Clinical trial NCT03285763
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Hoffmann-La Roche
Start date: 2017-10-25; Completion date: 2022-04-07
Enrollment: 619 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase III/IV, single-arm, multicenter study of the long-term safety and efficacy of atezolizumab treatment in participants with Stage IIIb or Stage IV NSCLC who have progressed after standard systemic chemotherapy (including if given in combination with anti-programmed cell death protein 1 \[anti-PD-1\] therapy, after anti-PD-1 as monotherapy, or after tyrosine kinase inhibitor \[TKI\] therapy). The study will consist of a Screening Period, a Treatment Period, a Treatment Discontinuation Visit, and a Follow-Up Period.

Detailed description:

Arms: arm 1: Participants with Stage IIIb or State IV NSCLC who have progressed after standard systemic chemotherapy will receive atezolizumab until Investigator-assessed loss of clinical benefit, unacceptable toxicity, investigator or participant's decision to withdraw from therapy, or death (whichever occurs first).
Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Participants will receive 1200 milligrams (mg) of atezolizumab administered by intravenous infusion on Day 1 of every 3-week cycle until Investigator-assessed loss of clinical benefit, unacceptable toxicity, investigator or participant's decision to withdraw from therapy, or death (whichever occurs first).

Protocol documents:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s 
local affiliates, including Genentech, Inc. in the United States.  The information 
contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in 
confidence as an investigator, potential investigator, or consultant, for review by you, 
your staff, and an applicable Ethics Committee or Institutional Review Board.  It is 
understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent 
from persons to whom the drug may be administered.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol MO39171, Final Version 6
PROTOCOL
TITLE:
A PHASE III/IV, SINGLE ARM, MULTICENTER 
STUDY OF ATEZOLIZUMAB (TECENTRIQ) TO 
INVESTIGATE LONG-TERM SAFETY AND 
EFFICACY IN PREVIOUSLY-TREATED PATIENTS 
WITH LOCALLY ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER (TAIL)
PROTOCOL NUMBER:
MO39171
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-001409-34
IND NUMBER:
NCT NUMBER:
Not applicable
NCT03285763
TEST PRODUCT:
Atezolizumab (RO5541267) 
MEDICAL MONITOR:
, MD
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 16 May 2017
 
03-Feb-2021 16:43:55
Title
Approver's Name
Company Signatory
Date and Time (UTC)
 
23-Mar-2021 08:11:21
Deputy EU QPPV
23-Mar-2021 14:59:11
Title
Approver's Name
Company Signatory
Date and Time (UTC)


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DATE AMENDED
Version 2: 04 September 2017
Version 3: 16 January 2018
Version 4: 14 January 2019
Version 5: 17 December 2019
Version 6: See electronic stamp above


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PROTOCOL AMENDMENT, VERSION 6: RATIONALE
The rationales for specific changes in Version 6 of this protocol are listed below: 

Approved indications for atezolizumab have been added (Section 1.2).

Text describing the current knowledge and risks of COVID-19 infection while 
receiving anti-programmed death-ligand 1 (PD-L1) immunotherapy are highlighted 
in the benefit-risk assessment as well as other relevant sections of the protocol 
(Section 1.3, Section 5.1, Section 10, Appendix 9).

Language has been added to indicate that sites should confirm that appropriate 
temperature conditions were maintained during IMP transit and that the sites are 
responsible for maintaining records of IMP accountability during the study 
(Section 4.3.3).

Immunosuppressive medications have been removed from the prohibited therapy 
section (Section 4.4.2) and added to the permitted therapy section (Section 4.4.1) to 
align with atezolizumab management guidelines in Appendix 9 that permit use of 
immunosuppressive medications for the treatment of corticosteroid-refractory 
immune-mediated adverse events. 

List of identified risks for atezolizumab have been revised to include severe 
cutaneous adverse reactions (Section 5.1.1).

Text has been added to clarify that hemophagocytic lymphohisiocytosis (HLH) and 
macrophage activation syndrome (MAS) are considered potential risks for 
atezolizumab (Section 5.1.1, Appendix 9).

To address a request by the French National Agency for the Safety of Medicines 
and Health Products (ANSM), HLH and MAS have replaced systemic inflammatory 
response syndrome on the list of atezolizumab-associated adverse events of special 
interest (Section 5.2.3).

Influenza-like illness was removed  from the list of immediately reportable adverse 
events of special interest as enough information regarding such events has been 
collected, in general is infrequently reported, and is a known adverse event of 
atezolizumab (Section 5.2.3).

Text has been added to clarify that adverse events associated with special 
situations that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.12).

Text has been added to indicate that the Informed Consent Form will instruct female 
patients to inform the investigator if they become pregnant (Section 5.4.3.1).

The name of a Roche policy on data sharing has been corrected (Section 9.5).

Appendix 5 was revised to indicate that caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or 
life-threatening skin adverse reaction while receiving another immunostimulatory 
anti-cancer agent.

To address a request by the French ANSM, the management guidelines for 
infusion-related reactions associated with atezolizumab have been updated to 


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include guidelines for cytokine-release syndrome (CRS) to align with the definition, 
grading, and management of CRS reflected in a recent publication (Lee et al. 2019) 
(Appendix 9). 

Guidelines for management of atezolizumab-associated dermatological adverse 
events have been revised to provide guidance on severe cutaneous adverse 
reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis 
(Appendix 9).

The management guidelines for Grade 4 myositis have been removed because 
Version 4.0 of the Common Terminology Criteria for Adverse Events does not have 
a Grade 4 category for myositis (Appendix 9).

To address a request by the French ANSM, the management guidelines for HLH 
and MAS have been modified to indicate that HLH should be considered when CRS 
presentation is atypical or prolonged, to add anticytokine therapy as an option for 
treating HLH or MAS, and to suggest that published guidelines should be followed 
for HLH or MAS events that do not respond to treatment within 24 hours 
(Appendix 9).
Additional clarifications have been included, and minor changes have been made to 
improve clarity and consistency.  Substantive new information appears in italics.  This 
amendment represents cumulative changes to the original protocol.


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PROTOCOL AMENDMENT, VERSION 6.0: SUMMARY OF CHANGES
Section 1.2: Background on Atezolizumab
[…]
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma.
Section 1.3: Study Rationale and Benefit-Risk Assessment
[…]
This study will enroll patients with NSCLC.  Given the relatively poor prognosis and 
limited treatment options for these patients, this population is considered appropriate for 
trials of novel therapeutic candidates.  The benefitrisk ratio for atezolizumab is expected 
to be acceptable in this setting.
In the setting of the COVID-19 pandemic, patients with comorbidities, including those 
with cancer, are considered a more vulnerable population, with the potential for more 
severe clinical outcomes from COVID-19.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of COVID-19.
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses. In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of acute 
(as opposed to chronic) viral infection with lymphocytic choriomeningitis virus (Clone 
13) (85).  However, there are insufficient and inconsistent clinical data to assess if 
outcome from COVID-19 is altered by cancer immunotherapy.
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-
(86).  While it is not known, there may be a potential for an increased risk of an enhanced 
inflammatory response if a patient develops acute SARS-CoV-2 infection while receiving 
atezolizumab.  At this time, there is insufficient evidence for causal association between 
atezolizumab and an increased risk of severe outcomes from COVID-19.
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for COVID-19related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms.


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Section 4.3.3: Investigational Medicinal Product Accountability
[…]  The study site is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each patient, and disposition or return of unused IMP, 
thus enabling reconciliation of all IMP received, and for ensuring that patients are 
provided with doses specified by the protocol.
The study site should follow all instructions included with each shipment of IMP.  […]  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and authorized 
staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
[…]
Refer to the pharmacy manual and/or the atezolizumab Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability. 
Section 4.4.1: Permitted Therapy
[…]

Systemic corticosteroids, immunosuppressive medications, and tumor necrosis 
factor−α inhibitors may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab, but may be administered at the discretion of the 
treating physician after consultation with the Medical Monitor (see Exclusion Criterion 
21 [Section 4.1.2] and Prohibited Therapy [Section 4.4.2]). […]
Section 4.4.2: Prohibited Therapy 
[…]
With the exception of autoimmune disease patients, patients should not receive 
immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide.  These agents could potentially alter the 
activity and the safety of atezolizumab.  
Systemic corticosteroids, immunosuppressive medications, and anti−TNF-α agents may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab, but 


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may be administered at the discretion of the treating physician after consultation with the 
Medical Monitor.  
Section 5.1: Safety Plan
[…]
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN-(86).  If a patient develops suspected CRS during 
the study, a differential diagnosis should include COVID-19, which should be confirmed 
or refuted through assessment of exposure history, appropriate laboratory testing, and 
clinical or radiologic evaluations per investigator judgment.  If a diagnosis of COVID-19 
is confirmed, the disease should be managed as per local or institutional guidelines.
Section 5.1.1: Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following: IRRs and 
immune-related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, and myositis, and severe cutaneous adverse reactions. 
Immune-related reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome
(MAS), which are considered to be potential risks for atezolizumab. […]
Section 5.2.3: Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor)
[…]

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS influenza like illness, and systemic inflammatory 
response syndrome
[…]
Section 5.3.5.12: Cases of Overdose or Medication Error
[…] If the associated adverse event fulfills seriousness criteria or qualifies as an adverse 
event of special interest, the event should be reported to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Section 5.4.2). […]


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Section 5.4.3.1: Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the last dose of atezolizumab or within 6 months after the last dose 
of single agent chemotherapy.  […]
Section 9.5: Dissemination of Data and Protection of Trade Secrets
[…] For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
DataStudy Information at the following website:
[…]
Section 10: References
[…]
85.
Frebel H, Nindl V, Schuepbach RA, et al. Programmed death 1 protects from fatal 
circulatory failure during systemic virus infection of mice. J Exp Med 
2012;209:248599.
86.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a 
key role for monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
[…]
Appendix 5: Preexisting Autoimmune (Chronic Inflammatory) Diseases and 
Immune Deficiencies
[…]
Caution should be used when considering atezolizumab for patients who have previously 
expereinced a servere or life-threatening skin adverse reaction while receiving another 
immunostimulatory anti-cancer agent. […]
Appendix 9: Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
[…]
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with Cycle 1 of atezolizumab may receive premedication with 
antihistamines or, anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs 
because of its potential for causing agranulocytosis.


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IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab.  These reactions, which are thought to be due to release of 
cytokines and/or other chemical mediators, occur within 24 hours of atezolizumab 
administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported with 
immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and Feldman 
2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated
Gguidelines for medical management of IRRs and CRSduring Cycle 1 are provided in
Table 7.  For subsequent cycles, IRRs should be managed according to institutional 
guidelines.
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a 
patient develops suspected CRS during the study, a differential diagnosis should include 
COVID-19, which should be confirmed or refuted through assessment of exposure 
history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines.


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


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


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Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCT American Society for Transplantation and Cellular Therapy; 
BiPAP bi-level positive airway pressure; CAR chimeric antigen receptor; 
CPAP continuous positive airway pressure; CRS cytokine-release syndrome; 
CTCAE Common Terminology Criteria for Adverse Events; eCRF electronic 
Case Report Form; HLH = hemophagocytic lymphohistiocytosis; ICU intensive 
care unit; IRR = infusion-related reaction; MAS = macrophage activation 
syndrome; NCCN National Cancer Comprehensive Network; NCI National 
Cancer Institute.
Note:  These management guidelines have been adapted from NCCN guidelines 
for management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus 
grading for CRS.  NCI CTCAE v4.0 should be used when reporting severity of 
IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event 
eCRF.  Organ toxicities associated with CRS should not influence overall CRS 
grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In 
patients who develop CRS and then receive anti-pyretic, anti-cytokine, or 
corticosteroid therapy, fever is no longer required when subsequently 
determining event severity (grade).  In this case, the grade is driven by the 
presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or 
dyspnea, additional treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as 
oxygen delivered at 6 L/min.
e Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the 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.  For 
subsequent infusions, administer oral premedication with antihistamines, anti-
pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be 
considered after consulting the Medical Monitor and considering the 
benefitrisk ratio.
f Refer to Riegler et al. (2019).


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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, IV fluids).

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 medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen, IV fluids).

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 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
[…] Although uncommon, cases of severe cutaneous adverse reactions such as 
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with 
atezolizumab. […] 


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Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if event 
does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist for evaluation and, if indicated, biopsy.

Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:
Withhold atezolizumab for suspected Stevens-Johnson syndrome 
or toxic epidermal necrolysis.
Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist or urologist as relevant) for 
evaluation and, if indicated, biopsy.
Follow the applicable treatment and management guidelines above.
If Stevens-Johnson syndrome or toxic epidermal necrolysis, 
permanently discontinue atezolizumab.
[…]


Atezolizumab—F. Hoffmann-La Roche Ltd
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IMMUNE-MEDIATED MYOSITIS
[…]
Table 13
Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-
mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune
mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone, or higher dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
[…]
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION
SYNDROME
Immune-mediated reactions may involve any organ system and may lead to HLH and 
MAS, which are considered to be potential risks for atezolizumab.  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.


Atezolizumab—F. Hoffmann-La Roche Ltd
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[…]
Table 14
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS
!
Permanently discontinue atezolizumab and contact Medical 
Monitor.
!
Consider patient referral to hematologist.
!
Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.
! Consider initiation of IV corticosteroids, and/or an 
immunosuppressive agent, and/or anti-cytokine therapy.
! If event does not respond to treatment within 24 hours, 
contact Medical Monitor and initiate treatment as 
appropriate according to published guidelines (La Rosée 2015; 
Schram and Berliner 2015; La Rosée et al. 2019)If event 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.
HLH % hemophagocytic lymphohistiocytosis; MAS % macrophage activation syndrome.
REFERENCES
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti∀programmed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:502∀4.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am 
Soc Hematol Educ Protram 2015;1:190∀6.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465∀77.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release 
syndrome and neurologic toxicity associated with immune effector cells. Biol Blood 
Marrow Transplant 2019;25:62538.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role 
for monocytes and macrophages. Nat Rev Immunol 2020;20:355∀62.


Atezolizumab—F. Hoffmann-La Roche Ltd
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Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving 
PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT, VERSION 6: RATIONALE ........................................ 3 
PROTOCOL AMENDMENT, VERSION 6.0: SUMMARY OF 
CHANGES.......................................................................................................... 5 
PROTOCOL ACCEPTANCE FORM ...................................................................... 25 
PROTOCOL SYNOPSIS......................................................................................... 26 
1. 
BACKGROUND ............................................................................................... 41 
1.1 
Background on Non-Small Cell Lung Cancer .......................... 41 
1.1.1 
Treatment of NSCLC................................................................. 41 
1.1.1.1 
Stage I–III NSCLC ..................................................................... 41 
1.1.1.2 
Metastatic NSCLC ..................................................................... 43 
1.2 
Background on Atezolizumab ................................................... 47 
1.2.1 
Clinical Trials in NSCLC............................................................ 48 
1.2.1.1 
FIR.............................................................................................. 48 
1.2.1.2 
BIRCH ........................................................................................ 48 
1.2.1.3 
POPLAR .................................................................................... 49 
1.2.1.4 
OAK............................................................................................ 50 
1.2.2 
Safety ......................................................................................... 50 
1.2.2.1 
Single-Agent Clinical Safety in Patients with Non-
Small Cell Lung Cancer in Study PCD4989g .......................... 51 
1.2.2.2 
Single-Agent Clinical Safety in Patients with Non-
Small Cell Lung Cancer in Study GO28753 
(POPLAR) .................................................................................. 52 
1.2.2.3 
Single-Agent Clinical Safety in Patients with Non-
Small Cell Lung Cancer in Study GO28754 
(BIRCH) ..................................................................................... 53 
1.3 
Study Rationale and Benefit-Risk Assessment ....................... 54 
2. 
OBJECTIVES AND ENDPOINTS ................................................................... 57 
3. 
STUDY DESIGN .............................................................................................. 60 
3.1 
Description of the Study ............................................................ 60 
3.2 
End of Study and Length of Study............................................ 62 
3.3 
Rationale for Study Design ....................................................... 63 


 
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3.3.1 
Rationale for Patient Population and Analysis 
Groups ....................................................................................... 63 
3.3.2 
Rationale for an Open-Label Single-Arm Design .................... 63 
3.3.3 
Rationale for Atezolizumab Dose and Schedule ..................... 63 
3.3.4 
Rationale for Biomarker Assessments ..................................... 64 
3.3.5 
Rationale for Patient-Reported Outcome 
Assessments ............................................................................. 65 
3.3.6 
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment Beyond Initial 
Progression................................................................................ 65 
4. 
MATERIALS AND METHODS ........................................................................ 66 
4.1 
Patients ...................................................................................... 66 
4.1.1 
Inclusion Criteria........................................................................ 66 
4.1.2 
Exclusion Criteria ...................................................................... 69 
4.2 
Method of Treatment Assignment and Blinding ...................... 71 
4.3 
Study Treatment ........................................................................ 71 
4.3.1 
Formulation, Packaging, and Handling .................................... 71 
4.3.2 
Dosage, Administration, and Compliance................................ 71 
4.3.3 
Investigational Medicinal Product Accountability..................... 73 
4.3.4 
Continued Access to Atezolizumab.......................................... 74 
4.4 
Concomitant Therapy ................................................................ 74 
4.4.1 
Permitted Therapy ..................................................................... 74 
4.4.2 
Prohibited Therapy .................................................................... 75 
4.5 
Study Assessments................................................................... 76 
4.5.1 
Informed Consent Forms and Screening Log.......................... 76 
4.5.2 
Medical History and Demographic Data .................................. 76 
4.5.3 
Physical Examinations .............................................................. 77 
4.5.4 
Vital Signs .................................................................................. 77 
4.5.5 
Tumor and Response Evaluations ........................................... 77 
4.5.6 
Ongoing Tumor Assessments .................................................. 79 
4.5.7 
Laboratory, Biomarker, and Other Biological 
Samples ..................................................................................... 79 
4.5.8 
Electrocardiograms ................................................................... 81 
4.5.9 
Patient-Reported Outcomes ..................................................... 82 


 
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4.5.10 
Optional Samples for Research Biosample 
Repository.................................................................................. 82 
4.5.10.1 
TAIL Substudy: Stool Sample Collection for the 
Research Biosample Repository .............................................. 82 
4.5.10.2 
Overview of the Research Biosample Repository ................... 83 
4.5.10.3 
Approval by the Institutional Review Board or 
Ethics Committee ...................................................................... 83 
4.5.10.4 
Sample Collection ..................................................................... 83 
4.5.10.5 
Confidentiality ............................................................................ 84 
4.5.10.6 
Consent to Participate in the Research 
Biosample Repository ............................................................... 84 
4.5.10.7 
Withdrawal from the Research Biosample 
Repository.................................................................................. 85 
4.5.10.8 
Monitoring and Oversight.......................................................... 85 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation .......................................................................... 85 
4.6.1 
Patient Discontinuation ............................................................. 85 
4.6.2 
Study Treatment Discontinuation ............................................. 86 
4.6.3 
Study and Site Discontinuation................................................. 88 
5. 
ASSESSMENT OF SAFETY........................................................................... 88 
5.1 
Safety Plan ................................................................................ 88 
5.1.1 
Risks Associated with Atezolizumab ........................................ 89 
5.1.2 
Management of Patients Who Experience 
Specific Adverse Events ........................................................... 89 
5.2 
Safety Parameters and Definitions........................................... 90 
5.2.1 
Adverse Events ......................................................................... 90 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .......................................................................... 91 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)....................................................... 92 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .................................................. 93 
5.3.1 
Adverse Event Reporting Period .............................................. 93 
5.3.2 
Eliciting Adverse Event Information ......................................... 93 
5.3.3 
Assessment of Severity of Adverse Events ............................. 93 
5.3.4 
Assessment of Causality of Adverse Events ........................... 94 


 
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5.3.5 
Procedures for Recording Adverse Events.............................. 95 
5.3.5.1 
Infusion-Related Reactions....................................................... 95 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................... 95 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events ........................................................................................ 96 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 96 
5.3.5.5 
Abnormal Laboratory Values .................................................... 96 
5.3.5.6 
Abnormal Vital Sign Values ...................................................... 97 
5.3.5.7 
Abnormal Liver Function Tests ................................................. 98 
5.3.5.8 
Deaths........................................................................................ 98 
5.3.5.9 
Preexisting Medical Conditions ................................................ 99 
5.3.5.10 
Lack of Efficacy or Worsening of Locally 
Advanced or Metastatic Non-Small Cell Lung 
Cancer........................................................................................ 99 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................... 99 
5.3.5.12 
Cases of Accidental Overdose or Medication 
Error ......................................................................................... 100 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 101 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................... 101 
5.4.1 
Emergency Medical Contacts ................................................. 102 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest .................... 102 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ................... 102 
5.4.2.2 
Events That Occur after Study Drug Initiation ....................... 102 
5.4.3 
Reporting Requirements for Pregnancies.............................. 103 
5.4.3.1 
Pregnancies in Female Patients............................................. 103 
5.4.3.2 
Abortions .................................................................................. 103 
5.4.3.3 
Congenital Anomalies/Birth Defects....................................... 103 
5.5 
Follow-Up of Patients after Adverse Events .......................... 104 
5.5.1 
Investigator Follow-Up ............................................................ 104 
5.5.2 
Sponsor Follow-Up.................................................................. 104 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period ........................................................... 104 


 
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5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees .................................................................. 104 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ...................... 105 
6.1 
Determination of Sample Size ................................................ 105 
6.2 
Analysis of the Conduct of the Study ..................................... 106 
6.3 
Summaries of Treatment Group ............................................. 106 
6.4 
Primary Endpoint Analysis ...................................................... 106 
6.5 
Main Secondary Endpoint Analyses ...................................... 106 
6.5.1 
Landmark Analysis .................................................................. 106 
6.6 
Other Secondary Endpoint Analyses ..................................... 107 
6.6.1 
Other Safety Analyses ............................................................ 107 
6.6.2 
Other Efficacy Analyses .......................................................... 107 
6.6.3 
Exploratory Efficacy Analysis ................................................. 108 
6.7 
Interim Analyses ...................................................................... 109 
7. 
DATA COLLECTION AND MANAGEMENT ................................................ 109 
7.1 
Data Quality Assurance .......................................................... 109 
7.2 
Electronic Case Report Forms ............................................... 109 
7.3 
Source Data Documentation................................................... 110 
7.4 
Use of Computerized Systems ............................................... 110 
7.5 
Retention of Records .............................................................. 110 
8. 
ETHICAL CONSIDERATIONS ..................................................................... 111 
8.1 
Compliance with Laws and Regulations ................................ 111 
8.2 
Informed Consent .................................................................... 111 
8.3 
Institutional Review Board or Ethics Committee ................... 112 
8.4 
Confidentiality .......................................................................... 113 
8.5 
Financial Disclosure ................................................................ 113 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ........................................................................................ 113 
9.1 
Study Documentation .............................................................. 113 
9.2 
Protocol Deviations ................................................................. 114 
9.3 
Site Inspections ....................................................................... 114 
9.4 
Administrative Structure .......................................................... 114 


 
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9.5 
Dissemination of Data and Protection of Trade 
Secrets ..................................................................................... 114 
9.6 
Protocol Amendments............................................................. 115 
10. REFERENCES .............................................................................................. 116 
 
 
LIST OF TABLES 
Table 1 
Summary of Key Surgical Outcome Trials in NSCLC................... 42 
Table 2 
Summary of Radiotherapy Trials in Patients With Medically 
Inoperable Stage I–III NSCLC........................................................ 43 
Table 3 
Summary of Trials Assessing First- and Second-line 
Treatment of Metastatic Non-Squamous NSCLC Patients 
Lacking an Actionable Mutation ..................................................... 44 
Table 4 
Summary of Trials Assessing First- and Second-line 
Treatment of Metastatic Squamous NSCLC Patients Lacking 
an Actionable Mutation ................................................................... 45 
Table 5 
Summary of Clinical Trials Assessing ALK-targeted Therapy 
in Patients with NSCLC Carrying ALK-positive Mutations............ 46 
Table 6 
Nivolumab and Pembrolizumab Immunotherapy in Advanced 
NSCLC ............................................................................................ 47 
Table 7 
Adverse Events Reported in ≥ 10% of Patients in Study 
PCD4989g ....................................................................................... 52 
Table 8 
Treatment-Related Adverse Events Reported in at Least 
10% of Patients in Either Treatment Arm in Study GO28753 
(POPLAR) ....................................................................................... 53 
Table 9 
Objectives and Corresponding Endpoints ..................................... 57 
Table 10 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE .................................................. 94 
Table 11 
Causal Attribution Guidance .......................................................... 95 
Table 12 
Adverse Event Incidence and Corresponding 95% 
Confidence Intervals ..................................................................... 106 
 
 
LIST OF FIGURES 
Figure 1 
OS Hazard Ratios Over Time and Updated Median OS .............. 49 
Figure 2 
Study Schema................................................................................. 61 
Figure 3 
Conditions for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size ............................................. 87 


 
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LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ............................................................ 125 
Appendix 2 
Response Evaluation Criteria in Solid Tumors, Version 1.1: 
Excerpt from Original Publication................................................. 130 
Appendix 3 
Modified Response Evaluation Criteria in Solid Tumors ............ 142 
Appendix 4 
EORTC QLQ-LC13 and EQ-5D-5L.............................................. 149 
Appendix 5 
Preexisting Autoimmune (Chronic Inflammatory) Diseases 
and Immune Deficiencies ............................................................. 152 
Appendix 6 
Anaphylaxis Precautions .............................................................. 154 
Appendix 7 
Eastern Cooperative Oncology Group Performance Status 
Scale.............................................................................................. 155 
Appendix 8 
American Joint Committee on Cancer  Non-Small Cell Lung 
Cancer Staging, 7th Edition........................................................... 156 
Appendix 9 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab................................................................................. 157 
Appendix 10 
Stool Sample Collection for the Roche Research BioSample 
Repository in Association With Protocol MO39171 .................... 184 


Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE III/IV, SINGLE ARM, MULTICENTER 
STUDY OF ATEZOLIZUMAB (TECENTRIQ) TO 
INVESTIGATE LONG-TERM SAFETY AND 
EFFICACY IN PREVIOUSLY-TREATED PATIENTS 
WITH LOCALLY ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER (TAIL)
PROTOCOL NUMBER:
MO39171
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-001409-34
IND NUMBER:
NCT NUMBER:
Not applicable
NCT03285763
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor.  


Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE III/IV, SINGLE ARM, MULTICENTER STUDY OF 
ATEZOLIZUMAB (TECENTRIQ) TO INVESTIGATE LONG-TERM 
SAFETY AND EFFICACY IN PREVIOUSLY-TREATED PATIENTS 
WITH LOCALLY ADVANCED OR METASTATIC NON-SMALL 
CELL LUNG CANCER (TAIL)
PROTOCOL NUMBER:
MO39171
VERSION NUMBER:
6
EUDRACT NUMBER:
2017-001409-34
IND NUMBER:
NCT NUMBER:
Not applicable
NCT03285763
TEST PRODUCT:
Atezolizumab (RO5541267)
PHASE:
Phase III/IV
INDICATION:
Non-small cell lung cancer (NSCLC)
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the long-term safety and efficacy of atezolizumab in patients with locally 
advanced or metastatic NSCLC who have progressed following standard systemic 
chemotherapy (including if given in combination with anti-PD-1 therapy, after anti-PD-1 as 
monotherapy, or after tyrosine kinase inhibitor [TKI] therapy).  Patients with a previously 
detected sensitizing EGFR mutation or ALK fusion oncogene must have received targeted 
therapy (TKI) followed by at least one line of standard systemic chemotherapy prior to receiving 
atezolizumab.  Overall, patients should not have received more than two lines of standard 
systemic chemotherapy.  Patients will also be eligible if they discontinued first-line or second-
line therapy due to intolerance.
Table 1 Objectives and Corresponding Endpoints
Primary Objective
Corresponding Endpoints
To evaluate the long-term safety of 
atezolizumab in previously treated 
patients with advanced NSCLC
Incidence of serious adverse events (SAEs) related to 
atezolizumab treatment

Incidence of immune-related adverse events (irAEs) 
related to atezolizumab treatment
Main Secondary Objective
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab in previously treated 
patients with advanced NSCLC
Overall survival (OS) rate at 2 years, defined as the 
proportion of patients remaining alive 2 years after 
initiation of study treatment


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Other Secondary Objectives
Corresponding Endpoints
To further evaluate the efficacy of 
atezolizumab in previously treated 
patients with advanced NSCLC
OS, defined as the time from initiation of study 
treatment to death from any cause
Progression-free survival (PFS), defined as the time 
from initiation of study treatment to the first 
occurrence of disease progression or death from any 
cause, whichever occurs first.  PFS will be calculated 
based on disease status evaluated by the investigator 
according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1) and also by 
disease status evaluated by the investigator according 
to modified RECIST
OS rate at 3 years, defined as the proportion of 
patients remaining alive 3 years after initiation of 
study treatment
Objective response rate (ORR), defined as the 
percentage of patients who attain complete response 
(CR) or partial response (PR) according to 
RECIST v1.1 and also by disease status evaluated by 
the investigator according to modified RECIST
Duration of response (DOR), defined as the time from 
initial response to disease progression or death 
among patients who have experienced a CR or PR 
(unconfirmed) during the study.  Duration of response 
will be calculated based on disease status evaluated 
by the investigator according to RECIST v1.1 and also 
by disease status evaluated by the investigator 
according to modified RECIST


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Exploratory Objectives
Corresponding Endpoints
To further evaluate the long-term safety 
and efficacy of atezolizumab in 
previously treated patients with 
advanced NSCLC
Safety and efficacy of atezolizumab in subgroups of 
the study population differentiated according to: 
Presence of CNS metastases at baseline (yes vs. 
no)
ECOG performance status (0 or 1 vs. 2)
Histologic subtype (squamous vs. non-squamous)
History of or current autoimmune disease 
(yes vs. no)
Prior anticancer treatment 
Progression-free survival from start of new anti-cancer 
therapy, defined as the time from initiation of new anti-
cancer therapy to objective tumor progression on 
next-line treatment or death from any cause
Objective response rate from start of new anti-cancer 
therapy, defined as the percentage of patients who 
attain complete response (CR) or partial response 
(PR)
Progression-free survival 2 (PFS2), defined as the 
time from initiation of study treatment to objective 
tumor progression on next-line treatment or death 
from any cause
Exploratory Biomarker Objectives
Corresponding Endpoints
To assess the role of PD-L1 and other 
biomarkers in the progression and 
fundamental biology of advanced 
NSCLC 
To evaluate PD-L1 and other 
biomarkers (e.g., cancer-related 
genes) as prognostic biomarkers
Safety and efficacy of atezolizumab in subgroups of 
the study population differentiated according to:
Expression of PD-L1 protein in tumor tissue
Presence/absence of other biomarkers in tumor 
tissue
Correlations between PD-L1 expression and other 
biomarkers
Patient-Reported Outcome 
Objectives
Corresponding Endpoint
To evaluate health status utility and 
HR QoL of atezolizumab in previously 
treated patients with advanced 
NSCLC
EQ-5D-5L index-based and VAS scores
EORTC QLQ-LC13 score
EORTC QLQ-LC13, European Organisation for Research and Treatment of Cancer Quality-of-
Life Questionnaire—Supplemental Lung Cancer Module; EQ-5D, EuroQol 5-Dimension 
Questionnaire; HR QoL, health-related quality of life; VAS, visual analog scale.
Study Design
Description of Study
Study MO39171 is a phase III/IV, single-arm, multicenter study of the long-term safety and 
efficacy of atezolizumab treatment in patients with Stage IIIb or Stage IV NSCLC who have 
progressed following standard systemic chemotherapy (including if given in combination with 




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of atezolizumab-related SAEs and atezolizumab-related irAEs.  An irAE is defined as any 
adverse event of special interest (AESI) associated with systemic corticosteroid use within 
30 days of the onset date.  All-causality AEs, all-causality SAEs, AEs and SAEs leading to 
atezolizumab interruption or discontinuation, and AESIs will also be reported, as well as causes 
of death, vital signs, physical findings and clinical laboratory results.  
Secondary objectives will assess the efficacy of atezolizumab.  The main efficacy objective will 
be to evaluate the OS rate 2 years after the first dose of atezolizumab.  Other efficacy 
objectives will include evaluation of OS, OS rate at 3 years, PFS, ORR, and DOR (additional 
efficacy assessments may occur on an exploratory basis).  All antitumor response assessments 
will be based on RECIST v1.1 and modified RECIST.
Exploratory objectives will include evaluation of the safety and efficacy of atezolizumab in 
patient subgroups differentiated by: presence or absence of CNS metastases at baseline; 
ECOG performance status; histological subtype; history of or current autoimmune disease; and 
prior anticancer treatment.  Other exploratory and PRO outcomes will include objective 
response rate and progression-free survival (PFS2) following start of new anticancer therapy, 
HR QoL as measured on the EORTC LQ-LC13, health utility score as measured on the EQ-5D-
5L instrument, and expression of PD-L1 protein and cancer-related genes in tumor samples 
obtained before treatment. Finally, exploratory biomarkers may be assessed in tissue to assist 
in the potential development of new diagnostic assays and to assess biomarkers in terms of 
prognosis, response/resistance and safety.
Following discontinuation of study treatment, safety assessments will be conducted for 30 days 
after the last study drug administration or until initiation of other anti-cancer therapy (whichever 
occurs first).  Thereafter, follow-up information on disease progression (unless this has already 
occurred), anti-cancer therapy and survival will be collected via telephone contact, patient 
medical records, and/or clinic visits approximately every 3 months until death, loss to follow-up, 
end of study (30 months after last patient in), patient withdrawal or study termination by the 
Sponsor, whichever occurs first.  In addition, irAEs, SAEs and AESIs will be collected as 
described in Section 5.4.2.
In those patients for whom tumor assessments are performed as part of local clinical practice 
and are available for report after PD or atezolizumab treatment discontinuation, overall 
response rate (ORR) and progression-free survival (PFS) will be assessed from the first date of 
the new anticancer therapy to the end of the study.  These data will be used in an exploratory 
fashion to assess whether prior atezolizumab treatment positively influences response to 
subsequent anticancer therapies.
An Independent Data Monitoring Committee (iDMC) will be established to review all AEs, irAEs, 
SAEs, AESIs and other cumulative safety data.
A Schedule of Assessments for this study is provided in Appendix 1.
Number of Patients
This study will enroll approximately 600 patients with Stage IIIb or Stage IV NSCLC who have 
progressed following standard systemic chemotherapy (including if given in combination with 
anti-PD-1 therapy or after anti-PD-1 as monotherapy).  Patients with a previously detected 
sensitizing EGFR mutation or ALK fusion oncogene must have received targeted therapy 
followed by one line of standard systemic chemotherapy prior to receiving atezolizumab.  
Overall, patients should not have received more than two lines of standard systemic 
chemotherapy.  Patients will also be eligible if they discontinued first-line or second-line therapy 
due to intolerance.  The recruitment of 600 patients is expected to take place over 
approximately 18 months.  Patients who discontinue the study prior to study treatment initiation 
will not be replaced.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
Signed Informed Consent Form
2.
Age ≥ 18 years


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3.
Able to comply with the study protocol, in the investigator’s judgment
4.
Histologically or cytologically documented Stage IIIb or Stage IV NSCLC that has 
progressed following standard systemic chemotherapy (including if given in combination 
with anti-PD-1 therapy, after anti-PD-1 as monotherapy, or after TKI therapy).  Patients with 
a previously detected sensitizing EGFR mutation or ALK fusion oncogene must have 
received targeted therapy (TKI), followed by at least one line of standard systemic 
chemotherapy, prior to receiving atezolizumab.  Overall, patients should not have received 
more than two lines of standard systemic chemotherapy.  Patients who have discontinued 
first-line or second-line therapy due to intolerance are also eligible
–
Staging must be according to the UICC/AJCC system, 7th edition (Detterbeck et al. 2009) 
(see Appendix 8)
–
Pathological characterization may be conducted on tumor specimens from earlier stage 
disease, but the tumor samples must be sufficient to distinguish squamous or non-
squamous histology
–
Chemotherapy regimens will be counted based on interval disease progression, and not on 
the number of agents or the number of switches in agents (e.g., a first-line or second-line 
therapy that consists of several cycles of a platinum doublet and subsequent maintenance 
therapy that introduces or switches to a new chemotherapy agent without interval disease 
progression will all be considered one chemotherapy regimen)
–
Patients with a previously-detected sensitizing EGFR mutation must have experienced 
disease progression (during or after treatment) on an EGFR TKI (erlotinib, gefitinib, 
osimertinib, etc.)  
–
Patients with a previously detected ALK fusion oncogene must have experienced disease 
progression (during or after treatment) with crizotinib, alectinib, or another ALK inhibitor
–
Prior radiation therapy is allowed, provided that the patient has recovered from any toxic 
effects thereof.  Combined radiation/chemotherapy treatment constitutes a single regimen
–
Combined radiation/chemotherapy treatment (chemoradiation) counts as one prior 
chemotherapy regimen if < 6 months have elapsed between the last dose and the date of 
recurrence
–
Adjuvant/neoadjuvant chemotherapy is not counted as a line of treatment
–
Debulking surgery and anticancer agents used for pleurodesis are not counted as lines of 
therapy
5.
The last dose of prior systemic anticancer therapy must have been administered ≥21 days 
prior to study treatment initiation
6.
The last dose of prior anti-PD-1 therapy must have been administered
–
Nivolumab must have been discontinued ≥ 14 days and pembrolizumab ≥21 days prior to 
study treatment initiation, providing that these treatments were not administered in a clinical 
trial setting
7.
Measurable disease, as defined by Response Evaluation Criteria for Solid Tumors, 
Version 1.1 (RECIST v1.1)
8.
Patients with asymptomatic CNS metastases (treated or untreated), as determined by CT 
or MRI evaluation during screening and prior radiographic evaluation, are eligible
9.
ECOG performance status 0, 1, or 2 [Appendix 7]
10.
Life expectancy ≥ 12 weeks
11.
Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 2 weeks prior to the first study treatment:
–
Absolute neutrophil count ≥1500 cells/µL (without granulocyte colony-stimulating factor 
support within 2 weeks prior to the first study treatment)
–
White blood cell count > 2500/µL
–
Lymphocyte count ≥500/µL
–
Platelet count ≥100,000/µL (without transfusion within 2 weeks prior to the first study 
treatment)


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–
Hemoglobin ≥9.0 g/dL (patients may be transfused or receive erythropoietic treatment to 
meet this criterion)
–
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase ≤
2.5 times the upper limit of normal (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’s Syndrome who have serum 
bilirubin level ≤3 × ULN may be enrolled.
–
Calculated creatinine clearance ≥15 mL/min (Cockcroft-Gault formula)
–
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 
×ULN.  This applies only to patients who are not receiving therapeutic anticoagulation 
agents
–
Patients receiving therapeutic anticoagulation agents must be on a stable dose
–
HIV-positive patients are allowed, so long as they are on stable anti-retroviral therapy, have 
a CD4 count ≥200 cells/µL, and have an undetectable viral load at the time of screening
12.
For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in 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 postmenarchal, 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, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices
–
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception
13.
Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute 
toxicities from previous therapy, excluding alopecia and toxicities related to prior anti-PD-1-
therapy
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1.
Symptomatic CNS metastases 
2.
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 study treatment initiation
3.
Leptomeningeal disease
4.
Uncontrolled pericardial effusion or ascites requiring recurrent drainage procedures
5.
Pregnant or lactating, or intending to become pregnant during the study
–
Women who are not postmenopausal (postmenopausal defined as ≥12 months of non-
drug-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result within 2 weeks prior to initiation of study drug


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6.
Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol, including significant liver disease (such as cirrhosis, uncontrolled major seizure 
disorder, or superior vena cava syndrome)
7.
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
≥Class III, myocardial infarction within 3 months, unstable arrhythmias, or unstable angina
–
Patients with known coronary artery disease 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
8.
Significant renal disorder requiring dialysis or indication for renal transplant
9.
Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 28 days prior to study treatment initiation
10. Major surgical procedure within 4 weeks prior to study treatment initiation or anticipation of 
need for a major surgical procedure during the course of the study other than for diagnosis
11. Inability to understand the local language(s) for which the EORTC QLQ-LC13 and 
EuroQol EQ-5D-5L questionnaires are available (see Appendix 4 for English versions)
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation
14. History of autoimmune disease (Appendix 5) are allowed if controlled and on stable 
treatment (i.e., same treatment, same dose) for the last 12 weeks, with the exception of:
–
Patients taking concurrent abatacept or belatacept treatment, unless therapy has been 
withdrawn for > 8 weeks
–
Patients with a history of serious or life threatening immune-related events
–
No more than 1 concomitant autoimmune disease at the time of study entry is allowed 
unless one of them is: 
Autoimmune-mediated hypothyroidism on a stable dose of thyroid replacement 
hormone 
Controlled Type I diabetes mellitus on a stable dose of insulin regimen
A medical history of such entities as atopic disease or childhood arthralgias, 
where the clinical suspicion of autoimmune disease is low.  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)
15. Prior allogeneic stem cell or solid organ transplantation
16. History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography (CT) scan
–
History of radiation pneumonitis in the radiation field (fibrosis) is permitted
17. Active tuberculosis
–
In patients who have a potentially high likelihood of latent tuberculosis (e.g., recent contact 
with an infectious carrier, residence in a locale with high TB burden), absence of 
Mycobacterium tuberculosis infection must be confirmed before enrollment according to 
local practice standards
18. Administration of a live, attenuated vaccine within 4 weeks prior to study treatment initiation
–
Influenza vaccination should be given during influenza season only (e.g., approximately 
October to March in the Northern Hemisphere). 
–
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks 
prior to study treatment initiation or at any time during the study


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19. Prior treatment with CD137 agonists or immune checkpoint blockade therapies other than 
anti-PD-1 therapy, including anti−PD-L1 therapeutic antibodies
20. Treatment with systemic immunostimulatory agents (including, but not limited to, interferons 
or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to 
initiation of study treatment
–
Prior cancer vaccines and cellular immunotherapy are permitted
21. Specifically for patients without autoimmune disease: 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 study 
treatment initiation, or anticipated requirement for systemic immunosuppressive 
medications during the trial
–
For patients with CNS metastases, use of prednisone at a stable dose (or dose equivalent) 
of ≤ 20 mg/day is acceptable 
–
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 and topical steroids for 
cutaneous diseases are allowed
End of Study and Length of Study
The end of study and final analysis will occur when all enrolled patients have either died, 
withdrawn consent, are lost to follow up, or have been followed for 30 months since the last 
study patient is enrolled, 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 4 years.
The primary analysis will occur approximately 6 months after the last patient has been enrolled.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is atezolizumab.
The dose of atezolizumab in this study will be 1200 mg (equivalent to an average body weight-
based dose of 15 mg/kg) administered by intravenous infusion every 3 weeks (21 [± 5] 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.  For detailed 
information on drug preparation, storage and administration, refer to the Atezolizumab 
Investigator’s Brochure.
The initial dose of atezolizumab will be administered over 60 (± 15) minutes.  If the first infusion 
is tolerated without infusion-associated AEs, 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 the first infusion, the patient’s vital signs (heart rate, 
respiratory rate, blood pressures, and temperature) should be determined within 60 minutes 
before, during (every 15 [± 5] minutes) if clinically indicated, and 30 (± 10) minutes after the 
infusion.  For subsequent infusions, vital signs will be collected within 60 minutes before the 
infusion, during the infusion if clinically indicated, and 30 minutes (± 10 minutes) after the 
infusion if clinically indicated or patient experienced symptoms during previous infusions.  
Patients will be informed about the possibility of delayed post-infusion symptoms and instructed 
to contact their study physician if they develop such symptoms.
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 (Grade 1) National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) infusion-related event, 
the infusion rate should be reduced to half the rate being given at the time of event 


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onset.  Once the event has resolved, the investigator should wait for 30 minutes while 
delivering the infusion at the reduced rate.  If tolerated, the infusion rate may then be 
increased to the original rate

In the event that a patient experiences a moderate infusion-related event (NCI CTCAE 
Grade 2) or flushing, fever, or throat pain, the patient should have his or her infusion 
immediately interrupted and should receive aggressive symptomatic treatment.  The 
infusion should be restarted only after the symptoms have adequately resolved to 
baseline grade.  The infusion rate at restart should be half of the infusion rate that was in 
progress at the time of the onset of the infusion-related event

For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), the 
infusion should be stopped immediately, and aggressive resuscitation and supportive 
measures should be initiated.  Patients experiencing severe or life-threatening infusion-
related events will not receive further infusion and will be further managed as clinically 
indicated until the event resolves
For anaphylaxis precautions, see Appendix 6.
Guidelines for dosage modification, treatment interruption or discontinuation, and the 
management of specific adverse events are provided in Section 5.1.2.
Each AE associated with a special situation should be recorded on the Adverse Event eCRF.
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage and 
administration.
Non-Investigational Medicinal Products
Permitted Therapy
Patients are permitted to use the following therapies during the study:

Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine and/or famotidine or another H2 
receptor antagonist, as per standard practice (equivalent medications may be 
substituted per local practice).  Serious infusion-associated events manifested by 
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation or respiratory distress should be managed with supportive therapies as 
clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists; see 
Appendix 6).

Systemic corticosteroids and tumor necrosis factor−α inhibitors may attenuate potential 
beneficial immunologic effects of treatment with atezolizumab, but may be administered 
at the discretion of the treating physician after consultation with the Medical Monitor (see 
Exclusion Criterion 21 [Section 4.1.2] and Prohibited Therapy [Section 4.4.2]).  If 
feasible, alternatives to corticosteroids should be considered.  Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician after consultation 
with the Medical Monitor.  The use of inhaled corticosteroids for COPD and 
mineralocorticoids (e.g., fludrocortisone) and low-dose corticosteroids for patients with 
orthostatic hypotension or adrenocortical insufficiency is allowed.  Megestrol
administered as an appetite stimulant is acceptable while the patient is enrolled in the 
study.

Colony-stimulating factors, such as granulocyte colony-stimulating factor and 
erythropoietin, should only be used according to manufacturers’ labels and the ASCO 
and ASCO/ASH guidelines.  

Influenza vaccination should be given during influenza season only (approximately 
October to March in the Northern Hemisphere).  Patients must not receive live, 
attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to study treatment 
initiation or at any time during the study.

Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low molecular weight heparin or warfarin at 
a stable dose level), or other allowed maintenance therapy (see Section 4.1.2) should 
continue their use.


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
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However, herbal therapies not intended for the treatment of cancer may be 
used during the study at the discretion of the investigator.
All concomitant medications should be reported to the investigator and recorded on the
appropriate eCRF.
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health authority-
approved or experimental, unless otherwise specified, is prohibited.  This includes but is not 
limited to the following:

Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, or investigational 
agents (except for maintenance therapies outlined in Section 4.1.1 and 4.1.2)
–
After completion of Cycle 1, certain forms of radiotherapy may be considered for palliation if 
patients are deriving benefit (e.g., treatment of known bone metastases) 
–
Patients experiencing a mixed response requiring local therapy (e.g., surgery, stereotactic 
radiosurgery, radiotherapy, radiofrequency ablation) for control of three or fewer lesions 
may still be eligible to continue study treatment.  Patients who receive local therapy directed 
at a target lesion will no longer be evaluable for radiographic response but will remain 
evaluable for progression. Such cases must be discussed with and approved by the 
Sponsor

Patients should not receive abatacept or belatacept treatment (those who were receiving 
it must stop it > 8 weeks before study entry)
Patients are not allowed to receive immunostimulatory agents, including but not limited to 
interferon (IFN)-α, IFN-γ, or IL-2, during the entire study.  These agents, in combination with 
atezolizumab, could potentially increase the risk for autoimmune conditions.
With the exception of autoimmune disease patients, patients should not receive 
immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine, 
methotrexate, and thalidomide.  These agents could potentially alter the activity and the safety 
of atezolizumab.  
Systemic corticosteroids and anti−TNF-α agents may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab, but may be administered at the discretion of the treating 
physician after consultation with the Medical Monitor.  If feasible, alternatives to these agents 
should be considered.
Patients with CNS metastases are allowed to receive anticonvulsants and steroid treatments if 
the dose of prednisone is stable and ≤ 20 mg/day (or equivalent). 
In addition, all patients (including those who discontinue the study early) should not receive 
other immunostimulatory agents for 10 weeks after the last dose of atezolizumab.
The above list of medications is not necessarily comprehensive.  The investigator should
consult the prescribing information for any concomitant medication and contact the Medical 
Monitor if questions arise regarding medications not listed above.
Statistical Methods
Primary Analysis
All safety analyses will be run on the Safety Analysis set, defined as all enrolled patients who 
had at least one administration of atezolizumab.
The incidence of SAEs related to atezolizumab and the incidence of irAEs related to 
atezolizumab will be summarized by incidence rates and 95% Pearson-Clopper confidence
intervals.
Determination of Sample Size  
No formal sample size calculation linked to hypothesis testing is done for this descriptive study.  
The sample size considerations are based upon estimation precision for the incidence of AEs.  


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With 600 patients, the following 95% CIs (Table 2) could be provided for the different incidences 
of AEs, which is deemed appropriate for the purposes of the study.
Table 2. Adverse Event Incidence and Corresponding 95% Confidence Intervals
Sample Size
AE Incidence 
95% Clopper-Pearson Exact CI
600 patients
1%
1% [0.2% ; 1.8%]
2%
2% [0.9% ; 3.1%]
3%
3% [1.6% ; 4.4%]
5%
5% [3.3% ; 6.7%]
10%
10% [7.6% ; 12.4%]
CI, confidence interval.
Interim Analyses
This study will have no formal interim analyses.  However, regular safety reviews of data will be 
performed by an Independent Data Monitoring Committee (iDMC).  The frequency of these 
reviews will be stated in the iDMC charter.
In addition, to adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim analysis for reporting and publication of safety and efficacy 
results.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
1L
first line 
2L
second line
3L
third line
AE
adverse event
AESI
adverse event of special interest
ALK
echinoderm microtubule-associated 
protein-like 4anaplastic lymphoma kinase
ALT
alanine transaminase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransaminase
ATA
anti-therapeutic antibodies
BCG
bacillus Clamette-Guerin
BOR
best overall response
BSC
best supportive care
Chemo-RT
chemoradiotherapy
CBC
complete blood count
CI
confidence interval
CNS
central nervous system
CR
complete response
CRO
contract research organization
CRS
cytokine-release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
DFS
disease-free survival
DLT
dose-limiting toxicity
DoR
duration of response
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EGFR
epidermal growth factor receptor
eGFR
estimated glomerular filtration rate
EDC
electronic data capture
EMA
European Medicines Agency


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Abbreviation
Definition
EORTC
European Organisation for the Research and 
Treatment of Cancer
Fc
crystallizable fragment
FDA
Food and Drug Administration
FDG
fludeoxyglucose (18F)
FFPE
formalin-fixed, paraffin-embedded
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLH
hemophagocytic lymphohistiocytosis
HR
hazard ratio
HRQoL
health-related quality of life
IC
tumor-infiltrating immune cells
ICH
International Conference on Harmonisation
iDMC
Independent Data Monitoring Committee
IFN
interferon
IgG1
immunoglobulin G, subclass 1
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (application)
irAE
immune-related adverse event
IRB
Institutional Review Board
IRF
independent review facility
ITT
intent-to-treat
IV
intravenous
IxRS
interactive response system
LDH
lactate dehydrogenase
MAS
macrophage activation syndrome
MTD
maximum tolerated dose
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed death-ligand 1
PET
positron emission tomography


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Abbreviation
Definition
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome
PRO-CTCAE
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events
PT
prothrombin time
PTT
partial thromboplastin time
q3w
every 3 weeks
QLQ-LC13
Quality-of-Life Questionnaire – Supplemental Lung 
Cancer Module
QTcF
QT interval corrected using Fridericia’s formula
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SABR
stereotactic ablative radiation therapy
SD
stable disease
SAE
serious adverse event
TC
tumor cells
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON NON-SMALL CELL LUNG CANCER
Nearly 1.6 million people die from lung cancer every year, making it the leading cause of 
cancer-related mortality worldwide (1).  In the European Union, 313,000 new cases of 
lung cancer were diagnosed in 2012 (214,000 men and 99,000 women) and 268,000 
people died of the disease (186,000 men and 82,000 women).  An estimated 158,080 
US citizens were expected to die from lung cancer in 2016, accounting for approximately 
27 percent of all cancer deaths (2).  Active and passive cigarette smoking is the main 
risk factor for lung cancer (2), but the disease can also develop in those who have never 
smoked.  Additional risk factors include age, exposure to radon or other environmental 
carcinogens, radiation therapy to the chest, personal or family history, and air pollution 
(3-6). 
The primary form of lung cancer is non-small cell lung cancer (NSCLC), which occurs in 
approximately 85% of all lung cancer cases (the other forms include small cell lung 
cancer [10%–15%] and lung carcinoid tumor [5%]) (7).  The two most predominant 
histologic types of NSCLC are adenocarcinoma (more than half of cases) and squamous 
cell carcinoma (approximately 25% of cases) (8, 9).  
Survival rates are lower for NSCLC than for other common cancers.  Thus, the expected 
5-year survival rate in NSCLC is 17.1%, compared with 65.2% for colon cancer, 
90.0% for breast cancer and 99.9% for prostate cancer (10).  More than half of patients 
with NSCLC present with distant metastatic disease at the time of initial diagnosis, which 
directly contributes to poor survival prospects.  The overall 5-year survival rate for 
advanced NSCLC is 2% to 4% depending on geographic location (11).  
1.1.1
Treatment of NSCLC
Treatment options for NSCLC are based primarily on the stage of the cancer (5, 12).
1.1.1.1
Stage I–III NSCLC
Surgery provides the best chance of cure for patients with early-stage NSCLC.  Adjuvant 
chemotherapy is of unproven benefit in Stage I NSCLC, but is recommended for Stage II 
and Stage III disease (4, 5).  Key surgical outcome trials in patients with Stage III 
NSCLC are summarized in Table 1.  


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Table 1
Summary of Key Surgical Outcome Trials in NSCLC
Treatment
Study 
Phase
Disease 
Stage
Median 
DFS 
(months)
Median 
OS
(months)
5-year 
DFS
(%)
5-year 
OS 
(%)
Surgery + adjuvant 
vinorelbine + 
cisplatin (13)
III
Ib/II
Not 
reported
94
61
69
Surgery + adjuvant 
cisplatin-based 
chemotherapy (14)
III
I–III
Not 
reported
Not 
reported
39.4
44.5
Surgery + adjuvant 
vinorelbine + 
cisplatin (15)
III
Ib–IIIa
36.3
65.7
Not 
reported
62 (stage Ib)
52 (stage II)
42 (stage IIIa)
Surgery + adjuvant 
paclitaxel + 
carboplatin (16)
III
Ib
89
95
52
60
Neoadjuvant 
cisplatin + 
etoposide + 
radiotherapy + 
surgery (17)
III
IIIa
12.8
23.6
22
27
DFS, disease-free survival; OS, overall survival
The type of surgery performed and survival rates depend on the stage of disease and 
the health of the patient (18).  Typical surgical modalities include sleeve resection, 
segmentectomy, wedge resection, lobectomy, or pneumonectomy (18).  In patients with 
medically inoperable Stage I–III NSCLC, stereotactic ablative radiation therapy, also 
known as stereotactic body radiation therapy, is recommended, with or without 
chemotherapy (Table 2).


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Table 2
Summary of Radiotherapy Trials in Patients With Medically 
Inoperable Stage I–III NSCLC
Treatment
Study 
Phase
ORR 
(%)
3-year 
DFS (%)
Median 
OS 
(months)
Survival Rate (%)
Stage I
SABR (19)
II
Not 
reported
48.3–86
40.6
1-year: 86
2-year: 65–70
3-year: 32–60
5-year: 42–72
Three-dimensional 
conformal radiotherapy 
(20, 21)
I
77
Not 
reported
24.6–38.5
5-year: 15.3
Stage II–III
Chemo-RT (22-24)
I/II, III
52–84
29
14.6–26
1-year: 71
2-year: 34.6–52
3-year: 22.3–40
5-year: 10.0–15.8
Chemo-RT, chemoradiotherapy; DFS, disease-free survival; OS, overall survival; 
SABR, stereotactic ablative radiation therapy
1.1.1.2
Metastatic NSCLC
The treatment landscape in metastatic NSCLC has evolved in recent decades.  Optimal 
treatment decisions are now based on two key features of the underlying disease: 
presence or absence of an actionable mutation; and histological subtype (5).
Patients without actionable mutations
In patients with metastatic non-squamous NSCLC who lack an actionable mutation, 
platinum-doublet chemotherapy with or without bevacizumab is recommended (Table 3) 
(5).  Following relapse, options for second-line therapy include chemotherapy, targeted 
therapies and cancer immunotherapies (Table 3).


