Clinical trial NCT02409355
Conditions: Non-Small Cell Lung Cancer
Sponsor: Hoffmann-La Roche
Start date: 2015-05-07; Completion date: 2017-12-07
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, open-label study was designed to evaluate and compare the safety and efficacy of atezolizumab with gemcitabine + cisplatin or carboplatin in PD-L1 selected participants with chemotherapy-naive, Stage IV squamous NSCLC. The study was closed due to low patient enrollment and the Sponsor's decision to include patients with squamous NSCLC into the GO29431 study, NCT02409342. Therefore the planned objectives of this study are no longer applicable and formal analyses of efficacy or safety have not been performed.

Detailed description:

Arms: arm 1: Participants will receive intravenous (IV) infusion of atezolizumab once on Day 1 of each 21-day cycle until loss of clinical benefit. arm 2: Participants will receive IV infusion of gemcitabine + cisplatin or gemcitabine + carboplatin once on Day 1 of each 21-day cycle for four or six cycles as per local standard of care.
Interventions: intervention 1: Atezolizumab intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: Gemcitabine
Intervention descriptions: intervention 1: Atezolizumab will be administered at a dose of 1200 milligrams (mg) by IV infusion on Day 1 of each 21-day cycle until loss of clinical benefit. intervention 2: Carboplatin will be administered at area under the concentration-time curve (AUC) 5 IV infusion once on Day 1 of each 21-day cycle for 4 or 6 cycles. intervention 3: Cisplatin will be administered at 75 milligrams per square meter (mg/m\^2) IV infusion once on Day 1 of each 21-day cycle for 4 or 6 cycles. intervention 4: Gemcitabine will be administered at 1000 mg/m\^2 (when coadministered with carboplatin) or 1250 mg/m\^2 (when coadministered with cisplatin) IV infusion on Days 1 and 8 of each 21-day cycle for 4 or 6 cycles.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase  
I
I
I
,  Open-Labe
l,  Randomized  Study  of Atezo
l
izumab 
(Anti-PD-L1  Antibody)  Compared  With Gemcitab
ine+Cisp
latin  or 
Carbop
latin  for PD-L1-Se
lected,  Chemotherapy  Na
ive  Patients 
With Stage  
IV  Squamous  Non-Sma
l
l  Ce
l
l Lung  Cancer 
NCT Number: NCT02409355     
Document Date: Protoco
l Version 5: 24 June 2016 
 
 
 
 




Atezolizumab—F. Hoffmann-La Roche Ltd 
2/Protocol GO29432, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol GO29432 has been amended to remove the option for erlotinib switch 
maintenance for patients randomized to Arm B of the study (see Sections 1.4, 3.1, 3.3.2, 
4.3.1.3, 4.3.2.2, 4.3.2.3, 4.4.1, 5.1.3.3).  Recent data from Study BO25460 have 
demonstrated that patients with advanced or recurrent (Stage IIIB) or metastatic 
(Stage IV) non−small cell lung cancer (NSCLC) whose tumor did not harbor an 
epidermal growth factor receptor (EGFR)-activating mutation did not achieve benefit 
from maintenance therapy with erlotinib compared with placebo.  Given the low 
incidence of EGFR-activating mutations in patients with squamous histology, the option 
of erlotinib switch maintenance therapy has been removed for all patients randomized to 
Arm B of the study.  Patients already on switch maintenance therapy with erlotinib that 
was permitted under previous protocol versions may be allowed to continue to receive 
treatment with erlotinib upon discussion of the risks, potential benefits, and alternative 
treatment options with the investigator. 
Furthermore, a recent communication (dated 18 April 2016) was sent to the investigators 
to inform of the Sponsor’s decision to close enrollment into Study GO29432 and to enroll 
patients with squamous NSCLC into the ongoing Study GO29431 (IMpower110) in order 
to streamline and simplify the design of both studies.  Patients already enrolled in 
Study GO29432 will remain on study and will be allowed to continue study treatment 
until radiographic disease progression per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 (or loss of clinical benefit for atezolizumab-treated patients who continue 
treatment beyond disease progression according to RECIST v1.1), withdrawal of 
consent, enrollment into an extension study, or death, whichever occurs first.   
This amendment will reduce the number and type of protocol-specified assessments for 
evaluation of study treatment but will retain the requirements for reporting of adverse 
events and to monitor patient safety.  Specifically, the following assessments have been 
removed: 
•   Pharmacokinetic  
•   Biomarker  
•   Anti-therapeutic antibody  
•   Tumor tissue sampling  
•   Patient-reported outcome assessments  
•   Survival follow-up 
 
