
survival outcomes were equally disappointing (median OS 14.4 vs 13.2 months; 
HR 1.02).  The prevalence of patients with 5% PD-L1 was roughly 75%.  The stark 
contrast in results from the pembrolizumab and nivolumab trials calls into question the 
reliability of using PD-L1 measured by IHC as a predictive biomarker and underscores 
the importance of identifying alternative methods of diagnostic selection for 
immunotherapy.
Emerging data in the field of cancer immunotherapy suggest that mutational load (or 
mutational burden) may be a better diagnostic for the selection of patients for PD-1/PD-
L1 inhibitors.  This hypothesis is supported by the notion that tumors with higher rates of 
somatic mutations, such as in NSCLC, may have increased immunogenicity and are 
therefore more susceptible to checkpoint inhibition (Chen et al. 2012).  In a recent study 
conducted by Rizvi et al. (2015), investigators reported that nonsynonymous mutation 
burden, as determined by whole-exome sequencing of NSCLC patients treated with 
pembrolizumab, was associated with improved outcomes such as ORRs, durable clinical 
benefit, and progression-free survival (PFS).
Additional considerations in the diagnostic selection of patients include whether an 
appropriate quality and quantity of tissue samples can be collected to test for the 
increasing array of oncogenic driver mutations.  Advances in diagnostic technologies are 
enabling newer less-invasive genomic profiling in the blood via detection of circulating 
tumor DNA (ctDNA) (Tsui et al. 2016).  Currently, commercial tests of ctDNA are 
available to guide treatment for targeted therapies.  The next advance in this field will be 
to develop a ctDNA-based diagnostic to guide treatment for immunotherapies through 
detection of mutational burden in the blood. 


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1.1.3
Diagnostic Testing for First-Line Treatment of NonSmall Cell 
Lung Cancer
The National Comprehensive Cancer Network (NCCN) treatment guidelines describe 
PD-L1 testing by IHC as part of the molecular diagnostic studies to be performed in lung 
cancer (NCCN Guidelines 2016).  Additionally, NCCN recommends upfront testing for 
EGFR and ALK to determine appropriate first-line therapy in patient subsets.  Of note, in 
patients with squamous cell carcinoma, the observed incidence of EGFR mutations is 
2.7%. This frequency of EGFR mutations does not justify routine testing of all tumor 
specimens (NCCN Guidelines 2017). Similarly, EGFR and KRAS mutations are 
mutually exclusive, with overlapping mutations occurring in1% of patients with lung 
cancer (Riely et al. 2006).  Therefore, patients with confirmed KRAS mutations do not 
require further EGFR testing for eligibility for the trial (see Section 4.1.2).  See Study 
Rationale and BenefitRisk Assessment section for additional details (Section 1.3).  
1.2
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab (Tecentriq) is a humanized immunoglobulin G subclass 1 (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.
Atezolizumab (Tecentriq) is approved in the United States for the treatment of locally 
advanced or metastatic urothelial cancer (UC), in combination with paclitaxel for adult 
patients with locally advanced metastatic triple negative breast cancer whose tumors 
express PD-L1, in combination with bevacizumab and chemotherapy for first- line
NSCLC, first-line extensive-stage small cell lung cancer, and metastatic NSCLC that 
has progressed during or following treatment with a platinum-containing regimen.  
Atezolizumab is also being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.
Refer to the Atezolizumab Investigator’s Brochure 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.


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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 
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 
biological activity of atezolizumab administered as a single agent by IV infusion 
given every 21 days (q21d) 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.


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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. It provides significant data 
(with 629 safety-evaluable patients across all cancer types as of the data cutoff date of 
15 December 2015) for the safety profile of atezolizumab as monotherapy.
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined.
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications, including small cell lung cancer, NSCLC, UC, renal cell carcinoma 
(RCC), melanoma, gastric cancer, colorectal cancer, head and neck cancer, breast 
cancer, and sarcoma.  
Of the 629 patients across all cancer types in Study PCD4989g, 619 patients (98.4%) 
experienced at least one adverse event, including 444 patients (70.6%) who 
experienced one treatment-related adverse event.  Commonly reported events (reported 
in 10% of all patients) included fatigue, nausea, decreased appetite, diarrhea, 
constipation, dyspnea, pyrexia, and cough (see Table 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 every 3 weeks and 135 patients were 
treated with docetaxel 75 mg/m2 IV q21d in Study GO28753.  The frequency of patients 
with any reported adverse event regardless of attribution was 96% in both arms.  Fewer 
patients in the atezolizumab arm (41%) experienced Grade 34 adverse events 
compared with the docetaxel arm (53%).  For Grade 34 adverse events that were 
assessed as treatment-related, the difference was greater between the two arms 
(12% vs. 39%, respectively).  The most common atezolizumab-related Grade 3 adverse 
events were pneumonia (2%) and increased aspartate aminotransferase (2%).  No


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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 q21d.  In Study GO28754,
93.8% of patients experienced at least one adverse event, 65% of patients experienced 
one treatment-related adverse event, and 12% of patients experienced a 
Grade 3 treatment-related adverse event.


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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.
1.2.2.2
Clinical Activity
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1based responses, have been observed in patients with different tumor types 
(including NSCLC, RCC, melanoma, gastric cancer, UC, 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 2 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 pretreated 
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 
cohorts (treatment dose levels:  1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 


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histology (66% for atezolizumab and 66% for docetaxel), and an Eastern Cooperative 
Oncology Group (ECOG) performance status of 1 (68% for atezolizumab and 68% for 
docetaxel).  More female patients were enrolled in the docetaxel arm (35% vs. 47%).
At the time of 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 
(hazard ratio [HR] 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.  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 naive 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 were not yet 
reached (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 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).
1.2.3
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 


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dose groups, the mean apparent clearance and the mean volume of distribution at 
steady state had a range of 3.20 4.44 mL/kg and 48.165.7mL/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.
1.2.4
Rationale for Atezolizumab Dosage
The fixed dose of 1200 mg (equivalent to an average body weightbased dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below.
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors.  The 
target trough concentration (Ctrough) was projected to be 6 mg/mL on the basis of several 
assumptions, including the following: 1) 95% tumor receptor saturation is needed for 
efficacy, and 2) the tumor interstitial concentrationto-plasma ratio is 0.30 based on 
tissue distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, 
pharmacokinetics, and immunogenicity data.  Anti-tumor activity has been observed 
across doses from 1 mg/kg to 20 mg/kg.  The MTD of atezolizumab was not reached, 
and no DLTs have been observed at any dose in Study PCD4989g.  Currently available 
PK and anti-therapeutic antibody (ATA) data suggest that the 15-mg/kg atezolizumab 
q21d regimen (or fixed-dose equivalent) for Phase II and Phase III studies would be 
sufficient to both maintain a 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 q21d regimen (or fixed-
dose equivalent).  From inspection of available observed Ctrough data, moving further to 
the 20-mg/kg atezolizumab q21d regimen does not appear to be warranted to maintain 
targeted Ctrough levels relative to the proposed 15-mg/kg atezolizumab q21d 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 


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15 mg/kg).  Selection of a q21d dosing interval is supported by this preliminary 
pharmacokinetics evaluation.
See the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012).
Clinical studies in NSCLC to date have focused on biomarker enrichment strategies 
through selection of patients whose tumors overexpress PD-L1.  In our Phase II 
POPLAR study of atezolizumab versus docetaxel in the refractory 2L/3L setting, PD-L1 
expression on both tumor cells and immune cells was found to be an independent 
predictor of improved survival (Fehrenbacher et al. 2016).  However, response rates 
were also noted in patients not expressing PD-L1 (8% in patients with no PD-L1 
expression), bringing to light the question of whether PD-L1 is the optimal predictive 
biomarker for agents such as atezolizumab. 
Continued research is underway to further characterize the molecular and genomic 
determinants of response for patients treated with immunotherapy. Lawrence et al. 
(2013) suggest that tumors such as lung cancer have a higher rate of somatic mutations
and that mutations provide the potential for neoantigens that can be recognized as 
foreign by T cells. This hypothesis will be tested in this study by treating patients with 
Stage IIIBIVB NSCLC (based on the International Association for the Study of Lung 
Cancer [IASLC] Lung Cancer Staging Project proposed for the eighth edition of the 
American Joint Committee on Cancer [AJCC] NSCLC staging system [Goldstraw et al. 
2015]; see Appendix 3) with atezolizumab monotherapy and testing blood samples 
collected at baseline and at progression to determine relative changes in tumor 
mutational burden in blood (bTMB) as a predictive biomarker for efficacy.
Because the response rate of single-agent atezolizumab in first-line treatment is 
unknown, we plan an interim futility analysis when 50% of enrolled patients have had at 
least 6 months of follow-up.  At this interim analysis, the study will be stopped if ORR is 
likely to be 5% or less compared with an ORR of 15% or more.  This reference endpoint 
is derived from preliminary evidence with nivolumab as first-line monotherapy in NSCLC 
in which ORR ranged from 15% to 26% depending on histology (Gettinger et al. 2015).  
Additionally, historical response rates for standard-of-care platinum-doublet 
chemotherapy are roughly 15% to 20% (Schiller et al. 2002).
Study ML39237 will enroll patients who are naive to immunotherapy and for whom 
atezolizumab can represent a reasonable benefitrisk option.  Patients whose tumors 


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are known to harbor sensitizing EGFR mutations or ALK rearrangements should be 
treated with appropriate targeted agents such as an EGFR tyrosine kinase or ALK 
inhibitor, respectively (see specific exclusion criteria in Section 4.1.2), and should not be 
enrolled in the study.  Patients are eligible for study regardless of PD-L1 status, even if 
the status is unknown (see specific inclusion criteria in Section 4.1.1).
In order to account for the possibility of pseudoprogression/tumor-immune infiltration 
(i.e., a radiographic increase in tumor volume caused by the influx of immune cells) 
(Hales et al. 2010) and the potential for delayed anti-tumor activity, this study will allow 
patients treated with atezolizumab to receive treatment beyond the initial apparent 
radiographic progression (see Section 3.3.3) to evaluate clinical benefit.  Although the 
risk of pseudoprogression in NSCLC is deemed to be relatively low compared with 
melanoma (Chiou and Burotto 2015), it is not yet possible to reliably differentiate 
pseudoprogression/tumor-immune infiltration from true tumor progression by using
standard radiographic assessments.  Therefore, the risk does exist that some patients 
who are not responding to treatment but are continuing to receive atezolizumab may 
experience further progression of NSCLC and may have a delay in treatment with 
subsequent therapies for which they are eligible.  Investigators should make every effort 
to fully inform patients of this risk.  Investigators should make a careful assessment of 
the potential benefit of continuing treatment with atezolizumab, taking into consideration 
radiographic data and the clinical status of the patient.  If, after an integrated 
assessment of radiographic data and clinical status, the decision is made to continue 
treatment with atezolizumab following apparent radiographic progression, patients for 
whom alternative approved anti-cancer therapies exist must provide written consent at 
that time to acknowledge deferring these treatment options in favor of continuing study 
drug.
Atezolizumab has been generally well tolerated (see Section 1.2.2.2).  Adverse events 
with potentially immune-mediated causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis, 
have been observed in Study PCD4989g.  To date, these events have been 
manageable with treatment.
In summary, treatment with atezolizumab as first-line therapy offers the potential for 
clinical benefit in patients with NSCLC.  Because most atezolizumab-related toxicities 
observed to date have been mild and transient in nature and are different from the 
adverse events observed from chemotherapy, the benefitrisk to patients is favorable for 
atezolizumab, especially when compared with the benefitrisk for conventional 
chemotherapy.  Because of the phenomenon of pseudoprogression, patients and 
investigators can elect to continue therapy beyond radiographic progression.  Patients 
should be fully informed of the risk of continuing study drug in spite of apparent 
radiographic progression, and investigators should make a careful assessment of the 
potential benefit of doing so, taking into consideration radiographic data, biopsy results
(if available), and the clinical status of the patient.






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Figure 1
Study Schema
AJCCAmerican Joint Committee on Cancer; Dx diagnosis; ECOG Eastern Cooperative 
Oncology Group; EGFR/ALKepidermal growth factor receptor/anaplastic lymphoma kinase;
IASLCInternational Association for the Study of Lung Cancer; IVintravenous;
mets metastases; NSCLC nonsmall cell lung cancer; PDprogressive disease; 
PSperformance status; q3wonce every three weeks; RECIST Response Evaluation Criteria 
in Solid Tumors.
a Staging criteria based on the IASLC Lung Cancer Staging Project proposed for the eighth
edition of the AJCC NSCLC staging system (see Appendix 3).  Patients with histologically or 
cytologically confirmed Stage IIIB-IV NSCLC based on the seventh edition of the AJCC
NSCLC staging system are also eligible for study entry.
b Blood samples will be taken at baseline and at progression (all samples will be tested 
retrospectively).
c Treatment beyond RECIST v1.1 progression may be permitted if the patient continues to 
derive clinical benefit as determined by the investigator.
Atezolizumab (fixed dose of 1200 mg) will be administered intravenously on Day 1 of 
each 21-day cycle. 
Patients who meet the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
criteria for progressive disease (PD) at any timepoint during treatment will be permitted 
to continue atezolizumab treatment if there is evidence of clinical benefit, defined as 
meeting all of the following criteria:

Evidence of clinical benefit as assessed by the investigator 

Absence of symptoms and signs (including worsening of laboratory values [e.g., 
new or worsening hypercalcemia]) indicating unequivocal progression of disease

No decline in ECOG performance status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions


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Patients for whom approved therapies exist must provide written consent to 
acknowledge deferring these treatment options in favor of continuing study drug at the 
time of initial progression.
Screening tests and evaluations will be performed within 28 days prior to treatment 
initiation.
Blood samples will be collected at screening, baseline, during therapy, and at first 
evidence of radiographic disease progression or loss of clinical benefit. Data from the 
latter blood draws will be used to explore whether the radiographic findings are 
consistent with changes in bTMB as measured by the blood-based diagnostic assays
and to explore possible mutational mechanisms of resistance. Additional blood samples 
may be taken at each scan as defined in Appendix 1.
Tissue biopsies (tissue blocks preferred) may be submitted at any time during the study, 
with biopsies from diagnosis (archival or fresh) and at progression preferred. For 
patients who provide tissue samples, next generation sequencing (NGS) may be 
performed by Foundation Medicine.  If performed by Foundation Medicine, the 
investigator can obtain results from these analyses in the form of an NGS report, which 
is available upon request directly from Foundation Medicine.  The investigator may share 
and discuss the results with the patient, unless the patient chooses otherwise.  The 
Foundation Medicine NGS assay, FoundationOne, has not been cleared or approved 
by health authorities.  The NGS report is generated for research purposes and is not 
provided for the purpose of guiding future treatment decisions (see Section 4.5.7).  
Results may not be available for samples that do not meet testing criteria.  Patients who 
are unable to undergo biopsy sample collection but otherwise meet the eligibility criteria 
listed in Section 4.1 may still be enrolled to receive atezolizumab.
All patients will undergo tumor assessment at baseline and every 6 weeks (7 days)
thereafter regardless of dose delays for the first 12 months following Cycle 1, Day 1.  
After 12 months, tumor assessment will be required every 9 weeks (7 days); tumor 
assessments will continue until disease progression per RECIST v1.1 or loss of clinical 
benefit, consent withdrawal, study discontinuation, study completion (i.e., end of study 
as defined in Section 3.2) or death, whichever occurs first.  Patients who discontinue 
treatment for reasons other than disease progression (e.g., toxicity) will continue 
scheduled tumor assessments until disease progression, withdrawal of consent, study 
discontinuation, study completion (i.e., end of study), or death, whichever occurs first. In 
the absence of disease progression, tumor assessments should continue regardless of 
whether patients start a new anti-cancer therapy, unless consent is withdrawn.
All patients will be followed for survival and anti-cancer therapy while in the study and 
will be given the option of participating in a long-term follow-up, which will include 
collection of long-term survival data beyond the end of the study. The optional long-
term follow-up will begin following the end of the study (as defined in Section 3.2).  