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Table 3
Summary of Trials Assessing First- and Second-line Treatment of 
Metastatic Non-Squamous NSCLC Patients Lacking an 
Actionable Mutation
Treatment Regimen
Study 
Phase
Response 
Rate (%)
Median 
PFS 
(months)
Median OS 
(months)
First-line treatment
Bevacizumab + paclitaxel/carboplatin 
(25, 26)
III
33–35
5.6–6.2
12.3–13.4
Bevacizumab + 
pemetrexed/carboplatin (26)
III
34.1
6.0
12.6
Cetuximab a + cisplatin/vinorelbine, 
with cetuximab maintenance (27)
III
Not reported
Not 
reported
12.0 b
Carboplatin/paclitaxel (25)
III
15
4.5
10.3
Cisplatin/docetaxel (28)
III
31.6
5.1ǁ
11.3
Cisplatin/vinorelbine (28)
III
24.5
5.3ǁ
10.1
Cisplatin/paclitaxel (29) c
III
31.8
4.2
8.1
Cisplatin/gemcitabine (29, 30) c
III
36.6
4.7
8.9–10.4
Cisplatin/pemetrexed (30)
III
Not reported
5.3
11.8
Second-line treatment
Nivolumab (31)
III
19
2.3
12.2
Pembrolizumab (32)
II/III
18.0 d
18.5 e
3.9 d
4.0 e
10.4 d
12.7 e
Ramucirumab + docetaxel (33)
III
23
4.5
10.5
Docetaxel (31, 33, 34)
III
8.8–14
2.9–4.2
7.9–9.4
Pemetrexed (34, 35)
III
9.1–11
2.9
8.3–10.1
Erlotinib (35-37)
III
7.9–9
2.2–3.6
5.3–8.2
Gemcitabine (38)
II
18.5
2.3 f
8.8 f
OS, overall survival; PFS, progression-free survival.
a Cetuximab is listed in NCCN guidelines but is not FDA or EMA approved for NSCLC;
b Patients with adenocarcinoma subtype; 
c Patients with non-squamous and squamous histology;
d 2 mg/kg dose;
e 10 mg/kg dose;
f
Estimated from original time in weeks.
In patients with metastatic squamous NSCLC who lack an actionable mutation, 
chemotherapy and best standard of care are recommended (5) (Table 4).


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Table 4
Summary of Trials Assessing First- and Second-line Treatment of 
Metastatic Squamous NSCLC Patients Lacking an Actionable 
Mutation
Treatment
Study 
Phase
ORR 
(%)
Median PFS 
(months)
Median OS 
(months)
First-line
Gemcitabine/cisplatin (30)
III
Not 
reported
5.5
10.8
First-line continuation maintenance therapy 
(combined squamous and non-squamous NSCLC population)
Gemcitabine (39)
III
Not 
reported
3.8
15.2
First-line switch therapy 
(combined squamous and non-squamous NSCLC population)
Docetaxel (40)
III
35.9
5.7
12.3
Second-line 
(combined squamous and non-squamous NSCLC population unless noted otherwise)
Docetaxel (34, 41, 42)
III
6.7–8.8
2.0a–2.9
5.7–7.9
Gemcitabine (43)
II
13
Not reported
6*
Nivolumab (44, 45) b
III
20
3.5
7.2
Pembrolizumab (46)
I
18.7
3.0
11.3
Ramucirumab + docetaxel 
(33)
III
23
4.5
10.5
a Estimated from original time in weeks; 
b Patients with squamous disease.
Patients with actionable mutations
Approximately 10% to 30% of patients with NSCLC harbor mutations in the epidermal 
growth factor receptor (EGFR) (47).  Four tyrosine kinase inhibitors (TKIs)—erlotinib, 
afatinib, gefitinib, and osimertinib—have been approved for treatment of EGFR mutation-
positive disease (48-50).  These agents are recommended for first-line use (5).  If the 
EFGR mutation is discovered after first-line chemotherapy has already been initiated, 
then the clinician has two options at his or her discretion: to interrupt chemotherapy 
immediately and switch to TKI therapy; or complete the ongoing chemotherapy before 
switching to TKI therapy (5).  Across multiple clinical trials, patients with EGFR mutation-
positive disease who were treated with one of these TKIs had median progression-free 
survival (PFS) of 8.0–16.0 months, compared with 4.6–6.9 months following treatment 
with platinum-doublet chemotherapy (51-56).


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Another approximately 5% of patients with NSCLC harbor the echinoderm microtubule-
associated protein-like 4 (EML4)anaplastic lymphoma kinase (ALK) fusion gene as a 
result of a chromosomal inversion at 2p21 and 2p23 (57-60).  Three specific ALK-
targeting agents have been approved for the treatment of patients with ALK-positive 
NSCLC, including crizotinib, ceritinib and alectinib (61-63).  Crizotinib is recommended 
for first-line use, as well as second-line use in asymptomatic patients who have relapsed 
on first-line crizotinib (5).  If the ALK mutation is discovered after first-line chemotherapy 
is already underway, then the chemotherapy can be either interrupted to start crizotinib 
therapy immediately or completed before starting crizotinib.  Alectinib and ceritinib are 
recommended in symptomatic and asymptomatic patients who have relapsed on 
crizotinib (5).  Results of pivotal phase 3 studies have shown that ALK-positive NSCLC 
is highly sensitive to ALK-targeting agents (Table 5).
Table 5
Summary of Clinical Trials Assessing ALK-targeted Therapy in 
Patients with NSCLC Carrying ALK-positive Mutations
Treatment
Study 
phase
ORR 
(%)
Median 
PFS 
(months)
Median 
OS
(months)
Study 
phase
ORR
(%)
Median 
PFS
(months)
Median 
OS 
(months)
First-line treatment outcomes
Second-line treatment outcomes
Crizotinib 
(64, 65)
III
74
10.9
Not 
reached
III
65
7.7
20.3
Crizotinib-naïve 
Crizotinib-refractory
Ceritinib 
(48, 49, 
66)
I, II
64–
72
11.1–
18.4
Not 
reached
I, II
39–56
5.7–6.9
14.9–
16.7
Alectinib 
(67-70)
I, III
93.5
Not 
reached
Not 
reached
II
50.8–
52.2
8.1–8.9
Not 
reached
Immunotherapy in metastatic NSCLC
Immunotherapeutic targeting of programmed death-ligand 1 (PD-L1) or programmed cell 
death protein 1 (PD-1) is revolutionizing the treatment of metastatic NSCLC (see next 
section for mechanism).  Currently, two anti-PD-1 therapeutic antibodies 
(pembrolizumab and nivolumab) (71, 72) and one anti-PD-L1 antibody (atezolizumab) 
(73) have been approved for treatment of NSCLC as monotherapy.  Atezolizumab and 
nivolumab are recommended as second-line agents in advanced NSCLC after prior 
progression on platinum-containing chemotherapy.  Pembrolizumab is approved as a 
first- and second-line agent in advanced NSCLC.
As the current clinical study focuses exclusively on atezolizumab, a detailed summary of 
the efficacy and safety profiles of atezolizumab is provided in subsequent sections.  A 
brief summary of the activities of the two approved anti-PD-1 agents is provided in 
Table 6.


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Table 6
Nivolumab and Pembrolizumab Immunotherapy in Advanced 
NSCLC
Trial
Checkmate 017 (44, 45)
Checkmate 057 (31)
Keynote 010 (32)
Therapy
2L nivo vs. doc
2/3L nivo vs. doc
≥2L pembro vs. 
doc
n
272
582
1033
Histology
Squamous
Non-squamous
All comers
PD-L1 selected
No
No
Yes (TPS ≥ 1) a
Median OS (months)
9.2 vs. 6.0
12.2 vs. 9.4
10.4 b vs. 8.5
Median PFS
(months)
3.5 vs. 2.8
2.3 vs. 4.2
3.9 b vs. 4.0
ORR (%)
20% vs. 9%
19% vs. 12%
18% b vs. 9%
doc, docetaxel; L, line; nivo, nivolumab; OS, overall survival; pembro, pembrolizumab; PFS, 
progression-free survival
a Tumor proportion score (TPS) is the proportion of viable tumor cells showing partial or 
complete membrane PD-L1 expression.
b 2 mg/kg Q3W dose.
1.2
BACKGROUND ON ATEZOLIZUMAB
Atezolizumab 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).  Atezolizumab was engineered to eliminate the crystallizable fragment (Fc)-
effector function via a single amino acid substitution that results in a non-glycosylated 
heavy chain that has minimal binding to Fc receptors and prevents Fc-effector function 
at expected concentrations in humans.  Atezolizumab targets human PD-L1 and inhibits 
the interaction with its receptor, PD-1.  Atezolizumab also blocks the binding of PD-L1 to 
B7.1, an interaction that is reported to provide additional inhibitory signals to T cells (74).  
Please refer to the Atezolizumab Investigator’s Brochure for further details on nonclinical 
studies with atezolizumab.
Therapeutic blockade of PD-L1 by atezolizumab enhances the magnitude and quality of 
tumor-specific T-cell responses, resulting in improved anti-tumor activity.  The US Food 
and Drug Administration (FDA) and the European Medicines Agency (EMA) have 
approved atezolizumab (TECENTRIQ®) for two indications: 1) treatment of patients with 
locally advanced metastatic urothelial carcinoma who have progressed during or 
following platinum-containing chemotherapy or who have disease progression within 12 
months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; 
and 2) patients with metastatic NSCLC who have disease progression during or 
following platinum-containing chemotherapy.  NSCLC patients with EGFR activating 
mutations or ALK-positive tumor mutations should also have received targeted therapy 
before receiving atezolizumab (73, 75).  


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An increasing number of clinical studies have examined or are examining the use of 
atezolizumab in NSCLC.  A summary of key clinical trials in NSCLC is presented in 
Section 1.2.1.  Please refer to the Atezolizumab Investigator’s Brochure for further
details on the nonclinical and clinical development program for atezolizumab.
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma.
1.2.1
Clinical Trials in NSCLC
1.2.1.1
FIR
FIR is a single-arm, phase II study of atezolizumab monotherapy in patients with 
stage IIIB/IV NSCLC (76, 77).  To be eligible, patients had to have PD-L1 expression 
levels of IC2/3 or TC2/3 at baseline, as determined in the SP142 PD-L1 IHC assay.  
Cohort 1 included chemotherapy-naive patients without brain metastases, Cohort 2 
included patients without brain metastases who had 2 or more prior lines of 
chemotherapy (2L+), and Cohort 3 included 2L+ patients with treated asymptomatic 
brain metastases.  
Immune-modified objective response rate (ORR), the primary endpoint in the trial, was 
29% in Cohort 1 (n=31), 17% in Cohort 2 (n=92), and 23% in Cohort 3 (n=13).  There 
was some evidence that higher PD-L1 expression (TC3 or IC3) was associated with 
higher ORR (29% in Cohort 1 [n=7]; 26% in Cohort 2 [n=38]; and 25% in Cohort 3 [n=8]).  
Higher PD-L1 expression may also have been associated with longer PFS and higher 
landmark PFS and landmark overall survival (OS) rates in previously treated NSCLC 
patients. 
In exploratory studies, results from FIR demonstrated that PD-L1 expression scored 
consistently across different types of tissue samples, indicating that tissue from primary 
or metastatic sites, as well as fresh or archival tissue, can be used for PD-L1 testing.  In 
addition, baseline metabolic tumor burden, as defined by FDG-positron emission 
tomography (PET), was a significant predictor of OS.
1.2.1.2
BIRCH
BIRCH is a phase II study of atezolizumab monotherapy in patients with PD-L1-selected 
(TC2/3 or IC2/3) advanced NSCLC (78).  BIRCH enrolled 3 cohorts of patients based on 
the number of previous lines of therapy: Cohort 1 included first line (1L) patients; Cohort 
2 included 2L patients; and Cohort 3 contained patients who had received third line (3L) 
therapy or greater.  BIRCH met its primary endpoint of achieving ORRs superior to 
historical controls in all subgroups.  ORRs were 19% in Cohort 1 (n=139), 17% in Cohort 
2 (n=267), and 17% in Cohort 3 (n=253).  Higher PD-L1 expression correlated with 
higher response.  Thus, in the TC3 or IC3 subgroup, ORRs were 26% in Cohort 1 
(n=65); 24% in Cohort 2 (n=122); and 27% in Cohort 3 (n=115).


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1.2.1.3
POPLAR
POPLAR is a randomized phase II study comparing atezolizumab versus docetaxel in 
patients with locally advanced or metastatic NSCLC who progressed during or following 
a platinum regimen (79-82). The co-primary endpoints were OS in the ITT population 
and OS in the PD-L1-expressing subgroups.  To date, three analyses have been 
conducted on the study population: an interim analysis (data cutoff: Jan 30, 2015) that 
included 153 events (53% event/patient ratio; 10 months minimum follow-up); the 
primary analysis (data cutoff: May 8, 2015) that included 173 events (60% event/patient 
ratio; 13 months minimum follow-up); and an updated analysis (data cutoff: Dec 1, 2015) 
that included 200 events (70% event/patient ratio; 20 months minimum follow-up).
At baseline, the atezolizumab (n=144) and docetaxel (n=143) treatment groups had well 
balanced demographics and baseline characteristics.  In the ITT population, median OS 
in the atezolizumab and docetaxel groups were 11.4 months (95% CI, 9.7–NE months) 
and 9.5 months (95% CI, 8.6–11.9 months) at the interim analysis, 12.6 months (95% 
CI, 9.7–16.4 months) and 9.7 months (95% CI, 8.6–12.0 months) at the primary 
analysis, and 12.6 months (95% CI, 9.7–16.0 months) and 9.7 months (95% CI, 8.6–
12.0 months) at the updated analysis.  The hazard ratios (HR) were 0.77 (p=0.107), 
0.73 (p=0.040) and 0.69 (p=0.011) at the three cutoff dates, indicating the clinical benefit 
of atezolizumab became more apparent with increasing data maturity. 
Improvements in OS correlated with increasing PD-L1 expression (Figure 1).  There was 
some evidence of a further separation between the atezolizumab and docetaxel survival 
curves as the data matured in all PD-L1 expression categories, but it was particularly 
evident in the TC0 and IC0 subgroup.  Further survival improvement with increasing data 
maturity was also observed in patients with squamous NSCLC who received 
atezolizumab (HR for primary analysis vs. updated analysis, 0.66 vs. 0.80).
Figure 1
OS Hazard Ratios Over Time and Updated Median OS
In the ITT population, efficacy as measured by PFS and ORR did not reflect the 
favorable treatment effect of atezolizumab on OS.  These data imply that atezolizumab 


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has benefits on survival that extend beyond disease progression by RECIST v1.1. in 
patients with locally advanced or metastatic NSCLC.
1.2.1.4
OAK
OAK is a phase III study of atezolizumab monotherapy versus docetaxel in 1225 patients 
with locally-advanced or metastatic NSCLC.  Eligible patients had relapsed disease that 
was progressing after 1–2 prior lines of chemotherapy (including at least 1 platinum-
based regimen) and were allowed to have any PD-L1 expression status.  OAK has two 
co-primary endpoints: OS in the ITT population; and OS in the TC1/2/3 or IC1/2/3 
subgroup (≥ 1% PD-L1 expression).  The primary outcome analysis (n=850 patients), 
which was sufficiently powered to test both co-primary endpoints, was presented at the 
2016 meeting of the European Society for Medical Oncology (83).
At baseline, the atezolizumab (n=425) and the docetaxel (n=425) treatment groups had 
similar histology distributions, performance statuses, prior therapy rate, tobacco use, 
CNS metastasis rates, and EGFR-mutation statuses.  
In all patients (ITT population), the median OS was 13.8 months (95% CI, 11.8–15.7 
months) in the atezolizumab group versus 9.6 months (95% CI, 8.6–11.2 months) in the 
docetaxel group, indicating a significant treatment effect in favor of atezolizumab 
(HR, 0.73; p=0.0003).  One-year survival rates were 55% and 41% in the atezolizumab 
and docetaxel groups of the ITT population, respectively, whereas the 18-month survival 
rates were 40% and 27% in the two treatment groups.  
In the TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression), which comprised 55% of 
enrolled patients, the median OS was 15.7 months (95% CI, 12.6–18.0 months) in the 
atezolizumab group versus 10.3 months (95% CI, 8.8–12.0 months) in the docetaxel 
group, again indicating a significant treatment effect in favor of atezolizumab (HR, 0.74; 
p=0.0102).  Median OS positively correlated with PD-L1 expression status.  Sixteen 
percent of patients were classified as TC3 or IC3; 31% were classified as TC2/3 or 
IC2/3; 55% were classified as TC1/2/3 or IC1/2/3; and 45% were classified as TC0 and 
IC0.  Median OS in these subgroups were 20.5 months, 16.3 months, 15.7 months, and 
12.6 months, respectively.  
In other analyses, patients with nonsquamous histology, squamous histology, CNS 
metastases, and no CNS metastases all had significantly longer median survival rates in 
the atezolizumab group, while patients in the TC3 or IC3 subgroup and in the TC2/3 or 
IC2/3 subgroup also had longer PFS times in the atezolizumab group.  In atezolizumab-
treated and docetaxel-treated patients, the ORR rates were 14% and 13%, respectively, 
in the ITT population and 31% and 11%, respectively, in the TC3 or IC3 subgroup.
1.2.2
Safety
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-related adverse events (irAEs) have been closely monitored during the 


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atezolizumab clinical program.  These include potential dermatologic, hepatic, 
endocrine, gastrointestinal and respiratory events. Refer to the Atezolizumab 
Investigator’s Brochure for details on irAEs that were observed in patients treated with 
atezolizumab.
1.2.2.1
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 MTD, no DLTs, and no clear dose-related trends in the incidence of 
adverse events have been determined.
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications, including small cell lung cancer, NSCLC, urothelial carcinoma, renal 
cell carcinoma, 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 (AE), including 444 patients (70.6%) who 
experienced one treatment-related AE.  Commonly reported events (reported in ≥10% 
of all patients) included fatigue, nausea, decreased appetite, diarrhea, constipation, 
dyspnea, pyrexia, and cough (see Table 7).
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 AE, including 
67 patients (75.3%) with treatment-related AEs, 35 (39.3%) patients with Grade 3-4 AEs, 
36 patients (40.4%) with serious adverse events (SAEs), 5 patients (5.6%) who 
discontinued study drug due to an AE, 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 7
Adverse Events Reported in ≥10% of Patients in Study 
PCD4989g
Preferred Term
Any AE ≥ 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%)
1.2.2.2
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 AE regardless of attribution was 96% in both arms.  Fewer patients in 
the atezolizumab arm (41%) experienced Grade 34 AEs compared with the docetaxel 
arm (53%).  For Grade 34 AEs 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 AEs were pneumonia (2%) and increased aspartate 
aminotransferase (AST; 2%).  No atezolizumab-related Grade 4 events have been 
reported.  Treatment-related AEs reported in at least 10% of patients in either treatment 
arm are listed in Table 8.


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Table 8
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%)
Dyspnea
39 (27.5%)
27 (20.0%)
Constipation
31 (21.8%)
32 (23.7%)
Diarrhea
25 (17.6%) 
38 (28.1%)
Alopecia
3 (2.1%) 
52 (38.5%)
Anemia
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%)
1.2.2.3
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 AE, 65% of patients experienced one 
treatment-related AE, and 12% of patients experienced a Grade ≥3 treatment-related 
AE.
For additional information, refer to the Atezolizumab Investigator’s Brochure.


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1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
As described Section 1.2.1, therapy with atezolizumab has been associated with 
significant survival benefits in patients with locally advanced or metastatic NSCLC in 
multiple clinical trial settings.  The improvement in OS was observed in all patients, as 
well as in patients with differing histologies (squamous and non-squamous), PD-L1 
expression statuses, CNS involvement (with or without CNS metastases at baseline), 
and anticancer response or PFS.  Increasing amounts of evidence also indicate that the 
atezolizumab treatment effect on OS correlated with the PD-L1 expression status as 
determined by the VENTANA SP142 PD-L1 assay.  Furthermore, across the NSCLC 
clinical developmental program, atezolizumab has been well tolerated, demonstrating a 
manageable toxicity profile characterized by a low frequency of mild to moderate AEs.  
Considering the data as a whole, atezolizumab represents an important new treatment 
modality for patients with locally advanced or metastatic NSCLC.  
Appropriate to their early stages in the clinical development plan, prior clinical trials 
assessing atezolizumab safety and efficacy in NSCLC had relatively stringent enrollment 
criteria.  This was done in part to ensure optimal safety conditions for the participants, 
i.e., to screen out participants with greater morbidity who might have been less tolerant 
of atezolizumab or docetaxel, or more susceptible to AEs arising during the course of the 
study.  The restrictions also helped to ensure a less heterogeneous study population, 
which in turn limited factors that could complicate the final analyses.  Specific examples 
of such constraints in earlier NSCLC clinical trials are as follows:

Participants were typically required to have an ECOG performance status of 0 or 1, 
meaning their disease at baseline imparted relatively limited impact on daily living 
abilities 

Participants were prohibited from having an autoimmune disease.  Treatment of 
autoimmune diseases typically requires immunosuppressive therapies.  It remains 
unknown how checkpoint inhibition with atezolizumab may impact symptoms and 
progression of autoimmune diseases.  For similar reasons, participants in prior 
studies were required to have disease that did not require treatment with systemic 
corticosteroids and/or other systemic immunosuppressive medications

Participants who had received prior anti-PD-1 therapy were excluded from earlier 
NSCLC studies.  This was appropriate, as anti-PD-1 therapies were relatively new, 
and few patients in the clinic would have been expected to be eligible to receive 
multiple lines of PD-1/PD-L1 immunotherapy.  However, as these agents become 
more widely used, it becomes of interest to assess the efficacy and safety profiles of 
atezolizumab therapy following prior anti-PD-1 therapy

Finally, in earlier clinical trials, potential enrollees were screened out if they had 
symptomatic CNS metastases at baseline, or if they had asymptomatic central 
nervous system (CNS) metastases that were at risk of converting into symptomatic 
ones (i.e., CNS metastases that had not yet been treated).  Patients who had CNS 
metastases that were effectively managed (i.e., CNS metastases that had received 
treatment and were asymptomatic) were allowed entry into some studies.  Since 


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CNS metastases are common among patients with lung cancer and have been 
associated with significant morbidity and mortality (84), a significant impetus exists 
to assess the effects of atezolizumab in a broader population of patients with brain 
metastases.  Furthermore, participants who had received prophylactic radiotherapy 
were excluded from earlier NSCLC trials, since radiotherapy delays commencement 
of systemic therapy and is associated with neurocognitive sequelae as early as 
3 months.  However, this constraint may not be necessary (to be proven in this 
study)
Given the high unmet need for new therapies for advanced NSCLC, it is of considerable 
interest to evaluate atezolizumab in a population of advanced patients that mimics more 
closely a standard clinical practice population.  As a first step in this process, the primary 
objective of Study MO39171 will be to analyze the long-term safety of atezolizumab in a 
population of advanced NSCLC patients that includes patients who would have been 
screened out of many of the previous studies.  The large majority of eligibility criteria in 
Study MO39171 remain unchanged from earlier trials and the safety of participants 
remains the highest priority.  However, a reasonable number of criteria have been 
broadened:

Patients with a baseline ECOG performance status of 2 will now be eligible for 
enrollment, in addition to patients with ECOG performance statuses of 0 and 1

Patients who had received prior anti-PD-1 therapy will be eligible for enrollment

Patients with untreated asymptomatic CNS metastases will be eligible, provided 
they meet the other criteria outlined in Inclusion Criterion # 6

Patients with CNS metastases will be allowed to receive steroid treatments if the 
dose of prednisone is ≤ 20 mg/day (or equivalent)

Patients with underlying controlled and stable autoimmune diseases will be allowed
In addition to assessing safety, the current study will have secondary objectives to 
assess OS, response, and patient-reported outcomes (PROs), which will further 
advance the understanding of atezolizumab therapy in patients with NSCLC.  Finally, in 
exploratory analyses, the study will assess ORR prior to the next subsequent line of 
therapy, evaluate PD-L1 and other biomarkers in tumor tissue, and correlate results with 
efficacy and safety outcomes.  These studies will continue to expand our understanding 
of atezolizumab and lay the groundwork for future clinical trials.
For additional rationale statements explaining the current study design, please refer to 
Section 3.3.
Several steps will be taken to ensure the safety of participants in MO39171.  First, 
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 
(Section 4.3).  Second, identified and potential risks associated with atezolizumab 
treatment will continue to be closely monitored throughout this study (Section 5.1.1).  


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Third, the study will have an independent data monitoring committee (iDMC) to assess 
safety signals on an ongoing basis.  Finally, the study contains protocol-specified drug 
interruption criteria designed to ensure safety (Section 5.1.2).  
Overall, the efficacy and safety data in ongoing studies have shown a favorable 
benefit/risk ratio for atezolizumab treatment in patients with NSCLC.  With the above 
safety precautions in place, the estimated benefits of atezolizumab treatment outweigh 
the risks in this study, especially given the potential of atezolizumab in patients with 
advanced NSCLC.  
This study will enroll patients with NSCLC.  Given the relatively poor prognosis and 
limited treatment options for these patients, this population is considered appropriate for 
trials of novel therapeutic candidates.  The benefitrisk ratio for atezolizumab is 
expected to be acceptable in this setting.
In the setting of the COVID-19 pandemic, patients with comorbidities, including those 
with cancer, are considered a more vulnerable population, with the potential for more 
severe clinical outcomes from COVID-19.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of COVID-19.
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  In nonclinical models, PD-1/PD-L1 blockade 
appears to be associated with serious exacerbation of inflammation in the setting of 
acute (as opposed to chronic) viral infection with lymphocytic choriomeningitis virus 
(Clone 13) (85).  However, there are insufficient and inconsistent clinical data to assess 
if outcome from COVID-19 is altered by cancer immunotherapy.
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-(86).  
While it is not known, there may be a potential for an increased risk of an enhanced 
inflammatory response if a patient develops acute SARS-CoV-2 infection while receiving 
atezolizumab.  At this time, there is insufficient evidence for causal association between 
atezolizumab and an increased risk of severe outcomes from COVID-19.
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab and clinical and radiologic 
features for COVID-19related interstitial pneumonia.  Thus, investigators should use 
their clinical judgment when evaluating and managing patients with pulmonary 
symptoms.