Additionally, this amendment includes the following changes: 
•   The recent approval in the United States of atezolizumab for the treatment of locally 
advanced or metastatic urothelial cancer has been added (see Sections 1.5 and 5). 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
3/Protocol GO29432, Version 5 
•   Objectives, endpoints, assessments noted above, and associated statistical 
analyses have been removed as they are no longer relevant (see Sections 2, 3.3.3, 
3.4, 4.3.4, 4.5.6, 4.5.9, 4.5.11, 4.5.13.3., and 4.5.13.4, 5.3.5.8, and 6). 
•   The tumor tissue biopsy at the time of radiographic progression has been made 
optional (see Sections 3.1, 3.3.6, 4.5.7.2, and 8.2). 
•   The requirement for independent Data Monitoring Committee (iDMC) reviews has 
been removed due to the closeout of the study (Section 3.1.1). 
•   Study language has been revised to reflect the study’s closure to enrollment due to 
a low number of patients (see Sections 3.2, 4.1, and 9.4).  
•   Based on the half-life of atezolizumab of 27 days, the use of contraception for 
female patients treated with atezolizumab has been extended from 90 days to 
5 months after the last dose of atezolizumab, and female patients treated with 
atezolizumab should be instructed to inform the investigator of any pregnancy that 
occurs during study treatment and within 5 months after the last dose of 
atezolizumab (see Sections 4.1.1 and 5.4.3.1). 
•   Hormone replacement therapy or oral contraceptive have been removed from the 
exclusion criteria (see Section 4.1.2.3).  
•   Drug formulation and handling information for atezolizumab has been removed, and 
investigators should refer ro the Pharmacy Manual and Investigator’s Brochure (see 
Section 4.3.1.1). 
•   Hormonal therapy with gonadotropin-releasing hormone agonists or antagonists for 
prostate cancer have been removed from the list of permitted therapy (see 
Section 4.4.1). 
•   Traditional herbal medicines have been removed from prohibited therapy, and 
language has been added to state that concomitant use of herbal therapies is not 
recommended because the pharmacokinetics, safety profile, and drug-drug 
interactions are unknown.  However, use of herbal therapies not intended for the 
treatment of cancer for patients in the study is allowed at the discretion of the 
investigator (see Section 4.4.3). 
•   Language around other therapeutic options and continuation of atezolizumab at time 
of radiographic progression has been clarified (see Sections 4.5.1 and 4.6.2). 
•   The requirement for urinalysis to be performed at all treatment cycles and the 
treatment discontinuation visit has been removed.  Urinalysis will be obtained during 
study treatment when clinically indicated (see Section 4.5.6). 
•   The Epstein-Barr virus serology sample testing for patients experiencing an acute 
inflammatory event has been removed (see Section 4.5.6). 
•   It has been clarified that tumor tissue samples collected at the time of clinical events 
are preferred (see Section 4.5.7.3). 
•   It is noted that the whole blood sample for DNA extraction may be collected at any 
time during the study (see Section 4.5.12.3). 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
4/Protocol GO29432, Version 5 
•   Screening assessments have been noted to be available in Version 4 of the protocol 
(see Section 4.5.13.1).  
•   The atezolizumab Investigator’s Brochure was revised to include updated 
approaches for the management of atezolizumab-specific adverse events.  
To ensure consistent application of the most updated guidelines across 
atezolizumab protocols at all times, management guidelines and tables for 
atezolizumab-specific adverse events have been deleted from the protocol and 
replaced by cross-references to the guidelines in the current version of the 
Investigator’s Brochure (see Sections 5.1.1, 5.1.5.1, 5.1.6, and 5.1.7). 
•   General guidelines regarding dose modifications have been added and that the 
investigator may use discretion in modifying or accelerating the dose modification 
guidelines depending on the severity of the toxicity and an assessment of the risk 
versus benefit for the patient, with the goal of maximizing patient compliance and 
access to supportive care (see Section 5.1.5.1) 
•   Revisions have been made for consistency with the guidelines for management of 
atezolizumab-specific adverse events in the atezolizumab Investigator’s Brochure 
(see Sections 5.1.1 and 5.1.7).The contraception requirements for male patients 
and pregnancy-reporting requirements for female partners of male patients who 
receive atezolizumab have been updated on the basis of the safety information for 
atezolizumab.  Atezolizumab is not expected to be genotoxic.  In addition, the 
anticipated concentrations of atezolizumab in seminal fluid as well as the potential 
risk to the developing conceptus is low following seminal transfer of atezolizumab to 
a female partner (see Section 5.4.3.2). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
5/Protocol GO29432, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