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Patients must provide additional consent to participate in this optional long-term follow-
up. Patients on study drug will continue therapy until they have received a total of 
2 years of atezolizumab treatment (32 cycles).  Thereafter, patients will continue 
overall survival follow-up every 3 months for the first year, then every 6 months 
thereafter, for up to 5 years from enrollment of the first patient into the study, until the 
last patient dies, withdraws consent, or is lost to follow-up, whichever occurs first.  
Safety will be assessed on the basis of vital sign measurements, ECOG performance 
status scores, physical examination findings, clinical laboratory test results, and the 
frequency, severity, and relationship to atezolizumab of adverse events. 
When a patient discontinues study drug, regardless of the reason for discontinuation, the 
patient will be asked to return to the clinic within 30 days after the last dose of study drug 
for a treatment discontinuation visit.  Patients who discontinue will not be replaced.
A schedule of activities is provided in Appendix 1.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date after which all enrolled patients who remain 
alive have been followed for at least 18 months from study-drug initiation.  Thereafter, 
patients who discontinue study drug will be followed for optional long-term survival as 
described in Section 4.5.8.
Patients who remain on study drug will continue therapy until they have received a 
total of 2 years of atezolizumab treatment (32 cycles), and will be followed for safety. 
Survival data will be collected during the optional long-term follow up period every 
3-months for the first year, then every 6 months thereafter, for up to 5 years from 
enrollment of the first patient into the study, until the last patient dies, withdraws 
consent, or is lost to follow-up, whichever occurs first
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 3 years.  In addition, the Sponsor may decide to terminate 
the study at any time.
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 and available clinical 
data from Study PCD4989g as described below.  This is the same dose and schedule 
being evaluated in the Phase II and Phase III program in NSCLC, urothelial carcinoma,
and other solid tumors. 
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 


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observed atezolizumab interim pharmacokinetics in humans, and other factors.  The 
target 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, PK, and 
immunogenicity data.  Anti-tumor activity has been observed across doses from 1 mg/kg 
to 20 mg/kg.  The MTD of atezolizumab was not reached, and no DLTs have been 
observed at any dose in Study PCD4989g.  Available preliminary PK data 
(0.0320 mg/kg) from Study PCD4989g suggest that for doses 1 mg/kg, overall 
atezolizumab exhibits pharmacokinetics that are both linear and consistent with typical 
IgG1 antibodies.  Detectable ATAs were observed in patients at all dose levels but were 
associated with changes in pharmacokinetics for some patients in only the lower dose 
cohorts (0.3, 1, and 3 mg/kg).  It is unclear from currently available data in these lower 
dose cohorts whether the administration of higher doses to patients with both detectable 
ATAs and reduced exposure would necessarily restore exposure to expected levels.  No 
clear relationship between the development of measurable ATAs and safety or efficacy 
has been observed.  Available data suggest that the development of detectable ATAs 
does not appear to have a significant impact on the pharmacokinetics for doses from 
10 to 20 mg/kg in most patients.  Correspondingly, patients dosed at the 10-, 15-, and 
20-mg/kg dose levels have maintained target trough levels of drug despite the detection 
of ATAs.  Currently available PK and ATA data suggest that the 15-mg/kg atezolizumab 
q21d regimen (or fixed-dose equivalent) for Phase II and Phase III studies would be 
sufficient to both maintain a 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 q21d regimen (or fixed-
dose equivalent).  From inspection of available observed Ctrough data, moving further to 
the 20-mg/kg atezolizumab q21d regimen does not appear to be warranted to maintain 
targeted Ctrough levels relative to the proposed 15-mg/kg atezolizumab q21d level.
Simulations do not suggest any clinically meaningful differences in exposure following a 
fixed dose or a dose adjusted for weight.  On the basis of this analysis, a fixed dose of 
1200 mg has been selected (equivalent to an average body weightbased dose of 
15 mg/kg).
Selection of a q21d dosing interval is supported by this preliminary PK evaluation.
3.3.2
Rationale for Patient Population
Despite recent improvements in treatment options, the prognosis for patients with 
advanced NSCLC remains dismal, with a median OS in first-line therapy of 
approximately 12.5 months (Sandler et al. 2006).  Platinum-based doublet 
chemotherapy is still the current standard of care, yet response rates have not improved 
beyond 20% (Schiller et al. 2002). These approved chemotherapies are associated with 


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significant toxicities (e.g., neuropathy, febrile neutropenia, myelosuppression, and 
alopecia) that negatively affect quality of life.  Therefore, there is a continuing need 
for more efficacious, better-tolerated treatments.
Inhibition of PD-L1/PD-1 signaling has been shown to produce durable responses in a 
proportion of patients in several solid tumor types, including NSCLC 
(Topalian et al. 2012). However, the majority of first-line clinical data in NSCLC are from 
biomarker-selected populations, or limited to patients who have been treated in 
refractory second-line disease and beyond. Early data from nivolumab, a PD-1 inhibitor, 
have been reported in first-line NSCLC with a median OS of 22.6 months (Gettinger et al. 
2015) and provide a strong rationale for evaluating atezolizumab as a first-line therapy in 
patients with Stage IIIBIVB NSCLC.
3.3.3
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment until Loss of Clinical Benefit
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because PD (by initial radiographic evaluation) does not 
necessarily reflect therapeutic failure (see Section 1.3).  Because of the potential for 
pseudoprogression/tumor immune infiltration, this study will allow patients to continue to 
receive study drug after apparent radiographic progression, provided the benefitrisk 
ratio is judged to be favorable by the investigator in consultation with the patient.  
Therapy may continue beyond radiographic PD as determined by the investigator until 
they deem there is further loss of clinical benefit for the patient.  Loss of clinical benefit is 
defined as unacceptable toxicity or symptomatic deterioration attributed to disease 
progression as determined by the investigator after an integrated assessment of
radiographic data and clinical status.
3.3.4
Rationale for Collection of Blood Specimens
The primary biomarker objective of this study is to measure bTMB in to evaluate 
predictive cutoffs for a novel blood-based diagnostic assay.  This may help predict which 
patients may benefit most from atezolizumab and may help future development of 
tissue-free diagnostic options for patients who have inadequate quality or insufficient 
quantity of tissue.
Blood samples will be collected at screening, baseline, during therapy, and at first 
evidence of radiographic disease progression or loss of clinical benefit in order to better 
understand the changes in bTMB and immune signature profiles and potential 
mechanisms of resistance upon progression. Blood samples will be collected at 
screening, on Day 1 of Cycles 1, 2, and 4 (mandatory), and on Day 1 of Cycle 3
(optional), to evaluate additional exploratory biomarker changes that may be associated 
with the therapeutic effects of atezolizumab or the pathogenesis of NSCLC (see 
Appendix 2).  Methods for exploratory analysis include, but are not limited to, NGS, 
PCR, and proteomics-based approaches.


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3.3.5
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens
In this study, archival and/or fresh tumor specimens from each patient will not be 
mandated but will be strongly encouraged.  Tissue biopsies (tissue blocks preferred) 
may be submitted at any time during the study, with biopsies from diagnosis (archival or 
fresh) and at progression preferred. For patients who provide tissue samples, NGS may 
be performed by Foundation Medicine.  If performed by Foundation Medicine, the 
investigator can obtain results from these analyses in the form of an NGS report, which 
is available upon request directly from Foundation Medicine.  The investigator may share 
and discuss the results with the patient, unless the patient chooses otherwise.  The 
Foundation Medicine NGS assay, FoundationOne, has not been cleared or approved 
by health authorities.  The NGS report is generated for research purposes and is not 
provided for the purpose of guiding future treatment decisions (see Section 4.5.7).  
Results may not be available for samples that do not meet testing criteria.
To assess mutational load in tissue (tissue tumor mutational burden [tTMB]), a 
mutational load algorithm will be applied to NGS data. Analysis will be retrospective.
In addition to the assessment of tTMB, other exploratory markers, such as those with
potential predictive and prognostic value related to the clinical benefit of atezolizumab, 
tumor immunobiology, mechanisms of resistance, or tumor type, may also be analyzed.  
DNA and/or RNA extraction may be performed to enable NGS and PCR to identify 
somatic mutations to increase understanding of disease pathobiology.
3.3.6
Rationale for Biomarker Assessments
Despite the promising clinical efficacy of PD-L1/PD-L1 inhibitors in NSCLC, PD-L1 
expression as determined by immunohistochemistry does not appear to identify all of the 
patients who derive clinical benefit from these drugs.  Emerging evidence suggests that 
patients with a high burden of somatic mutations derive significant clinical benefit from 
antiPD-1/PD-L1 therapy; thus, further development of mutation load as a predictive 
biomarker for atezolizumab is warranted.
Blood samples (mandatory) will be collected at baseline, during therapy, and at first 
evidence of radiographic disease progression or loss of clinical benefit.  Tissue biopsies 
(tissue blocks preferred) may be submitted at any time during the study, with biopsies 
from diagnosis (archival or fresh) and at progression preferred. DNA and RNA 
extraction to enable analysis via NGS, expression, and/or PCR to identify somatic 
mutations that are predictive of response to study drug can increase the knowledge and 
understanding of disease biology.  NGS techniques such as targeted sequencing may 
offer a unique opportunity to identify biomarkers of response.  NGS may be performed 
by a clinical cancer genomic profiling laboratory (e.g., Foundation Medicine).
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
Targeted NGS provides a multiplex characterization of the genome and, along with 


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clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches.  Data will be analyzed in the context of this study but will also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification of important pathways, guiding the development of 
new targeted agents.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 150 patients with Stage IIIBIVB, locally advanced or metastatic, 
EGFR/ALKnegative NSCLC who are immunotherapy-naive will be enrolled.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for study entry:

Signed Informed Consent Form

Age 18 years

ECOG performance status of 0 or 1

Histologically or cytologically confirmed Stage IIIBIVB NSCLC (based on the 
IASLC Lung Cancer Staging Project proposed for the eighth edition of the AJCC 
NSCLC staging see Appendix 3)
–
Patients with histologically or cytologically confirmed Stage IIIB-IV NSCLC 
based on the seventh edition of the AJCC NSCLC staging system are also 
eligible for study entry.

For patients who have received prior neo-adjuvant/adjuvant chemotherapy or 
chemoradiotherapy with curative intent for non-metastatic disease:  a treatment-free 
interval of at least 6 months prior to enrollment.

Patients with any PD-L1 test result by IHC are eligible for the study.

Patients without a PD-L1 test result are eligible for the study.

Measurable disease, as defined by RECIST v1.1 (based on the assessments 
detailed in Section 4.5.5.
–
Previously irradiated lesions can only be considered measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of measureable 
disease

Adequate hematologic and end-organ function, defined by the following laboratory 
test results obtained within 14 days prior to the first dose of study drug:
–
ANC 1500 cells/L without granulocyte colony-stimulating factor support
–
Lymphocyte count500 cells/L
–
Platelet count100,000 cells/L without transfusion
–
Hemoglobin9.0 g/dL 


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Patients may be transfused to meet this criterion.
–
International normalized ratio (INR) or activated partial thromboplastin time 
(aPTT)1.5the upper limit of normal (ULN)
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation must have an INR or aPTT 
within therapeutic limits for at least 1 week prior to enrollment.
–
AST, ALT, and alkaline phosphatase2.5ULN with the following exceptions:
Patients with documented liver metastases:  AST and/or ALT5ULN
Patients with documented liver or bone metastases:  alkaline 
phosphatase5ULN
–
Serum bilirubin1.5ULN
Patients with known Gilbert disease who have a serum bilirubin level 
3ULN may be enrolled.
–
Calculated creatinine clearance30 mL/min

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.
–
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 study 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.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry.

Prior treatment with immunotherapy for any stage NSCLC, including early-stage 
(neoadjuvant or adjuvant) disease. 

Patients with EGFR-sensitizing mutations and ALK rearrangements are excluded 
from the study and should be treated according to standard clinical guidelines.
Refer to NCCN guidelines for recommendations on molecular testing 
(NCCN Guidelines 2016).