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the long-term safety and efficacy of atezolizumab in patients with 
locally advanced or metastatic NSCLC who have progressed following standard 
systemic chemotherapy (including if given in combination with anti-PD-1 therapy, after 
anti-PD-1 as monotherapy, or after tyrosine kinase inhibitor [TKI] therapy).  Patients with 
a previously detected sensitizing EGFR mutation or ALK fusion oncogene must have 
received targeted therapy (TKI) followed by at least one line of standard systemic 
chemotherapy prior to receiving atezolizumab.  Overall, patients should not have 
received more than two lines of standard systemic chemotherapy.  Patients will also be 
eligible if they discontinued first-line or second-line therapy due to intolerance.
Specific objectives and corresponding endpoints for the study are outlined below.
Table 9
Objectives and Corresponding Endpoints
Primary Objective
Corresponding Endpoints
To evaluate the long-term safety of 
atezolizumab in previously treated 
patients with advanced NSCLC
Incidence of serious adverse events (SAEs) related to 
atezolizumab treatment
Incidence of immune-related adverse events (irAEs) 
related to atezolizumab treatment
Main Secondary Objective
Corresponding Endpoint
To evaluate the efficacy of 
atezolizumab in previously treated 
patients with advanced NSCLC
Overall survival (OS) rate at 2 years, defined as the 
proportion of patients remaining alive 2 years after 
initiation of study treatment


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Other Secondary Objectives
Corresponding Endpoints
To further evaluate the efficacy of 
atezolizumab in previously treated 
patients with advanced NSCLC
OS, defined as the time from initiation of study 
treatment to death from any cause
PFS, defined as the time from initiation of study 
treatment to the first occurrence of disease 
progression or death from any cause, whichever 
occurs first.  PFS will be calculated based on disease 
status evaluated by the investigator according to 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) and also by disease status 
evaluated by the investigator according to modified 
RECIST
OS rate at 3 years, defined as the proportion of 
patients remaining alive 3 years after initiation of 
study treatment
ORR, defined as the percentage of patients who 
attain complete response (CR) or partial response 
(PR) according to RECIST v1.1 and also by disease 
status evaluated by the investigator according to 
modified RECIST
Duration of response (DOR), defined as the time from 
initial response to disease progression or death 
among patients who have experienced a CR or PR 
(unconfirmed) during the study.  Duration of response 
will be calculated based on disease status evaluated 
by the investigator according to RECIST v1.1, and 
also by disease status evaluated by the investigator 
according to modified RECIST


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Exploratory Objectives
Corresponding Endpoints
To further evaluate the long-term safety 
and efficacy of atezolizumab in 
previously treated patients with 
advanced NSCLC
Safety and efficacy of atezolizumab in subgroups of 
the study population differentiated according to: 
Presence of CNS metastases at baseline (yes vs. 
no)
ECOG performance status (0 or 1 vs. 2)
Histologic subtype (squamous vs. non-squamous)
History of or current autoimmune disease 
(yes vs. no)
Prior anticancer treatment 
Progression-free survival from start of new anti-cancer 
therapy, defined as the time from initiation of new anti-
cancer therapy to objective tumor progression on 
next-line treatment or death from any cause
Objective response rate from start of new anti-cancer 
therapy, defined as the percentage of patients who 
attain complete response (CR) or partial response 
(PR)
Progression-free survival 2 (PFS2), defined as the 
time from initiation of study treatment to objective 
tumor progression on next-line treatment or death 
from any cause
Exploratory Biomarker Objectives
Corresponding Endpoints
To assess the role of PD-L1 and other 
biomarkers in the progression and 
fundamental biology of advanced 
NSCLC 
To evaluate PD-L1 and other 
biomarkers (e.g., cancer-related 
genes) as prognostic biomarkers
Safety and efficacy of atezolizumab in subgroups of 
the study population differentiated according to:
Expression of PD-L1 protein in tumor tissue
Presence/absence of other biomarkers in tumor 
tissue
Correlations between PD-L1 expression and other 
biomarkers
Patient-Reported Outcome 
Objectives
Corresponding Endpoints
To evaluate health status utility and 
HR QoL of atezolizumab in previously 
treated patients with advanced 
NSCLC
EQ-5D-5L index-based and VAS scores
EORTC QLQ-LC13
EORTC QLQ-LC13, European Organisation for Research and Treatment of Cancer Quality-of-
Life Questionnaire—Supplemental Lung Cancer Module; EQ-5D, EuroQol 5-Dimension 
Questionnaire; HR QoL, health-related quality of life; VAS, visual analog scale.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study MO39171 is a phase III/IV, single-arm, multicenter study of the long-term safety 
and efficacy of atezolizumab treatment in patients with Stage IIIb or Stage IV NSCLC 
who have progressed following standard systemic chemotherapy (including if given in 
combination with anti-PD-1 therapy, after anti-PD-1 as monotherapy, or after TKI 
therapy).  Patients with a previously detected sensitizing EGFR mutation or ALK fusion 
oncogene must have received targeted therapy (TKI) followed by at least one line of 
standard systemic chemotherapy prior to receiving atezolizumab.  Overall, patients 
should not have received more than two lines of standard systemic chemotherapy.  
Patients will also be eligible if they discontinued first-line or second-line therapy due to 
intolerance.
The study will consist of a Screening Period (Day –28 to Day –1), a Treatment Period, a 
Treatment Discontinuation Visit occurring ≤30 days after the last dose of study 
medication, and a Follow-Up Period.  Day 1 (baseline) will be defined as the first day the 
patient receives atezolizumab.  It is anticipated that the trial will enroll 600 patients at 
140 sites globally.
Enrolled patients will receive atezolizumab at a fixed dose of 1200 mg administered 
intravenously on the first day of each cycle (Figure 2).  One cycle of therapy will be 
defined as 21 days (± 5 days).  Atezolizumab treatment will continue until investigator-
assessed loss of clinical benefit, unacceptable toxicity, investigator or patient decision to 
withdraw from therapy, or death (whichever occurs first).  




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Other efficacy objectives will include evaluation of OS, OS rate at 3 years, PFS, ORR, 
and DOR (additional efficacy assessments may occur on an exploratory basis).  All 
antitumor response assessments will be based on RECIST v1.1 and modified RECIST.
Exploratory objectives will include evaluation of the safety and efficacy of atezolizumab 
in patient subgroups differentiated by: presence or absence of CNS metastases at 
baseline; ECOG performance status; histological subtype; history of or current 
autoimmune disease; and prior anticancer treatment.  Other exploratory and PRO 
outcomes will include objective response rate and progression-free survival 2 (PFS2) 
following start of new anticancer therapy, HR QoL as measured on the EORTC LQ-
LC13, health utility score as measured on the EQ-5D-5L instrument, and expression of 
PD-L1 protein and cancer-related genes in tumor samples obtained before treatment.  
Finally, exploratory biomarkers may be assessed in tissue to assist in the potential 
development of new diagnostic assays and to assess biomarkers in terms of prognosis, 
response/resistance and safety.
Following discontinuation of study treatment, safety assessments will be conducted for 
30 days after the last study drug administration or until initiation of other anti-cancer 
therapy (whichever occurs first).  Thereafter, follow-up information on disease 
progression (unless this has already occurred), anti-cancer therapy and survival will be 
collected via telephone contact, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, end of study (30 months 
after last patient in), patient withdrawal or study termination by the Sponsor, whichever 
occurs first.  In addition, irAEs, SAEs and AESIs will be collected as described in 
Section 5.4.2.
In those patients for whom tumor assessments are performed as part of local clinical 
practice and are available for report after PD or atezolizumab treatment discontinuation, 
overall response rate (ORR) and progression-free survival (PFS) will be assessed from 
the first date of the new anticancer therapy to the end of the study.  These data will be 
used in an exploratory fashion to assess whether prior atezolizumab treatment positively 
influences response to subsequent anticancer therapies.
An Independent Data Monitoring Committee (iDMC) will be established to review all 
AEs, irAEs, SAEs, AESIs and other cumulative safety data.
A Schedule of Assessments for this study is provided in Appendix 1.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of study and final analysis will occur when all enrolled patients have either died, 
withdrawn consent, are lost to follow up, or have been followed for 30 months since the 
last study patient is enrolled, whichever occurs first.


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The primary analysis will occur approximately 6 months after the last patient has been 
enrolled.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population and Analysis Groups
Please refer to Section 1.3, Study Rationale and Benefit Risk Assessment.
3.3.2
Rationale for an Open-Label Single-Arm Design
The primary objective of this study is to assess the long-term safety profile of 
atezolizumab in a noncomparative fashion.  Thus, as all patients are pre-specified to 
receive active treatment, the study will have an open-label and non-randomized design. 
3.3.3
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.
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 (PK) in humans, and other factors.  
The target trough concentration (Ctrough) was projected to be 6 µg/mL on the basis of 
several assumptions, including: 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 maximum tolerated dose of atezolizumab was not reached, and no 
dose-limiting toxicities 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 anti-therapeutic antibodies (ATAs) were observed in patients at all dose 
levels but were associated with changes in PK 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 if 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 PK for doses from 10 to 20 mg/kg in most 


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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 q3w 
regimen (or fixed-dose equivalent) for Phase II and Phase III studies would be sufficient 
to both maintain Ctrough ≥6 µg/mL and further safeguard against both interpatient 
variability and the potential effect of ATAs that could lead to subtherapeutic levels of 
atezolizumab relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose 
equivalent).  From inspection of available observed Ctrough data, moving further to the 
20-mg/kg atezolizumab q3w regimen does not appear to be warranted to maintain 
targeted Ctrough levels relative to the proposed 15-mg/kg atezolizumab q3w level.
Simulations 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 an every-21-day dosing interval is supported by this preliminary PK 
evaluation and allows for a convenient integration with common chemotherapeutic 
regimens.
3.3.4
Rationale for Biomarker Assessments
PD-L1 expression on tumor cells (TC) and immune cells (IC) varies significantly among 
patients with NSCLC, and these differing levels of PD-L1 expression have been shown 
to correlate with atezolizumab response in several studies (76, 79, 80, 87).  Further 
defining the relationship between atezolizumab treatment outcomes in NSCLC and 
PD-L1 expression continues to be important, as it will advance the understanding of a 
potential differential benefit from atezolizumab treatment across PD-L1-defined patient 
subgroups, as well as add to the understanding of the basic biology underlying immune 
checkpoints and their role in cancer.  
Therefore, to address these issues, the current study will collect, if available, tumor 
tissue obtained at the time of diagnosis (archival tissue) or at any time before the start of 
atezolizumab therapy and analyze PD-L1 expression by immunohistochemistry (IHC).  
As PD-L1 IHC is also tested routinely, results from local PD-L1 analysis will be collected 
instead of central testing or in addition to central testing.  Results from the IHC assay will 
be used to correlate baseline levels of PD-L1 with subsequent safety and efficacy 
outcomes.  If tissue quantity allows, other PD-L1 tests may be conducted to, e.g., assess 
concordance of methods (the pretreatment sample may also be used for other 
exploratory biomarker analyses [see next paragraph]).  
For patients who received prior PD-1-targeted therapy, results from local PD-L1 testing 
should be provided, and whenever feasible, archival tissue obtained before the start of 
PD-1 therapy should be submitted for central IHC analysis.  In order to better understand 


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the effect of anti-PD-1 therapy on PD-L1 expression, as well as its effects on anti-PD-L1 
treatment efficacy, a biopsy should be taken prior to receiving atezolizumab therapy 
(screening biopsy).
NSCLC is a heterogeneous disease involving multiple genetic lesions and alterations in 
expression patterns (88-90).  Therefore, in addition to PD-L1, other biomarkers may be 
examined in this study on an exploratory basis.  This will be accomplished by, e.g., IHC 
and/or a variety of protein-, DNA- and RNA-based profiling methodologies.  These 
analyses are of significant interest for their potential of revealing molecular mechanisms 
involved in advanced NSCLC carcinogenesis and susceptibility to atezolizumab 
treatment.
3.3.5
Rationale for Patient-Reported Outcome Assessments
PRO assessments improve our understanding of a treatment’s impact from the patient’s 
perspective, an important consideration in many of today’s quality initiatives (91).  This 
study will therefore employ the EORTC QLQ-LC13 instrument to assess self-reported 
outcomes in all enrolled patients (Appendix 4).  The EORTC QLQ-LC13 is a lung-
cancer-specific module designed to supplement the more general EORTC QLQ-C30 
core measure (92).  Developed for use with lung cancer patients undergoing anticancer
therapy, the EORTC QLQ-LC13 includes 13 items that address key lung cancer 
symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related 
adverse effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain 
medication.  The dysphagia scale is multi-item, while the rest are single-item scales.
In addition, patients in this trial will complete the EuroQol EQ-5.  The EQ-5D-5L is a self-
report health status questionnaire that consists of six questions used to calculate a 
health utility score for use in health economic analysis (93-96).  The EuroQol EQ-5D has 
two components: a five-item health state profile that assesses mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression, as well as a visual analog scale that 
measures health state.  Published weighting systems allow for creation of a single 
summary score.  Overall scores range from 0 to 1, with low scores representing a higher 
level of dysfunction.  The EQ-5D will be utilized in this study for economic modeling.
3.3.6
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment Beyond Initial Progression
Anti-tumor immune responses such as those associated with atezolizumab may result in 
objective responses that are delayed and that can be preceded by initial apparent 
radiological progression.  This initial apparent progression may occur as a result of either 
delayed anti-tumor activity and/or robust tumor immune cell infiltration with a 
concomitant increase in tumor size (pseudo-progression).  In addition, lesions that might 
otherwise be undetectable with conventional imaging may increase in size as a result of 
these processes and be recorded as new lesions (97).


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Furthermore, prior clinical evidence indicates that treatment with atezolizumab beyond 
apparent PD can have beneficial effects in patients with NSCLC:

In Study PCD4989g, several patients with NSCLC who progressed by RECIST v1.1 
criteria continued on atezolizumab treatment and demonstrated durable anti-tumor 
activity.  In some responding patients, the growth of known lesions or the 
appearance of new radiographic lesions were shown to contain immune cells and 
no viable cancer cells on biopsy.

In POPLAR, 47% of patients who continued atezolizumab after PD had subsequent 
stable or reduced target lesions relative to baseline (80).  Moreover, in the 
atezolizumab arm of the study, OS from the time of first RECIST v1.1 PD was 11.1 
months for patients who continued atezolizumab post PD versus 8.3 months for 
patients who received a different anti-cancer therapy post PD.  These data suggest 
that continuation of atezolizumab after progression can, in some patients, have a 
positive benefit-risk profile. 
Based on the previous considerations, this study will allow patients to remain on 
atezolizumab after apparent radiographic progression, provided the benefit-risk ratio is 
judged to be favorable by the investigator.  Patients should be discontinued for 
unacceptable toxicity or symptomatic deterioration attributed to disease progression as 
determined by the investigator after an integrated assessment of radiographic data and 
clinical status, as described in Section 4.6.2.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study will enroll approximately 600 patients with Stage IIIb or Stage IV NSCLC 
who have progressed following standard systemic chemotherapy (including if given in 
combination with anti-PD-1 therapy or after anti-PD-1 as monotherapy).  Patients with a 
previously detected sensitizing EGFR mutation or ALK fusion oncogene must have 
received targeted therapy followed by one line of standard systemic chemotherapy prior 
to receiving atezolizumab.  Overall, patients should not have received more than two 
lines of systemic chemotherapy.  Patients will also be eligible if they discontinued first-
line or second-line therapy due to intolerance.  
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:
1.
Signed Informed Consent Form
1.
Age ≥ 18 years
2. Able to comply with the study protocol, in the investigator’s judgment
3. Histologically or cytologically documented Stage IIIb or Stage IV NSCLC that has 
progressed following standard systemic chemotherapy (including if given in 
combination with anti-PD-1 therapy, after anti-PD-1 as monotherapy, or after TKI 
therapy).  Patients with a previously detected sensitizing EGFR mutation or ALK 


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fusion oncogene must have received targeted therapy (TKI), followed by at least one 
line of standard systemic chemotherapy, prior to receiving atezolizumab.  Overall, 
patients should not have received more than two lines of standard systemic 
chemotherapy .  Patients who have discontinued first-line or second-line therapy due 
to intolerance are also eligible
–
Staging must be according to the UICC/AJCC system, 7th edition (Detterbeck et 
al. 2009) (see Appendix 8)
–
Pathological characterization may be conducted on tumor specimens from earlier 
stage disease, but the tumor samples must be sufficient to distinguish squamous 
or non-squamous histology
–
Chemotherapy regimens will be counted based on interval disease progression, 
and not on the number of agents or the number of switches in agents (e.g., a 
first-line or second-line therapy that consists of several cycles of a platinum 
doublet and subsequent maintenance therapy that introduces or switches to a 
new chemotherapy agent without interval disease progression will all be 
considered one chemotherapy regimen)
–
Patients with a previously-detected sensitizing EGFR mutation must have 
experienced disease progression (during or after treatment) on an EGFR TKI 
(erlotinib, gefitinib, osimertinib, etc.)  
–
Patients with a previously detected ALK fusion oncogene must have experienced 
disease progression (during or after treatment) with crizotinib, alectinib, or 
another ALK inhibitor
–
Prior radiation therapy is allowed, provided that the patient has recovered from 
any toxic effects thereof.  Combined radiation/chemotherapy treatment 
constitutes a single regimen
–
Combined radiation/chemotherapy treatment (chemoradiation) counts as one 
prior chemotherapy regimen if < 6 months have elapsed between the last dose 
and the date of recurrence
–
Adjuvant/neoadjuvant chemotherapy is not counted as a line of treatment
–
Debulking surgery and anticancer agents used for pleurodesis are not counted 
as lines of therapy
4. The last dose of prior systemic anticancer therapy or targeted therapy must have 
been administered ≥21 days prior to study treatment initiation
5. The last dose of prior anti-PD-1 therapy must have been administered
–
Nivolumab must have been discontinued ≥ 14 days and pembrolizumab 
≥21 days prior to study treatment initiation, providing that these treatments were 
not administered in a clinical trial setting
6. Measurable disease, as defined by Response Evaluation Criteria for Solid Tumors, 
Version 1.1 (RECIST v1.1)


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7. Patients with asymptomatic CNS metastases (treated or untreated), as determined 
by CT or MRI evaluation during screening and prior radiographic evaluation, are 
eligible
8. ECOG performance status 0, 1, or 2 [Appendix 7]
9. Life expectancy ≥ 12 weeks
10. Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 2 weeks prior to the first study treatment:
–
Absolute neutrophil count ≥1500 cells/µL (without granulocyte colony-stimulating 
factor support within 2 weeks prior to the first study treatment)
–
White blood cell count > 2500/µL
–
Lymphocyte count ≥500/µL
–
Platelet count ≥100,000/µL (without transfusion within 2 weeks prior to the first 
study treatment)
–
Hemoglobin ≥9.0 g/dL (patients may be transfused or receive erythropoietic 
treatment to meet this criterion)
–
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline 
phosphatase ≤2.5 times the upper limit of normal (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’s Syndrome who have 
serum bilirubin level ≤3 × ULN may be enrolled.
–
Calculated creatinine clearance ≥15 mL/min (Cockcroft-Gault formula)
–
International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT) ≤1.5 ×ULN.  This applies only to patients who are not receiving 
therapeutic anticoagulation agents
–
Patients receiving therapeutic anticoagulation agents must be on a stable dose
–
HIV-positive patients are allowed, so long as they are on stable anti-retroviral 
therapy, have a CD4 count ≥200 cells/µL, and have an undetectable viral load at 
the time of screening
11. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in 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 postmenarchal, 
has not reached a postmenopausal state (≥12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus)


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–
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, established, proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices
–
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception
12. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute 
toxicities from previous therapy, excluding alopecia and toxicities related to prior anti-
PD-1-therapy
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1.
Symptomatic CNS metastases 
13. 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 study treatment initiation
14. Leptomeningeal disease
15. Uncontrolled pericardial effusion or ascites requiring recurrent drainage procedures
16. Pregnant or lactating, or intending to become pregnant during the study
–
Women who are not postmenopausal (postmenopausal defined as ≥12 months 
of non-drug-induced amenorrhea) or surgically sterile must have a negative 
serum pregnancy test result within 2 weeks prior to initiation of study drug
17. Evidence of significant uncontrolled concomitant disease that could affect 
compliance with the protocol, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome)
18. Significant cardiovascular disease, such as New York Heart Association cardiac 
disease ≥Class III, myocardial infarction within 3 months, unstable arrhythmias, or 
unstable angina
–
Patients with known coronary artery disease 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
19. Significant renal disorder requiring dialysis or indication for renal transplant
20. Treatment with any other investigational agent or participation in another clinical trial 
with therapeutic intent within 28 days prior to study treatment initiation
21. Major surgical procedure within 4 weeks prior to study treatment initiation or 
anticipation of need for a major surgical procedure during the course of the study 
other than for diagnosis


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22. Inability to understand the local language(s) for which the EORTC QLQ-LC13 and 
EuroQol EQ-5D-5L questionnaires are available (see Appendix 4 for English 
versions)
23. History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins
24. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary cells or any component of the atezolizumab formulation
25. History of autoimmune disease (Appendix 5) are allowed if controlled and on stable 
treatment (i.e., same treatment, same dose) for the last 12 weeks, with the 
exception of:
–
Patients taking concurrent abatacept or belatacept treatment, unless therapy has 
been withdrawn for > 8 weeks
–
Patients with a history of serious or life threatening immune-related events
–
No more than 1 concomitant autoimmune disease at the time of study entry is 
allowed unless one of them is: 
Autoimmune-mediated hypothyroidism on a stable dose of thyroid 
replacement hormone 
Controlled Type I diabetes mellitus on a stable dose of insulin regimen
A medical history of such entities as atopic disease or childhood 
arthralgias, where the clinical suspicion of autoimmune disease is low.  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)
26. Prior allogeneic stem cell or solid organ transplantation
27. History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest 
computed tomography (CT) scan
–
History of radiation pneumonitis in the radiation field (fibrosis) is permitted
28. Active tuberculosis
–
In patients who have a potentially high likelihood of latent tuberculosis (e.g., recent 
contact with an infectious carrier, residence in a locale with high TB burden), 
absence of Mycobacterium tuberculosis infection must be confirmed before 
enrollment according to local practice standards
29. Administration of a live, attenuated vaccine within 4 weeks prior to study treatment 
initiation
–
Influenza vaccination should be given during influenza season only (e.g., 
approximately October to March in the Northern Hemisphere). 


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–
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 
weeks prior to study treatment initiation or at any time during the study
30. Prior treatment with CD137 agonists or immune checkpoint blockade therapies 
other than anti-PD-1 therapy, including anti−PD-L1 therapeutic antibodies
31. Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is 
longer, prior to initiation of study treatment
–
Prior cancer vaccines and cellular immunotherapy are permitted
32. Specifically for patients without autoimmune disease: 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 study treatment initiation, or anticipated requirement for systemic 
immunosuppressive medications during the trial
–
For patients with CNS metastases, use of prednisone at a stable dose (or dose 
equivalent) of ≤20 mg/day is acceptable 
–
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 and 
topical steroids for cutaneous diseases are allowed
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label (unblinded) study in which all subjects will be assigned to receive 
the same treatment, i.e., atezolizumab.
4.3
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is atezolizumab.
4.3.1
Formulation, Packaging, and Handling
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials. The 
vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution, but may contain 
more than the stated volume to enable delivery of the entire 20 mL volume. 
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.
For information on the formulation and handling of atezolizumab, refer to the 
Atezolizumab Investigator’s Brochure and Pharmacy Manual.
4.3.2
Dosage, Administration, and Compliance
The dose of atezolizumab in this study will be 1200 mg (equivalent to an average body 
weight-based dose of 15 mg/kg) administered by intravenous infusion every 3 weeks 
(21 [± 5] days).  


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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.  
For detailed information on drug preparation, storage and administration, refer to the 
Atezolizumab Investigator’s Brochure.
The initial dose of atezolizumab will be administered over 60 (± 15) minutes.  If the first 
infusion is tolerated without infusion-associated AEs, 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 the first infusion, the 
patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) 
should be determined within 60 minutes before, during (every 15 [± 5] minutes if 
clinically indicated), and 30 (± 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before the infusion, during the infusion if 
clinically indicated, and 30 minutes (± 10 minutes) after the infusion if clinically indicated 
or patient experienced symptoms during previous infusions.
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms.
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 (Grade 1) National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) infusion-related 
event, the infusion rate should be reduced to half the rate being given at the time of 
event onset.  Once the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.  If tolerated, the infusion 
rate may then be increased to the original rate

In the event that a patient experiences a moderate infusion-related event (NCI 
CTCAE Grade 2) or flushing, fever, or throat pain, the patient should have his or her 
infusion immediately interrupted and should receive aggressive symptomatic 
treatment.  The infusion should be restarted only after the symptoms have 
adequately resolved to baseline grade.  The infusion rate at restart should be half of 
the infusion rate that was in progress at the time of the onset of the infusion-related 
event

For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), 
the infusion should be stopped immediately, and aggressive resuscitation and 
supportive measures should be initiated.  Patients experiencing severe or life-
threatening infusion-related events will not receive further infusion and will be further 
managed as clinically indicated until the event resolves
For anaphylaxis precautions, see Appendix 6.


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Guidelines for dosage modification, treatment interruption or discontinuation, and the 
management of specific adverse events are provided in Section 5.1.2.
Each AE associated with a special situation should be recorded on the Adverse Event 
eCRF.
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, 
storage and administration.
4.3.3
Investigational Medicinal Product Accountability
IMP required for completion of this study (atezolizumab) will be provided by the Sponsor.  
The study site is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each patient, and disposition or return of unused IMP, 
thus enabling reconciliation of all IMP received, and for ensuring that patients are 
provided with doses specified by the protocol.
The study site should follow all instructions included with each shipment of IMP. The 
study site will acknowledge receipt of IMP using the interactive response system (IxRS) 
to confirm the shipment condition and content.  Any damaged shipments will be replaced.
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and time) 
or temperature monitoring, for all IMPs received and that any discrepancies have been 
reported and resolved before use of the IMPs.  All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions, with access limited to the investigator and authorized 
staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
IMP will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or 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 IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
Refer to the pharmacy manual and/or the atezolizumab Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability.


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4.3.4
Continued Access to Atezolizumab
The Sponsor will offer continued access to Sponsor study drug (atezolizumab) free of 
charge to eligible patients in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Sponsor study drug (atezolizumab) after completing 
the study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires continued 
Sponsor study drug treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Sponsor study drug (atezolizumab) after 
completing the study if any of the following conditions are met:

The Sponsor study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the drug or data suggest that the drug 
is not effective for non-small cell lung cancer

The Sponsor has reasonable safety concerns regarding the drug as treatment for 
non-small cell lung cancer

Provision of the drug is not permitted under the laws and regulations of the patient's 
country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any prescription medications or over-the-counter 
preparations (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by a patient in addition to 
protocol-mandated treatment from 7 days preceding the screening evaluation to the 
treatment discontinuation visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Patients who experience infusion-associated symptoms may be treated 
symptomatically with acetaminophen, ibuprofen, diphenhydramine and/or famotidine 


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or another H2 receptor antagonist, as per standard practice (equivalent medications 
may be substituted per local practice).  Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation or respiratory distress should be managed with 
supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-
adrenergic agonists; see Appendix 6).

Systemic corticosteroids, immunosuppressive medications, and tumor necrosis 
factor−α inhibitors may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab, but may be administered at the discretion of the 
treating physician after consultation with the Medical Monitor (see Exclusion 
Criterion 21 [Section 4.1.2] and Prohibited Therapy [Section 4.4.2]).  If feasible, 
alternatives to corticosteroids should be considered.  Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician after 
consultation with the Medical Monitor.  The use of inhaled corticosteroids for COPD 
and mineralocorticoids (e.g., fludrocortisone) and low-dose corticosteroids for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed.  
Megestrol administered as an appetite stimulant is acceptable while the patient is 
enrolled in the study.

Colony-stimulating factors, such as granulocyte colony-stimulating factor and 
erythropoietin, should only be used according to manufacturers’ labels and the 
ASCO and ASCO/ASH guidelines (98, 99).  

Influenza vaccination should be given during influenza season only (approximately 
October to March in the Northern Hemisphere).  Patients must not receive live, 
attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to study treatment 
initiation or at any time during the study.

Patients who use 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), or other allowed maintenance 
therapy (see Section 4.1.2) should continue their use.

Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However, herbal therapies not intended for the treatment of cancer may 
be used during the study at the discretion of the investigator.
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF.
4.4.2
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health authority-
approved or experimental, unless otherwise specified, is prohibited.  This includes but is 
not limited to the following:

Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, or investigational 
agents (except for maintenance therapies outlined in Sections 4.1.1 and 4.1.2)


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–
After completion of Cycle 1, certain forms of radiotherapy may be considered for 
palliation if patients are deriving benefit (e.g., treatment of known bone metastases) 
–
Patients experiencing a mixed response requiring local therapy (e.g., surgery, 
stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control of three 
or fewer lesions may still be eligible to continue study treatment.  Patients who 
receive local therapy directed at a target lesion will no longer be evaluable for 
radiographic response but will remain evaluable for progression. Such cases must 
be discussed with and approved by the Sponsor

Patients should not receive abatacept or belatacept treatment (those who were 
receiving it must stop it > 8 weeks before study entry)
Patients are not allowed to receive immunostimulatory agents, including but not limited 
to interferon (IFN)-α, IFN-γ, or IL-2, during the entire study.  These agents, in 
combination with atezolizumab, could potentially increase the risk for autoimmune 
conditions.
Systemic corticosteroids, immunosuppressive medications, and anti−TNF-α agents may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab, but 
may be administered at the discretion of the treating physician after consultation with the 
Medical Monitor.  If feasible, alternatives to these agents should be considered.
Patients with CNS metastases are allowed to receive anticonvulsants and steroid
treatments if the dose of prednisone is stable and ≤20 mg/day (or equivalent). 
The above list of medications is not necessarily comprehensive.  The investigator should 
consult the prescribing information for any concomitant medication and contact the 
Medical Monitor if questions arise regarding medications not listed above.
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments 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 
performing any study-related procedures.  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 study treatment initiation.  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases (including autoimmune diseases), 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 


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status, smoking history, and all medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient within 7 days prior to the screening visit.  A history of pleural or pericardial 
effusion or of ascites requiring intervention should be entered in the medical history.
Cancer history will also include the histopathologic subtype for all patients and results 
from molecular analysis (including EGFR mutation and ALK fusion status) for all patients 
with non-squamous NSCLC.  EGFR mutation and ALK testing should be considered for 
patients with squamous NSCLC who are never smokers, have mixed histology or small 
biopsy specimen.
If available, PD-L1 immunohistochemistry results, including the name of the assay used, 
should be documented.
Demographic data will include age, ECOG performance status, 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, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.  Height and weight should be 
measured and recorded in the 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, pulse rate, systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature.
For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood 
pressures, and temperature) should be determined within 60 minutes before, during 
(every 15 [± 5] minutes) if clinically indicated, and 30 (± 10) minutes after the infusion.  
For subsequent infusions, vital signs will be collected within 60 minutes before the 
infusion, during the infusion if clinically indicated, and 30 minutes (± 10 minutes) after the 
infusion if clinically indicated or patient experienced symptoms during previous infusions.  
4.5.5
Tumor and Response Evaluations
Measurable and non-measurable disease must be documented at screening and re-
assessed at each subsequent tumor evaluation.  