•   The Medical Monitor contact information has been updated. 
•   Abbreviations have been spelled out in headings, where appropriate. 
•   The specific brand has been removed from references to prescribing information, 
where appropriate. 
•   References to the Independent Data Monitoring Committee have been removed 
from the text. 
•   The 12-month timepoint around tumor assessments has been clarified to be 
48 weeks. 
•   The option of enrollment into the extension study has been added, where applicable. 
 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.4: Maintenance Therapy for Non−Small Cell Lung Cancer 
When the study was started, switch maintenance with erlotinib in unselected patients 
could be considered fFor patients with stable disease or continued response to therapy 
after four to six cycles of chemotherapy, switch maintenance treatment with erlotinib in 
unselected patients or pemetrexed in those with nonsquamous histology can be 
considered (NCCN Guidelines 2014).  This recommendation iswas based on two 
randomized Phase III trials, which have shown a PFS and OS benefit after the initiation 
of pemetrexed or erlotinib after induction treatment in patients with no disease 
progressionthe Sequential Tarceva Unresectable NSCLC study (SATURN) .  In 
theSATURN trialstudy, the median PFS in patients receiving maintenance therapy with 
erlotinib was significantly longer than in patients receiving placebo (12.3 vs. 11.1 weeks; 
hazard ratio [HR] 0.71, 95% CI: 0.62−0.81; p
 <
 0.0001).  Maintenance treatment with 
erlotinib also yielded a statistically significant yet clinically modest improvement in OS 
(12.0 vs. 11.0 months; HR 0.81, 95% CI: 0.70−0.95; p
 =
 0.0088).  A statistically 
significant improvement in PFS and OS was observed in patients with EGFR−wild-type 
and EGFR−mutation-positive tumors (Cappuzzo et al. 2010).  In the Phase III clinical 
trial evaluating pemetrexed maintenance therapy following four cycles of platinumbased 
doublet chemotherapy, pemetrexed significantly improved PFS (4.3 vs. 2.6 months; HR 
0.50, 95% CI: 0.42 0.61; p
 <
 0.0001) and OS (13.4 vs. 10.6 months; HR 0.79, 95% CI: 
0.65−0.95; p
 =
 0.012) when compared with placebo (Ciuleanu et al. 2009).  These This 
Phase III trials resulted in regulatory approval by the U.S. Food and Drug 
Administration (FDA) and European Medicines Agency for erlotinib in (unselected 
NSCLC) and pemetrexed (nonsquamous NSCLC), respectively, as maintenance 
therapy of patients with locally advanced or metastatic NSCLC whose disease has not 
progressed after four cycles of platinum-based first-line chemotherapy.  However, recent 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
6/Protocol GO29432, Version 5 
data from Study BO25460, a randomized, double-blind, placebo-controlled Phase III 
study, have demonstrated that patients with advanced or recurrent (Stage IIIB) or 
metastatic (Stage IV) NSCLC whose tumor did not harbor an EGFR-activating 
mutation did not achieve benefit from first-line maintenance therapy with erlotinib 
compared with placebo.  OS was not superior in patients randomized to receive 
maintenance erlotinib followed by chemotherapy or best supportive care upon disease 
progression compared with patients randomized to receive maintenance placebo 
followed by erlotinib upon disease progression (HR
 =
 1.02, 95% CI, 0.85−1.22, p
 =
 0.82).  
In the maintenance phase, patients who received erlotinib also did not have superior 
PFS compared with patients who received placebo (HR =
 0.94, 95% CI, 0.80−1.11, 
p
 =
 0.48).  This change in the benefit-risk assessment of erlotinib as switch maintenance 
therapy in patients whose tumors do not harbor an activating EGFR mutation has led 
to the removal of this treatment option from this protocol.  Patients already receiving 
the switch maintenance therapy with erlotinib, permitted under previous protocol 
versions, may be allowed to continue to receive treatment with erlotinib upon 
discussion of the risks, potential benefits, and alternative treatment options with the 
investigator. 
SECTION 1.5:  Background on Atezolizumab (MPDL3280A) 
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial cancer.  
SECTION 1.6.2.1:  Single-Agent Clinical Safety in Patients with Non−Small 
Cell Lung Cancer 
Study PCD4989g is a Phase Ia dose escalation and expansion study, in which 
atezolizumab is being used as a single agent in patients with locally advanced or 
metastatic solid tumors or hematologic malignancies, and provides the majority of data 
(with 558 safety evaluable patients as of the data extraction cutoff date of 11 May 2015) 
for the safety profile of atezolizumab as monotherapy. 
SECTION 2:  Objectives 
The study is currently closed to enrollment due to a low number of patients; therefore, 
the objectives of this study are no longer applicable and formal analyses of efficacy or 
safety will not be performed.Analyses of all objectives specified below will be performed 
in chemotherapynaive patients with Stage IV squamous NSCLC who are selected on 
the basis of high PDL1 expression on TCs and/or ICs (TC3 or IC3) using a centrally 