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
Active CNS metastases requiring treatment as determined by computed 
tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening 
and prior radiographic assessments
–
Patients with a history of treated asymptomatic CNS metastases are eligible, 
provided they meet all of the following criteria:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord)
No ongoing requirement for corticosteroids as therapy for CNS disease
No stereotactic radiation within 7 days or whole-brain radiation within 14 days 
prior to enrollment
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening 
scan must receive radiation therapy and/or surgery for CNS metastases.  
Following treatment, these patients may then be eligible without the need for 
an additional brain scan prior to enrollment, if all other criteria are met.

Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for 2 weeks prior to enrollment

Leptomeningeal disease

Uncontrolled tumor-related pain
–
Patients requiring pain medication must be on a stable regimen at study entry.
–
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to enrollment.  Patients should be recovered from the effects of radiation.  
There is no required minimum recovery period.
–
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
–
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or 
calcium12 mg/dL or corrected serum calciumgreater thanULN)
–
Patients who are receiving denosumab prior to enrollment must be willing and 
eligible to discontinue its use and replace it with a bisphosphonate instead while 
in the study.

Malignancies other than NSCLC within 5 years prior to enrollment, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 


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5-year OS90%) treated with an 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)

Women who are pregnant, lactating, or intending to become pregnant during the 
study
–
Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result within 14 days prior to initiation of study drug.

History of severe allergic, anaphylactic, or other hypersensitivity reactions 
to chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 7 for a 
more comprehensive list of autoimmune diseases)
–
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid-replacement hormone may be eligible for this study.
–
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are 
eligible for this study.
–
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
Rash must cover <10% of body surface area
Disease is well controlled at baseline and only requiring low-potency topical 
steroids
No acute exacerbations of underlying condition within the last 12 months 
requiring treatment with either psoralen plus ultraviolet A radiation, 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-
potency or oral steroids.

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
–
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Positive HIV test

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a 
positive hepatitis B surface antigen (HBsAg) test at screening


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–
Patients with past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody (HBcAb) test, are 
eligible for the study.  An HBV DNA test must be performed in these patients 
prior to enrollment.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test and a positive HCV RNA test at screening

Active tuberculosis

Severe infections within 4 weeks prior to enrollment, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to 
enrollment, unstable arrhythmias, or unstable angina
–
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or left ventricular ejection fraction <50% must be on 
a stable medical regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist if appropriate.

Major surgical procedure other than for diagnosis within 28 days prior to enrollment
or anticipation of need for a major surgical procedure during the course of the study

Prior allogeneic bone marrow transplantation or solid organ transplant

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
antiPD-1, and antiPD-L1 therapeutic antibodies

Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or interleukin 2) within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to enrollment

Any approved anti-cancer therapy or hormonal therapy within 3 weeks prior to 
enrollment; the following exceptions are allowed:
–
Hormone-replacement therapy or oral contraceptives
–
TKIs approved for treatment of NSCLC discontinued7 days prior to enrollment; 
the baseline scan must be obtained after discontinuation of prior TKIs.

Treatment with any other investigational agent or participation in another clinical 
study with therapeutic intent within 28 days prior to enrollment

Received therapeutic oral or IV antibiotics within 2 weeks prior to enrollment
–
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible.


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
Administration of a live, attenuated vaccine within 4 weeks before enrollment or 
anticipation that such a live attenuated vaccine will be required during the study or 
for 5 months after the last dose of atezolizumab
–
Influenza vaccination should be given during influenza season only 
(approximately October to March).  
–
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) 
within 4 weeks prior to enrollment, at any time during the study, or for 5 months
after the last dose of atezolizumab.

Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor [TNF] agents) within 2 weeks prior to enrollment
–
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled in the study after discussion with and approval by the Medical Monitor.
–
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical 
insufficiency are allowed.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label single-arm study. Patients who meet all of the inclusion criteria 
and none of the exclusion criteria as assessed during the screening period will be 
enrolled in the study to receive treatment with atezolizumab.
The screening tests and evaluations will be performed within 28 days prior to Cycle 1, 
Day 1.  Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to Cycle 1, Day 1 may be used; such tests do 
not need to be repeated for screening.
After written informed consent has been obtained and eligibility has been established, 
the study site will obtain the patient’s unique identification number by registering the 
patient in an interactive voice/Web response system (IxRS) on the day of enrollment.   
Patients should receive their first dose of study drug on the day of enrollment if possible.  
If this is not possible, the first dose should occur within 5 business days after the patient 
is registered in the 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 (MPDL3280A) will be supplied by the Sponsor in a single-use, 20-mL 
USP/European Pharmacopoeia 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) atezolizumab solution but may contain more than the stated 
volume to enable delivery of the entire 20 mL volume.  For information on the 
formulation and handling of atezolizumab, see the Atezolizumab Pharmacy Manual and 
Investigator’s Brochure.
4.3.2
Dosage, Administration, and Compliance
The dose level of atezolizumab proposed to be tested in this study is 1200 mg 
(equivalent to an average body weightbased dose of 15 mg/kg) administered by IV 
infusion every 21 (3) days.
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.
The initial dose of atezolizumab will be delivered via IV infusion 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.  For all 
infusions, vital signs will be assessed per the local standard of care (see Appendix 1).
Dose modifications to atezolizumab are not permitted.  
No premedication will be allowed for the first dose of atezolizumab.  Premedication may 
be administered for Cycles 2 at the discretion of the treating physician.  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 one-half the rate being given at the 
time of event onset.  Once the event has resolved, the investigator should continue 
to deliver the infusion at the reduced rate for 30 minutes.  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 the baseline grade.  The infusion rate at restart should be 
one-half of the 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 


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life-threatening infusion-related events will not receive further infusion and will be 
further managed as clinically indicated until the event resolves.
See Appendix 5 for anaphylaxis precautions.
Atezolizumab infusions will be administered per the instructions outlined in Table 4.
Table 4
Administration of First and Subsequent Infusions 
of Atezolizumab
First Infusion
Subsequent Infusions

No premedication administered for 
atezolizumab specifically is permitted 

Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion.

Infuse atezolizumab (1200 mg in a 250-mL 
0.9% NaCl intravenous infusion bag) 
over 60 (15) minutes.

If clinically indicated, record patient’s vital 
signs (heart rate, respiratory rate, blood 
pressure, and temperature) during the 
infusion at 15, 30, 45, and 60 minutes 
(5-minute windows are allowed for all 
timepoints).

Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) at 30 (10) minutes after the 
infusion.

Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If patient experienced infusion-related reaction 
during any previous infusion, premedication 
with antihistamines may be administered for 
Cycles 2 at the discretion of the treating 
physician.

Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before starting 
infusion.

If the patient tolerated the first infusion well 
without infusion-associated adverse events, 
the second infusion may be delivered over 
30 (10) minutes.

If no reaction occurs, subsequent infusions 
may be delivered over 30 (10) minutes.
Continue to record vital signs within 
60 minutes before starting infusion and during 
and after the infusion, if clinically indicated.

If the patient had an infusion-related reaction 
during the previous infusion, the subsequent 
infusion must be delivered over 60 (15) 
minutes.
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) every 15 (5) minutes during 
the infusion if clinically indicated or patient 
experienced symptoms during the previous 
infusion. 

Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) 30 min (10 min) after the 
infusion if clinically indicated or patient 
experienced symptoms during previous 
infusion.
NaClsodium chloride.
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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.
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (atezolizumab) will be provided by the 
Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs by using the IxRS 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
The Sponsor will evaluate the appropriateness of continuing to provide atezolizumab to 
patients who are still on therapy at the end of study. Decisions will be made 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, and nutritional supplements) used by 
a patient from 7 days prior to screening until the study completion/discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Premedication with antihistamines may be administered for any atezolizumab infusions 
after Cycle 1.


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Patients should continue use of maintenance therapy as follows:

Hormonal therapy with gonadotropin-releasing hormone agonists or antagonists for 
prostate cancer

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as low-molecular-weight 
heparin or warfarin at a stable dose level)

Palliative radiotherapy (e.g., treatment of known bony metastases), provided it does 
not interfere with the assessment of tumor target lesions (e.g., the lesion being 
irradiated is not the only site of disease, because that would render the patient not 
evaluable for response by tumor assessments according to RECIST v1.1) 
–
It is not a requirement to withhold atezolizumab during palliative radiotherapy

Inactive vaccinations, but not live, attenuated vaccinations, are permitted during the 
course of the study (i.e., only inactivated forms of the Influenza vaccinations are 
permitted).  Live, attenuated vaccinations are prohibited (see Section 4.4.3).

Megestrol administered as an appetite stimulant 

Inhaled corticosteroids for chronic obstructive pulmonary disease

Mineralocorticoids (e.g., fludrocortisone) 

Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2-receptor antagonist per standard 
practice.  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and 2-adrenergic agonists) see Appendix 5.
All medications must be recorded on the appropriate Concomitant Medications eCRF.
4.4.2
Cautionary Therapy for Atezolizumab-Treated Patients
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in which 
systemic corticosteroids or TNF-inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered first by the treating physician.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the treating physician except in the case of patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance) (see also Section 4.4.1).


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Systemic corticosteroids are recommended, with caution at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with 
atezolizumab therapy.  Guidelines for the management of immune-mediated adverse 
events are described in the Investigator’s Brochure.
The concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  Their use for patients on this study is allowed at the discretion of the 
investigator, however the herbal therapy must have no known interactions with any study 
treatment nor can it be used specifically for the treatment of cancer (see Section 4.4.3).
4.4.3
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited for various time periods prior to 
starting study drug, depending on the anti-cancer agent (see Section 4.1.2), and during 
study drug treatment until disease progression is documented and the patient has 
discontinued study drug.  This includes but is not limited to chemotherapy, hormonal 
therapy, immunotherapy, radiotherapy, investigational agents, or herbal therapy (unless 
otherwise noted).
The following medications are prohibited while in the study, unless otherwise noted:

Traditional herbal medicines intended for the treatment of cancer or those with 
known interactions with the study treatment, because their use may result in 
unanticipated drugdrug interactions that may cause or confound assessment of 
toxicity

Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to Cycle 1, Day 1, 
at any time during the study, or for 5 months after the last dose of atezolizumab

Use of corticosteroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 
such patients, non-contrast CT scans of the chest and non-contrast CT scans or 
MRIs of the abdomen and pelvis should be performed.
4.5
STUDY ASSESSMENTS
Please see Appendix 1 for the schedule of activities to be performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
any study-related procedures are performed.  Informed Consent Forms for enrolled 
patients and for patients who are not subsequently enrolled will be maintained at the 
study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 


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record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and all medications (e.g., prescription drugs, vaccines, over-the-counter drugs, herbal or 
homeopathic remedies, and nutritional supplements) used by the patient within 7 days 
prior to the screening visit.
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems.  
Any abnormality 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.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, heart rate, and systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature.
Baseline vital sign assessment will be done on Cycle 1, Day 1 prior to the first dose of 
study drug.  All subsequent vital sign assessments (i.e., during study drug cycles and 
treatment discontinuation visits) will be done per the local standard of care, as outlined in 
the schedule of activities (see Appendix 1). Specific requirements for the monitoring of 
vital signs during atezolizumab infusions are provided in Section 4.3.2.
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.
4.5.5
Tumor and Response Evaluations
Tumor assessments will be performed at screening and then every 6 weeks (7 days)
thereafter, regardless of dose delays, for the first 12 months following Cycle 1, Day 1.  
After 12 months, tumor assessments will be required every 9 weeks (7 days) until 
disease progression or treatment discontinuation.  Disease status (complete response 
[CR], partial response [PR], stable disease, or PD) will be assessed by the investigator 
with the use of RECIST v1.1 (see Appendix 4).  


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The same radiographic procedure used at screening should be used throughout the 
study (e.g., the same contrast protocol for CT scans).  Assessments should be 
performed by the same evaluator, if possible, to ensure internal consistency across visits.
Results must be reviewed by the investigator before dosing at the next cycle.  In addition, 
all radiographic images will be sent to an independent review facility to standardize 
results and interpretation.  Further details on radiographic methods are described in the 
IRF charter.  
Bone scans (Technetium-99m) or sodium fluoride positron emission tomography (NaF-
PET) may be performed at screening if clinically indicated.  If bone metastases are
present at screening and cannot be seen on CT or MRI scans, Technetium-99m or NaF-
PET bone scans should be repeated at the discretion of the investigator when complete 
response is identified in the target disease or when progression in bone is suspected. 
Patients who continue treatment beyond radiographic disease progression assessed per 
RECIST v1.1 should be monitored with a follow-up scan at the next scheduled tumor 
assessment when the scan frequency is every 6 weeks (7 days).  If the scan frequency 
is every 9 weeks, the follow-up scan is recommended at 6 weeks (7 days) or earlier if 
clinically indicated, or per local standard of care.
For patients who discontinue study drug for any reason other than radiographic PD per 
RECIST v1.1, tumor assessments should continue at the same frequency as would have 
been followed if the patient had remained on the study drug until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for patients who continued 
treatment after disease progression according to RECIST v1.1), withdrawal of consent, 
death, or study termination by the Sponsor, whichever occurs first.
At the investigator’s discretion, tumor assessments may be repeated at any time if PD is 
suspected.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
4.5.6.1
Samples for Safety Laboratory Tests
Samples for the following safety laboratory tests will be sent to the study site's local 
laboratory for analysis:

Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count)

Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate or total CO2, calcium, phosphorus, total and 
direct bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin)

Coagulation (aPTT or INR)

For all women of childbearing potential (including those who have had a tubal 
ligation), a serum pregnancy test at screening.  Urine pregnancy tests will be 


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performed at specified subsequent visits (see Appendix 1).  If a urine pregnancy test 
is positive, it must be confirmed by a serum pregnancy test.

Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood); dipstick 
permitted

Thyroid function testing (thyroid-stimulating hormone, free T3, free T4)

HBV serology:  HBsAg, total HBcAb
–
If a patient has a negative HbsAg test and a positive total HBcAb test at 
screening, an HBV DNA test should be performed at screening.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
–
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must be performed to determine if the patient has an active HCV infection.