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Tumor assessments are to be performed at the timepoints specified in Appendix 1
(± 5 days) regardless of drug delays or interruptions (i.e., independent of 
treatment cycles).
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRI of the chest, abdomen, and pelvis.  A spiral CT scan of the chest 
may be obtained, but is not a requirement.  MRIs of the chest, abdomen, and pelvis with 
a noncontrast CT scan of the chest may be used in patients for whom CT scans with 
contrast are contraindicated (i.e., patients with contrast allergy or impaired renal 
clearance).
A CT (with contrast if not contraindicated) or MRI scan of the brain is required at 
screening for patients with known or suspected CNS metastases, or to confirm or refute 
a diagnosis of CNS metastases at baseline.  Patients with active CNS metastases 
(treated or untreated) are eligible for this study if they are asymptomatic.  
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a full-
contrast diagnostic CT scan.
Bone scans (Technetium-99m [TC-99m]) or sodium fluoride PET (NaF-PET) should be 
performed at screening if clinically indicated.  If bone metastases are present at 
screening and cannot be seen on CT or MRI scans, or if clinically indicated, TC-99m or 
NaF-PET bone scans should be repeated when complete response is identified in target 
disease or when progression in bone is suspected.
CT scans of the neck or extremities should also be performed if clinically indicated and 
followed throughout the study if there is evidence of disease at screening.  At the 
investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.
Results of standard of care tests or examinations performed prior to obtaining Informed 
Consent and ≤ 28 days prior to study entry may be used for the purposes of Screening 
rather than repeating such tests.
For subsequent tumor assessments, procedures for tumor assessment should be 
performed as clinically indicated.  The same radiographic procedure used to assess 
disease sites at screening should be used throughout the study (e.g., the same contrast 
protocol for CT scans).  All known sites of disease must be documented at screening 
and reassessed at each subsequent tumor evaluation.  Response will be assessed by 
the investigator using RECIST v1.1 (see Appendix 2) and modified RECIST (see 
Appendix 3).  The same evaluator should perform assessments if possible to ensure 
internal consistency across visits.


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At the investigator’s discretion, CT scans should be repeated at any time if progressive 
disease is suspected.
Patients who continue atezolizumab treatment beyond radiographic disease progression 
assessed per RECIST v1.1 will be monitored with a follow-up scan at the next scheduled 
tumor assessment when the scan frequency is every 6 weeks.  If the scan frequency is 
every 9 weeks (see Appendix 1), a follow-up scan is recommended at 9 weeks or earlier 
if clinically indicated.  Patients will be assessed by modified RECIST criteria (see 
Appendix 3) until treatment discontinuation.
4.5.6
Ongoing Tumor Assessments
Patients who discontinue study treatment early for reasons other than disease 
progression (e.g., toxicity) should continue to undergo scheduled tumor assessments 
(See Appendix 1) until the patient dies, experiences confirmed disease progression, 
withdraws consent, until study termination, or until the study closes, whichever occurs 
first.
Patients who start a new anti-cancer therapy in the absence of disease progression 
should continue to be followed for progression according to the protocol schedule of 
response assessments, unless consent is withdrawn or the patient experiences disease 
progression or death or until study termination or withdrawal from study, whichever 
occurs first.
In those patients for whom tumor assessments are performed as part of local clinical 
practice and are available for report after PD or atezolizumab treatment discontinuation, 
overall response rate (ORR) and progression-free survival (PFS) will be assessed from 
the first date of the new anticancer therapy to the end of the study.  These data will be 
used in an exploratory fashion to assess whether prior atezolizumab treatment positively 
influences response to subsequent anticancer therapies.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (complete blood count, including red blood cell count, hemoglobin, 
hematocrit, white blood cell 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 carbon dioxide (if considered standard of 
care for the region), calcium, phosphorus, total bilirubin, ALT, AST, alkaline 
phosphatase, LDH, total protein, and albumin) 

Coagulation panel (aPTT and INR) 

Serum pregnancy test (for women of childbearing potential, including 
premenopausal women who have had a tubal ligation) 


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
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood)

Thyroid function testing (thyroid-stimulating hormone, free triiodothyronine [T3] [or 
total T3 for sites where free T3 is not performed], free thyroxine [also known as T4])

HBV serology (HBsAg, antibodies against HBsAg, antibodies against hepatitis B 
core antigen [anti−HBcAb]) 

HBV DNA should be obtained prior to Cycle 1, Day 1 if patient has positive serology 
for anti-HBc Ab. 

HCV serology (anti-HCV) 

HIV serology 
–
HIV testing is not required in the absence of clinical symptoms and signs suggestive 
of HIV infection.  HIV-positive patients are allowed, so long as they are stable on 
anti-retroviral therapy, have a CD4 count ≥200 cells/µL, and have an undetectable 
viral load at the time of screening

Central EGFR/ALK testing for sites that do not routinely perform testing: 
–
Patients with non-squamous NSCLC are required to be tested.  Patients with 
squamous NSCLC will not be required to be tested.  However, EGFR mutation and 
ALK testing should be considered for patients with squamous NSCLC who are 
never-smokers, have mixed histology or small biopsy specimen.  At least 7 slides 
from the most recent FFPE tumor tissue sample (archival material or screening 
biopsy) must be submitted for central testing during the Screening Period
Samples for exploratory biomarker analyses will be sent to one or several central 
laboratories for analysis:

For patients who were not treated with anti-PD1 therapies: 
–
If available, pre-treatment FFPE tumor tissue (most recent sample) for PD-L1 
testing and exploratory biomarkers.  Most recent archival sample or a sample 
obtained during screening should be submitted if available (1 FFPE tissue block or 
5–10 slides)
–
For patients who have already been tested for PD-L1 by IHC, results and assay 
name are to be submitted

For patients who were treated with anti-PD-1 therapy, sites are highly encouraged to 
submit the following samples if available:
–
Archival tissue taken prior to treatment with PD-1 targeting agents (FFPE tissue 
block or 5–10 slides) 
–
Screening biopsy taken prior to treatment with atezolizumab (after PD-1 targeting 
agents (FFPE tissue block or 5–10 slides)
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 


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Exploratory biomarker research may include, but will not be limited to, the following 
analyses:

PD-L1 IHC assessment

Tumor DNA isolation for detection of gene alterations

Tumor RNA isolation for gene expression profiling
Unless the patient gives specific consent for his or her leftover or unused samples to be 
stored for optional exploratory research (see Section 4.5.10.6), biological samples will be 
destroyed no later than the time of completion of the final Clinical Study Report, with the 
following exception:

Leftover tumor tissue that remains after a maximum of 10 slides have been cut will 
be returned to the study site
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, will be subject to the confidentiality standards 
described in Section 8.4.
4.5.8
Electrocardiograms
Single 12-lead ECG recordings will be obtained at specified timepoints, as outlined in the 
Schedule of Assessments (see Appendix 1), and may be obtained at unscheduled 
timepoints as indicated. 
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.  
If at a particular postdose timepoint the mean QT interval corrected using Fridericia’s 
formula (QTcF) is 500 ms and/or 60 ms longer than the baseline value, another ECG 
must be recorded, ideally within the next 5 minutes, and ECG monitoring should 
continue until QTcF has stabilized on two successive ECGs.  The Medical Monitor 
should be notified.  Standard-of-care treatment may be instituted per the discretion of the 


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investigator.  A decision on study drug discontinuation should be made, as described in 
Section 4.6.2.  The investigator should also evaluate the patient for potential concurrent 
risk factors (e.g., electrolyte abnormalities, co-medications known to prolong the QT 
interval, severe bradycardia).
4.5.9
Patient-Reported Outcomes
PRO data will be collected via questionnaires to document the treatment benefit and 
more fully characterize the safety profile of atezolizumab.   The questionnaires, 
translated into the local language as required, will be completed in their entirety at 
specified timepoints during the study.  To ensure instrument validity and that data 
standards meet health authority requirements, questionnaires will be self-administered 
or interviewer-administered (as appropriate) before the patient or clinician receives any 
information on disease status, prior to the performance of non-PRO assessments, and 
prior to the administration of study treatment, unless otherwise specified.  
One PRO questionnaire will be used in this study:

EORTC QLQ-LC13: The EORTC QLQ-LC13 is a lung-cancer-specific module 
designed to supplement the more general EORTC QLQ-C30 core measure (92).  
Developed for use with lung cancer patients undergoing anticancer therapy, the 
EORTC QLQ-LC13 includes 13 items that address key lung cancer symptoms 
(cough, hemoptysis, dyspnea, and site-specific pain), treatment-related adverse 
effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain 
medication.  The dysphagia scale is multi-item, while the rest are single-item scales.
In addition, subjects in this study will complete the EuroQol 5-Dimension Questionnaire 
(EQ-5D-5L).  

The EQ-5D-5L is a self-report health status questionnaire that consists of six 
questions used to calculate a health utility score for use in health economic analysis 
(93-96).  There are two components to the EuroQol EQ-5D: a five-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analogue scale (VAS) that measures health 
state.  Published weighting systems allow for creation of a single summary score.  
Overall scores range from 0 to 1, with low scores representing a higher level of 
dysfunction.  The EQ-5D will be utilized in this study for economic modeling
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
TAIL Substudy: Stool Sample Collection for the Research 
Biosample Repository
At selected sites in participating countries, a substudy will be conducted to examine stool 
samples collected from patients in Study MO39171.  Please refer to Appendix 10
for 
detailed information about the substudy’s rationale and sample collection procedures.


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4.5.10.2
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, 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.
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 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
4.5.10.3
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 or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RBR sampling, this section of the protocol (Section 4.5.10) will not be 
applicable at that site.
4.5.10.4
Sample Collection
The following optional samples will be stored in the RBR and used for research 
purposes, including, but not limited to, research on biomarkers related to atezolizumab 
and advanced or metastatic NSCLC:

Leftover or unused FFPE tissue samples or derivatives thereof after study-related 
tests have been performed

Ten milliliters (10 mL) whole blood for plasma preparation will be collected at 
baseline and at the time of disease progression
The above samples may be sent to one or more laboratories for DNA and RNA 
extraction to enable analysis of tumor mutations via next-generation sequencing (NGS), 
or other genetic analysis methods, as well as for gene expression or protein analyses.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  


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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).
4.5.10.5
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.
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.
4.5.10.6
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.


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4.5.10.7
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.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RBR samples have been tested prior to withdrawal of consent, results from those tests 
will remain as part of the overall research data.  If a patient wishes to withdraw consent 
to the testing of his or her 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 trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples after closure of the site, the investigator must 
inform the Sponsor by emailing the study number and patient number to the following 
email address: 
global_rcr-withdrawal@roche.com
The patient will be provided with instructions on how to withdraw consent after the trial is 
closed.  A patient's withdrawal from Study MO39171 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 MO39171.
4.5.10.8
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, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance


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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.  Subjects who discontinue will be asked to provide consent allowing 
the Study Investigator and/or F. Hoffman-La Roche Ltd to collect follow up information 
regarding disease progression and survival. Otherwise, without this consent, patients 
will not be followed for any reason after withdrawal.  Patients who withdraw from the 
study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment (but will continue to receive tumor 
assessments) if they experience any of the following:

Intolerable toxicity related to study treatment

Myocarditis of any grade

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another systemic anti-cancer therapy (see Section 4.4.2)

Pregnancy

Radiographic disease progression per RECIST v1.1
Exception: Patients will be permitted to continue atezolizumab after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the 
following criteria (see Figure 3 for schematic representation):
o
Evidence of clinical benefit (defined as the stabilization or improvement of 
disease-related symptoms) as assessed by the investigator
o
Absence of symptoms and signs (including worsening of laboratory 
values [e.g., new or worsening hypercalcemia]) indicating unequivocal 
progression of disease
o
No decline in ECOG performance status that can be attributed to disease 
progression
o
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
Patients who demonstrate confirmed radiographic disease progression may be 
considered for continued study treatment at the discretion of the investigator, 
provided they continue to meet all the criteria above
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.


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Figure 3
Conditions for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size
ECOG PS, Eastern Cooperative Oncology Group performance status; ICF, Informed Consent 
Form; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, Version 1.1.


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4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is derived from 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 carefully chosen 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 treatment, all adverse events will be reported until 30 days after 
the last dose of study treatment 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 treatment 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 
(Section 5.1.2), in Appendix 9 and in the Atezolizumab Investigator’s Brochure.  Refer to 
Sections 5.2–5.6 for details on safety reporting during the study.


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Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology).
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN-(86).  If a patient develops suspected CRS during 
the study, a differential diagnosis should include COVID-19, which should be confirmed 
or refuted through assessment of exposure history, appropriate laboratory testing, and 
clinical or radiologic evaluations per investigator judgment.  If a diagnosis of COVID-19 
is confirmed, the disease should be managed as per local or institutional guidelines.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following: IRRs and 
immune-related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  
Immune-related reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome
(MAS), which are considered to be potential risks for atezolizumab.  Refer to Appendix 9
of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab.  
5.1.2
Management of Patients Who Experience Specific Adverse 
Events
There will be no dose modifications for atezolizumab in this study.  
Atezolizumab may be temporarily suspended in patients who experience toxicity 
considered to be related to study treatment.  If atezolizumab is withheld for > 12 weeks 
after event onset, the patient will be discontinued from study drug.  If the investigator 
believes the patient is likely to derive clinical benefit and the Medical Monitor is in 
agreement, atezolizumab can be resumed after being withheld for > 12 weeks after 
event onset.  
If a patient must be tapered off steroids that have been used to treat adverse events, 
then atezolizumab may be withheld for more than 12 weeks after event onset until the 
steroids are discontinued or reduced to a prednisone dose (or dose equivalent) of 
≤10 mg/day.  For patients with CNS metastases or autoimmune disease who require 
chronic steroid therapy, who have been receiving additional steroids to treat adverse 
events, and who now require a reduction in steroid dosage, atezolizumab may be 
withheld for more than 12 weeks after event onset until the steroid dosage has returned 


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to its baseline value.  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.
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-related adverse events (irAEs) have been closely monitored during the 
atezolizumab clinical program. Guidelines for the management of patients who 
experience specific adverse events associated with atezolizumab (i.e., pulmonary, 
hepatic, gastrointestinal, endocrine, ocular, infusion-related [IRR], pancreatic, 
dermatologic, neurologic, or autoimmune events) are provided in Appendix 9 and 
Section 6 (Guidance for the Investigator) of the Atezolizumab Investigator's Brochure.
For patients developing a new autoimmune disease not listed in the Atezolizumab 
Investigator’s Brochure, or for patients with an autoimmune disease who develop a flare, 
the following dosing guidance should be applied:

Grade 1 event: atezolizumab dosage should be maintained

Grade 2 or 3 event: atezolizumab should be suspended until the subject responds to 
treatment of the autoimmune disease and the disease becomes stable (see rules 
above regarding maximum suspended time).  The subject should be referred to an 
appropriate specialist

Grade 4 event: atezolizumab should be permanently discontinued and the subject 
should be referred to an appropriate specialist
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 


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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 
Sections 5.3.5.9 and 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 treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).


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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include:

Pneumonitis

Colitis

Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, 
hypothyroidism, hypophysitis or hyperthyroidism

Hepatitis, including AST or ALT > 10 x ULN

Systemic lupus erythematosus

Neurologic disorders: Guillain-Barré syndrome, myasthenia gravis, 
meningoencephalitis

Nephritis

Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, HLH, and MAS

Cardiac disorders – Grade ≥2 in severity (e.g., atrial fibrillation, myocarditis, 
pericarditis)

Vasculitis

Myositis

Myopathies, including rhabdomyolysis

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis)

Autoimmune hemolytic anemia

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis)

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 


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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 Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study 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 and 90 days for serious adverse events or adverse events of 
special interest.  
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 10 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 10 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 11):

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 11 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 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3xbaseline value) in combination with either 
an elevated total bilirubin (2 xULN) 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 xbaseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 xbaseline 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 locally advanced or metastatic NSCLC should be 
recorded on the Death Attributed to Progressive Disease eCRF.  All other deaths that 
occur during the adverse event reporting period, regardless of relationship to study drug, 
must be recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2).  An iDMC will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. The term ‘sudden death’ should not be 
used unless combined with the presumed cause of death (e.g., “sudden cardiac death”).
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches," “flare,” etc.).
5.3.5.10
Lack of Efficacy or Worsening of Locally Advanced or 
Metastatic Non-Small Cell Lung Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST and modified RECIST.  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., in-patient 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 assessment for the study)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as “special 
situations”) are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded on 
the Adverse Event eCRF.  If the associated adverse event fulfills seriousness criteria or 
qualifies as an adverse event of special interest, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). For atezolizumab, adverse events associated with special situations 
should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "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 "Overdose" and "Medication error" boxes.
In addition, all special situations associated with atezolizumab, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF as 
described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "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 "Overdose" and "Medication error" boxes.  
Enter a description of the error in the additional case details.


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
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Overdose" and "Medication error" boxes would need 
to be checked for both entries.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
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 (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor/Roche Medical Responsible:
, M.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, all adverse events will be reported until 30 days after the 
last dose of study drug and until 90 days for serious adverse events or adverse events of 
special interest.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur > 30 days after the last dose 
of study treatment are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the last dose of 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 emailing the form using the fax number or email address provided to 
investigators.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.     
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).


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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.
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
After the end of the adverse event reporting period (defined as 30 days after the last 
dose of study drug for all AEs and 90 days for serious adverse events and adverse 
events of special interest), all deaths, regardless of cause, should be reported through 
use of the Long-Term Survival Follow-Up eCRF.  
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Atezolizumab Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An IDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is an open-label, single-arm safety study.  
Analysis populations
This study will include the following analysis populations:

Safety population: The primary analysis population for this study will include all
enrolled patients who have received at least one dose of atezolizumab.  The safety 
population will be used for all baseline and safety analyses, unless otherwise stated

Intent-to-treat population: The intent-to-treat (ITT) population will include all enrolled 
patients
A per-protocol population will not be defined for this study.  However all major deviations 
(at study entry and on study) will be summarized and reported.
6.1
DETERMINATION OF SAMPLE SIZE
No formal sample size calculation linked to hypothesis testing is done for this descriptive 
study.  The sample size considerations are based upon estimation precision for the 
incidence of AEs.  With 600 patients, the following 95% CIs (Table 12) could be provided 
for the different incidences of AEs, which is deemed appropriate for the purposes of the 
study.


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Table 12 Adverse Event Incidence and Corresponding 95% Confidence 
Intervals
Sample Size
AE Incidence 
95% Clopper-Pearson Exact CI
600 patients
1%
1% [0.2% ; 1.8%]
2%
2% [0.9% ; 3.1%]
3%
3% [1.6% ; 4.4%]
5%
5% [3.3% ; 6.7%]
10%
10% [7.6% ; 12.4%]
CI, confidence interval.
6.2
ANALYSIS OF THE CONDUCT OF THE STUDY
Enrollment (e.g., by country, by site), screening failures, study treatment administration, 
and discontinuation (including reasons) from the study will be summarized using 
descriptive statistics.  
6.3
SUMMARIES OF TREATMENT GROUP 
Demographic and other baseline characteristics (at patient and disease level), medical 
history, prior treatments (study and non-study condition related) will be presented 
descriptively using the overall safety population.  These may also be presented using the 
ITT population if the difference is more than 5 patients compared with the number of 
patients in the safety population.
6.4
PRIMARY ENDPOINT ANALYSIS
All safety analyses will be run on the Safety Analysis set, defined as all enrolled patients 
who had at least one administration of atezolizumab.  The primary analysis will occur 
approximately 6 months after the last patient has been enrolled.
The incidence of SAEs related to atezolizumab and the incidence of irAEs related to 
atezolizumab will be summarized by incidence rates and 95% Pearson-Clopper 
confidence intervals.
6.5
MAIN SECONDARY ENDPOINT ANALYSES
6.5.1
Landmark Analysis
Estimates of OS rates at 24 and 36 months in the ITT population will be provided using 
the Kaplan-Meier methodology, along with 95% CIs calculated using Greenwood’s 
formula.


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6.6
OTHER SECONDARY ENDPOINT ANALYSES
6.6.1
Other Safety Analyses
Safety analyses include the following:

All causality AEs

All causality AEs (Grades 3–5)

All causality SAEs

AEs and SAEs leading to atezolizumab interruption or discontinuation

AESIs

irAEs

Causes of deaths

Changes from baseline in vital signs during and following atezolizumab 
administration

Changes from baseline in clinical laboratory results during and following 
atezolizumab administration

Concomitant medications
AEs will be displayed in standard frequency tables according to overall frequency and 
severity.  Time to first incidence of AEs, SAEs, AEs (Grades 3–5) and irAEs will be 
estimated using the Kaplan-Meier approach.  AEs and laboratory parameters will be 
assessed by the investigator according to the National Cancer Institute Common 
Terminology Criteria, Version 4.0 (NCI CTC v4.0).  AEs and/or SAEs will be coded and 
analyzed by “preferred terms” according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and evaluated descriptively
6.6.2
Other Efficacy Analyses
Overall Survival
OS is defined as the time from initiation of study treatment to death from any cause.  
Data for patients who are not reported as having died at the time of analysis will be 
censored at the date they were last known to be alive.  Patients who do not have post-
baseline information will be censored at the date of initiation of study treatment plus 1 
day. 
Progression-Free Survival
PFS is defined as the time (in months) between the date of initiation of study treatment 
and the date of first documented disease progression or death, whichever occurs first.  
PFS will be calculated based on disease status evaluated by the investigator according 
to RECIST v1.1 and also by disease status according to modified RECIST.  Patients 
who are alive and have not experienced disease progression 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 initiation of study treatment plus 1 day.


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Objective Response Rate
Objective response is defined as a confirmed complete or a partial response per 
RECIST v1.1 and/or modified RECIST.  Patients without any post-baseline tumor 
assessments will be considered non-responders.  An estimate of ORR will be provided 
along with the corresponding 95% CIs calculated using the Clopper-Pearson method.
Duration of Response
For patients who have experienced an objective response (CR or PR) during the study 
as assessed by the investigator, DOR is defined as the duration from the first tumor 
assessment that supports the patient’s objective response (CR or PR, whichever is first 
recorded) to disease progression or death due to any cause, whichever occurs first.  
Patients who are alive and who have not experienced disease progression at the time of 
analysis will be censored at the time of the last tumor assessment date.  If no tumor 
assessments were performed after the date of the first occurrence of a complete or 
partial response, DOR will be censored at the date of the first occurrence of a complete 
or partial response plus 1 day.  Two separate analyses will be presented for 
RECIST v1.1 and modified RECIST.  
6.6.3
Exploratory Efficacy Analysis
The following efficacy endpoints will be evaluated to further asses the efficacy of 
atezolizumab after disease progression (no confirmation of response will be required for 
these analyses)
In those patients who received further anti-cancer therapy:

Progression-free survival from start of new anti-cancer therapy, defined as the time 
from initiation of new anti-cancer therapy to objective tumor progression on next-line 
treatment or death from any cause

Objective response rate from start of new anti-cancer therapy, defined as the 
percentage of patients who attain complete response (CR) or partial response (PR)
In the ITT population:

Progression-free survival 2 (PFS2), defined as the time from initiation of study 
treatment to objective tumor progression on next-line treatment or death from any 
cause
The prior analyses might be repeated in the following subgroups, if enough patients are 
available: 

Presence of CNS metastases at baseline (yes vs. no)

ECOG performance status (0 or 1 vs. 2)

Histologic subtype (squamous vs. non-squamous)

History of or current autoimmune disease (yes vs. no)

Prior anticancer treatment 


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6.7
INTERIM ANALYSES
This study will have no formal interim analyses.  However, regular safety reviews of data 
will be performed by an Independent Data Monitoring Committee (iDMC).  The 
frequency of these reviews will be stated in the iDMC charter.
In addition, to adapt to information that may emerge during the course of this study, the 
Sponsor may choose to conduct one interim analysis for reporting and publication of 
safety and efficacy results.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data.  Data entered manually will be 
collected via EDC through use of eCRFs.  Sites will be responsible for data entry into the 
EDC system.  In the event of discrepant data, the CRO will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system.  
The Sponsor will perform oversight of the data management of this study.  The CRO will 
produce eCRF Specifications for the study based on the Sponsor’s templates, including 
quality-checking procedures to be performed on the data.  Central laboratory data will be 
sent directly to the Sponsor, using the Sponsor’s standard procedures to handle and 
process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the CRO.
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.


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7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and Institutional Review board (IRB)/Ethics 
Committee (EC) review.  The study site must also allow inspection by applicable health 
authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 


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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. Roche  will retain study data for 25 
years after the final Clinical Study Report has been completed or for the length of time 
required by relevant national or local health authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (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.


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The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
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. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
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 (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.