performed IHC assay (see Appendix 6). 
SECTION 2.1:  Efficacy Objectives 
SECTION 2.1.1:  Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab 
compared with gemcitabine
 +
 cisplatin or carboplatin in PDL1−selected patients with 
Stage IV squamous NSCLC, as measured by investigator−assessed PFS according to 
RECIST v1.1 (see Appendix 4). 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
7/Protocol GO29432, Version 5 
SECTION 2.1.2:  Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are: 
•  To evaluate the efficacy of atezolizumab compared with gemcitabine
 +
 cisplatin or 
carboplatin as measured by investigatorassessed ORR (partial response [PR] plus 
complete response [CR]) according to RECIST v1.1 
•  To evaluate the efficacy of atezolizumab compared with gemcitabine
 +
 cisplatin or 
carboplatin as measured by OS 
•  To determine the impact of atezolizumab compared with gemcitabine
 +
 cisplatin or 
carboplatin as measured by time to deterioration (TTD) in patientreported lung 
cancer symptom (cough, dyspnea, chest pain) score as assessed by the Symptoms 
in Lung Cancer (SILC) scale symptom score (Appendix 9) 
•  To evaluate the efficacy of atezolizumab compared with gemcitabine
 +
 cisplatin or 
carboplatin as measured by Independent Review Facility (IRF)−assessed PFS 
according to RECIST v1.1 
•  To evaluate the efficacy of atezolizumab as measured by investigatorassessed 
DOR according to RECIST v1.1 
•  To evaluate the efficacy of atezolizumab as measured by investigatorassessed 
time in response (TIR) according to RECIST v1.1 
•  To evaluate the OS rate at 1 and 2 years in each treatment arm 
•  To determine the impact of atezolizumab compared with gemcitabine
 +
 cisplatin or 
carboplatin as measured by TTD in patientreported lung cancer symptoms of cough, 
dyspnea (singleitem and multiitem subscales), chest pain, arm/shoulder pain, or 
fatigue with use of the European Organisation for the Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQC30) (see 
Appendix 7) and the supplementary Lung Cancer Module (EORTC QLQLC13) (see 
Appendix 8)  
SECTION 2.2:  Safety Objectives 
The safety objectives for this study are as follows: 
•  To evaluate the safety and tolerability of atezolizumab compared with 
gemcitabine
 +
 cisplatin or carboplatin. 
•  To evaluate the incidence and titers of ATAs against atezolizumab and to explore 
the potential relationship of the immunogenicity response with pharmacokinetics, 
pharmacodynamics, safety, and efficacy 
SECTION 2.3:  Pharmacokinetic Objective 
The PK objective for this study is to characterize the pharmacokinetics of atezolizumab. 
SECTION 2.4:  Exploratory Objectives 
The exploratory objectives for this study are: 
•  To evaluate the efficacy of atezolizumab compared with gemcitabine
 +
 cisplatin or 
carboplatin as measured by IRFassessed ORR, disease control rate (DCR), DOR, 
and TIR according to RECIST v1.1 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
8/Protocol GO29432, Version 5 
•  To evaluate the efficacy of atezolizumab as measured by IRFassessed PFS, ORR, 
DCR, DOR, and TIR according to modified RECIST (ONLY in the atezolizumab arm; 
see Appendix 5) 
•  To evaluate the efficacy of atezolizumab as measured by investigatorassessed 
PFS, ORR, DCR, DOR, and TIR according to modified RECIST (ONLY in the 
atezolizumab arm; see Appendix 5) 
•  To evaluate the efficacy of atezolizumab as measured by investigatorassessed 
DCR according to RECIST v1.1 
•  Landmark PFS at 6 months and 1 year 
•  To evaluate the OS rate at 3 years in each treatment arm 
•  To evaluate the relationship between tumor biomarkers (including but not limited to 
PDL1, PD1, somatic mutations, and others), as defined by IHC, quantitative 
reverse transcriptase−polymerase chain reaction (qRTPCR) nextgeneration 
sequencing (NGS), and/or other methods and measures of efficacy 
•  To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers in 
archival and/or fresh tumor tissue and blood, and their association with disease 
status, mechanisms of resistance, and/or response to atezolizumab 
•  To evaluate the utility of biopsy at the time of apparent disease progression to 
distinguish apparent increases in tumor volume related to the immunomodulatory 
activity of atezolizumab (i.e., pseudoprogression/tumor immune infiltration) from true 
disease progression 
•  To evaluate and compare patient’s health status as assessed by the 
EuroQoL 5Dimension, 3 Level (EQ5D3L) questionnaire to generate utility scores 
for use in economic models for reimbursement 
•  To determine the impact of atezolizumab compared with gemcitabine
 +
 cisplatin or 
carboplatin as measured by change from baseline in patientreported outcomes 
(PROs) of healthrelated quality of life, lung cancer related symptoms, and health 
status as assessed by the EORTC QLQC30 and LC13 
SECTION 3.1:  Description of Study 
•   Patients for whom approved therapies exist must provide written consent to 
acknowledge deferring theseother treatment options in favor of continuing study 
treatment with atezolizumab at the time of initial progression. 
 