HIV testing
–
All patients will be tested for HIV prior to inclusion in the study; HIV-positive 
patients will be excluded.

EGFR testing 
–
If EGFR testing is not available as a part of standard-of-care diagnostic workup, 
contact the Medical Monitor for additional options.  (See Section 4.1.2 for 
exclusion criteria).
4.5.6.2
Biomarker Samples
A central laboratory will coordinate the sample collection of tissue and blood samples for 
research-related testing at central laboratories or at the Sponsor. Instruction manuals 
and supply kits will be provided for all central laboratory assessments.  Samples for the 
following laboratory tests will be sent to one or several central laboratories or to the 
Sponsor for analysis:

Biomarker assays in blood samples
–
Blood samples will be obtained for biomarker evaluation (including but not 
limited to biomarkers related to NSCLC or tumor immune biology) from all 
eligible patients according to the schedule in Appendix 2.  Samples will be 
processed to obtain plasma and PBMCs for the determination of changes in 
blood-based biomarkers (e.g., ctDNA).  Whole-blood samples may be 
processed to obtain their derivatives (e.g., RNA and DNA) and evaluated for 
immune-related, tumor typerelated, and other exploratory biomarkers (e.g., 
alterations in gene expression or single-nucleotide polymorphisms).
–
Any remaining samples collected for biomarker assays may be used for 
exploratory biomarker profiling, identification, and pharmacodynamic assay 
development purposes as appropriate.  

Optional collection of tumor tissue
–
Although this study includes all otherwise-eligible patients irrespective of tissue-
related biomarker status, tissue biopsies (tissue blocks preferred) may be 
submitted at any time during the study, with biopsies from diagnosis (archival or 


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fresh) and at progression preferred, for exploratory biomarker and correlative 
analysis.  If tissue samples are submitted, NGS may be performed by 
Foundation Medicine.  If performed by Foundation Medicine, the investigator 
can obtain results from these analyses in the form of an NGS report, which is 
available upon request directly from Foundation Medicine.  The investigator 
may share and discuss the results with the patient, unless the patient chooses 
otherwise. The Foundation Medicine NGS assay, FoundationOne, has not 
been cleared or approved by health authorities.  The NGS report is generated 
for research purposes and is not provided for the purpose of guiding future 
treatment decisions (see Section 4.5.7).  Results may not be available for 
samples that do not meet testing criteria
–
Representative formalin-fixed paraffin-embedded tumor specimens in paraffin 
blocks (blocks preferred) from a recent (the most recent diagnosis of metastatic 
NSCLC) biopsy specimen with a minimum volume of 0.2mm3 viable tumor 
tissue can be provided at any time during the study.  Tissue quality should be 
confirmed by a local pathologist and should adhere to the Foundation Medicine 
Pathology Review Process for Optimal Tissue Utilization.
–
Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone 
metastases, and lavage samples are not acceptable. For core-needle biopsy 
specimens, at least 3 cores should be submitted for evaluation.
–
Patients who do not have tissue specimens meeting eligibility requirements may
still be eligible for enrollment provided all other eligibility criteria are met. 
Acceptable samples include core needle biopsies for deep tumor tissue
(minimum 3 cores) or excisional, incisional, punch, or forceps biopsies for
cutaneous, subcutaneous, or mucosal lesions.
For patients who consent to the optional collection of samples for the Research 
Biosample Repository (RBR), any leftover material from the above sample collection will 
be stored and used for exploratory analyses as indicated in Section 4.5.7.
Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Appendix 2.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.7), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exception(s):

PBMCs and plasma and tumor tissue samples collected for biomarker analysis will 
be destroyed no later than 15 years after the final Clinical Study Report has been 
completed.


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When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.
Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 4.5.7.4.
4.5.7
Optional Samples for Research Biosample Repository
4.5.7.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, and peptides).  The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase the knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.7.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board (IRB) or Ethics Committee (EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.7) will not be 
applicable at that site.
4.5.7.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to atezolizumab or diseases:

Blood samples and/or plasma and/or PMBCs collected at screening; on Day 1 of 
Cycles 1, 2, 3 and 4; and at first evidence of radiographic progression or loss of 
clinical benefit


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
Tumor (e.g., primary tumor, metastatic site, or site of local recurrence or 
advancement, if appropriate) samples collected at diagnosis or later

Leftover blood, serum, plasma, PBMC, and tumor tissue samples
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations or somatic mutations via whole genome 
sequencing (WGS), whole exome sequencing (WES), NGS, or other genomic analysis 
methods. 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, along with clinical data collected in this study, may increase the opportunity 
for developing new therapeutic approaches.  Data will be analyzed in the context of this 
study, but will also be explored in aggregate with data from other studies.  The 
availability of a larger dataset will assist in the identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.7.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities and Sponsor monitors, 
representatives, and collaborators, as appropriate.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.7.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
A separate, specific signature is not required for the following mandatory RBR samples:

Blood taken at screening, baseline, and progression
4.5.7.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the study is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  The patient will be 
provided with instructions on how to withdraw consent after the study is closed.  A 
patient's withdrawal from Study ML39237 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study ML39237.
4.5.7.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality, as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 


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IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.5.8
On-Study Survival Follow-Up
While in the study, patients will be followed for survival and anti-cancer therapy.  Survival 
follow-up assessments will occur at specified intervals until study completion or 
discontinuation.  Assessments will include survival status, date of death, cause of death, 
and any new anti-cancer treatment.  
4.5.9
Optional Long-Term Follow-Up
Patients enrolled in the study will be asked to participate in optional long-term follow-up, 
which will include collection of long-term survival data beyond the end of the study.  This 
long-term data collection will be managed by the Sponsor’s designee.  The patient may 
withdraw consent from optional long-term follow-up at any time during or after the study 
by e-mail.
Long-term follow-up will be initiated after the study end or if the study is terminated for 
any reason.  Survival data will be collected during the optional long-term follow-up period 
every 3 months for the first year, then every 6 months thereafter for up to 5 years from enrollment 
of the first patient into the study, until the last patient dies, withdraws consent, or is lost to 
follow-up, whichever occurs first.
4.5.10
ECOG Performance Status
ECOG performance status (see Appendix 6) will be measured at the visits specified in
Appendix 1.
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 that it is in the best interest of the patient

Patient non-compliance

Patient is lost to follow-up
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.


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4.6.2
Study Treatment Discontinuation
Patients must discontinue study drug if they experience any of the following (but will 
remain in the study and be evaluated for safety and efficacy):

Pregnancy

Intolerable toxicity related to study drug

Any medical condition that may jeopardize the patient’s safety if he or she continues 
with study drug

Use of another systemic anti-cancer therapy (see Section 4.1.2)

Radiographic disease progression per RECIST v1.1 
–
Exception:  Patients will be permitted to continue atezolizumab after 
RECIST v1.1 criteria for PD are met if they meet all of the following criteria:
Evidence of clinical benefit (defined as the stabilization or improvement of 
disease-related symptoms) as assessed by the investigator
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression 
of disease
No decline in ECOG Performance Status that can be attributed to disease 
progression
Absence of tumor progression at critical anatomical sites 
(e.g., leptomeningeal disease) that cannot be readily managed and stabilized 
by protocol-allowed medical interventions prior to repeat dosing
When a patient discontinues study drug, regardless of the reason for discontinuation, the 
patient will be asked to return to the clinic within 30 days after the last dose of study drug 
for a study drug discontinuation visit.  The visit at which the decision is made to 
discontinue treatment (e.g., loss of clinical benefit is confirmed or disease progression 
occurs) may be used as the study-drug discontinuation visit.  The primary reason for 
study drug discontinuation should be documented on the appropriate eCRF.  Patients 
who discontinue study drug 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 prespecified futility analysis is met (see Section 6.7)
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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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 are outlined below (see Section 5.1.1).  
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.  After initiation of study 
drug, all adverse events will be reported until 30 days after the last dose of study drug or 
until initiation of new anti-cancer therapy, whichever occurs first, and serious adverse 
events and adverse events of special interest will continue to be reported until 90 days 
after the last dose of study drug or until initiation of new anti-cancer therapy, whichever 
occurs first.  Guidelines for managing anticipated adverse events, including criteria for 
dosage modification and treatment interruption or discontinuation, are provided below 
(see Section 5.1.2).  Refer to Section 5.2, Section 5.3, Section 5.4, Section 5.5, and 
Section 5.6 for details on safety reporting during the study.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  infusion-related 
reactions and immune-related hepatitis, pneumonitis, colitis, pancreatitis, diabetes 
mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, 
Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis, and myocarditis.
Refer to the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for atezolizumab.


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Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab.  
The initial evaluation should include the following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations.
5.1.2
Management of Patients Who Experience Specific Adverse 
Events
There will be no dose modifications for atezolizumab in this study.  
Study treatment may be temporarily suspended in patients experiencing toxicity that is
considered to be related to study drug.  If atezolizumab is withheld for 105 days, the 
patient will be discontinued from atezolizumab.  If the investigator believes the patient is 
likely to derive clinical benefit and the Medical Monitor is in agreement, atezolizumab 
treatment can be resumed after being withheld for 105 days.  If a patient must be 
tapered off corticosteroids used to treat adverse events, study drug may be withheld for 
105 days.  The investigator and the Medical Monitor will determine the acceptable 
length of treatment interruption.
Dose interruptions for reasons other than toxicity (e.g., surgical procedures) may be 
allowed with Medical Monitor approval.  The investigator and the Medical Monitor will 
determine the acceptable length of treatment interruption.
Guidelines for management of patients who experience specific adverse events 
associated with atezolizumab are provided in the Atezolizumab Investigator's Brochure
and in Appendix 8.  


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study drug or concomitant 
therapy or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study drug (e.g., screening invasive procedures 
such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
–
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study 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 the NCI 
CTCAE; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.3.5.4 for reporting instructions). Adverse events of special interest for this 
study include the following:

Any of the following confirmed treatment-emergent autoimmune conditions:
–
Pneumonitis
–
Colitis
–
Endocrinopathies: diabetes mellitus, pancreatitis, or adrenal insufficiency or 
hyperthyroidism
–
Hepatitis
–
Transaminitis: Grade ≥2 (AST or ALT 3ULN and bilirubin2ULN) OR AST 
or ALT10ULN
–
Systemic lupus erythematosus
–
Neurologic: Guillain-Barré syndrome, myasthenia gravis, meningoencephalitis
–
Nephritis

Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response system, systemic immune activation, or 
infusion-reaction syndromes


 
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• 
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. 
 
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 Section 5.4, Section 5.5, and 
Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 30 days after the 
last dose of study drug or until initiation of new anti-cancer therapy, whichever occurs 
first, and serious adverse events and adverse events of special interest will continue to 
be reported until 90 days after the last dose of study drug or until initiation of new anti-
cancer therapy, whichever occurs first. 
For patients participating in the optional long term follow-up (as outlined in 
Section 4.5.9) who continue to receive atezolizumab, all AE’s will be reported until 30 
days after the last dose of atezolizumab during this period of the study.  Additionally, 
serious adverse events and non-serious adverse events of special interest will be 
reported until 90 days after the last dose of atezolizumab. 


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Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the optional long-term follow-up period or 
within 5 months after receiving their last dose of atezolizumab.   
Pregnancies are to be reported to the Sponsor, as applicable, according to the same 
guidelines as outlined in Section 5.4.3.1.
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 NCI CTCAE v4.0 will be used for assessing 
adverse event severity.  Table 5 will be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE.


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Table 5
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the 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 the NCI CTCAE (v 4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refers 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.
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 6):

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 
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Table 6
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.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction 
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events, 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 


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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.
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.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it is a change from baseline and meets any of 
the following criteria:

Is accompanied by clinical symptoms

Results in a change in study drug (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 studies, certain abnormal values may not qualify as 
adverse events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it is a change from baseline and meets any of the 
following criteria:

Is accompanied by clinical symptoms

Results in a change in study drug (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 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either an 
elevated total bilirubin (2 ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of NSCLC should be recorded on the Study
Completion/Study Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).
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 


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used unless combined with the presumed cause of death (e.g., "sudden cardiac death").  
Deaths that occur after the adverse event reporting period should be reported as
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of NSCLC
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v 1.1 criteria.  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or to perform an efficacy measurement for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
–
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
–
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study drug is not itself an 
adverse event, but it may result in an adverse event.  All adverse events associated with 
an overdose or incorrect administration of study drug should be recorded on the Adverse 
Event eCRF.  If the associated adverse event fulfills seriousness criteria, 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).
No safety data related to overdosing of atezolizumab are available.
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)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
 Medical Monitoring Support Center (North America) Medical 
Monitor contact information:
Medical Monitor:
, M.D. (Primary Contact)
Telephone Nos.: 
 (toll-free) or 
 (direct; USA)
Fax Nos.: 
 (toll-free) or 
 (direct; USA)
E-mail:
Genentech Medical Monitor contact information: 
Medical Monitor:
, Pharm.D. (Secondary Contact)
Telephone No.:
(USA)
E-mail:
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 Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and e-mailing the form by using the fax number or e-mail address provided 
to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug or initiation of new 
anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of study drug
or initiation of new anti-cancer therapy, whichever occurs first.  
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 Serious Adverse Event/Adverse
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and e-mailing the form by 
using the fax number or e-mail 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 study drug 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 to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and e-mailing the form by 
using the fax number or e-mail address provided to investigators.  Pregnancy should not 
be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
drug and counsel the patient, discussing the risks of the pregnancy and the possible 
effects on the fetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an event in 
the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
5.4.3.2
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 (because the Sponsor considers abortions to be medically significant).
5.4.4
Reporting Requirements for Cases of Atezolizumab Accidental 
Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to 
administration of the drug.


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Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with atezolizumab, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
Each adverse event associated with a special situation should be recorded separately 
on the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria, 
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).  Adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.