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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of 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, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. and was 
designed in collaboration with outside guidance from a Steering Committee.  The 
Sponsor will provide clinical operations management, data management, and medical 
monitoring.  An iDMC will review SAEs and accumulating safety data.
Approximately 140 sites globally will participate to enroll approximately 600 patients. 
Enrollment will occur through an IxRS system.  Central facilities will be used for certain 
study assessments throughout the study (e.g., specified laboratory tests and biomarker 
analyses) as specified in Section 4.5.  Accredited local laboratories will be used for 
routine monitoring; local laboratory ranges will be collected.  
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 


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has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
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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Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
127/Protocol MO39171, Final Version 6
b.
Medical history includes surgical and cancer histories.  Cancer history includes stage, date of diagnosis, prior anti-cancer treatment, EGFR/ALK 
status and, if available, PD-L1 status.  Reproductive status and smoking history should also be captured.  Demographic information includes 
age, sex, and self-reported race/ethnicity. 
c.
A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.  At subsequent visits (or as clinically indicated), limited, 
symptom-directed physical examinations should be performed.  Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse events on the Adverse Event eCRF.
d.
Limited physical examination, ECOG performance status (Appendix 7), and local laboratory assessments may be obtained ≤96 hours before 
Day 1 of each cycle. It is not necessary to repeat these assessments again prior to Cycle 1 if they have been conducted for screening within 
this time period.
e.
See Appendix 7.
f.
Vital signs include respiratory rate, heart rate, systolic and diastolic blood pressures while the patient is in a seated position, and temperature.  
Treatment cycle Day 1 vital sign assessments will be done prior to study treatment. 
g.
ECG recordings will be obtained during screening and when clinically indicated.  Patients should be resting and in a supine position for at least 
10 minutes prior to each ECG recording. 
h.
Refer to Section 4.5.7.  HIV testing is not required in the absence of clinical symptoms and signs suggestive of HIV infection; patients with a 
positive serological test may be enrolled so long as they are stable on anti-retroviral therapy, have a CD4 count ≥200 cells/µL, and have an 
undetectable viral load at the time of screening.
i.
Hematology consists of CBC (including RBC count), hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells), and platelet count.  A manual differential may be done if clinically indicated.
j.
Includes thyroid-stimulating hormone (TSH), free triiodothyronine (T3) (or total T3 for sites where free T3 is not performed), free thyroxine (also 
known as T4).
k.
Serum chemistry includes glucose, BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate or total carbon dioxide (if 
considered standard of care for the region), calcium, phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and 
albumin. 
l.
Urinalysis includes specific gravity, pH, glucose, protein, ketones, and blood.
m. A serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 14 days prior to Day 1.  On study pregnancy tests performed every 3 treatment cycles can be conducted with 
serum or urine.
n.
The same radiographic procedure should be used throughout the study for each patient.  A CT (with contrast) or MRI of the head must be 
included in screening tumor assessments for patients with known or suspected CNS disease.  Results must be reviewed by the investigator 
before dosing at the next cycle.  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, and will be assessed 


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
128/Protocol MO39171, Final Version 6
by modified RECIST criteria (see Appendix 3) until treatment discontinuation.  If the scan frequency is every 9 weeks, a follow-up scan is 
recommended at 9 weeks or earlier if clinically indicated.  Investigators may perform additional scans or more frequent assessments if clinically 
indicated.
o.
Ideally within 14 days of the start of study treatment.
p.
Patients will undergo tumor assessments at baseline, every 6 weeks ± 5 days for the first 48 weeks following treatment initiation, and every 
9 weeks thereafter until radiographic disease progression per RECIST v1.1 or (for patients who continue atezolizumab after radiographic 
disease progression) loss of clinical benefit as determined by the investigator (see Section 4.6.2 for details).  Thus, tumor assessments are to 
continue according to schedule in patients who discontinue treatment for reasons other than disease progression or loss of clinical benefit, even 
if they start new anti-cancer therapy.
q.
For sites where EGFR/ALK testing is not routinely performed at local laboratories, a minimum of 7 consecutively cut slides from a most recent 
FFPE tumor tissue block must be submitted for EGFR/ALK testing for all patients with non-squamous NSCLC.  Testing is not required for 
patients who have squamous NSCLC.  EGFR mutation and ALK testing should be considered for patients with squamous NSCLC who are 
never-smokers, have mixed histology or small biopsy specimen.
r.
If available, pre-treatment FFPE tumor tissue (most recent sample) for PD-L1 testing and exploratory biomarkers.  Most recent archival sample 
or a sample obtained during screening should be submitted if available (1 FFPE tissue block or 5–10 slides).
s.
From patients who received anti-PD-1 therapy, sites are highly encouraged to provide archival FFPE tissue (prior anti-PD1 therapy) and an 
FFPE tissue biopsy obtained during screening (archival and screening tissue sample).
t.
Ten milliliters (10 mL) whole blood for plasma.  Not applicable for a site that has not been granted approval for RBR sampling.  Performed only 
for patients at participating sites who have provided written informed consent to participate.
u.
Only to be shipped if the patient is eligible for enrollment.
v.
See Appendix 4.
w.
Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to the screening visit should be documented.  At subsequent visits, changes to current medications or medications 
used since the last documentation of medications will be recorded.
x.
After informed consent has been obtained, but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should be 
reported.  After initiation of study drug, all SAEs and AESIs, 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 AEs, 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 SAEs or AESIs believed to be related to prior study drug treatment.  The investigator should follow each AE 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 SAEs considered to be related to study drug or study-related procedures 
until a final outcome can be reported.
y.
Survival and new anti-cancer therapy follow-up information will be collected via telephone contact, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, end of study (30 months after the last patient in), patient withdrawal or study 


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
129/Protocol MO39171, Final Version 6
termination by the Sponsor, whichever occurs first.  In those patients for whom tumor assessments are performed and available for report after 
PD or treatment discontinuation, best overall response (BOR) will be assessed from the first date of the new anticancer therapy to the end of 
the study per RECIST v1.1.  These data will be used in an exploratory fashion to assess whether prior atezolizumab treatment positively 
influences response to subsequent anticancer therapies.


Atezolizumab—F. Hoffmann-La Roche Ltd
130/Protocol MO39171, Final Version 6
Appendix 2
Response Evaluation Criteria in Solid Tumors, Version 1.1: 
Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 1 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 
                                           
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.


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Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

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.

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.
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.


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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 
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.


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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.

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


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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135/Protocol MO39171, Final Version 6
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 eCRF 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.
Evaluation of Nontarget Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of nontarget lesions.  Whereas some nontarget lesions may actually be 


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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 
point.  Whereas 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.


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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.
When patients have nonmeasurable (therefore nontarget) disease only, Table 2 is to be 
used.


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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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 


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
139/Protocol MO39171, Final Version 6
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and, during the study, only two lesions were assessed, but 
those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
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 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
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140/Protocol MO39171, Final Version 6
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.
NOTE: In this study, stable disease must persist for at least 6 weeks (minimum duration) to be 
considered a bona fide SD. 
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.


Appendix 2
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol MO39171, Final Version 6
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and 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.


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Appendix 3
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment. 
Modified RECIST is derived from RECIST, Version 1.1 conventions 3 and 
immune-related response criteria 4 (irRC). 
Modified RECIST and RECIST, Version 1.1:  Summary of Changes
RECIST v1.1
Modified RECIST
New lesions after baseline
Define progression.
New measurable lesions are 
added into the total tumor 
burden and followed.
Non-target lesions
May contribute to the 
designation of overall 
progression
Contribute only in the 
assessment of a complete 
response
Radiographic progression
First instance of 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease
Determined only on the basis 
of measurable disease; may 
be confirmed by a 
consecutive assessment 4 
weeks from the date first 
documented 
RECIST Response Evaluation Criteria in Solid Tumors.
DEFINITIONS OF MEASURABLE/NON-MEASURABLE LESIONS
All measurable and non-measurable lesions should be assessed at screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
                                           
3
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
4
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
antiPD-1 antibody in cancer. N Engl J Med 2012;366:244354.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Can Res 2009;15:741220.


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol MO39171, Final Version 6
performed, as clinically indicated for suspicion of progression.  The investigator will 
evaluate response to treatment using modified RECIST.
MEASURABLE LESIONS
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)
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 follow-up, 
only the short axis will be measured and followed.  
NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 but 15 mm), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. Lytic bone 
lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. Blastic bone lesions are non-measurable.


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol MO39171, Final Version 6
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. Cystic lesions thought to represent cystic metastases 
can be considered as measurable lesions, if they meet the definition of measurability 
described above.  However, if non-cystic lesions are present in the same patient, these 
are preferred for selection as target lesions.
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable.
TUMOR RESPONSE EVALUATION
DEFINITIONS OF TARGET/NON-TARGET LESIONS
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one 
or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those
organs will be recorded as non-measurable lesions (even if the size is 10 mm by 
CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance, the next largest lesion that can be measured reproducibly 
should be selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol MO39171, Final Version 6
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm 30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis 10 mm but 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of 10 mm are considered non-pathological and should not be 
recorded or followed. Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not 
be counted as target lesions.
Non-Target Lesions
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required.
It is possible to record multiple non-target lesions involving the same organ as a single 
item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
After baseline, changes in non-target lesions will contribute only in the assessment 
of complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including non-target lesions) and will not be used 
to assess progressive disease. 
CALCULATION OF SUM OF THE DIAMETERS 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden.  
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses.
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1.
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated, the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions and all new 
measurable lesions that have emerged after baseline will contribute to the sum of the 
diameters at tumor assessment.  Hence, each net percentage change in tumor burden 


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol MO39171, Final Version 6
per assessment with use of modified RECIST accounts for the size and growth kinetics 
of both old and new lesions as they appear. 
RESPONSE CRITERIA
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Lymph nodes that 
shrink to 10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR.
Note:  The appearance of new measurable lesions is factored into the overall tumor 
burden but does not automatically qualify as progressive disease until the sum of the 
diameters increases by 20% when compared with the sum of the diameters at nadir.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and all new measurable lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution 
to total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response. 
EVALUATION OF BEST OVERALL RESPONSE USING MODIFIED RECIST
TIMEPOINT 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.
MISSING ASSESSMENTS AND INEVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is 
not evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered NE at that timepoint, unless a 


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol MO39171, Final Version 6
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and at follow-up 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.
Table 1  Modified RECIST Timepoint Response Definitions
% Change in 
Sum of the 
Diameters 
(Including 
Measurable New 
Lesions When 
Present)
Target 
Lesion 
Definition
Non-Target 
Lesion 
Definition
New 
Measurable 
Lesions
New 
Unmeasurable 
Lesions
Overall 
Modified 
RECIST 
Timepoint 
Response
100% a
CR
CR
No
No
CR
100% a
CR
Non-CR or 
not all 
evaluated
No
No
PR
30%
PR
Any
Yes or no
Yes or no
PR
30% to 
20%
SD
Any
Yes or no
Yes or no
SD
Not all evaluated
Not 
evaluated
Any
Yes or no
Yes or no
NE
20%
PD
Any
Yes or no
Yes or no
PD
CR complete response; NE not evaluable; PD progressive disease; PR partial 
response; RECIST Response Evaluation Criteria in Solid Tumors; SD stable disease.
a When lymph nodes are included as target lesions, the % change in the sum of the diameters 
may not be 100% even if complete response criteria are met since a normal lymph node is 
defined as having a short axis of 10 mm.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to 10 mm in order to meet the definition of CR.
BEST OVERALL RESPONSE:  ALL TIMEPOINTS
The best overall response is determined once all the data for the patient are known.


Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol MO39171, Final Version 6
The best overall response according to modified RECIST is interpreted as below:

CR:  Complete disappearance of all tumor lesions (target and non-target) and no new 
measurable or unmeasurable lesions, confirmed by a consecutive assessment 4 weeks from 
the date first documented.  All lymph nodes short axes must be 10 mm.

PR:  Decrease in the sum of the diameters of all target and all new measurable lesions 30% 
relative to baseline, in the absence of CR, confirmed by a consecutive assessment 4 weeks 
from the date first documented.  

SD: Criteria for CR, PR, and PD are not met. 

PD:  Increase in the sum of the diameters of all target and all new measurable lesions 20% 
relative to the nadir, which may be confirmed by a consecutive assessment 4 weeks from 
the date first documented as follows: 
The confirmatory assessment shows an additional measurable increase in tumor burden 
as measured by the sum of the diameters of all target and all new measurable lesions.


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Appendix 4
EORTC QLQ-LC13 and EQ-5D-5L
ENGLISH
EORTC  QLQ - LC13
Patients sometimes report that they have the following symptoms or problems. Please indicate the
extent to which you have experienced these symptoms or problems during the past week. Please
answer by circling the number that best applies to you.
______________________________________________________________________________________ 
During the past week : 
Not at
A
Quite
Very
 
 
All
Little 
a Bit
Much
31
How much did you cough?
1
2
3
4
32
Did you cough up blood? 
1
2
3
4
33
Were you short of breath when you rested?
1 
2 
3 
4
34
Were you short of breath when you walked?
1
2
3
4
35
Were you short of breath when you climbed stairs?
1 
2
3
4
36
Have you had a sore mouth or tongue?
1 
2 
3 
4
37
Have you had trouble swallowing?
1 
2 
3 
4
38
Have you had tingling hands or feet?
1
2
3
4
39
Have you had hair loss? 
1 
2 
3 
4
40
Have you had pain in your chest?
1
2
3
4
41
Have you had pain in your arm or shoulder?
1
2
3
4
42
Have you had pain in other parts of your body?
1
2
3 
4
 
If yes, where
43
Did you take any medicine for pain?  
 
1
No
2
Yes
If yes, how much did it help?
1
2
3
4
 QLQ-C30-LC13 Copyright 1994 EORTC Quality of life Group. All rights reserved


Appendix 4
EORTC QLQ-LC13 and EQ-5D-5L (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol MO39171, Final Version 6


Appendix 4
EORTC QLQ-LC13 and EQ-5D-5L (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol MO39171, Final Version 6


Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol MO39171, Final Version 6
Appendix 5
Preexisting Autoimmune (Chronic Inflammatory) Diseases and 
Immune Deficiencies
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with an history of immune 
deficiencies or autoimmune disease (see Table below) are allowed in the study. 
Patients with a history of more than one immune deficiency or autoimmune disease are 
excluded from participating in the study unless one of them is: 

Autoimmune-mediated hypothyroidism on a stable dose of thyroid replacement 
hormone 

Controlled Type I diabetes mellitus on a stable dose of insulin regimen

A medical history of such entities as atopic disease or childhood arthralgias where 
the clinical suspicion of autoimmune disease is low.  In addition, transient 
autoimmune manifestations of an acute infectious disease that resolved upon 
treatment of the infectious agent are not excluded (e.g., acute Lyme arthritis).  
Caution should be used when considering atezolizumab for patients who have 
previously experienced a severe or lifethreatening skin adverse reaction while receiving 
another immunostimulatory anti-cancer agent.  Please contact the Medical Monitor 
regarding any uncertainty over autoimmune exclusions.
Acute disseminated 
encephalomyelitis
Epidermolysis bullosa 
acquista
Ord’s thyroiditis
Addison’s disease
Gestational pemphigoid
Pemphigus
ANKA positive vasculitis
Giant cell arteritis
Pernicious anemia
Ankylosing spondylitis
Glomerulonephritis
Polyarteritis nodusa
Antiphospholipid antibody 
syndrome
Goodpasture’s syndrome
Polyarthritis
Aplastic anemia
Graves’ disease
Polychondritis
Autoimmune hemolytic 
anemia
Guillain-Barré syndrome
Polyglandular autoimmune 
syndrome
Autoimmune hepatitis
Hashimoto’s disease
Polymyositis
Autoimmune 
hypoparathyroidism
IgA nephropathy
Primary biliary cirrhosis
Autoimmune hypophysitis
Inflammatory bowel disease
Psoriasis
Autoimmune myocarditis
Interstitial cystitis
Pyoderma gangrenosum
Autoimmune oophoritis
Kawasaki’s disease
Reactive arthritis
Autoimmune orchitis
Lambert-Eaton myasthenia 
syndrome
Rheumatoid arthritis


Appendix 5
Preexisting Autoimmune (Chronic Inflammatory) Diseases (cont’d) 
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Autoimmune 
thrombocytopenic purpura
Lupus erythematosus
Sarcoidosis
Behcet’s disease
Lyme disease – chronic
Scleroderma
Bullous pemphigold
Mixed connective tissue 
disease
Sjögren’s syndrome
Celiac disease
Mooren’s ulcer
Stiff-Person syndrome
Chronic fatigue syndrome
Morphea
Takayasu’s arteritis
Chronic inflammatory
demyelinating polyneuropathy
Multiple sclerosis
Ulcerative colitis
Chung-Strauss syndrome
Myasthenia gravis
Vitiligo
Crohn’s disease
Neuromyotonia
Vogt-Kovanagi-Harada 
disease
Dermatomyositis
Opsoclonus myoclonus 
syndrome
Wegener’s granulomatosis
Dysautonomia
Optic neuritis


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Appendix 6
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.


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


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Appendix 8
American Joint Committee on Cancer 
Non-Small Cell Lung Cancer Staging, 7th Edition


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157/Protocol MO39171, Final Version 6
Appendix 9
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
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 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. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to the equivalent of 10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 12 weeks if the Medical Monitor agrees that the patient is likely to derive 
clinical benefit.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 


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pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) and/or magnetic resonance imaging (MRI) 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.
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 corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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. 


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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 or to 
baseline values. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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. 


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Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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. 


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Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with corticosteroids equivalent to 12 mg/kg/day oral prednisone. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the 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. 


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Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the 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.


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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 the equivalent of 
10 mg/day oral prednisone.  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 the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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. 


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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 corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 
diabetes, treat as per institutional guidelines.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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. 


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Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset.
a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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. 


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OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the 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. 


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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, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, 
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 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


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Table 6
Management Guidelines for Immune-Related Myocarditis
Event
Management
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 corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
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 corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VADventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the 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.
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines, anti-
pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole 


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(dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential 
for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.  
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-(Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
COVID-19, which should be confirmed or refuted through assessment of exposure 
history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines.


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


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


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Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCTAmerican Society for Transplantation and Cellular Therapy; BiPAPbi-level 
positive airway pressure; CARchimeric antigen receptor; CPAPcontinuous positive 
airway pressure; CRScytokine-release syndrome; CTCAECommon Terminology 
Criteria for Adverse Events; eCRF electronic Case Report Form; HLHhemophagocytic 
lymphohistiocytosis; ICUintensive care unit; IRRinfusion-related reaction; 
MASmacrophage activation syndrome; NCCNNational Cancer Comprehensive 
Network; NCINational Cancer Institute.
Note:  These management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for these management guidelines is based on ASTCT consensus 
grading for CRS.  NCI CTCAE v4.0 should be used when reporting severity of IRRs, 
CRS, or organ toxicities associated with CRS on the Adverse Event eCRF.  Organ 
toxicities associated with CRS should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients 
who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, 
fever is no longer required when subsequently determining event severity (grade).  In 
this case, the grade is driven by the presence of hypotension and/or hypoxia.
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as 
oxygen delivered at 6 L/min.
e Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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.  For subsequent infusions, administer 
oral premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS.  Premedication with corticosteroids and extending the 
infusion time may also be considered after consulting the Medical Monitor and 
considering the benefitrisk ratio.
f
Refer to Riegler et al. (2019).


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PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab.  The differential diagnosis of acute abdominal pain should include 
pancreatitis.  Appropriate workup should include an evaluation for ductal obstruction, as 
well as serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0ULN:

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone.
Asymptomatic with amylase and/or lipase 2.05.0ULN:

Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset.
a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with corticosteroids 
equivalent to 12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the 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. 


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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 corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-related pancreatitis, 
Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the 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. Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab. A 


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dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 
be considered unless contraindicated.  Management guidelines for dermatologic events 
are provided in Table 9. 


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Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist for evaluation and , if indicated, 
biopsy.

Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 12 mg/kg/day if event does 
not improve within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
Stevens-Johnson 
syndrome or 
toxic epidermal 
necrolysis (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis:

Withhold atezolizumab for suspected Stevens-Johnson 
syndrome or toxic epidermal necrolysis.

Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist or urologist as relevant) for 
evaluation and, if indicated, biopsy.

Follow the applicable treatment and management guidelines 
above.

If Stevens-Johnson syndrome or toxic epidermal necrolysis, 
permanently discontinue atezolizumab.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  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 the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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. 


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NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-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 corticosteroids equivalent to 12 mg/kg/day 
oral or IV prednisone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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 


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or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Related 
Meningoencephalitis
Event
Management
Immune-related 
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the 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.
RENAL EVENTS
Immune-related nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function. Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.


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Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event,
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the 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 MYOSITIS
Immune-related myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.


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Table 13
Management Guidelines for Immune-Related Myositis
Event
Management
Immune-related
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-related
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event 
onset a and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not 
improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
a
Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b
If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the 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. 


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Table 13
Management Guidelines for Immune-Related Myositis (cont.)
Immune-related
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event 
onset a and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe 
cases.

Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day IV methylprednisolone, or higher-dose 
bolus if patient is severely compromised (e.g., cardiac or 
respiratory symptoms, dysphagia, or weakness that 
severely limits mobility); convert to 1-2 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
a
Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b
If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the 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. 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION 
SYNDROME
Immune-related reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS), which are considered to be potential risks for atezolizumab.  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:


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
Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:

Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)

Platelet count 100 109/L (100,000/L)

ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:

Platelet count 181 109/L (181,000/L)

AST 48 U/L

Triglycerides 1.761 mmol/L (156 mg/dL)

Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.
Table 14
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate 


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Event
Management
according to published guidelines (La Rosée 2015; Schram 
and Berliner 2015; La Rosée et al. 2019).

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
References
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024.
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577.
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 29 October 
2018; cited: 17 May 2019]. Available from: https://www.uptodate.com/contents/clinical-
features-and-diagnosis-of-hemophagocytic-lymphohistiocytosis.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk 
Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814.


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Appendix 10
Stool Sample Collection for the Roche Research BioSample 
Repository in Association With Protocol MO39171
PROTOCOL
TITLE:
STOOL SAMPLE COLLECTION FOR THE ROCHE 
RESEARCH BIOSAMPLE REPOSITORY IN 
ASSOCIATION WITH PROTOCOL MO39171
PROTOCOL NUMBER:
MO39171 (Stool Sample Substudy in Selected 
Countries and Selected Sites)
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-001409-34
IND NUMBER:
Not applicable
TEST PRODUCT:
Atezolizumab (RO5541267)
MEDICAL MONITOR:
, M.D.
SPONSOR
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below


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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM ................................................................ 186
11. BACKGROUND ........................................................................................ 188
11.1
Background ......................................................................... 188
11.2
Study Rationale ................................................................... 188
12. OBJECTIVES............................................................................................ 189
13. MATERIALS AND METHODS .................................................................. 189
13.1
Overview of the Roche Research Biosample 
Repository ........................................................................... 189
13.2
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 190
13.3
Sample Collection................................................................ 190
13.4
Confidentiality...................................................................... 190
13.5
Consent to Participate in the Research
Biosample Repository.......................................................... 191
13.6
Withdrawal from the Research Biosample 
Repository ........................................................................... 191
13.7
Monitoring and Oversight..................................................... 192
14. REFERENCES ......................................................................................... 193




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
EC
Ethics Committee
eCRF
electronic Case Report Form
IFN
interferon-gamma
IRB
Institutional Review Board
NSCLC
non-small cell lung cancer
PD-1
Programmed cell death protein 1
PD-L1
Programmed-death ligand 1
RBR
Research Biosample Repository
WMS
whole metagenomic sequencing


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11.
BACKGROUND
Study MO39171 is an ongoing, phase III/IV, single arm, multicenter clinical trial that is 
investigating the long-term safety and efficacy of atezolizumab (Tecentriq®) in 
previously-treated patients with locally advanced or metastatic non-small cell lung 
cancer (NSCLC) (TAIL).  The study is planned to enroll approximately 600 patients.  
Exploratory biomarker analyses are being performed on samples collected under the 
main study protocol.
This protocol describes an optional substudy of MO39171 (MO39171 Stool Sample 
Substudy), which will collect stool samples for the Research Biosample Repository 
(RBR) at Roche. 
11.1
BACKGROUND
Response to cancer immunotherapy is under intense research, and possible 
determinants include genetic variations, activation of the immune system, and the 
bacterial communities living on our mucosal surfaces (referred to as the microbiome), 
which are shaped by diet, environment, and antibiotic exposure (3).  Preclinical studies 
and clinical data suggest that variability in the microbiome influences response to 
chemotherapy and immunotherapy (7-8,10-12).  Additionally, it has been shown that 
bacterial communities associate with treatment-induced adverse effects (e.g., colitis) (4).  
Recent studies show that antibiotic therapy was negatively associated with treatment 
outcome (10).  These findings are intriguing and fit with a growing understanding of how 
bacteria-derived metabolites influence systemic immune responses. 
Roche / Genentech is interested in building a gut microbiome sample repository, which 
would permit examination of how microbial heterogeneity among patients contributes to 
the variable response of atezolizumab-based immunotherapy (including monotherapy 
and combination therapy).  Patient donation of a stool sample (prior to treatment and on 
treatment) will support our ability to define the role of the microbiome as a determinant of 
treatment response and safety in cancer immunotherapy.  Whole metagenomic 
sequencing (WMS) of microbial communities and identification of bacterial-derived 
metabolites in plasma, which may affect systemic immune responses, will allow us to 
understand how the microbiome affects response to treatment.  These studies will also 
establish a foundation for the discovery of new targets. 
11.2
STUDY RATIONALE 
Checkpoint inhibitors targeting the PD1 / PD-L1 axis have shown efficacy in the 
treatment of NSCLC (1-2,5-6,13).  While the success of immunotherapy has been 
encouraging, not all patients respond to treatment, suggesting that genetics, tumor 
microenvironment, stage of disease and other host-related factors may have bearing on 
this response and determine the “immune set point” (3).  For example, the overall 
survival rate in NSCLC patients treated with atezolizumab was higher in those with 
increased PD-L1 expression and associated with preexisting T-effector / IFNhigh 


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gene signatures (5).  Another study showed that high non-synonymous tumor mutation 
burden in patients treated with pembrolizumab was associated with increased 
progression-free survival (9).  The gut microbiome has been established as another of 
the key determinants in immune regulation, in part by influencing T-cell-driven anti-tumor 
responses (7,10-11).  Finally, antibiotic treatment has been associated with poor survival 
outcomes to immunotherapy (10).
In this study, we aim to determine whether an individual’s microbiome can determine 
response to atezolizumab and, conversely, whether atezolizumab alters the microbiome 
such that on-treatment changes could be early predictors of adverse events, including 
colitis (5).  Analyzing the microbiome in NSCLC may also provide an opportunity to 
discover systemic effects in gut distal cancers. 
12.
OBJECTIVES
The objective of this study is to obtain stool samples from patients who participate in 
Study MO39171 for the Roche RBR in order to assess the micobiome, metabolites and 
other biomarkers in the stool of patients.  The samples will be stored in the RBR and 
used for research purposes, including, but not limited to, research on biomarkers related 
to the response to atezolizumab and the development of adverse events in NSCLC.
13.
MATERIALS AND METHODS
13.1
OVERVIEW OF THE ROCHE RESEARCH BIOSAMPLE
REPOSITORY
The Roche RBR is a centrally administered group of facilities used for the long-term 
storage of human biologic specimens, including body fluids, solid tissues, and 
derivatives thereof (e.g., DNA, RNA, proteins, 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 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


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13.2
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 or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.
13.3
SAMPLE COLLECTION
The following samples and/or derivatives thereof will be stored in the RBR and used for 
research purposes, including, but not limited to, research on biomarkers related to 
atezolizumab or diseases:

Stool sample collected during screening 

Stool sample collected at the Day 1 (± 5 days) of Cycle 3 (i.e., at the time of tumor 
assessment) 

Plasma samples at baseline 

Plasma samples at disease progression
The above samples may be sent to one or more laboratories for analysis of microbial 
communities through WMS, bacterial culture, or metabolomics profiling. 
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.
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).
13.4
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 of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 


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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.
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.
13.5
CONSENT TO PARTICIPATE IN THE RESEARCH BIOSAMPLE 
REPOSITORY
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR 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.
13.6
WITHDRAWAL FROM THE RESEARCH BIOSAMPLE 
REPOSITORY
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  However, if RBR specimens have been tested prior 
to withdrawal of consent, results from those tests will remain as part of the overall 
research data.  If a patient wishes to withdraw consent to the testing of his or her 
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 trial 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 trial is closed.  A patient's withdrawal from this substudy of 
Study MO39171 will not, by itself, constitute withdrawal of specimens from the RBR.  
Likewise, a patient's withdrawal from the RBR does not constitute withdrawal from 
Study MO39171.


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13.7
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, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.


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14.
REFERENCES
1. Borghaei H, Paz-Ares L, Horn L, Spigel DR et al. Nivolumab versus Docetaxel in 
Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 
22;373(17):1627-39.
2. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-
35.
3. Chen D and Mellman I. Elements of cancer immunity and cancer-immune set point. 
Nature. 2017 Jan 18;541(7637):321-330. 
4. Dubin K, Callahan MK, Ren B, et al. Intestinal microbiome analyses identify 
melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun. 
2016 Feb 2;7:10391.
5. Fehrenbacher L, Spira A, Ballinger M et al. Atezolizumab versus docetaxel for 
patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, 
open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 
30;387(10030):1837-46.
6. Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small-cell 
lung cancer. N Engl J Med. 2015 May 21;372(21):2018-28. doi: 
10.1056/NEJMoa1501824. 
7. Gopalakrishnan V, Spencer CN, Nezi L et al, Gut microbiome modulates response to 
anti-PD-1 immunotherapy in melanoma patients. Science. 2017 Nov 2. pii: 
eaan4236.
8. Lida N, Dzutsev A, Stewart CA, et al. Commensal bacterial control cancer response 
by modulating the tumor microenvironment. Science. 2013 Nov 22;342(6161):967-
70.
9. Rizvi NA, hellmann MD, Snyder A et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 
Apr 3;348(6230):124-8.
10. Routy B, Le Chatelier E, Derosa L et al. Gut microbiome influences efficacy of PD-1-
based immunotherapy against epithelial tumors. Science. 2017 Nov 2. pii: eaan3706.
11. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes anti-
tumor immunity and facilitates anti-PDL1 efficacy. Science. 2015 Nov 
27;350(6264):1084-9.