Patients in both treatment arms willmay undergo an optionalmandatory tumor tissue 
collection for biopsy, unless not clinically feasible as assessed by investigators, at the 
time of radiographic disease progression if clinically feasible.  To do this, patients must 
sign a separate consent.  (…)  Patients who are unable to undergo biopsy sample 
collection but otherwise meet criteria listed above may continue to receive atezolizumab. 
For patients with nonprogressive disease after the platinumbased chemotherapy, 
switch maintenance with erlotinib can be considered by the investigator in accordance 
with the NCCN guidelines (see Section 1.4). 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
9/Protocol GO29432, Version 5 
All patients will undergo tumor assessments at baseline and every 6 weeks thereafter, 
regardless of dose delays, for the first 12 months48 weeks following Cycle 1, Day 1, 
regardless of treatment delays.  After 12 months48 weeks, tumor assessments will be 
required every 9 weeks after completion of the Week 48 tumor assessment, regardless of 
treatment delays, until disease progression per RECIST v1.1 (for patients in both 
treatment arms) or loss of clinical benefit (for atezolizumab-treated patients who 
continue treatment after disease progression according to RECIST v1.1), consent 
withdrawal, study termination by the Sponsor, or death, enrollment into an extension 
study, or death, whichever occurs first.  Patients who discontinue treatment for reasons 
other than disease progression (e.g., toxicity) will continue scheduled tumor 
assessments until disease progression, withdrawal of consent, study termination by 
Sponsor, or death, or are eligible to roll over to an extension study, whichever occurs 
first.  A secondary endpoint of this study is IRFassessed PFS according to RECIST v1.1.  
Therefore, an IRF will conduct an independent review of the responses of all patients, 
including a review of blinded computed tomography (CT) scans.  All primary imaging 
data used for tumor assessment will be collected by the Sponsor to enable centralized, 
independent review of response endpoints.  Independent reviews will be performed prior 
to the final efficacy analyses. 
SECTION 3.1.1:  Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will be used to evaluate safety data 
during the study on a periodic basis, approximately every 6 months from the time when 
the first patient is enrolled.  Members of the iDMC will be external to the Sponsor and will 
follow a Charter that outlines their roles and responsibilities. 
All summaries and analyses by treatment arm for the iDMC review will be prepared by 
an independent Data Coordinating Center (iDCC).  The safety data will include 
demographic data, adverse events, serious adverse events, and relevant laboratory 
data. 
Following the data review, the iDMC will provide a recommendation to the Sponsor as to 
whether the study may continue, whether amendment(s) to the protocol should be 
implemented, or whether the study should be stopped.  The final decision will rest with 
the Sponsor. 
Any outcomes of these safety reviews that affect study conduct will be communicated in 
a timely manner to the investigators for notification of the Institutional Review 
Boards/Ethics Committees (IRBs/ECs). 
No interim efficacy analysis is planned for the primary endpoint of PFS.An independent 
Data Monitoring Committee (iDMC) was in place to evaluate the safety data during 
the study on a periodic basis.  However, as of 20 April 2016 the study was closed to 
enrollment due to a low number of patients; therefore, an iDMC will no longer be used 
to evaluate safety data. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
10/Protocol GO29432, Version 5 
SECTION 3.2:  End of Study 
The study is currently closed to enrollment due to a low number of patients.  
The end of study will be when all enrolled patients have discontinued study treatment  
or all patients have been enrolled into an extension study.  Patients already enrolled 
will remain on study and will be allowed to continue study treatment until 
radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who continue treatment beyond disease progression 
according to RECIST v1.1), withdrawal of consent, enrollment into an extension study, 
or death, whichever occurs first.  In addition, the Sponsor may decide to terminate the 
study at any time  
If the Sponsor decides to end the study, patients still receiving study treatment may be 
offered enrollment in an extension study if, in the opinion of the investigator and in 
consultation with the Medical Monitor, the patient would potentially benefit from 
continuing therapy. 
The primary PFS analysis will be performed when approximately 
238 investigatorassessed PFS events in the ITT population have occurred or when the 
last patient has been randomized, whichever occurs last. 
The end of study is when approximately 291 deaths in the ITT population have been 
observed.  In addition, the Sponsor may decide to terminate the study at any time. 
SECTION 3.3.2:  Rationale for Gemcitabine, Cisplatin, or Carboplatin as a 
Comparator 
On the basis of results from a Phase III randomized trial, which has shown a PFS and 
OS benefit for erlotinib after induction treatment in unselected patients who have not 
progressed (Cappuzzo et al. 2010), erlotinib was approved as maintenance treatment for 
patients with NSCLC in the firstline setting.  Therefore, in accordance with the NCCN 
guidelines, switch maintenance therapy with erlotinib can be considered for patients 
randomized to the control arm in this study (see Section 1.4). 
SECTION 3.3.3:  Rationale for ProgressionFree Survival as Primary 
Endpoint 
Investigatorassessed PFS (which will be supported by an IRFassessed PFS analysis, 
one of the secondary endpoints of the study) is the primary endpoint for this study. 
PFS as an endpoint can reflect tumor growth and can be assessed before the 
determination of a survival benefit; additionally, its determination is not generally 
confounded by subsequent therapies.  Whether an improvement in PFS represents a 
direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the 
effect and the benefitrisk of the new treatment compared to available therapies 
(Guidance for Industry 2007; European Medicines Agency 2012).  A PFS HR of 0.60 will 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
11/Protocol GO29432, Version 5 
be targeted in PDL1−selected population, which constitutes a clinically meaningful 
benefit in this patient population. 
New treatment modalities such as targeted therapies and immunotherapy are emerging 
as highly effective regimens that are providing improvements in patient outcomes far 
beyond what has been achieved prior (Ellis et al. 2014).  In particular, immunotherapy 
has been correlated and/or associated with durable responses, significant prolongation 
of PFS, and improvement of quality of life.  Additionally, metaanalyses have indicated 
that PFS can be considered a good measure of clinical benefit for patients with locally 
advanced/metastatic NSCLC (Laporte et al. 2013).  This study will test the 
hypothesis/assumption that treatment with atezolizumab will provide prolonged PFS 
compared with treatment with platinumbased chemotherapy in patients with squamous 
Stage IV NSCLC. 
SECTION 3.3.3:  Rationale for Allowing Patients to Continue Atezolizumab 
Treatment until Loss of a Clinical Benefit 
In addition, while the primary endpoint measure (PFS by investigator) and secondary 
endpoint measures (ORR, DOR, and TIR by investigator and PFS by IRF) comparing 
the atezolizumab and gemcitabine
 +
 cisplatin or carboplatin arms will use RECIST v1.1, 
exploratory analyses of PFS, ORR, DCR, and DOR with use of modified RECIST criteria 
will be performed for patients randomized to receive atezolizumab.  Modified RECIST 
allows the incorporation of new lesions into the calculation of total tumor burden after 
baseline and takes into account the potential for pseudoprogression/tumor immune 
infiltration. 
SECTION 3.3.4:  Rationale for PatientReported Outcome Assessments 
In the treatment of lung cancer, it is important to both increase survival and palliate 
symptoms because disease symptoms have negative impacts on healthrelated quality 
of life (HRQoL) (Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al. 2004).  
This is especially true for trials that use PFS as a primary endpoint, where it is important 
to translate the delay in disease progression into an endpoint that is meaningful to 
patients. 
Chest pain, dyspnea, and cough have been regarded as the most frequent and clinically 
relevant diseaserelated symptoms experienced by patients with NSCLC.  Therefore, in 
order to assess TTD of lung cancer symptoms (cough, dyspnea, and chest pain) in this 
study, the SILC scale will be used.  The SILC scale will be used to assess the delay of 
onset of primary distressing lung cancer symptoms reported by patients with Stage IV 
squamous NSCLC in the firstline setting. 
In addition, the BR.21 study (erlotinib vs. BSC in second or thirdline NSCLC) 
demonstrated that longer TTD in the pain, dyspnea, and cough scales of the 
EORTC QLQ C30 and QLQLC13 was consistent with superior PFS, OS, and 
qualityoflife benefits in the erlotinib arm compared with the placebo arm 