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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The sponsor should be notified if the investigator becomes aware of any serious adverse
event or adverse event of special interest that occurs after the end of the adverse event 
reporting period (defined as 30 days after the last dose of study drug or until initiation of 
new anti-cancer therapy, whichever occurs first, for adverse events and until 90 days 
after the last dose of study drug or until initiation of new anti-cancer therapy, whichever 
occurs first for serious adverse events and adverse events of special interest), if the 
event is believed to be related to prior study drug treatment.  All such events should be 
reported until the end of study (defined as the date after which all enrolled patients who 
remain alive have been followed for at least 18 months from the start of study drug.)
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and e-mailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form with use of the fax number or e-mail 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 with the use of the following reference 
document:

Atezolizumab Investigator's Brochure


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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
There will be approximately 150 patients enrolled in the study.  Safety analyses will 
include all patients who receive at least one dose of study drug.  Biomarker analyses will 
include all patients who received at least one dose of study drug and have baseline 
biomarker assessment.  The primary efficacy analysis measured by ORR and the 
primary biomarker analysis will be performed after all patients complete 6 months of 
follow-up (i.e., 6 months after the final patient has been enrolled).  The final 
analysis will be performed at the end of the study, 18 months after all patients have been 
enrolled. The overall survival analysis will be updated once the long-term follow-up 
data is available, and will be summarized in a separate report. Safety reporting for 
patients who remain on study drug will also be included.
In addition, OS data collected through the external death registry data after study 
completion during the optional long-term follow-up will be updated periodically (e.g.,
every 12 years) based on data availability.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size for this study is based on the primary efficacy objective and primary 
biomarker objective.
Based on 150 patients, the maximum half width of the 2-sided 95% CI of the estimated 
ORR will be within 8%.
Additionally, based on 120 biomarker-evaluable patients (80% of the study population), 
with a minimum follow-up of 6 months during the primary analysis, and with 28 patients 
in the smaller biomarker positive or negative group (19% of the study population), the 
study primary biomarker analysis will have 89% and 79% power to detect PFS difference 
if the HRs of PFS between the biomarker positive vs. negative group is 0.50 or 0.55, 
respectively.  The above-mentioned power is for a 2-sided test with a significance level 
of 0.1, assuming a median PFS of 4 months for the subgroup with a shorter median PFS.  
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll in, 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 and baseline characteristics (e.g., age, sex) will be summarized by using 
means, SDs, medians, and ranges for continuous variables, and proportions for 
categorical variables, as appropriate.  
6.4
EFFICACY ANALYSES
The efficacy analysis population will be based on all patients who have received at least 
one dose of study drug.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is investigator-assessed ORR, defined as the 
proportion of patients whose confirmed best overall response is either a PR or CR per 
RECIST v1.1. For this analysis, patients not meeting these criteria, including patients 
without at least one post-baseline response assessment, will be considered non-
responders. An estimate of the ORR from all patients who received study drug and the 
95% CI will be calculated by using the Blaker method. 
6.4.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints include OS and investigator (INV)-assessed duration 
of response (DOR) and PFS per RECIST v1.1.
DOR will be analyzed for the subset of patients who achieved an objective response.  
DOR is defined as the time from the initial occurrence of documented CR or PR until 
documented disease progression as determined by the investigator, or death, whichever 
occurs first.  Median and range will be presented for a descriptive summary.
PFS is defined as the time from the first dose of study drug to the time of disease 
progression or death from any cause during the study, whichever occurs first.  Patients 
who have not experienced disease progression or death at the time of analysis will be 
censored at the time of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored at the time of first dose. 
OS is defined as the time from the first dose of study drug to the time of death from any 
cause during the study.  Patients who are still alive at the time of analysis will be 
censored at the time of their last study assessment (for active patients) or at the last 
date known alive (for patients in follow-up). 
PFS and OS of patients in this study will be summarized graphically and with descriptive 
statistics such as median and landmark PFS by using the Kaplan-Meier (K-M) 
methodology.  The Brookmeyer-Crowley methodology will be used to construct the 95% 
CI for the median PFS and OS (Brookmeyer and Crowley 1982).  K-M methods will also 
be used to estimate landmark PFS, along with the corresponding 95% CI, by using 
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6.4.3
Exploratory Efficacy Endpoints
The relationship between efficacy, baseline characteristics, and biomarkers may also be 
explored. 
6.5
SAFETY ANALYSES
Safety will be assessed through summaries of adverse events, including protocol-
defined events of special interest, changes in laboratory test results, changes in vital 
signs, and exposure to study.
Verbatim descriptions of adverse events will be mapped to thesaurus terms using
MedDRA.  Adverse event data will be listed by study site, patient number, and study day.  
Events occurring on the day of or after administration of the first dose of treatment will be 
summarized by thesaurus term, appropriate thesaurus levels, and NCI CTCAE v4.0 
grade.  Serious adverse events, including deaths, will be listed separately and will be 
summarized.  For events of varying severity, the highest grade will be used in 
summaries. 
Relevant laboratory tests and vital sign (heart rate, respiratory rate, blood pressures, and 
temperature) data will be displayed by time, with Grade 3 and 4 values identified, where 
appropriate.  Additionally, all laboratory data will be summarized by NCI CTCAE v4.0 
grade. 
6.6
BIOMARKER ANALYSES
Biomarker analysis population will be based on all patients who have received at least 
one dose of study drug and have baseline biomarker assessment.
6.6.1
Primary Biomarker Analyses
K-M curves and a log-rank test will be used to evaluate the differences in INV-assessed 
PFS between mutation positive versus negative groups at various cutoff points. Tests 
will be two-sided at a significance level of 0.10.
6.6.2
Secondary Biomarker Analyses 
K-M curves and a log-rank test will be used to evaluate the differences in INV-assessed 
PFS between mutation positive versus negative groups at various cutoff points. 
Descriptive statistics for PFS curves including median PFS time and 6-, 9-, and 12-
month PFS probabilities will be estimated for various cutoff points.  OS will be analyzed 
in a similar way as PFS.  INV-assessed ORR will also be summarized by various MLs
and by immune signature expression level.  The Brookmeyer-Crowley methodology will 
be used to construct the 95% CI for the median.  Greenwood’s formula will be used to 
construct the 95% CI for the landmark PFS.


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6.6.3
Exploratory Biomarker Analyses
Change in bTMB after immunotherapy will be analyzed.  Status of additional circulating 
biomarkers, including but not limited to expression of immune genes, as well as others
related to immunotherapy and NSCLC may be examined at prespecified timepoints. 
Outcomes with the study drug will be summarized.  A historical control cohort may 
also be used to evaluate outcomes.
The relationship between bTMB and tTMB may be explored by visual data display and 
correlation coefficient if enough tTMB data is available.
6.7
INTERIM ANALYSES
6.7.1
Planned Interim Analysis
One interim analysis is planned 6 months after approximately one-half of the patients
have been enrolled.  The purpose of the interim analysis is to provide preliminary results 
in evaluating the biomarker cutoff and to perform a futility analysis.  The futility criteria to 
stop the study will be met if the true ORR is more likely 5% rather than 15%, or if 4 or 
fewer patients have an objective response from the first 75 enrolled patients.  The 
chance of stopping the study is 67% if the true ORR is 5% or less.  The chance of 
stopping the study is 1% if the true ORR is 15% or larger.
No conclusions or study alterations/terminations are to be made based on the biomarker 
interim analysis results.  No type-1 error adjustments will be made for the interim 
analysis. 
The study may continue while the interim analysis is being performed.
6.7.2
Optional Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim 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 data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC through 
the 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.


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The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data will be sent directly to the CRO with the 
use of the CRO’s standard procedures to handle and process the electronic transfer of 
these data.
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  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.  
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures. 
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through the 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 to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 


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entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, 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, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
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 FDA regulations and 


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applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed 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 with the use 
of 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 uses 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 datasets 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 trial will be sponsored by Genentech, a member of the Roche group, and will be 
managed by Genentech and CROs.  CROs will provide clinical operations management, 
data management, biostatistics, and medical monitoring. 


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An IxRS will be used to assign patient numbers, monitor enrollment and patient status, 
and manage study treatment requests and study drug shipments.
A central laboratory will be used for the optional tumor assessment and collection of 
blood specimens. 
Patient data will be recorded via an EDC system with the use of eCRFs (see 
Section 7.2).
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 health care professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for the publication of study results.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pd
f
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.


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


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10.
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Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: 
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Hales RK, Banchereau J, Ribas A, et al. Assessing oncologic benefit in clinical trials of 
immunotherapy agents. Ann Oncol 2010:mdq048.


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based on November 2013 SEER data submission, posted to the SEER web site, 
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2010;28(36):531120.
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Atezolizumab—Genentech, Inc.
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at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 
14LBA. 


Atezolizumab—Genentech, Inc.
94/Protocol ML39237, Version 5
Appendix 1a
Schedule of Activities
Activity
Screening a
All Treatment Cycles b
Treatment DC c
On-Study 
Follow-Up
Study 
Completion/ DC d
Optional 
Long-Term 
Follow-Up e
Days 28 
to 1
Day 1, 
Cycle 1
Day 1, Cycle 2 and 
Beyond
Every 21 (3) Days
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months 
until Study 
Completion/DC
30 Days after 
Study 
Completion/DC
Informed consent
x f
Review of eligibility criteria
x
Demographics
x
Medical history and baseline 
conditions g
x
Vital signs h
x
x
x
Weight
x
Height
x
Complete physical examination i
x
Limited physical examination j
x
x
ECOG performance status
x
x
x
x
x
Concomitant medications k
x
x
x
x
Hematology l
x
x
x
x
Serum chemistry m
x
x
x
x
Coagulation test (aPTT or INR)
x
Pregnancy test
x n
Every 3 cycles n
TSH, free T3/T4 o
x
Every 3 
cycles 


Appendix 1a
Schedule of Activities
Atezolizumab—Genentech, Inc.
95/Protocol ML39237, Version 5
Activity
Screening a
All Treatment Cycles b
Treatment DC c
On-Study 
Follow-Up
Study 
Completion/ DC d
Optional 
Long-Term 
Follow-Up e
Days 28 
to 1
Day 1, 
Cycle 1
Day 1, Cycle 2 and 
Beyond
Every 21 (3) Days
30 Days after 
Last Dose of 
Study Treatment
Every 3 Months 
until Study 
Completion/DC
30 Days after 
Study 
Completion/DC
Urinalysis p
x
HIV, HBV, HCV serology q
x
EGFR/ALK testing
x r
Whole-blood samples for biomarker 
analyses s (mandatory)
x
Day 1 of Cycles 2 and 4, and at 
disease progression or loss of 
clinical benefit
Whole-blood sample for RBR s & 
exploratory biomarker analyses 
(optional)  s, t
Day 1, Cycle 3 only
Tissue biopsies s (optional)
x u
x u
x u
Study drug administration v
x
x
Tumor response assessment w
x w
Every 6 weeks (7 days) during treatment regardless of dose delays, for the 
first 12 months following Cycle 1, Day 1.  After 12 months, tumor assessment will be 
required every 9 weeks (7 days). w
Adverse events x
x
x
x
x
x
x
Survival and anti-cancer therapy 
follow-up y
x
Long-term survival follow-up 
(optional)e
x


Appendix 1a
Schedule of Activities
Atezolizumab—Genentech, Inc.
96/Protocol ML39237, Version 5
ALKanaplastic lymphoma kinase; aPTTactivated partial thromboplastin time; CT computed tomography; ECOG Eastern Cooperative 
Oncology Group; eCRFelectronic Case Report Form; EGFRepidermal growth factor receptor; HBcAbhepatitis B core antibody;
HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; INRinternational normalized ratio; MRImagnetic 
resonance image; NSCLC nonsmall cell lung cancer; RBRResearch Biomarker Repository; THthyroid hormone; TSHthyroid 
stimulating hormone.
Notes:  Dosing and all assessments coinciding with Day 1 of each cycle should be performed within 3 days of the specified visit date, 
unless otherwise noted.  Physical examinations, safety laboratory assessments, and assessment of ECOG performance status may be 
done within 96 hours prior to dosing.
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to study entry 
(except where otherwise specified) may be used for screening assessments rather than repeating such tests.
b All assessments should be performed on the day of the specified visit unless a time window for that assessment is otherwise specified.  
Assessments scheduled on the day of study drug administration (Day 1) of each cycle should be performed prior to study drug infusion 
unless otherwise noted.  If scheduled dosing and study assessments are precluded because of a holiday, weekend, or other event, then 
dosing may be postponed to the soonest following date, with subsequent dosing continuing on a 21-day schedule.  If treatment was 
postponed for fewer than 3 days, the patient can resume the original schedule.
c Patients will be asked to return to the clinic no more than 30 days after the last dose for a treatment discontinuation visit.  Note that the 
Study Discontinuation eCRF should not be completed until after the patient has discontinued from the study.  
d A patient is considered to have completed the study if he or she does not discontinue from the study prior to the end of the study.  The 
end of this study is defined as the date after which all enrolled patients who remain alive have been followed for at least 18 months from 
the start of study drug.  Thereafter, patients will be followed for long-term survival.  Patients who complete the study will return to the 
clinic for a study completion visit within 30 days following study completion.  Patients who discontinue the study prematurely will return 
to the clinic for a study discontinuation visit within 30 days following discontinuation from the study.
e For patients who provide consent for optional long-term follow-up, refer to Appendix 1b.for the schedule of assessments.
f
Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained no more than 
28 days before initiation of study drug.
g Includes clinically significant diseases, surgeries, cancer history (including stage and date of diagnosis, prior cancer therapies, and 
procedures), reproductive status, and smoking history.  
h Includes heart rate, respiratory rate, and systolic and diastolic blood pressures while the patient is in a seated position, and temperature.  
For specific requirements during atezolizumab infusions, refer to Section 4.3.2.