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194/Protocol MO39171 Optional Stool Sample Substudy, Version 2
12. Viaud S, Saccheri F, Mignot G et al. Intestinal microbiota modulates anti-cancer 
immune effects of cyclophosphamide. Science. 2013 Nov 22;342(6161):971-6.
13. Zou W, Wolchok J,  Chen L et al. PD-L1 (B7-H1) and PD-1 pathway blockade for 
cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl 
Med. 2016 Mar 2;8(328):328rv4.

SAP_001.pdf: 
Official Title: A Phase III/IV, Single Arm, Multicenter Study of Atezolizumab 
(Tecentriq) to Investigate Long-Term Safety and Efficacy in 
Previously-Treated Patients With Locally Advanced or Metastatic Non-
Small Cell Lung Cancer (Tail) 
NCT Number: NCT03285763  
  Document Date: SAP Version 1.0: 17-July-2019 




Atezolizumab —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO39171, Version 1 
1 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III/IV, SINGLE ARM, MULTICENTER STUDY OF 
ATEZOLIZUMAB (TECENTRIQ) TO INVESTIGATE LONG-
TERM SAFETY AND EFFICACY IN PREVIOUSLY-TREATED 
PATIENTS WITH LOCALLY ADVANCED OR METASTATIC 
NON-SMALL CELL LUNG CANCER (TAIL) 
PROTOCOL NUMBER: 
MO39171 
STUDY DRUG: 
Atezolizumab (RO5541267) 
VERSION NUMBER: 
1 
IND NUMBER: 
NA 
EUDRACT NUMBER: 
2017-001409-34 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Cytel, Inc. 
, F. Hoffmann - La Roche Ltd 
DATE FINAL: 
17-07-2019 
 
 


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Statistical Analysis Plan MO39171, Version 1 
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TABLE OF CONTENTS 
1. 
BACKGROUND .............................................................................................6 
2. 
STUDY DESIGN ............................................................................................6 
2.1 
Protocol Synopsis .....................................................................6 
2.2 
Endpoints .................................................................................6 
2.3 
Determination of Sample Size ..................................................6 
2.4 
Analysis Timing ........................................................................6 
3. 
STATISTICAL METHODS .............................................................................6 
3.1 
Analysis Populations ................................................................7 
3.1.1 
Safety Population .....................................................................7 
3.1.2 
Intent-to-treat Population (ITT) .................................................7 
3.1.3 
Biomarker Evaluable Population (BEP) ....................................7 
3.2 
Analysis of Study Conduct .......................................................7 
3.3 
Analysis of Treatment Group ....................................................7 
3.4 
Efficacy Analysis ......................................................................8 
3.4.1 
Efficacy Endpoints ....................................................................8 
3.4.2 
Patient-Reported Outcomes ................................................... 10 
3.4.3 
Exploratory Efficacy Endpoints ............................................... 11 
3.4.4 
Subgroup Analyses ................................................................ 11 
3.5 
Safety Analyses ...................................................................... 12 
3.5.1 
Exposure of Study Medication ................................................ 13 
3.5.2 
Primary Safety Endpoints ....................................................... 13 
3.5.3 
Adverse Events ...................................................................... 13 
3.5.4 
Time to first onset of AE ......................................................... 13 
3.5.5 
Long-Term Safety ................................................................... 14 
3.5.6 
Duration of AEs ...................................................................... 14 
3.5.7 
Subgroup Analyses ................................................................ 14 
3.5.8 
Laboratory Data ...................................................................... 14 
3.5.9 
Vital Signs and ECOG Performance Status ........................... 15 
3.6 
Missing Data........................................................................... 15 
4. 
REFERENCES ............................................................................................ 16 


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Statistical Analysis Plan MO39171, Version 1 
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LIST OF TABLES 
Table 1: Adverse Events Incidence and Corresponding 95% Confidence 
Interval ...........................................................................................6 
 
 
LIST OF APPENDICES 
Appendix  1 
 Protocol Synopsis Version 3 ....................................................... 17 
Appendix 2 
 Schedule of Assessments .......................................................... 28 
Appendix  3 
 EORTC QLQ-LC13: Scoring Rules ............................................. 32 
 
 


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Statistical Analysis Plan MO39171, Version 1 
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List of Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse events 
AESI 
Adverse events of special interest 
ALK 
Echinoderm microtubule-associated protein-like 4-
anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for the Research and Treatment of 
Cancer 
EQ-5D-5L 
EuroQoL 5 Dimension questionnaire 
FFPE 
Formalin-fixed, paraffin-embedded 
HRQoL 
Health-related quality of life 
iDMC 
INR 
Independent Data Monitoring Committee 
International normalized ratio 
IgG1 
Immunoglobulin G, subclass 1 
irAE 
Immune-related adverse event 
ITT 
Intent-to-treat 
IV 
Intra-venous 
KM 
Kaplan Meier 
LATAM 
Latin America 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute  
NE 
Not evaluable 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective response rate 
OS 
Overall survival 


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Statistical Analysis Plan MO39171, Version 1 
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Abbreviation 
Definition 
PD 
Progressive disease 
PDMS 
Protocol Deviation Management System 
PFS 
Progression free survival 
PR 
Partial response 
PRO 
Patient-reported outcome 
PS 
Performance status 
PT 
Preferred term 
QLQ-LC13 
Quality-of-Life Questionnaire – Supplemental Lung Cancer 
Module 
RBC 
Red blood cell 
RBR 
Research biosample repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RS 
Raw Score 
SAE 
Serious adverse event 
SAF 
Safety population 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SE 
Standard error 
SI 
System International 
SOC 
System Organ Class 
T3 
Free triiodothyronine 
T4 
Free thyroxine 
TKI 
TSH 
Tyrosine kinase inhibitor 
Thyroid-stimulating hormone 
TTD 
Time to deterioration 
WBC 
White blood cell 
 
 


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Statistical Analysis Plan MO39171, Version 1 
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1.
BACKGROUND
This Statistical Analysis Plan (SAP) describes the planned analyses and statistical methods 
used for Study MO39171 (TAIL). 
2.
STUDY DESIGN
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in 


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Appendix  1  
Protocol Synopsis Version 3 
 
.  For additional details, see the Schedule of Assessments in Appendix 2. 
2.2 
ENDPOINTS 
See the Protocol Synopsis in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix  1  
Protocol Synopsis Version 3 
 
 for a description of the outcome measures.  
2.3 
DETERMINATION OF SAMPLE SIZE 
The sample size considerations are based upon estimation precision for the incidence of AEs. 
With 600 patients, the following 95% confidence intervals (CIs) (Table 1) could be provided 
for the different incidences of AEs, which is deemed appropriate for the purposes of the study.  
 
 
Table 1: Adverse Events Incidence and Corresponding 95% Confidence 
Interval  
Sample Size 
AE Incidence 
95% Clopper-Pearson Exact CI 
600 patients 
1% 
[0.2%; 1.8%] 
 
2% 
[0.9%; 3.1%] 
 
3% 
[1.6%; 4.4%] 
 
5% 
[3.3%; 6.7%] 
 
10% 
[7.6%; 12.4%] 
CI, confidence interval 
2.4 
ANALYSIS TIMING 
The following analyses are scheduled: 
 
Primary analysis that will occur approximately 6 months after the last patient has been 
enrolled. 
 
Final analysis that will occur at the end of the study, i.e. when all enrolled patients 
have either died, withdrawn consent, are lost to follow up, or have been followed for 
30 months since the last study patient is enrolled, 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 4 years. 
 
3. 
STATISTICAL METHODS 
The analyses outlined in this SAP supersede those specified in the protocol. 
3.1 
ANALYSIS POPULATIONS 
3.1.1 
Safety Population 
The primary safety population will be based on all patients who received any dose of 
atezolizumab during the study treatment. Patients who were enrolled to the study but who did 
not receive any study drug will not be included in the safety population. 


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3.1.2 
Intent-to-treat Population (ITT) 
The ITT population will be based on all enrolled patients regardless of whether they received 
any study drug. 
3.1.3 
Biomarker Evaluable Population (BEP) 
Patients from the safety population with at least one result for PD-L1 expression on tumor 
cells (TC) in either central or local assessments available. In case both central and local 
assessments are available, central assessments should be used. 
3.2 
ANALYSIS OF STUDY CONDUCT 
Study enrollment, patient disposition, reasons for discontinuation from the study treatment and 
reason for study termination will be summarized for all patients in the ITT population.  
Major protocol deviations, including violations of inclusion/exclusion criteria and deviations 
during study conduct will be reported and summarized. 
3.3 
ANALYSIS OF TREATMENT GROUP  
The following analyses will be based on the Safety population. 
Demographic characteristics, such as age, sex, race, ethnicity, and baseline disease 
characteristics, such as histology subtype, ECOG performance status, tobacco use history, 
number of prior cancer treatments, history of autoimmune disease and serology values will 
be summarized for the Safety population using means, standard deviations (SDs), medians, 
ranges and inter-quartile ranges for continuous variables and frequencies and percentages 
for categorical variables, as appropriate.  
The baseline value will be defined as the last available value recorded on or prior to the first 
administration of any study medication.  
Lung cancer history (including PD-L1 expression from local and/or central labs), CNS 
metastasis at baseline and details on the tumor metastasis at baseline and organs involved 
will also be summarized. 
Prior and concurrent medical history, including but not limited to prior anti-cancer surgery, prior 
lines of NSCLC therapy, prior cancer immunotherapy, prior radiotherapy, prior TKI therapy, 
systemic therapy and medications will be summarized overall.  
Subsequent anti-cancer therapies administered after progression, anti-cancer therapies 
administered before progression or for patients with no progression, follow-up cancer 
radiotherapy, on-study radiotherapy, on-study and follow-up cancer-related medical/surgical 
procedures will be summarized overall. 


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Statistical Analysis Plan MO39171, Version 1 
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3.4 
EFFICACY ANALYSIS 
All efficacy analysis are descriptive and considered as secondary endpoints with the primary 
objective of the study being safety. The Safety population will be used for all efficacy analyses, 
unless otherwise stated. 
3.4.1 
Efficacy Endpoints 
3.4.1.1 
Overall Survival  
OS is defined as the time (in months) from initiation of study treatment to death from any cause. 
Patients alive at the time of clinical cut-off date will be censored on the date the patient was 
last known to be alive. If no post-baseline data are available, OS will be censored at the start 
date of study treatment plus 1 day. 
OS Rate at the 6, 12, 24 and 36-Months Timepoints 
The OS rate at the 6, 12, 24 and 36-months timepoints after initiation of study treatment will 
be estimated using Kaplan-Meier methodology, along with 95% CI calculated with the 
standard error (SE) derived from the Greenwood formula. For the primary analysis, only OS 
rate at 6 and 12 months will be estimated. 
3.4.1.2 
Progression-Free Survival 
PFS according to RECIST 1.1 is defined as the time (in months) from initiation of study 
treatment to the first documented disease progression as determined by the investigator per 
RECIST 1.1, or death from any cause, whichever occurs first. Patients who are alive and who 
have not experienced disease progression at the time of clinical cut-off date will be censored: 
i) at the date of the last tumor assessment, if post-baseline tumor assessment available, ii) at 
the start date of study treatment plus 1 day, if no post-baseline tumor assessment available 
or at study enrollment plus 1 day for patients who were not treated. 
 
3.4.1.3 
Best Overall Response 
BOR according to RECIST v1.1, for a subject is defined as the most favorable outcome, at 
any visit after the start date of study treatment and up to the first documented disease 
progression per RECIST v1.1. Confirmation of response according to RECIST v1.1 is required. 
 
A minimum interval of 6 weeks (42 days) will be considered for Stable Disease (SD) to be 
assigned as best overall response, i.e. in the case the single response is SD, PR or CR, 
thissingle response must have been assessed no less than 6 weeks (at least 42 days) after 
start date of study treatment.  
 
A patient is assigned a BOR of PD if he has a response assessment of PD at any visit, and 
not a BOR of CR, PR, or SD otherwise the best overall response will be Non-Evaluable (NE). 
 
3.4.1.4 
Objective Response Rate 
ORR, according to RECIST v1.1, is defined as the proportion of patients with a confirmed BOR, 
either CR or PR, as determined by the investigator using RECIST v1.1. Patients not meeting 
this criterion, including those without any post-baseline assessment, will be considered non-
responders.  
 


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Statistical Analysis Plan MO39171, Version 1 
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An estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson method.  
 
3.4.1.5 
Duration of Response  
DOR according to RECIST 1.1 is defined as the time from the first tumor assessment that 
supports the patient’s objective response (CR or PR, whichever is first reported) to 
documented disease progression as determined by the investigator according to RECIST v1.1 
or death from any cause, whichever occurs first, among patients who have a best overall 
response as CR or PR. 
 
Patients who are alive and have not experienced disease progression at the time of clinical 
cut-off date will be censored at the time of the last tumor assessment date. If no tumor 
assessments were performed after the date of the first occurrence of a CR or PR, DOR will 
be censored at the date of the first occurrence of a CR or PR plus 1 day. 
 
3.4.1.6 
Objective Response Rate, Progression Free Survival, and Duration 
of Objective Response per Modified RECIST 
ORR, PFS, and DOR analyses using modified RECIST criteria. The investigator-assessed 
ORR is defined as the proportion of patients whose confirmed best overall response is either 
a PR or CR per modified RECIST.  An estimate of ORR and its 95% CI will be calculated for 
the ITT population using the Clopper-Pearson method.   
For patients experienced an objective response (CR or PR per modified RECIST) during the 
study as assessed by the investigator, DOR is defined as the duration from the first tumor 
assessment that supports the patient’s objective response (CR or PR, whichever is first 
recorded) to disease progression or death due to any cause, whichever occurs first.  
Patients who are alive and who have not experienced disease progression at the time of 
analysis will be censored at the last tumor assessment date.  DOR will be assessed using 
Kaplan-Meier methodology.   
PFS by modified RECIST is defined as the time from first treatment taken to disease 
progression as determined by the investigator per modified RECIST or death from any 
cause, whichever occurs first.  A patient is considered to have disease progression by 
modified RECIST if either of the following conditions were met: 
a) Modified RECIST criteria for progression were met at a tumor assessment and no 
subsequent tumor assessment was performed. 
b) Modified RECIST criteria for progression were met at a tumor assessment, and at the 
subsequent tumor assessment, the criteria for confirmed progression by modified 
RECIST were also met.  
 
For patients who meet criterion a, the date of progression is the date of the tumor 
assessment that met the criteria for modified RECIST.  For patients who meet criterion b, the 
date of progression is the date of the tumor assessment at which the modified RECIST 
criteria for progression were first met.  Patients who did not meet either of the above criteria 
are not considered to have had disease progression by modified RECIST.  


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Statistical Analysis Plan MO39171, Version 1 
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PFS and DOR per modified RECIST will be summarized using the Kaplan-Meier 
methodology. 
3.4.2 
 Patient-Reported Outcomes 
Patient-reported outcomes (PROs) of lung cancer-related symptoms (i.e., cough, dyspnea, 
pain in chest, pain in arm/shoulder) will be assessed using the EORTC QLQ LC13 (Bergman 
et al. 1994).  Summary statistics (mean, SD, median, and range) of linear transformed scores 
will be reported for all the items and the dyspnea subscale of the EORTC QLQ-LC13 according 
to the EORTC scoring manual guidelines. The mean change of the linear transformed scores 
from baseline will also be assessed as well as the proportion of patients with improved, stable, 
or worsened outcomes.  
 
Completion and compliance rates will be summarized at each time point will be calculated as 
the number of patients who completed the assessment divided by the number of patients 
expected to complete the assessment at each time. Reasons for missing assessments, if 
available, will be summarized using frequencies and percentages.  
 
The analysis of PRO measures will be conducted on the safety population, and will include all 
assessments until progressive disease as per RECIST 1.1. All assessments performed strictly 
after progressive disease as per RECIST 1.1 will only be listed. 
 
The percentage for baseline will be calculated based on safety population. Only patients with 
a baseline assessment and at least one non-missing post-baseline assessment will be 
included in the analyses. 
 
Time to Confirmed Symptom Deterioration (TTCSD): 
 
Time to confirmed symptom deterioration using the EORTC symptom scores is defined as the 
time from baseline to the first confirmed clinically meaningful deterioration in the EORTC 
symptom score. Confirmed clinically meaningful deterioration in lung cancer symptoms is 
defined as a ≥ 10-point increase above baseline in a symptom score that must be held for at 
least two consecutive assessments or an initial ≥ 10-point increase above baseline followed 
by death within 3 weeks from the last assessment. A ≥ 10-point change in the EORTC scale 
score is perceived by patients as clinically significant (Osoba et al. 1998).  
 
TTCSD will be documented for each of the following EORTC-based symptom scores:  
 
Cough (Question 31 on the EORTC QLQ-LC13)  
 
Chest pain (Question 40 on the QLQ-LC13)  
 
Dyspnea multi-item subscale (Questions 33-35 on the QLQ-LC13)  
 
Arm and/or shoulder pain (Question 41 on the QLQ-LC13)  
 
Composite of the 3 symptoms: cough, dyspnea (multi-item subscales QLQ-LC13) and 
chest pain 
If no baseline or post-baseline assessment is performed, patients will be censored at the start 
date of study treatment plus 1 day. Patients without deterioration at the time of clinical cut-off 
date will be censored at the last time they were known to have not deteriorated.    
 
TTD of the pre-specified symptoms will be summarized using the Kaplan-Meier method. The 
median time and two-sided 95% CI for the median will also be provided.   


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3.4.3 
Exploratory Efficacy Endpoints 
3.4.3.1 
PFS from Start of New Anti-Cancer Therapy 
For patients who started a new anti-cancer therapy, PFS from start of new cancer therapy is 
defined as the time (in months) from start of new anti-cancer treatment to the first occurrence 
of disease progression on next-line treatment or death from any cause, whichever occurs first. 
  
Patients who are alive and who have not experienced disease progression on next-line 
treatment at the time of clinical cut-off date will be censored at the last date known to be alive.  
 
The same analysis as the analysis of PFS RECIST 1.1 will be repeated for PFS from start of 
new anti-cancer therapy. 
3.4.3.2 
ORR from Start of New Anti-Cancer Therapy 
For patients who started a new anti-cancer therapy, ORR from start of new cancer therapy is 
defined as the proportion of patients with a best response of CR or PR, following the start of 
new anticancer therapy. Patients not meeting this criterion will be considered non-responders. 
The same analysis as the analysis of ORR will be repeated for ORR from start of new anti-
cancer therapy. 
3.4.3.3 
Progression-Free Survival 2  
PFS2 is defined as the time (in months) from initiation of study treatment to the first occurrence 
of disease progression on next-line treatment or death from any cause, whichever occurs first. 
Patients who are alive and who have not experienced disease progression on next-line 
treatment at the time of clinical cut-off date will be censored at the last date known to be alive. 
 
The same analysis as the analysis of PFS RECIST 1.1 will be repeated for PFS2. 
 
3.4.3.4 
Sensitivity Analysis 
If there is a difference between the number of patients in the ITT and the SAF population, 
the outputs for OS and PFS will be repeated on the ITT population using the date of 
enrollment as start date. Patients without any post-enrollment data will be censored at the 
date of enrollment plus 1 day. 
3.4.4 
Subgroup Analyses 
The OAK-LIKE Subgroup is defined as patients with the next characteristics: 
 
 
ECOG Performance status of 2: no 
 
Patients with previous anti-PD-1, anti-PD-L1, or ant-CTLA-4 therapy: no 
 
Presence of untreated CNS metastases at baseline: no 
 
Renal impairment (creatine clearance < 30 mL/min (CKD-EPI)): no 
 
Liver 
o AST and ALT ≤ 2.5 times the upper limit of normal (ULN), with alkaline 
phosphatase ≤ 2.5 ULN OR  
o AST and ALT ≤ 1.5 x ULN, with alkaline phosphatase > 2.5 x ULN  
 
HIV-positive: no 
 
HBV/HVC status: not active 


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 
History of autoimmune disease: no 
 
Concomitant steroid treatment ongoing at baseline: no 
OS and PFS results across subgroups will be examined in the following subgroups. Subgroups 
with ≤10 patients will not be included. 
 
 
OAK-LIKE 
 
Demographics:  
o Age (<, >= 65 years), 
o Sex,  
o Region (EMEA, Asia, LATAM), 
o Smoking status (never, current/previous) 
 
Baseline disease characteristics:  
o Histologic subtype (squamous, non-squamous), 
o ECOG performance status at baseline (0/1, 2),  
o Brain metastases at baseline (yes, no)  
o Liver metastases at baseline (yes, no),  
o History of autoimmune disease (yes, no),  
o Prior anti-PD-1 therapies (yes, no),  
o Renal impairment (eGFR<, >= 60 mL/min/m2), 
o EGFR positive at baseline (yes, no),  
o ALK positive at baseline (yes, no), 
o Active hepatitis B or C at baseline (positive, negative),  
 
PD-L1 status (Central): 
o PD-L1 Expression on TC (<1%, ≥1%, [1-50[%, ≥50%) 
 
PD-L1 status (Local): 
o PD-L1 Expression on TC (<1%, ≥1%, [1-50[%, ≥50%) 
 
PD-L1 (BEP): 
o PD-L1 Expression on TC (<1%, ≥1%, [1-50[%, ≥50%) 
o Yes vs No 
 
PD-L1 (OAK-LIKE/BEP): 
o PD-L1 Expression on TC (<1%, ≥1%, [1-50[%, ≥50%) 
o Yes vs No 
 
 
Summaries of OS and PFS, including Kaplan-Meier estimates of median OS and PFS, OS 
rate at 6, 12, 24 and 36 months, PFS rate at 6, 12 and 24 months will be produced separately 
for each level of the subgroup. For the primary analysis, only the rate at 6 and 12 months will 
be estimated. 
3.5 
SAFETY ANALYSES 
Safety summaries will be produced on the safety population.  
3.5.1 
Exposure of Study Medication 
Treatment exposure, including treatment duration and number of doses received will be 
summarized as both continuous and categorical variables.  
3.5.2 
Primary Safety Endpoints  
The primary endpoints are the following AE categories:  
 
Serious AE related to study drug 
 
Immune-related AE related to study drug 


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Incidence rates will be provided along with the corresponding 95% Pearson-Clopper CIs. 
Additionally, both categories will be summarized by SOC, PT and NCI CTCAE grade. 
 
3.5.3 
Adverse Events 
Verbatim description of adverse events will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms and graded according to the NCI CTCAE v4.0.  
Summary tables will include only the treatment emergent adverse events up to the data cutoff 
date. 
 
The following Adverse Events will be summarized: 
 
 
All Adverse Events 
 
Treatment Related Adverse Events 
 
Grade ≥3 adverse events 
 
Serious Adverse Events 
 
Adverse events leading to Atezoliumab discontinuation 
 
Adverse events leading to Atezoliumab discontinuation or interruption 
 
Adverse Events with Fatal Outcome 
 
Adverse Events of Special Interest 
 
Treatment Related Adverse Events of Special Interest 
 
Serious Adverse Events of Special Interest 
 
Immune-Related Adverse Events 
The AE tables will include the number and percentage of patients with at least one AE, by 
MedDRA primary System Organ Classes (SOC) and MedDRA Preferred Terms (PT) and by 
NCI CTCAE grade. A patient with more than one occurrence of the same adverse event in a 
particular SOC/PT will be counted only once in the total of those experiencing adverse events 
in that particular SOC/PT. For immune-related AE related to study drug, similar summary will 
be provided by AESI category and PT. Summary tables displaying number of patients with at 
least one AE by PT will also be provided. 
 
Deaths reported during the study treatment period and those reported during the 
follow-up period after treatment completion/discontinuation and causes of death will 
be summarized by treatment arm. 
3.5.4 
Time to first onset of AE 
The time to first onset of specific AE (AESI) (in months) will be analyzed and be summarized 
using Kaplan Meier methodology. 
The time to first onset of any specific AE is defined as the time (in months) from initiation of 
study treatment until the date of first onset of a specific AE. Patients without any occurrence 
of specific AE will not be counted.  
The analysis described above will be conducted for the following categories of AEs: 
 
AESI, 
 
Immune-related AE 


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3.5.5 
Long-Term Safety 
The incidence of AEs recorded 30 days after last treatment taken will be summarized and will 
display number of patients with at least one AE by SOC/PT, for the following AE: 
 
SAEs 
 
AESIs 
 
3.5.6 
Duration of AEs 
The time to resolution of specific AEs (in months) for AESI and irAE by Category will be 
analyzed and summarized using Kaplan Meier methodology. 
 
 
The start date will be the onset date recorded 
 
If AE is ongoing (no end-date), then the end date will be imputed at the cutoff date and 
the event will be censored. 
 
If a patient has ≥ 2 AE events, the worst grade will be taken into account 
 
If a patient has ≥ 2 AE events with the same grade, the longest will be taken into 
account 
 
3.5.7 
Subgroup Analyses 
Safety summary tables and summary of AE by SOC/PT will be repeated for the following 
subgroups: 
 
 
OAK-LIKE Population 
 
Demographics:  
o Age (<, >=65 years), 
o Age (<, >=80 years),   
o Region (Europe, Asia, LATAM) 
 
Baseline disease characteristics:  
o Histologic subtype (squamous, non-squamous),  
o ECOG performance status at baseline (0/1, 2),  
o Brain metastases at baseline (yes, no)  
o Liver metastases at baseline (yes, no),  
o History of autoimmune disease (yes, no), 
o Prior anti-PD-1 therapy (yes, no), 
o Renal impairment (eGFR<, >= 60 mL/min/m2),  
o EGFR positive at baseline (yes, no), 
o ALK positive at baseline (yes, no), 
o Active hepatitis B or C at baseline (positive, negative), 
3.5.8 
Laboratory Data 
Laboratory parameters will be summarized by using shift table of baseline versus worst post-
baseline category (grade for gradable parameters as per NCI CTCAE version 4.0 and 
low/normal/high for non-gradable parameters). The first abnormal category for patients with 
High and Low for the same laboratory test (at different visits) will be considered. A “Missing” 
category will be reported for subjects with missing grades or missing reference range 
indicators at baseline and/or post-baseline and subjects with no laboratory assessments. 
In addition, a summary table will be provided for clinically relevant laboratory shifts from 
baseline defined as shifts from Grade 0, 1, or 2 at baseline to Grade 3 or 4 post-baseline. 
 


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All laboratory values will be listed. Separate listings will be generated to include all abnormal 
laboratory values for hematology, biochemistry, coagulation and thyroid function. 
3.5.9 
Vital Signs and ECOG Performance Status 
Vital Signs of each patient, actual value and change from baseline for vital signs parameters 
will be summarized using descriptive statistics. ECOG PS will be summarized in a shift table 
of baseline versus worst post-baseline value. 
 
3.6 
MISSING DATA  
For the flagging of a treatment emergent adverse event or concomitant medication with partial 
start and/or end date: the AE/medication will be assumed to be treatment-
emergent/concomitant if it could possibly have started or been taken after the first dose of 
study drug. 
Imputation of partial/missing death date will be done as follows:  
 
If the date is completely missing, then the day of “Last known to be alive” +1 will be 
used  
 
If only day is missing and year and month are same as “Last known to be alive”, then 
the day of “Last known to be alive”+1 will be used otherwise the 1st day of the month 
will be used 
 
If day and month are missing and year is same as “Last known to be alive”, then the 
“Last known to be alive”+1 will be used, otherwise 1st of January will be used 
 


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4. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29−41.  
Clopper, C.; Pearson, E. S. (1934). "The use of confidence or fiducial limits illustrated in the 
case of the binomial". Biometrika. 26: 404–413. 
Fayers PM, Aaronson NK, Bjordal K, et al. The EORTC QLQ-C30 scoring manual. 3rd ed. 
Brussels: European Organisation for Research and Treatment of Cancer, 2001. 
Kaplan, E. L.; Meier, P. (1958): Nonparametric estimation from incomplete observations. J. 
Amer. Statist. Assn. 53:457–481. 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol 1998;16:139−44.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix  1  
Protocol Synopsis Version 3 
 
Objectives and Endpoints 
This study will evaluate the long-term safety and efficacy of atezolizumab in patients with locally 
advanced or metastatic NSCLC who have progressed following standard systemic chemotherapy 
(including if given in combination with anti-PD-1 therapy, after anti-PD-1 as monotherapy, or after 
tyrosine kinase inhibitor [TKI] therapy).  Patients with a previously detected sensitizing EGFR 
mutation or ALK fusion oncogene must have received targeted therapy (TKI) followed by at least 
one line of standard systemic chemotherapy prior to receiving atezolizumab.  Overall, patients 
should not have received more than two lines of standard systemic chemotherapy.  Patients will also 
be eligible if they discontinued first-line or second-line therapy due to intolerance. 
 