 
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12/Protocol GO29432, Version 5 
(Aaronson et al. 1993; Bergman et al. 1994; Bezjak et al. 2006).  In addition, patients in 
the afatinib LUXLung firstline study reported significant delay of TTD in lung cancer 
symptoms (cough, pain, dyspnea) as measured by the EORTC QLQC30 and 
QLQ LC13 (Yang et al. 2013).  In order to assess the HRQoL health−related quality of 
life and symptom severity of patients in this trial, PRO data will be collected from 
patients enrolled in this study using the validated questionnaires EORTC QLQC30 and 
QLQ LC13. 
The EQ5D3L PRO instrument (see Appendix 10) is included in the trial to generate 
health related quality of life utility scores for use in economic models for reimbursement. 
SECTION 3.3.6:  Rationale for the Collection of MandatoryOptional Tumor 
Specimens at Radiographic Progression 
A mandatory tumor biopsy will be performed (both treatment arms), if clinically feasible, 
at the time of radiographic progression in orderPatients in both treatment arms may 
undergo an optional tumor biopsy at the time of radiographic disease progression if 
clinically feasible.  To do this, patients must sign a separate consent.  These data will be 
used to evaluate the utility of the biopsy in distinguishing pseudoprogression/tumor 
immune infiltration from true progression.   
SECTION 3.4:  Outcome Measures 
The study is currently closed to enrollment due to a low number of patients; therefore, 
the outcome measures of this study are no longer applicable and formal analyses of 
efficacy or safety will not be performed. 
SECTION 3.4.1:  Efficacy Outcome Measures 
SECTION  3.4.1.1:  Primary Efficacy Outcome Measure 
The primary efficacy outcome measure for this study is as follows: 
•  PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator with use of RECIST v1.1 or death 
from any cause, whichever occurs first.  Patients who have not experienced disease 
progression or death at the time of analysis will be censored at the time of last tumor 
assessment.  Patients with no postbaseline tumor assessment will be censored at 
the randomization date plus 1 day. 
SECTION 3.4.1.2:  Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
•  Objective response (PR plus CR) as determined by the investigator according to 
RECIST v1.1 
•  OS, defined as the time from randomization to death from any cause 
•  TTD in patientreported lung cancer symptoms (cough, dyspnea, or chest pain, 
whichever occurs first) with use of the SILC scale symptom score, defined as time 
from randomization to the first deterioration maintained for two assessments or one 
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•  PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by IRF with use of RECIST v1.1 or death from any cause, 
whichever occurs first 
•  DOR, defined as the time from the first occurrence of a documented objective 
response to the time of disease progression, as determined by the investigator with 
use of RECIST v1.1, or death from any cause, whichever occurs first 
•  TIR, defined as the same as DOR for responders.  For nonresponders, TIR is 
defined as date of randomization plus 1 day. 
•  1year OS and 2year OS 
•  TTD in patientreported lung cancer symptoms, defined as time from randomization 
to deterioration (10point change) on each of the EORTC QLQC30 and 
EORTC QLQ LC13 symptom subscales (cough, dyspnea [singleitem and multiitem 
subscales], chest pain, arm/shoulder pain, or fatigue) maintained for two 
assessments or one assessment followed by death from any cause within 3 weeks 
•  Change from baseline in patientreported lung cancer symptoms (chest pain, 
dyspnea, and cough) on the symptom severity score of the SILC scale 
SECTION  3.4.2:  Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
•  Incidence, nature, and severity of adverse events graded according to the 
NCI CTCAE v4.0 
•  Changes in vital signs, physical findings, and clinical laboratory test results during 
and following atezolizumab administration 
•  Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters 
SECTION 3.4.3:  Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
•  Maximum serum atezolizumab concentration observed (Cmax) after infusion on 
Day 1 of Cycle 1 
•  Minimum serum atezolizumab concentration observed (Cmin) prior to infusion on 
Day 1 of Cycles 2, 3, 4, 8, 16, and every eight cycles thereafter, at treatment 
discontinuation, and at 120 (±
 30) days after the last dose of atezolizumab 
SECTION 3.4.4:  Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
•  ORR, DCR, DOR, and TIR as determined by IRF according to RECIST v1.1 
•  PFS, ORR, DCR, DOR, and TIR as determined by IRF according to modified 
RECIST (atezolizumab only; see Appendix 5) 
•  PFS, ORR, DCR, DOR, and TIR as determined by the investigator according to 
modified RECIST (atezolizumab only; see Appendix 5) 