Appendix 1a
Schedule of Activities
Atezolizumab—Genentech, Inc.
97/Protocol ML39237, Version 5
i
A complete physical examination 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 Events eCRF.  
j
Perform a limited, symptom-directed physical examination within 96 hours prior to dosing at specified timepoints, and as clinically 
indicated.  Changes from baseline abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. (See Section 4.5.3)
k Includes any medication (e.g., prescription drugs, vaccines, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by the patient from 7 days prior to screening until the study completion/discontinuation visit.  At each post-screening 
visit, changes to current medications or new medications used since the last documentation of medications will be recorded.
l
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, lymphocytes, 
eosinophils, monocytes, basophils, and other cells), and platelet count.
m Serum chemistry includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total CO2, 
calcium, phosphorus, total and direct bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin.  Serum will be collected 
every 3 cycles to test thyroid function.  HBV and HCV will be tested as clinically indicated.  CRP from screening and Cycle 3, Day 1 will 
be tested centrally from previously obtained samples; no additional samples will be needed.
n All women of childbearing potential (including those who have had a tubal ligation) must have a negative serum pregnancy test at 
screening (within 14 days prior to Cycle 1, Day 1).  Perform urine or serum pregnancy test every three cycles thereafter.  Confirm any 
positive urine pregnancy test with a serum pregnancy test.  Patients with positive serum pregnancy tests should be discontinued from 
study drug.
o Thyroid function testing (TH, free T3, free T4) will be performed at screening, Cycle 1, Day 1, and every three cycles thereafter.
p Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood).
q At screening, patients will be tested for HIV, HBsAg, total HBcAb, and HCV antibody. If a patient has a negative HBsAg test and a 
positive total HBcAb test at screening, an HBV DNA test should be performed. If a patient has a positive HCV antibody test at 
screening, an HCV RNA test must be performed to determine if the patient has an active HCV infection.
r
EGFR and ALK testing with approved test to be conducted at or prior to screening to rule out presence of EGFR-sensitizing mutations 
or ALK rearrangements.  If either test is confirmed positive, the patient will be ineligible for enrollment (see Section 4.1.2 for exclusion 
criteria and Section 1.1.3 for NCCN guidelines on testing).  For patients who are unable or unwilling to provide a tissue sample to 
determine EGFR status, the EGFR Cobasplasma test is available.  Please contact the Medical Monitor for additional options.
s See Appendix 2 for detailed schedule.


Appendix 1a
Schedule of Activities
Atezolizumab—Genentech, Inc.
98/Protocol ML39237, Version 5
t
The optional RBR whole blood sample requires separate specific informed consent and the sample can be collected at any time during 
the course of the study.
u Optional tissue biopsy specimen(s) may be submitted at any time prior to or during enrollment at the following timepoints: from the most 
recent diagnosis of metastatic NSCLC, during treatment, and/or at progression.  The quality of the sample should be confirmed by a 
local pathologist and conform to the Foundation Medicine Pathology Review Process for Optimal Tissue Utilization.
v The initial dose will be delivered over 60 (15) minutes.  If the first infusion is well tolerated, all subsequent infusions may be delivered 
over 30 (10) minutes.  Atezolizumab treatment may be continued until lack of clinical benefit, unacceptable toxicity, withdrawal of 
consent, patient or physician decision to discontinue treatment, or death.
w CT scans (with oral/intravenous contrast unless contraindicated) or MRI scans of the chest and abdomen.  A CT scan of the pelvis is 
required at screening and as clinically indicated or as per local standard of care at subsequent response evaluations.  A CT (with 
contrast) or MRI scan of the head must be done at screening to evaluate CNS metastasis in all patients.  See Section 4.5.5 for details.  
Perform tumor assessment at baseline and every 6 weeks (± 7 days) thereafter regardless of dose delays for the first 12 months 
following Cycle 1, Day 1.  After 12 months, tumor assessment will be required every 9 weeks (± 7 days); tumor assessments will 
continue until disease progression per RECIST v1.1 or loss of clinical benefit, consent withdrawal, study discontinuation, study 
completion or death, whichever occurs first.  Patients who discontinue treatment for reasons other than disease progression (e.g., 
toxicity) will continue scheduled tumor assessments until disease progression, withdrawal of consent, study discontinuation, study 
completion (i.e., end of study), or death, whichever occurs first.  In the absence of disease progression, tumor assessments should 
continue regardless of whether patients start a new anti-cancer therapy, unless consent is withdrawn.
x All serious adverse events and adverse events of special interest, regardless of relationship to study drug, will be reported until 90 days 
after the last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first.  After this period, the investigator should report any serious adverse events or adverse events of special interest. 
y Survival follow-up should continue until at least 18 months following the start of the study for each patient and at end of study defined as 
18 months after the last patient’s C1D1, death, withdrawal of consent, the patient is lost to follow-up, or whichever occurs first.


Atezolizumab—Genentech, Inc.
99/Protocol ML39237, Version 5
Appendix 1b
Optional Long-Term Follow-Up Schedule of Assessments
Activity
All Treatment Cycles 
Treatment Completion/DC
b,c
Safety Follow- Up 
(Phone Call) 
Overall Survival Follow-Up
(Phone Call)
Study 
Completion/ DC
Continued dosing
Every 21 (3) Days a
30 days post-last 
treatment
Every 3 months for the first 
year, then every 6 months 
thereafter, or up to 5 years 
from enrollment of the first 
patient into the study until 
the last patient dies, 
withdraws consent, is lost to 
follow-up, whichever occurs 
first
Study drug 
administration
x
Adverse Event
x
x
x
Survival Information
x
x
DCdiscontinuation
a
Patients on study drug will continue therapy until they have received a total of 2 years of atezolizumab treatment (32 cycles).
b Patients will be asked to return to the clinic no more than 30 days after the last dose for a treatment discontinuation visit.  Note that the Study 
Discontinuation eCRF should not be completed until after the patient has discontinued from the study.  
c
Patients who complete the optional long-term follow-up study will return to the clinic for a study completion visit within 30 days following study 
completion.  Patients who discontinue the study prematurely will return to the clinic for a study discontinuation visit within 30 days following 
discontinuation from the study.


Atezolizumab—Genentech, Inc.
100/Protocol ML39237, Version 5
Appendix 2
Schedule of Biomarker Samples
Visit
Timepoint
Sample Type
Proposed 
Biomarkers
Mandatory/
Optional
Screening
(Day 28 to Day 1)
NA
Plasma
bTMB
Mandatory
Baseline
(Day 1 of Cycle 1)
Prior to infusion
Plasma
bTMB
Mandatory
Baseline
(Day 1 of Cycle 1)
Prior to infusion
PBMC
Immune gene 
expression
Mandatory
Day 1 of Cycle 2
Prior to infusion
Plasma
bTMB
Mandatory
Day 1 of Cycle 2
Prior to infusion
PBMC
Immune gene 
expression
Mandatory
Day 1 of Cycle 3
Prior to infusion
Plasma
bTMB
Optional
Day 1 of Cycle 4
Prior to infusion
Plasma
bTMB
Mandatory
During treatment 
At radiographic 
progression or 
loss of clinical 
benefit
Plasma
bTMB
Mandatory
During treatment 
At radiographic 
progression or 
loss of clinical 
benefit
PBMC
Immune gene 
expression
Mandatory
NA
Anytime during 
study
Tissue
tTMB and somatic 
alterations
Optional
bTMBblood tumor mutational burden; NAnot applicable; PBMCperipheral blood 
mononuclear cells; tTMBtissue tumor mutational burden.


Atezolizumab—Genentech, Inc.
101/Protocol ML39237, Version 5
Appendix 3
IASLC Lung Cancer Staging Project Proposed for the Eighth
Edition of the American Joint Committee on Cancer NonSmall 
Cell Lung Cancer Staging System1


Appendix 3
IASLC Lung Cancer Staging Project Proposed for the Eighth 
Edition of the American Joint Committee on Cancer NonSmall 
Cell Lung Cancer Staging System1 (cont.)
Atezolizumab—Genentech, Inc.
102/Protocol ML39237, Version 5
1 Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals 
for Revision of the TNM Stage Groupings in the Fourthcoming (Eighth) Edition of the TNM 
Classification for Lung Cancer. J Thorac Onc 2015;11(1): 39-51.


Atezolizumab—Genentech, Inc.
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Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
nonmeasurable as follows:
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 computed tomography (CT) or magnetic resonance imaging (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 nonmeasurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Nontarget Lesions” for information on lymph node 
measurement.
Nonmeasurable Tumor Lesions
Nonmeasurable tumor lesions encompass small lesions (longest diameter 10 mm 
or pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
nonmeasurable lesions.  Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumors: Revised RECIST guideline (Version 1.1).  Eur J Cancer 2009;45:22847.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
104/Protocol ML39237, Version 5
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.  
When a bone scan is the sole indicator of progression, progression in bone will be 
defined as when at least two or more new lesions are seen on bone scan compared 
with screening.  In situations where the scan findings are suggestive of a flare 
reaction, or apparent new lesion(s) which may represent trauma, these results must 
be confirmed with other imaging modalities such as MRI or fine-cut CT to constitute 
progression.  Only a single new bone lesion on bone scan is required for 
progression if the lesion can be correlated on CT, MRI or plain film.

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 nonmeasurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) 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 noncystic 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.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
105/Protocol ML39237, Version 5
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions
All measurements should be recorded in metric notation, with use of calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
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 only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans 
with intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a noncontrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether noncontrast CT or MRI (enhanced or nonenhanced) 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 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
106/Protocol ML39237, Version 5
and interpretation of nontarget disease or new lesions since the same lesion may appear 
to have a different size with use of a new modality.
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, 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 NONTARGET 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 
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 nonmeasurable 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 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
107/Protocol ML39237, Version 5
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 nontarget lesions.  Nodes that have a short axis 
10 mm are considered nonpathological and should not be recorded or followed.
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 nontarget 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 nontarget lesions involving the same organ as 
a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
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 nontarget) 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.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
108/Protocol ML39237, Version 5
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
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 since 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 the 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 too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked.) 
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.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
109/Protocol ML39237, Version 5
Evaluation of Nontarget Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of nontarget lesions.  While some nontarget 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 nontarget 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 nontarget lesion(s) and/or (if applicable) 
maintenance of tumor marker level above the normal limits
PD:  unequivocal progression of existing nontarget lesions

The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Nontarget Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the nontarget disease, there must be an overall 
level of substantial worsening in nontarget 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 nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in nontarget 
disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has Only Nonmeasurable 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 
nonmeasurable disease burden.  Because worsening in nontarget disease cannot be 
easily quantified (by definition:  if all lesions are truly nonmeasurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in nonmeasurable 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 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
110/Protocol ML39237, Version 5
point.  While it would be ideal to have objective criteria to apply to nonmeasurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.
When the patient has bone lesions at baseline.  When a bone scan is the sole 
indicator of progression, progression in bone will be defined as when at least two or 
more new lesions are seen on bone scan compared with screening.  In situations where 
the scan findings are suggestive of a flare reaction, or apparent new lesion(s) which may 
represent trauma, these results must be confirmed with other imaging modalities such as 
MRI or fine-cut CT to constitute progression.  Only a single new bone lesion on bone 
scan is required for progression if the lesion can be correlated on CT, MRI or plain film.
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 partial or 
complete response.  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.
New osteoblastic bone lesions identified on plain films, CT, or MRI will not be considered 
progression in an otherwise stable or responding subject, if, in the opinion of the 
physician, the osteoblastic lesion appears to be healing or a response to therapy.
EVALUATION OF RESPONSE
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.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
111/Protocol ML39237, Version 5
When patients have nonmeasurable (therefore nontarget) disease only, Table 2 is to be 
used.
Table 1
Timepoint Response:  Patients with Target Lesions
(with or without Nontarget Lesions)
Target Lesions
Nontarget 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 Nontarget Lesions Only
Nontarget 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 nontarget 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.
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 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
112/Protocol ML39237, Version 5
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. 
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 nontarget lesions are not assessed, the response for 
nontarget 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 
nontarget 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.


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
113/Protocol ML39237, Version 5
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.
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 


Appendix 4
Response Evaluation Criteria in Solid Tumors (RECIST): 
Excerpt from Original Publication (cont.)
Atezolizumab—Genentech, Inc.
114/Protocol ML39237, Version 5
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 nontarget disease as shown in Table 1, Table 2, and Table 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.
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 nontarget 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or nontarget lesion.


Atezolizumab—Genentech, Inc.
115/Protocol ML39237, Version 5
Appendix 5
Anaphylaxis Precautions
EQUIPMENT NEEDED

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice 

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
1.
Stop the study drug infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible.
5.
Administer antihistamines, epinephrine, or other medications as required by patient
status and directed by the physician in charge.
6.
Continue to observe the patient and document observations.


Atezolizumab—Genentech, Inc.
116/Protocol ML39237, Version 5
Appendix 6
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead


Atezolizumab—Genentech, Inc.
117/Protocol ML39237, Version 5
Appendix 7
Preexisting Autoimmune Diseases
Subjects should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Subjects with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be subjects with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Contact the Medical Monitor regarding any 
uncertainty over autoimmune exclusions.
Autoimmune Diseases and Immune Deficiencies
Acute disseminated 
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody 
syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune thrombocytopenic 
purpura
Behcet’s disease
Bullous pemphigold
Chronic fatigue syndrome
Chronic inflammatory 
demyelinating polyneuropathy
Chung-Strauss syndrome
Crohn’s disease 
Dermatomyositis
Diabetes mellitus type 1
Dysautonomia 
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia 
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular 
autoimmune syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada 
disease
Wegener’s 
granulomatosis


Atezolizumab—Genentech, Inc.
118/Protocol ML39237, Version 5
Appendix 8
Management of Atezolizumab-Specific Adverse Events
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-related adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated 
promptly to avoid potential major complications.  Discontinuation of atezolizumab may 
not have an immediate therapeutic effect, and in severe cases, immune-related toxicities 
may require acute management with topical corticosteroids, systemic corticosteroids, or 
other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 
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 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
119/Protocol ML39237, Version 5
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.
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 12 mg/kg/day oral prednisone or equivalent.

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 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 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
120/Protocol ML39237, Version 5
HEPATIC EVENTS
Immune-related hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
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 12 mg/kg/day oral prednisone or 
equivalent.

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 tests.
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 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent 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-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
121/Protocol ML39237, Version 5
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 12 mg/kg/day oral prednisone or 
equivalent.

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 tests.
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 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent 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-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-related 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 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
122/Protocol ML39237, Version 5
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 12 mg/kg/day oral prednisone or equivalent. 