Table 1 Objectives and Corresponding Endpoints 
 
Primary Objective 
Corresponding Endpoints 
 To evaluate the long-term safety of 
atezolizumab in previously treated 
patients with advanced NSCLC 
 
 Incidence of serious adverse events (SAEs) related to 
atezolizumab treatment 
 
Incidence of immune-related adverse events (irAEs) 
related to atezolizumab treatment 
Main Secondary Objective 
Corresponding Endpoint 
 To evaluate the efficacy of 
atezolizumab in previously treated 
patients with advanced NSCLC 
 Overall survival (OS) rate at 2 years, defined as the 
proportion of patients remaining alive 2 years after 
initiation of study treatment 
 
TITLE: 
A PHASE III/IV, SINGLE ARM, MULTICENTER STUDY OF 
ATEZOLIZUMAB (TECENTRIQ) TO INVESTIGATE LONG-TERM 
SAFETY AND EFFICACY IN PREVIOUSLY-TREATED PATIENTS 
WITH LOCALLY ADVANCED OR METASTATIC NON-SMALL 
CELL LUNG CANCER (TAIL) 
PROTOCOL NUMBER: 
MO39171 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2017-001409-34 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
PHASE: 
Phase III/IV 
INDICATION: 
Non-small cell lung cancer (NSCLC) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 


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Other Secondary Objectives 
Corresponding Endpoints 
 To further evaluate the efficacy of 
atezolizumab in previously treated 
patients with advanced NSCLC 
 OS, defined as the time from initiation of study 
treatment to death from any cause 
 Progression-free survival (PFS), defined as the time 
from initiation of study treatment to the first 
occurrence of disease progression or death from any 
cause, whichever occurs first.  PFS will be calculated 
based on disease status evaluated by the investigator 
according to Response Evaluation Criteria in Solid 
Tumors, Version 1.1 (RECIST v1.1) and also by 
disease status evaluated by the investigator according 
to modified RECIST 
 OS rate at 3 years, defined as the proportion of 
patients remaining alive 3 years after initiation of 
study treatment 
 Objective response rate (ORR), defined as the 
percentage of patients who attain complete response 
(CR) or partial response (PR) according to 
RECIST v1.1 and also by disease status evaluated by 
the investigator according to modified RECIST 
 Duration of response (DOR), defined as the time from 
initial response to disease progression or death 
among patients who have experienced a CR or PR 
(unconfirmed) during the study.  Duration of response 
will be calculated based on disease status evaluated 
by the investigator according to RECIST v1.1 and also 
by disease status evaluated by the investigator 
according to modified RECIST 
 
Exploratory Objectives 
Corresponding Endpoints 
 To further evaluate the long-term safety 
and efficacy of atezolizumab in 
previously treated patients with 
advanced NSCLC 
 Safety and efficacy of atezolizumab in subgroups of 
the study population differentiated according to:  
Presence of CNS metastases at baseline (yes vs. 
no) 
ECOG performance status (0 or 1 vs. 2) 
Histologic subtype (squamous vs. non-squamous) 
History of or current autoimmune disease 
(yes vs. no) 
Prior anticancer treatment  
 
 Progression-free survival from start of new anti-cancer 
therapy, defined as the time from initiation of new anti-
cancer therapy to objective tumor progression on 
next-line treatment or death from any cause 
 Objective response rate from start of new anti-cancer 
therapy, defined as the percentage of patients who 
attain complete response (CR) or partial response 
(PR) 
 Progression-free survival 2 (PFS2), defined as the 
time from initiation of study treatment to objective 
tumor progression on next-line treatment or death 
from any cause 
 


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Exploratory Biomarker Objectives 
Corresponding Endpoints 
 To assess the role of PD-L1 and other 
biomarkers in the progression and 
fundamental biology of advanced 
NSCLC  
 To evaluate PD-L1 and other 
biomarkers (e.g., cancer-related 
genes) as prognostic biomarkers 
 Safety and efficacy of atezolizumab in subgroups of 
the study population differentiated according to: 
Expression of PD-L1 protein in tumor tissue 
Presence/absence of other biomarkers in tumor 
tissue 
 
 Correlations between PD-L1 expression and other 
biomarkers 
 
Patient-Reported Outcome 
Objectives 
Corresponding Endpoint 
 To evaluate health status utility and 
HR QoL of atezolizumab in previously 
treated patients with advanced 
NSCLC 
 
 EQ-5D-5L index-based and VAS scores 
 EORTC QLQ-LC13 score 
EORTC QLQ-LC13, European Organisation for Research and Treatment of Cancer Quality-of-
Life Questionnaire—Supplemental Lung Cancer Module; EQ-5D, EuroQol 5-Dimension 
Questionnaire; HR QoL, health-related quality of life; VAS, visual analog scale. 
 
Study Design 
Description of Study 
Study MO39171 is a phase III/IV, single-arm, multicenter study of the long-term safety and efficacy 
of atezolizumab treatment in patients with Stage IIIb or Stage IV NSCLC who have progressed 
following standard systemic chemotherapy (including if given in combination with anti-PD-1 therapy, 
after anti-PD-1 as monotherapy, or after TKI therapy).  Patients with a previously detected 
sensitizing EGFR mutation or ALK fusion oncogene must have received targeted therapy (TKI) 
followed by at least one line of standard systemic chemother apy prior to receiving atezolizumab.  
Overall, patients should not have received more than two lines of standard systemic chemotherapy.  
Patients will also be eligible if they discontinued first-line or second-line therapy due to intolerance. 
The study will consist of a Screening Period (Day –28 to Day –1), a Treatment Period, a Treatment 
Discontinuation Visit occurring ≤ 30 days after the last dose of study medication, and a Follow-Up 
Period.  Day 1 (baseline) will be defined as the first day the patient receives atezolizumab.  It is 
anticipated that the trial will enroll 600 patients at 140 sites globally. 
Enrolled patients will receive atezolizumab at a fixed dose of 1200 mg administered intravenously on 
the first day of each cycle (Figure 1).  One cycle of therapy will be defined as 21 days (± 3 days).  
Atezolizumab treatment will continue until investigator-assessed loss of clinical benefit, 
unacceptable toxicity, investigator or patient decision to withdraw from therapy, or death (whichever 
occurs first).   
 


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Figure 1 
Study Schema 
 
Chemo, standard systemic chemotherapy; CNS, central nervous system; ECOG PS, Eastern 
Cooperative Oncology Group performance status; FFPE, formalin-fixed paraffin-embedded; 
IV, intravenous; L, line; NSCLC, non-small cell lung cancer; RBR, Research Biosample Repository; 
TKI, tyrosine kinase inhibitor. 
a. Patients with a previously detected sensitizing EGFR mutation or ALK fusion oncogene must have 
received targeted TKI therapy (no restrictions on number or sequence) followed by at least one line 
of standard systemic chemotherapy prior to receiving atezolizumab.  Patients will also be eligible if 
they discontinued first-line or second-line therapy due to intolerance. 
b. Response will be assessed by the investigator using RECIST v1.1 and modified RECIST.  Patients 
who continue atezolizumab treatment beyond radiographic disease progression assessed per 
RECIST v1.1 will be monitored with a follow-up scan at the next scheduled tumor assessment 
when the scan frequency is every 6 weeks, and will be assessed by modified RECIST criteria until 
treatment discontinuation.  If the scan frequency is every 9 weeks, a follow-up scan is 
recommended at 9 weeks or earlier if clinically indicated. 
c. In those patients for whom tumor assessments are performed as part of local clinical practice and 
are available for report after PD or atezolizumab treatment discontinuation, best overall response 
(BOR) and PFS will be assessed from the first date of the new anticancer therapy to the end of the 
study per RECIST v1.1 and modified RECIST.   
 
The primary objective of the study is to evaluate the long-term safety of atezolizumab.  Long-term 
safety will be assessed by monitoring the nature, severity, duration, frequency and timing of 
atezolizumab-related SAEs and atezolizumab-related irAEs.  An irAE is defined as any adverse 
event of special interest (AESI) associated with systemic corticosteroid use within 30 days of the 
onset date.  All-causality AEs, all-causality SAEs, AEs and SAEs leading to atezolizumab 
interruption or discontinuation, and AESIs will also be reported, as well as causes of death, vital 
signs, physical findings and clinical laboratory results.   
Secondary objectives will assess the efficacy of atezolizumab.  The main efficacy objective will be to 
evaluate the OS rate 2 years after the first dose of atezolizumab.  Other efficacy objectives will 
include evaluation of OS, OS rate at 3 years, PFS, ORR, and DOR (additional efficacy assessments 
may occur on an exploratory basis).  All antitumor response assessments will be based on RECIST 
v1.1 and modified RECIST. 
Exploratory objectives will include evaluation of the safety and efficacy of atezolizumab in patient 
subgroups differentiated by: presence or absence of CNS metastases at baseline; ECOG 
performance status; histological subtype; history of or current autoimmune disease; and prior 
anticancer treatment.  Other exploratory and PRO outcomes will include objective response rate and 
progression-free survival (PFS2) following start of new anticancer therapy, HR QoL as measured on 
the EORTC LQ-LC13, health utility score as measured on the EQ-5D-5L instrument, and expression 
of PD-L1 protein and cancer-related genes in tumor samples obtained before treatment. Finally, 
exploratory biomarkers may be assessed in tissue to assist in the potential development of new 
diagnostic assays and to assess biomarkers in terms of prognosis, response/resistance and safety. 
Following discontinuation of study treatment, safety assessments will be conducted for 30 days after 
the last study drug administration or until initiation of other anti-cancer therapy (whichever occurs 


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first).  Thereafter, follow-up information on disease progression (unless this has already occurred), 
anti-cancer therapy and survival will be collected via telephone contact, patient medical records, 
and/or clinic visits approximately every 3 months until death, loss to follow-up, end of study (30 
months after last patient in), patient withdrawal or study termination by the Sponsor, whichever 
occurs first. 
In those patients for whom tumor assessments are performed as part of local clinical practice and 
are available for report after PD or atezolizumab treatment discontinuation, overall response rate 
(ORR) and progression-free survival (PFS) will be assessed from the first date of the new anticancer 
therapy to the end of the study.  These data will be used in an exploratory fashion to assess whether 
prior atezolizumab treatment positively influences response to subsequent anticancer therapies. 
An Independent Data Monitoring Committee (iDMC) will be established to review all AEs, irAEs, 
SAEs, AESIs and other cumulative safety data. 
A Schedule of Assessments for this study is provided in Appendix 1. 
 
Number of Patients 
This study will enroll approximately 600 patients with Stage IIIb or Stage IV NSCLC who have 
progressed following standard systemic chemotherapy (including if given in combination with anti-
PD-1 therapy or after anti-PD-1 as monotherapy).  Patients with a previously detected sensitizing 
EGFR mutation or ALK fusion oncogene must have received targeted therapy followed by one line 
of standard systemic chemotherapy prior to receiving atezolizumab.  Overall, patients should not 
have received more than two lines of standard systemic chemotherapy.  Patients will also be eligible 
if they discontinued first-line or second-line therapy due to intolerance.  The recruitment of 600 
patients is expected to take place over approximately 18 months.  Patients who discontinue the 
study prior to study treatment initiation will not be replaced. 
 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Signed Informed Consent Form 
2. 
Age ≥ 18 years 
3. 
Able to comply with the study protocol, in the investigator’s judgment 
4. 
Histologically or cytologically documented Stage IIIb or Stage IV NSCLC that has progressed 
following standard systemic chemotherapy (including if given in combination with anti-PD-1 
therapy, after anti-PD-1 as monotherapy, or after TKI therapy).  Patients with a previously 
detected sensitizing EGFR mutation or ALK fusion oncogene must have received targeted 
therapy (TKI), followed by at least one line of standard systemic chemotherapy, prior to 
receiving atezolizumab.  Overall, patients should not have received more than two lines of 
standard systemic chemotherapy.  Patients who have discontinued first-line or second-line 
therapy due to intolerance are also eligible 
– 
Staging must be according to the UICC/AJCC system, 7th edition (Detterbeck et al. 2009) 
– 
Pathological characterization may be conducted on tumor specimens from earlier stage 
disease, but the tumor samples must be sufficient to distinguish squamous or non-
squamous histology 
– 
Chemotherapy regimens will be counted based on interval disease progression, and not on 
the number of agents or the number of switches in agents (e.g., a first-line or second-line 
therapy that consists of several cycles of a platinum doublet and subsequent maintenance 
therapy that introduces or switches to a new chemotherapy agent without interval disease 
progression will all be considered one chemotherapy regimen) 
– 
Patients with a previously-detected sensitizing EGFR mutation must have experienced 
disease progression (during or after treatment) on an EGFR TKI (erlotinib, gefitinib, 
osimertinib, etc.)   
– 
Patients with a previously detected ALK fusion oncogene must have experienced disease 
progression (during or after treatment) with crizotinib, alectinib, or another ALK inhibitor 
– 
Prior radiation therapy is allowed, provided that the patient has recovered from any toxic 
effects thereof.  Combined radiation/chemotherapy treatment constitutes a single regimen 
– 
Combined radiation/chemotherapy treatment (chemoradiation) counts as one prior 
chemotherapy regimen if < 6 months have elapsed between the last dose and the date of 
recurrence 


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– 
Adjuvant/neoadjuvant chemotherapy is not counted as a line of treatment 
– 
Debulking surgery and anticancer agents used for pleurodesis are not counted as lines of 
therapy 
 
5. 
The last dose of prior systemic anticancer therapy must have been administered ≥ 21 days prior 
to study treatment initiation 
6. 
The last dose of prior anti-PD-1 therapy must have been administered 
– 
Nivolumab must have been discontinued ≥ 14 days and pembrolizumab ≥ 21 days prior to 
study treatment initiation, providing that these treatments were not administered in a clinical 
trial setting 
 
7. 
Measurable disease, as defined by Response Evaluation Criteria for Solid Tumors, Version 1.1 
(RECIST v1.1) 
8. 
Patients with asymptomatic CNS metastases (treated or untreated), as determined by CT or 
MRI evaluation during screening and prior radiographic evaluation, are eligible 
9. 
ECOG performance status 0, 1, or 2 [Appendix 7] 
10. Life expectancy ≥ 12 weeks 
11. Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 2 weeks prior to the first study treatment: 
– 
Absolute neutrophil count ≥ 1500 cells/µL (without granulocyte colony-stimulating factor 
support within 2 weeks prior to the first study treatment) 
– 
White blood cell count > 2500/µL 
– 
Lymphocyte count ≥ 500/µL 
– 
Platelet count ≥ 100,000/µL (without transfusion within 2 weeks prior to the first study 
treatment) 
– 
Hemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to 
meet this criterion) 
– 
Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase ≤ 
2.5 times the upper limit of normal (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’s Syndrome who have serum 
bilirubin level ≤ 3 × ULN may be enrolled. 
– 
Calculated creatinine clearance ≥ 15 mL/min (Cockcroft-Gault formula) 
– 
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 
×ULN.  This applies only to patients who are not receiving therapeutic anticoagulation 
agents 
– 
Patients receiving therapeutic anticoagulation agents must be on a stable dose 
– 
HIV-positive patients are allowed, so long as they are on stable anti-retroviral therapy, have 
a CD4 count ≥ 200 cells/µL, and have an undetectable viral load at the time of screening 
 
12. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive methods that result in 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 postmenarchal, 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, established, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices 
– 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception 


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13. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities 
from previous therapy, excluding alopecia and toxicities related to prior anti-PD-1-therapy 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
Symptomatic CNS metastases  
2. 
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 study treatment initiation 
3. 
Leptomeningeal disease 
4. 
Uncontrolled pericardial effusion or ascites requiring recurrent drainage procedures 
5. 
Pregnant or lactating, or intending to become pregnant during the study 
– 
Women who are not postmenopausal (postmenopausal defined as ≥ 12 months of non-
drug-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result within 2 weeks prior to initiation of study drug 
 
6. 
Evidence of significant uncontrolled concomitant disease that could affect compliance with the 
protocol, including significant liver disease (such as cirrhosis, uncontrolled major seizure 
disorder, or superior vena cava syndrome) 
7. 
Significant cardiovascular disease, such as New York Heart Association cardiac disease 
≥ Class III, myocardial infarction within 3 months, unstable arrhythmias, or unstable angina 
– 
Patients with known coronary artery disease 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 
 
8. 
Significant renal disorder requiring dialysis or indication for renal transplant 
9. 
Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 28 days prior to study treatment initiation 
10. Major surgical procedure within 4 weeks prior to study treatment initiation or anticipation of need 
for a major surgical procedure during the course of the study other than for diagnosis 
11. Inability to understand the local language(s) for which the EORTC QLQ-LC13 and EuroQol EQ-
5D-5L questionnaires are available 
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
14. History of autoimmune disease (Appendix 5) are allowed if controlled and on stable treatment 
(i.e., same treatment, same dose) for the last 12 weeks, with the exception of: 
– 
Patients taking concurrent abatacept or belatacept treatment, unless therapy has been 
withdrawn for > 8 weeks 
– 
Patients with a history of serious or life threatening immune-related events 
– 
No more than 1 concomitant autoimmune disease at the time of study entry is allowed 
unless one of them is:  
Autoimmune-mediated hypothyroidism on a stable dose of thyroid replacement 
hormone  
Controlled Type I diabetes mellitus on a stable dose of insulin regimen 
A medical history of such entities as atopic disease or childhood arthralgias, where the 
clinical suspicion of autoimmune disease is low.  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) 
 
15. Prior allogeneic stem cell or solid organ transplantation 
16. History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest computed tomography (CT) scan 


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– 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
 
17. Active tuberculosis 
– 
In patients who have a potentially high likelihood of latent tuberculosis (e.g., recent contact 
with an infectious carrier, residence in a locale with high TB burden), absence of 
Mycobacterium tuberculosis infection must be confirmed before enrollment according to 
local practice standards 
 
18. Administration of a live, attenuated vaccine within 4 weeks prior to study treatment initiation 
– 
Influenza vaccination should be given during influenza season only (e.g., approximately 
October to March in the Northern Hemisphere).  
– 
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks 
prior to study treatment initiation or at any time during the study 
 
19. Prior treatment with CD137 agonists or immune checkpoint blockade therapies other than anti-
PD-1 therapy, including anti−PD-L1 therapeutic antibodies 
20. Treatment with systemic immunostimulatory agents (including, but not limited to, interferons or 
interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to initiation 
of study treatment 
– 
Prior cancer vaccines and cellular immunotherapy are permitted 
 
21. Specifically for patients without autoimmune disease: 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 study treatment initiation, or anticipated 
requirement for systemic immunosuppressive medications during the trial 
– 
For patients with CNS metastases, use of prednisone at a stable dose (or dose equivalent) 
of ≤ 20 mg/day is acceptable  
– 
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 and topical steroids for 
cutaneous diseases are allowed 
 
End of Study and Length of Study 
The end of study and final analysis will occur when all enrolled patients have either died, withdrawn 
consent, are lost to follow up, or have been followed for 30 months since the last study patient is 
enrolled, 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 4 years. 
The primary analysis will occur approximately 6 months after the last patient has been enrolled. 
 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The investigational medicinal product (IMP) for this study is atezolizumab. 
The dose of atezolizumab in this study will be 1200 mg (equivalent to an average body weight-
based dose of 15 mg/kg) administered by intravenous infusion every 3 weeks (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.  For detailed information 
on drug preparation, storage and administration, refer to the Atezolizumab Investigator’s Brochure. 
The initial dose of atezolizumab will be administered over 60 (± 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, 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 the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood 
pressures, and temperature) should be determined within 60 minutes before, during (every 15 [± 5] 
minutes) if clinically indicated, and 30 (± 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before the infusion, during the infusion if clinically 
indicated, and 30 minutes (± 10 minutes) after the infusion if clinically indicated or patient 
experienced symptoms during previous infusions.   


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Patients will be informed about the possibility of delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such symptoms. 
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 (Grade 1) National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) infusion-related event, the infusion 
rate should be reduced to half the rate being given at the time of event onset.  Once the 
event has resolved, the investigator should wait for 30 minutes while delivering the infusion 
at the reduced rate.  If tolerated, the infusion rate may then be increased to the original rate 
 
In the event that a patient experiences a moderate infusion-related event (NCI CTCAE 
Grade 2) or flushing, fever, or throat pain, the patient should have his or her infusion 
immediately interrupted and should receive aggressive symptomatic treatment.  The infusion 
should be restarted only after the symptoms have adequately resolved to baseline grade.  
The infusion rate at restart should be half of the infusion rate that was in progress at the time 
of the onset of the infusion-related event 
 
For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), the infusion 
should be stopped immediately, and aggressive resuscitation and supportive measures 
should be initiated.  Patients experiencing severe or life-threatening infusion-related events 
will not receive further infusion and will be further managed as clinically indicated until the 
event resolves 
 
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage and 
administration. 
 
Non-Investigational Medicinal Products 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine and/or famotidine or another H2 receptor 
antagonist, as per standard practice (equivalent medications may be substituted per local 
practice).  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation or respiratory distress 
should be managed with supportive therapies as clinically indicated (e.g., supplemental 
oxygen and β2-adrenergic agonists. 
 
Systemic corticosteroids and tumor necrosis factor−α inhibitors may attenuate potential 
beneficial immunologic effects of treatment with atezolizumab, but may be administered at 
the discretion of the treating physician after consultation with the Medical Monitor (see 
Exclusion Criterion 21 and Prohibited Therapy.  If feasible, alternatives to corticosteroids 
should be considered.  Premedication may be administered for Cycles ≥ 2 at the discretion of 
the treating physician after consultation with the Medical Monitor.  The use of inhaled 
corticosteroids for COPD and mineralocorticoids (e.g., fludrocortisone) and low-dose 
corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is 
allowed.  Megestrol administered as an appetite stimulant is acceptable while the patient is 
enrolled in the study. 
 
Colony-stimulating factors, such as granulocyte colony-stimulating factor and erythropoietin, 
should only be used according to manufacturers’ labels and the ASCO and ASCO/ASH 
guidelines.   
 
Influenza vaccination should be given during influenza season only (approximately October 
to March in the Northern Hemisphere).  Patients must not receive live, attenuated influenza 
vaccine (e.g., FluMist®) within 4 weeks prior to study treatment initiation or at any time 
during the study. 
 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low molecular weight heparin or warfarin at a 
stable dose level), or other allowed maintenance therapy should continue their use. 
 


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All concomitant medications should be reported to the investigator and recorded on the appropriate 
eCRF. 
 
Prohibited Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health authority-approved or 
experimental, unless otherwise specified, is prohibited.  This includes but is not limited to the 
following: 
 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, or investigational agents 
(except for maintenance therapies outlined in Section 4.1.1 and 4.1.2 of the protocol) 
– 
After completion of Cycle 1, certain forms of radiotherapy may be considered for palliation if 
patients are deriving benefit (e.g., treatment of known bone metastases)  
– 
Patients experiencing a mixed response requiring local therapy (e.g., surgery, stereotactic 
radiosurgery, radiotherapy, radiofrequency ablation) for control of three or fewer lesions 
may still be eligible to continue study treatment.  Patients who receive local therapy 
directed at a target lesion will no longer be evaluable for radiographic response but will 
remain evaluable for progression. Such cases must be discussed with and approved by the 
Sponsor 
 
 
Traditional herbal medicines are not recommended because the ingredients of many herbal 
medicines are not fully studied, and their use may result in unanticipated drug-drug 
interactions that may cause or confound assessment of toxicity 
 
Patients should not receive abatacept or belatacept treatment (those who were receiving it 
must stop it > 8 weeks before study entry) 
 
Patients are not allowed to receive immunostimulatory agents, including but not limited to interferon 
(IFN)-α, IFN-γ, or IL-2, during the entire study.  These agents, in combination with atezolizumab, 
could potentially increase the risk for autoimmune conditions. 
With the exception of autoimmune disease patients, patients should not receive immunosuppressive 
medications, including but not limited to cyclophosphamide, azathioprine, methotrexate, and 
thalidomide.  These agents could potentially alter the activity and the safety of atezolizumab.   
Systemic corticosteroids and anti−TNF-α agents may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab, but may be administered at the discretion of the treating 
physician after consultation with the Medical Monitor.  If feasible, alternatives to these agents should 
be considered. 
Patients with CNS metastases are allowed to receive anticonvulsants and steroid treatments if the 
dose of prednisone is stable and ≤ 20 mg/day (or equivalent).  
In addition, all patients (including those who discontinue the study early) should not receive other 
immunostimulatory agents for 10 weeks after the last dose of atezolizumab. 
The above list of medications is not necessarily comprehensive.  The investigator should consult the 
prescribing information for any concomitant medication and contact the Medical Monitor if questions 
arise regarding medications not listed above. 
 
Statistical Methods 
Primary Analysis 
All safety analyses will be run on the Safety Analysis set, defined as all enrolled patients who had at 
least one administration of atezolizumab. 
The incidence of SAEs related to atezolizumab and the incidence of irAEs related to atezolizumab 
will be summarized by incidence rates and 95% Pearson-Clopper confidence intervals. 
 
Determination of Sample Size   
No formal sample size calculation linked to hypothesis testing is done for this descriptive study.  The 
sample size considerations are based upon estimation precision for the incidence of AEs.  With 600 
patients, the following 95% CIs (Table 2) could be provided for the different incidences of AEs, 
which is deemed appropriate for the purposes of the study. 
 
Table 2. Adverse Event Incidence and Corresponding 95% Confidence Intervals 
 


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Sample Size 
AE Incidence  
95% Clopper-Pearson Exact CI 
600 patients 
1% 
1%  [0.2% ; 1.8%] 
2% 
2%  [0.9% ; 3.1%] 
3% 
3%  [1.6% ; 4.4%] 
5% 
5%  [3.3% ; 6.7%] 
10% 
10%  [7.6% ; 12.4%] 
CI, confidence interval. 
 
Interim Analyses 
This study will have no formal interim analyses.  However, regular safety reviews of data will be 
performed by an Independent Data Monitoring Committee (iDMC).  The frequency of these reviews 
will be stated in the iDMC charter. 
In addition, to adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim analysis for reporting and publication of safety and efficacy 
results. 


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Appendix 2 
 
Schedule of Assessments 
 


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Appendix  3  
EORTC QLQ-LC13: Scoring Rules 
 
The lung cancer module (EORTC QLQ-LC13) is meant for use among a wide range of lung 
cancer patients varying in disease stage and treatment modality (Bergman et al., 1994). The 
module comprises 13 questions and is designed for use among patients receiving treatment 
with chemotherapy and/or radiotherapy. The QLQ-LC13 includes questions assessing lung 
cancer-associated symptoms (cough, hemoptysis, dyspnea and site specific pain), treatment-
related side effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain 
medication. 
 
Scoring of QLQ-LC13 
The lung cancer module incorporates one multi-item scale to assess dyspnea, and a series of 
single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, 
alopecia, and hemoptysis. Details of multi-item scales information are in Error! Reference 
source not found.. 
 
A score for a specific scale will be calculated only if all items of the scale are non-missing; 
otherwise, it will be set as missing.  
 
Table 33: Scoring the QLQ-LC13 
Scale name 
Scale 
Number 
of items 
Item 
range* 
QLQ-LC13 Item 
numbers 
Dyspnoea 
LCDY 
3 
3 
33,34,35 
Coughing 
LCCO 
1 
3 
31 
Haemoptysis 
LCHA 
1 
3 
32 
Sore mouth 
LCSM 
1 
3 
36 
Dysphagia 
LCDS 
1 
3 
37 
Peripheral neuropathy 
LCPN 
1 
3 
38 
Alopecia 
LCHR 
1 
3 
39 
Pain in chest 
LCPC 
1 
3 
40 
Pain in arm or shoulder 
LCPA 
1 
3 
41 
Pain in other parts 
LCPO 
1 
3 
42 
Dyspnoea at Resting 
LCDYR 
1 
3 
33 
Dyspnoea at Walking 
LCDYW 
1 
3 
34 
Dyspnoea at Climbing Stairs 
LCDYC 
1 
3 
35 
* “Item range” is the difference between the possible maximum and the minimum response to individual 
items.