 
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•  DCR, defined as the rate of patients with a complete or partial response as best 
response or with stable disease maintained for
 ≥
 6 weeks, as determined by the 
investigator according to RECIST v1.1 
•  PFS at 6months and at 1 year 
•  OS rate at 3 years 
•  Status of immune cell infiltrate and other exploratory biomarkers in mandatory 
biopsy specimens collected at progression 
•  Status of PDL1−, immune, and NSCLCrelated and other exploratory biomarkers 
in archival and/or freshly obtained tumor tissues and blood (or blood derivatives) 
collected before, during, or after treatment with atezolizumab or at progression and 
association with disease status and/or response to atezolizumab 
•  Utility scores of the EQ5D3L questionnaire 
•  Change from baseline in PROs of healthrelated quality of life, lung cancerrelated 
symptoms, and health status as assessed by the EORTC QLQC30 and LC13 
 
SECTION 4.1:  Patients 
Approximately 155 sites globally will participate in the study, and approximately 
400 PD-L1−selected chemotherapy naive patients with Stage IV squamous non−small 
cell lung cancer will be enrolled in this study. 
SECTION 4.1.1:  Inclusion Criteria 
•   For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement (by patient and/or partner) to use a highly 
effective form(s) of contraception during study treatment that results in a low failure 
rate of
 <
 1% per year when used consistently and correctly.  Female and male 
patients treated with atezolizumab should continue contraception use for 90 days 
5 months after the last dose. 
 