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 12 mg/kg/day IV methylprednisolone or 
equivalent 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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
123/Protocol ML39237, Version 5
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 12 mg/kg/day IV methylprednisolone or 
equivalent 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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
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.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
124/Protocol ML39237, Version 5
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

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.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
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-related hyperthyroidism. c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
125/Protocol ML39237, Version 5
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
126/Protocol ML39237, Version 5
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 12 mg/kg/day IV methylprednisolone or 
equivalent 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 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
127/Protocol ML39237, Version 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 12 mg/kg/day oral prednisone or equivalent.  

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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
128/Protocol ML39237, Version 5
IMMUNE-RELATED MYOCARDITIS
Immune-related myocarditis has been associated with the administration of 
atezolizumab.  Immune-related myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-related myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of GI illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
129/Protocol ML39237, Version 5
Table 6
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-related 
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-related 
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.a

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-related 
myocarditis, Grade 3-4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. a,b

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 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 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
130/Protocol ML39237, Version 5
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7.  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.
Table 7
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of 
event onset.

After the event has resolved, the investigator should wait for 30 
minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

Permanently discontinue atezolizumab and contact Medical 
Monitor. a
IRRinfusion-related reaction.
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be
re-challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
131/Protocol ML39237, Version 5
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 work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
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 12 mg/kg/day 
oral prednisone or equivalent.

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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
132/Protocol ML39237, Version 5
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-related pancreatitis, 
Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent 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-related pancreatitis, 
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent 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 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
133/Protocol ML39237, Version 5
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.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
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
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 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent 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-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
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 work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
134/Protocol ML39237, Version 5
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-related 
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-related 
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

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-related 
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

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 12 mg/kg/day oral or IV prednisone or 
equivalent.
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 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent 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-related event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
IMMUNE-RELATED MENINGOENCEPHALITIS
Immune-related meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-related 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.  


APPENDIX 8
Management of Atezolizumab-Specific Adverse Events (cont.)
Atezolizumab—Genentech, Inc.
135/Protocol ML39237, Version 5
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-Related 
Meningoencephalitis
Event
Management
Immune-related 
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent 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-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.

SAP_001.pdf: 
 
Official Title: 
 
A PHASE II SINGLE-ARM STUDY OF ATEZOLIZUMAB 
MONOTHERAPY IN LOCALLY ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER: CLINICAL EVALUATION OF 
NOVEL BLOOD-BASED DIAGNOSTICS 
NCT Number: 
NCT02848651 
Document Date: 
SAP Version 1: 17-January-2018 
 
 


 
                                      
 
 
 
Statistical Analysis Plan 
  
PROTOCOL TITLE:     A PHASE II SINGLE-ARM STUDY OF ATEZOLIZUMAB 
MONOTHERAPY IN LOCALLY ADVANCED OR 
METASTATIC NON−SMALL CELL LUNG CANCER: 
CLINICAL EVALUATION OF NOVEL BLOOD-BASED 
DIAGNOSTICS 
 
PROTOCOL NUMBER: ML39237 
 
TEST PRODUCT:  
  Atezolizumab (MPDL3280A) 
 
SPONSOR:   
      Genentech, Inc. 
 
PLAN PREPARED BY: 
 
 
ERSION: 
 
      version 1.0 (January 17, 2018) 
 
DATE FINAL: 
      VERSION 1.0: 01/17/2018 
 
 


 
 
 
                           Statistical Analysis Plan 
Data Sources/Protocol: ML39237 
                                                Date: July 19 2017 
                                             (Page 2 of 13) 
   
2 
 
Table of Contents 
1. 
ABBREVIATIONS ................................................................................................................ 3 
2. 
BACKGROUND .................................................................................................................. 4 
3. 
STUDY DESIGN .................................................................................................................. 4 
3.1 
Protocol Synopsis ....................................................................................................... 6 
3.2 
Objectives and Endpoints: .......................................................................................... 6 
3.3 
Timing of Analyses ...................................................................................................... 7 
4. 
STATISTICAL METHODOLOGIES ...................................................................................... 8 
4.1 
Sample size: ............................................................................................................... 8 
4.2 
Analysis Populations ................................................................................................... 8 
4.3 
Demographic and Baseline Characteristics ................................................................. 8 
4.4 
Analysis of Study Conduct .......................................................................................... 9 
4.5 
Efficacy Analyses ........................................................................................................ 9 
4.5.1 
Primary Efficacy Endpoint .............................................................................. 9 
4.5.2 
Secondary Efficacy Endpoints ........................................................................ 9 
         4.5.3     Exploratory Analysis                                                                                       10 
4.6 
Safety Analyses ........................................................................................................ 10 
4.6.1 
Exposure of Study Drug ............................................................................... 10 
4.6.2 
Adverse Events ............................................................................................ 10 
4.6.3 
Laboratory Data ........................................................................................... 11 
4.6.4 
Vital Signs .................................................................................................... 11 
4.6.5 
Medications and Other Treatments .............................................................. 11 
4.7 
Biomarker Analyses .................................................................................................. 11 
4.7.1 
Primary Biomarker Analyses ........................................................................ 12 
4.7.2 
Secondary Biomarker Analyses ................................................................... 12 
4.7.3 
Exploratory Biomarker Analyses................................................................... 12 
5. 
REFRENCES ..................................................................................................................... 13 
 


 
 
 
                           Statistical Analysis Plan 
Data Sources/Protocol: ML39237 
                                                Date: July 19 2017 
                                             (Page 3 of 13) 
   
3 
 
1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ALK 
anaplastic lymphoma kinase 
ATA 
anti-therapeutic antibody 
Baseline 
last available data obtained prior to patients 
receiving the first dose of study drug.In case of 
multiple assesments, average will be taken 
CR  
complete response 
CT  
computed tomography 
CTCAE 
 Common Terminology Criteria for Adverse 
Events 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
HR  
hazard ratio 
ICH 
International Conference on Harmonisation 
IgG1 
immunoglobulin G subclass 1 
IMP 
investigational medicinal product 
ITT 
intent-to-treat 
IRB 
Institutional Review Board 
IV  
Intravenous 
IxRS 
interactive voice/Web response system 
KM 
Kaplan-Meier 
ML 
 mutational load 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NaF-PET 
 sodium fluoride positron emission tomography 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NSCL 
C non−small cell lung cancer 
ORR 
objective response rate 
OS 
 overall survival 
PBMC 
peripheral blood mononuclear cell 
PD  
progressive disease 
PD-1 
programmed death-1 
PD-L 
1 programmed death-ligand 1 
PFS 
progression-free survival 
PK  
pharmacokinetic 
PR  
partial response 
q21d 
every 21 days 
RCC 
renal cell carcinoma 


 
 
 
                           Statistical Analysis Plan 
Data Sources/Protocol: ML39237 
                                                Date: July 19 2017 
                                             (Page 4 of 13) 
   
4 
 
2. 
BACKGROUND  
(See protocol background section for study scientific background)  
This document specifies the statistical analyses for Study ML39237.   
 
3. 
STUDY DESIGN 
This is a Phase II, open-label, prospective, multicenter study designed to evaluate the efficacy 
and safety of single-agent atezolizumab as a first-line therapy in patients with locally advanced 
or metastatic NSCLC In addition, the primary biomarker objective is to measure bTMB and 
evaluate whether it can predict for improved clinical outcome with atezolizumab.  
 
There will be approximately 150 patients with Stage IIIB−IVB, locally advanced or metastatic, 
EGFR/ALK−negative NSCLC (any histology) who are immunotherapy-naive enrolled at 
approximately 25−30 study sites in the United States. In case there are patients who are 
determined to be EGFR/ALK−positive by retrospective blood analysis, recruitment will continue 
until 150 patients who are negative for EGFR and ALK are enrolled. 
 
 
 
AJCC = American Joint Committee on Cancer; Dx = diagnosis; ECOG = Eastern Cooperative 
Oncology Group; EGFR/ALK = epidermal growth factor receptor/anaplastic lymphoma kinase; 
IASLC = International Association for the Study of Lung Cancer; IV = intravenous; mets = metastases; NSCLC = 
non−small cell lung cancer; PD = progressive disease; PS =performance status; q3w = once every three weeks; 
RECIST = Response Evaluation Criteria in Solid Tumors. 
 
a Staging criteria based on the IASLC Lung Cancer Staging Project proposed for the eighth edition of the AJCC 
NSCLC staging system (see Appendix 3). Patients with histologically or cytologically confirmed Stage IIIB-IV 
NSCLC based on the seventh edition of the AJCC NSCLC staging system are also eligible for study entry. 
b Blood samples will be taken at baseline and at progression (all samples will be tested retrospectively). 
c Treatment beyond RECIST v1.1 progression may be permitted if the patient continues to derive clinical benefit as 
determined by the investigator. 
 


 
 
 
                           Statistical Analysis Plan 
Data Sources/Protocol: ML39237 
                                                Date: July 19 2017 
                                             (Page 5 of 13) 
   
5 
 
 
Atezolizumab (fixed dose of 1200 mg) will be administered intravenously on Day 1 of 
each 21-day cycle. 
 
Patients who meet the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
criteria for progressive disease (PD) at any timepoint during treatment will be permitted 
to continue atezolizumab treatment if there is evidence of clinical benefit, defined as 
meeting all of the following criteria: 
• Evidence of clinical benefit as assessed by the investigator 
• Absence of symptoms and signs (including worsening of laboratory values [e.g. new or  
    worsening hypercalcemia]) indicating unequivocal progression of disease 
• No decline in ECOG performance status that can be attributed to disease progression 
• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that  
   cannot be managed by protocol-allowed medical interventions 
 
Patients for whom approved therapies exist must provide written consent to acknowledge 
deferring these treatment options in favor of continuing study drug at the time of initial 
progression. 
 
When a patient discontinues study drug, regardless of the reason for discontinuation, the 
patient will be asked to return to the clinic within 30 days after the last dose of study drug for a 
treatment discontinuation visit. Patients who discontinue will not be replaced. 
 
Screening tests and evaluations will be performed within 28 days prior to treatment initiation. 
 
Blood samples will be collected at screening, baseline, during therapy, and at first evidence of 
radiographic disease progression or loss of clinical benefit. Data from the latter blood draws 
will be used to explore whether the radiographic findings are consistent with changes in bTMB 
as measured by the blood-based diagnostic assays and to explore possible mutational 
mechanisms of resistance. Additional blood samples may be taken at each scan as defined in 
protocol Appendix 1. 
 
Tissue biopsies (tissue blocks preferred) may be submitted at any time during the study, with 
biopsies from diagnosis (archival or fresh) and at progression preferred. For patients who 
provide tissue samples, next generation sequencing (NGS) may be performed by Foundation 
Medicine. Results may not be available for samples that do not meet testing criteria. Patients 
who are unable to undergo biopsy sample collection but otherwise meet the eligibility criteria 
may still be enrolled to receive atezolizumab. 
 
All patients will undergo tumor assessment at baseline and every 6 weeks (± 7 days) thereafter 
regardless of dose delays for the first 12 months following Cycle 1, Day 1. After 12 months, 
tumor assessment will be required every 9 weeks (± 7 days); tumor assessments will continue 
until disease progression per RECIST v1.1 or loss of clinical benefit, consent withdrawal, study 
discontinuation, study completion or death, whichever occurs first. All patients will be followed 
for survival and anti-cancer therapy while in the study and will be given the option of 
participating in a long-term follow-up during which survival data will be collected from public 
resources (e.g., death dates from online obituaries or the National Death Index).  


 
 
 
                           Statistical Analysis Plan 
Data Sources/Protocol: ML39237 
                                                Date: July 19 2017 
                                             (Page 6 of 13) 
   
6 
 
Safety will be assessed on the basis of vital sign measurements, ECOG performance status 
scores, physical examination findings, clinical laboratory test results, and the frequency, 
severity, and relationship to atezolizumab of adverse events. 
 
3.1 
Protocol Synopsis 
The protocol synopsis (see protocol). 
 
3.2 
Objectives and Endpoints: 
The objectives and corresponding endpoints for the study are outlined in table below. 
 
Objectives  
Corresponding Endpoints 
Primary Efficacy Objective: 
To evaluate the clinical efficacy of 
Atezolizumab 
ORR according to RECIST v1.1 as assessed 
by the investigator 
Secondary Efficacy Objective: 
To evaluate the efficacy of 
Atezolizumab 
Investigator-assessed PFS according to 
RECIST v1.1 
   
Investigator-assessed disease control 
rate and duration of response according 
to RECIST v1.1 
  
Overall survival 
Safety Objective: 
To evaluate the safety and 
tolerability of atezolizumab 
Incidence of adverse events, with severity 
determined through use of NCI CTCAE v4.0 
Primary Biomarker Objectives: 
To evaluate whether “positive” 
bTMB (defined as bTMB >=16, and 
bTMB >=10) is associated with 
improved PFS with the treatment of 
atezolizumab 
Relationship between PFS and bTMB (≥16 
vs <16) and between PFS and bTMB (≥10 vs 
<10) 
Secondary Biomarker Objective: 
To evaluate whether “positive 
bTMB” defined at various bTMB 
cutoff points or quantiles can 
predict for improved PFS with 
atezolizumab.  
 
Relationship between PFS and various 
bTMB cutoff points, defined as range 4 to 24 
by twos, and quartiles, except the primary 
cutoff points16 and 10  
To evaluate the correlation 
between clinical outcomes 
including but not limited to PFS 
rate at 6, 9, and 12 months, 
ORR, disease control rate and 
various definitions of positive 
bTMB. 
Relationship between efficacy endpoints 
including PFS rate at 6, 9, and 12 
months, disease control rate, ORR and 
various bTMB cutoff pints and quantiles 


 
 
 
                           Statistical Analysis Plan 
Data Sources/Protocol: ML39237 
                                                Date: July 19 2017 
                                             (Page 7 of 13) 
   
7 
 
Exploratory Biomarker Objectives in Blood: 
To evaluate whether higher 
expression of an immune-
related gene signature in blood 
PBMCs predicts for improved 
PFS with atezolizumab 
Relationship between PFS and 
expression of an immune gene signature 
in PBMCs 
To assess whether bTMB is 
altered as a result of treatment 
with immunotherapy 
Relationship between bTMB and 
treatment with immunotherapy 
To assess the status of 
additional circulating 
biomarkers related to 
immunotherapy and NSCLC 
and outcomes with 
atezolizumab 
Relationship between circulating 
biomarkers related to immunotherapy 
and NSCLC and efficacy  
Exploratory Biomarker Objectives in Tissue: 
To perform retrospective tTMB 
analysis and NGS-based 
mutation testing on tissue 
biopsies for patients providing 
specific consent and viable 
samples 
Relationship between somatic mutations 
and tTMB on efficacy. All mutations will 
be identified through NGS performed on 
DNA extracted from tumor tissue. 
 
 
 
3.3 
Timing of Analyses 
 
The primary efficacy analysis measured by ORR may be performed after all patients complete 
6 months of follow-up (i.e. 6 months after last patient enrolled into the study). If the primary 
efficacy analysis is not performed at 6 months of follow-up, it will be performed during the final 
analysis. The final analysis will be performed at the end of the study, 18 months after all 
patients have been enrolled. 
 
One interim analysis is planned 6 months after one-half of the patients have been enrolled. 
The purpose of the interim analysis is to provide preliminary results in evaluating the biomarker 
cutoff and to perform a futility analysis. The futility criteria to stop the study will be met if the 
true ORR is more likely ≤5% rather than ≥ 15%, or if 4 or fewer patients have an objective 
response from the first 75 enrolled and treated patients. The chance of stopping the study is > 
67% if the true ORR is 5% or less. The chance of stopping the study is < 1% if the true ORR is 
15% or larger. No type-1 error adjustments will be made for the interim analysis.


   
 
8 
 
4. 
STATISTICAL METHODOLOGIES 
4.1 
Sample size: 
The sample size for this study is based on the primary efficacy objective and primary biomarker 
objectives. Based on 150 patients, the maximum half width of the 2-sided 95% CI of the 
estimated ORR will be within 8%. Additionally, based on 150 patients, there will be at least 80% 
power to detect a statistical improvement in PFS for bTMB high group vs bTMB low subgroup. 
The power listed in the table below is based on the following assumptions: the test is 2-sided, 
significance level is 0.10, both biomarker subgroups have at least 25% of the patients (i.e., 37 or 
more patients in both groups), median PFS is 4 months for the subgroup with a shorter median 
PFS, the HR of PFS between the subgroup with a shorter PFS versus the other subgroup is 0.6 
or lower, the recruitment duration is one year, the follow-up time from last patient in is 18 
months, and the dropout rate is 5%. 
 
 
4.2 
Analysis Populations  
Efficacy Analysis Population: 
The primary Efficacy analyses will include all patients who receive at least one dose of study 
drug.  
Safety Analysis Population: 
The safety analyses will be based on all patients who received any dose of atezolizumab during 
the study treatment period.  
Biomarker Analysis Population:  
Biomarker analyses will include all patients who receive at least one dose of study drug and 
have evaluable baseline biomarker assessment. 
4.3 
Demographic and Baseline Characteristics 
Demographic characteristics, such as age, sex, race/ethnicity, and baseline characteristics, 
such as weight, BMI, tobacco use history, histology subtype, ECOG performance status, 
metastatic lung cancer history, prior cancer radiotherapy, and PD-L1 status, will be summarized. 
Descriptive statistics (mean, median, standard deviation, and range) will be presented for 
continuous data, and frequencies and percentages will be presented for categorical data.  
 
n =150 
Power 
Hazard 
Ratio 
Biomarker ≥ 25th 
percentile vs.< 25th 
percentile 
Biomarker ≥ 50th 
percentile vs. < 50th 
percentile 
Biomarker ≥ 75th 
percentile vs. < 75th 
percentile 
0.4 
100% 
100% 
100% 
0.5 
97% 
99% 
97% 
0.6 
83% 
92% 
84% 
0.7 
58% 
69% 
58% 


   
 
9 
 
Demographic and baseline characteristics will be summarized for safety analysis population and 
possibly additional analysis populations including selected biomarker sub-populations if 
necessary. 
  
4.4 
Analysis of Study Conduct  
The number of patients who enroll in, discontinue, or complete the treatment and study will be 
summarized. Major protocol deviation including enrollment criteria exceptions will be listed and 
evaluated for their potential effects on the interpretation of study results. 
 
4.5 
Efficacy Analyses 
The efficacy analysis will be based on Efficacy Analysis Population (see section 4.2) 
 
4.5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is investigator-assessed ORR, defined as the 
proportion of patients whose confirmed best overall response is either a PR or CR per RECIST 
v1.1. For this analysis, patients not meeting these criteria, including patients without at least one 
post-baseline response assessment, will be considered non-responders. An estimate of the 
ORR from all patients who received study drug and the 95% CI will be calculated by using the 
Blaker method. 
 
4.5.2 
 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include disease control rate (DCR), duration of response (DOR), 
and PFS, per RECIST v1.1, and OS. Disease control rate (DCR) is defined as the rate of 
patients with complete or partial response as best response or stable disease maintained for 24 
weeks per RECIST v1.1. DOR will be analyzed for the subset of patients who achieved an 
objective response. DOR is defined as the time from the initial occurrence of documented CR or 
PR until documented disease progression as determined by the investigator or death, whichever 
occurs first. Median and range will be presented for a descriptive summary. Responders with no 
PD or death, DOR will be censored at last post-baseline tumor assessment. Responders with 
no post-baseline tumor assessment will be censored at the date of first dose plus 1. 
 
PFS is defined as the time from the first dose of study drug to the time of disease progression or 
death from any cause during the study, whichever occurs first. Patients who have not 
experienced disease progression or death at the time of analysis will be censored at the time of 
the last tumor assessment. Patients with no post-baseline tumor assessment will be censored at 
the date of first dose plus 1. 
 
OS is defined as the time from the first dose of study drug to the time of death from any cause 
during the study. Patients who are still alive at the time of analysis will be censored at the date 
of their last study assessment (for active patients) or at the last date known alive (for patients in 
follow-up). Patients with no post-baseline assessment will be censored at the date time of first 
dose plus 1. 
 


   
 
10 
 
PFS and OS of patients in this study will be summarized graphically and with descriptive 
statistics such as median and landmark PFS by using the Kaplan-Meier (K-M) methodology. 
The Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median PFS 
and OS (Brookmeyer and Crowley 1982). K-M methods will also be used to estimate landmark 
PFS and OS at various time points (i.e., 6, 12, 18, and 24 months), along with the 
corresponding 95% CI, by using Greenwood’s formula. 
4.5.3 
Exploratory Analysis  
Unconfirmed ORR will be summarized. Duration of stable disease or response will also be 
summarized for the subset of patients who were responders or achieved stable disease. 
Duration of stable disease or response is defined as the time from the start of study medication 
to documented disease progression as determined by the investigator or death, whichever 
occurs first.    
The relationship between efficacy and baseline characteristics may also be explored. 
Descriptive statistics for efficacy endpoints in important subgroups defined by baseline 
characteristics may be summarized. The impact of baseline characteristics on efficacy may be 
also evaluated using Cox model for time to event endpoints and logistic regression model for 
dichotomous endpoints respectively.  
 
4.6 
Safety Analyses 
Safety analysis will be performed on safety analysis population (see section 4.2). Safety will be 
assessed through summaries of adverse events, including protocol defined events of special 
interest, changes in laboratory test results, changes in vital signs, and exposure to study drug. 
Additional safety summaries may also be provided for applicable biomarker selected sub-
groups. 
 
4.6.1 
 Exposure of Study Drug 
Study drug exposure, including treatment duration, number of cycles, and dose intensity, will be 
summarized with descriptive statistics. 
 
4.6.2 
 Adverse Events 
Verbatim description of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the NCI CTCAE v4.0. 
AEs will be summarized by NCI CTCAE grade. Multiple occurrences of the same event will be 
counted once at the maximum severity.  
 
All AE data will be listed by study site, patient number, AE starting and ending study days, and 
study day of initiation of another non-protocol anti-cancer therapy after the last administration of 
study drug. SAEs and deaths data will also be listed. 
 
All AEs occurring on the day of or after administration of the first dose of treatment will be 
summarized by thesaurus term, appropriate thesaurus levels, and NCI CTCAE v4.0 grade. 
Severe AEs (Grade >=3), infusion related reactions, AEs relation to study drug, and AEs leading 
to study drug discontinuation or interruption will be summarized.  
 


   
 
11 
 
Serious adverse events (SAEs), AESIs, and adverse events leading to study drug 
discontinuation or interruption will be summarized separately.  
 
Deaths and causes of death will be summarized.  
 
 
Protocol Defined AE Reporting Period 
 
After initiation of study drug, all AEs will be reported until 30 days after the last dose of study 
drug or until initiation of new anti-cancer therapy, whichever occurs first; SAEs and adverse 
events of special interest will continue to be reported until 90 days after the last dose of study 
drug or until initiation of new anticancer therapy, whichever occurs first. Any and treatment 
related SAEs and AESIs will be reported until study completion.  
 
The above AEs reporting rules may be used to select AEs to be summarized if significant 
among of AEs are reported outside of the protocol defined AE reporting period.  
 
4.6.3 
Laboratory Data 
Laboratory data collected during study treatment and for 30 days after the last dose of study 
drug were classified according to NCI CTCAE grade and following analysis will be performed.  
 
1) Summary of Laboratory Values over Time, including descriptive statistics for change 
from baseline.  
2) Listing and summary of lab values above or below the normal range and above or below 
the marked laboratory abnormalities. 
3) Clinically relevant shifts in laboratory parameters defined as shifts from Grade 0, 1, 
or 2 at baseline to Grade 3 or 4 post baseline. 
 
4.6.4 
Vital Signs 
Vital sign (heart rate, respiratory rate, blood pressures, and temperature) data will be 
summarized by time and by NCI CTCAE grade, where appropriate. 
 
4.6.5 
Medications and Other Treatments 
Previous and concurrent medical conditions, previous and concomitant medications, and other 
anti-cancer treatment will be summarized.  .  
 
4.7 
 Biomarker Analyses 
Biomarker analysis will be based on Biomarker analysis population, which is all patients who 
receive at least one dose of study drug and have evaluable baseline biomarker assessment, as 
defined in section 4.2.  
The blood tumor mutational burden (bTMB) assay is a blood-based, circulating tumor DNA 
(ctDNA) next generation sequencing (NGS) test that will be used as an aid in the identification 
of non-small cell lung cancer (NSCLC) patients most likely to respond to atezolizumab, a 


   
 
12 
 
programmed death-ligand (PD-L1) blocking antibody. The NGS-based assay counts the total 
number of somatic mutations (single nucleotide variants (SNVs) excluding driver mutations) 
over a 1.25 megabase (Mb) region of coding DNA in ctDNA isolated from fresh plasma derived 
from whole blood. bTMB is reported as a whole integer score. 
 
The bTMB assay has been analytically validated and clinically validated retrospectively (ESMO 
2017 Gandara presentation and Fabrizio poster and manuscript in review). The assay detects 
SNVs down to 0.5% allele frequency across 394 genes from as little as 1% tumor content in a 
cell free DNA (cfDNA) sample. Tumor content is estimated by determining the maximum 
somatic allele frequency (MSAF). All samples in the biomarker evaluable population have MSAF 
>=1%. The FDA approved the IDE for the bTMB assay in 2017, and the assay is now being 
used to prospectively enroll 1L NSCLC patients in the BFAST trial. 
  
4.7.1 
Primary Biomarker Analyses 
K-M curves and a log-rank test will be used to evaluate the differences in PFS between bTMB 
high versus low groups at 16 and 10 two different cutoff points (i.e. bTMB ≥16 vs <16, and bTMB 
≥10 vs <10).  The Gatekeeping testing procedures will be used to test PFS differences at these 
two primary bTMB cut off points.  PFS difference at cutoff point 16 will be tested first. If there is 
statistically significance in PFS difference bTMB ≥16 vs <16 groups, we will claim statistical 
significant difference in PFS between bTMB ≥16 vs <16 groups, and we will further test PFS 
difference at cutoff 10. We can only claim PFS difference between bTMB ≥10 vs <10 groups if 
both tests for cutoff point 16 and cut off point 10 are statistically significant. 
 
The statistical tests for primary analysis as well as for other analyses comparing efficacy 
differences between bTMB high group vs low group will be two-sided at a significance level of 
0.10. he corresponding bTMB group differences will be estimated and two-sided 90% 
confidence interval will be provided. All other statistical tests used in the study will be two-sided 
at level of 0.05. Their corresponding point estimators will be estimated and two-sided 95% 
confidence interval will be provided. 
 
4.7.2 
 Secondary Biomarker Analyses 
K-M curves and a log-rank test will be used to evaluate the differences in PFS between bTMB  
mutation high versus low groups as measured by an NGS-based mutation burden assay in 
blood at various cutoff points other than the primary cut off points 16 and 10. These cutoff points 
are defined as range 4 to 24 by twos and quartiles.  
 
Descriptive statistics for PFS curves including median PFS time and 6-, 9-, and 12-month PFS 
probabilities will be estimated for various bTMB cutoff points. OS will be analyzed in a similar 
way as PFS. ORR and DCR will also be summarized by various bTMB cutoff points. The 
Brookmeyer-Crowley methodology will be used to construct the CI for the median. Greenwood’s 
formula will be used to construct the CI for the landmark PFS. 
4.7.3 
 Exploratory Biomarker Analyses 
Change in blood-based mutational load after immunotherapy will be analyzed.  
 


   
 
13 
 
The relationship between PBMCs and PFS may be analyzed in a similar way similar as bTMB 
and PFS, in order to explore whether higher expression of an immune-related gene signature in 
blood PBMCs predict improved PFS with atezolizumab.  
 
Status of additional circulating biomarkers related to immunotherapy in NSCLC at pre-specified 
timepoints and outcomes with the study drug will also be summarized in a similar way as bTMB. 
 
The relationship between blood-based mutation load and tissue-based mutation load may also 
be explored. 
 
5. 
REFRENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29−41.