SECTION 4.1.2.3:  Exclusion Criteria Related to Medications 
Hormonereplacement therapy or oral contraceptives 
SECTION 4.3.1.1: Atezolizumab (MPDL3280A) 
The atezolizumab (MPDL3280A) drug product is provided as a sterile liquid in a 
single-use, 20-mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, 
preservativefree clear liquid solution intended for IV administration.  The atezolizumab 
drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 
120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use.  
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer.  No preservative is used in the atezolizumab drug product; therefore, each 
vial is intended for single use only.  Vial contents should not be frozen or shaken and 
should be protected from direct sunlight. 


 
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For further details on the storage and preparationformulation and handling of 
atezolizumab, see the Pharmacy Manual and Investigator’s Brochure. 
SECTION 4.3.1.3:  Erlotinib 
Switch maintenance to erlotinib is no longer permitted for patients randomized to Arm B.  
However, patients who had already started switch maintenance treatment with erlotinib 
under previous protocol versions may be allowed to continue treatment with erlotinib 
upon discussion of the risks, potential benefits, and alternative treatment options with 
the investigator. 
Erlotinib will be obtained from commercial sources at each participating siteprovided by 
the Sponsor if required by local health authority regulations.   
SECTION 4.3.2.2:  Gemcitabine  +
 Cisplatin or Carboplatin 
For patients with nonprogressive disease after the platinumbased chemotherapy, 
switch maintenance with erlotinib can be considered by the investigator in accordance 
with the NCCN guidelines. 
SECTION 4.3.2.3:  Erlotinib 
For those patients who receive switch maintenance with erlotinib, institutions should 
follow the NCCN guidelines and dosage and administration instructions in the package 
insert.   
See the package insert for erlotinib (TARCEVA®) for more information on erlotinib 
dosingSwitch maintenance treatment with erlotinib is no longer permitted.  However, 
patients who had already started switch maintenance treatment with erlotinib under 
previous protocol versions may be allowed to continue treatment with erlotinib upon 
discussion of the risks, potential benefits, and alternative treatment options with the 
investigator. 
SECTION 4.3.3:  Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (atezolizumab, gemcitabine, cisplatin, and 
carboplatin, and erlotinib) will be provided by the Sponsor where required by local 
health authority regulations. 
SECTION 4.3.4:  Post-Study Access to Atezolizumab Investigational 
Medicinal Product Accountability 
The Sponsor will evaluate the appropriateness of continuing to provide atezolizumab to 
patients assigned to this treatment after evaluating the primary and secondary efficacy 
outcome measures and safety data gathered in the study and in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


 
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These analyses may be conducted prior to completion of the study. 
SECTION 4.4.1:  Permitted Therapy 
The following therapies should continue while patients are in the study: 
•  Hormonal therapy with gonadotropinreleasing hormone agonists or antagonists for 
prostate cancer 
 
All medications must be recorded on the appropriate Concomitant Medications electronic 
Case Report Form (eCRF). 
Switch maintenance therapy with erlotinib is permitted and can be considered for 
patients randomized to the control arm.  Investigators should follow the NCCN guidelines 
and dosage and administration instructions in the package insert for erlotinib 
(TARCEVA®)treatment with erlotinib is no longer permitted.  However, patients who 
had already started switch maintenance treatment with erlotinib under previous 
protocol versions may be allowed to continue treatment with erlotinib upon discussion 
of the risks, potential benefits, and alternative treatment options with the investigator. 
Erlotinib use as the protocol allowed maintenance therapy for the control arm should be 
recorded on the specific erlotinib eCRF and not as a concomitant medication. 
SECTION 4.4.2:  Cautionary Therapy for Atezolizumab-Treated Patients 
Guidelines for the management of immune-mediated adverse events are provided in 
Section 6 (Guidance for the Investigator) of the atezolizumab Investigator’s 
Brochuredescribed in Section 5.1.7. 
SECTION 4.4.3:  Prohibited Therapy 
The following medications are prohibited while in the study, unless otherwise noted: 
•  Traditional herbal medicines as their use may result in unanticipated drugdrug 
interactions that may cause or confound assessment of toxicity 
 
The concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However, their use for patients in the study is allowed at the discretion of the 
investigator, provided that there are no known interactions with any study 
treatment.  As noted above, herbal therapies intended for the treatment of cancer are 
prohibited. 
SECTION 4.5.1:  Informed Consent Forms and Pre-Screening/Screening 
Log 
Patients who are treated with atezolizumab and who show apparent radiographic 
progression at a tumor response evaluation and have alternative anticancer therapies 
available to them must sign consent at that time to have a biopsy of the progressing 
lesion and acknowledge deferring theseother treatment options in favor of continuing 
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Patients in both treatment arms may undergo an optional tumor biopsy at the time of 
radiographic disease progression if clinically feasible.  To do this, patients must sign a 
separate consent. 
SECTION 4.5.5:  Tumor and Response Evaluations 
Tumor assessments will be performed every 6 weeks (±
 7 days) for 12 months48 weeks 
following Cycle 1, Day 1 and then every 9 weeks (±
 7 days) thereafter, regardless of 
treatment delays, until radiographic disease progression per RECIST v1.1 (for patients in 
both treatment arms) or loss of clinical benefit (for atezolizumab-treated patients who 
continue treatment beyond disease progression according to RECIST v1.1), withdrawal 
of consent, death, or study termination by the Sponsor, enrollment into an extension 
study, or death, whichever occurs first.   
Scans will be submitted for central review to an IRF. 
SECTION 4.5.6:  Laboratory, Biomarker, and Other Biological Samples 
The schedule of laboratory assessments should be performed according to Appendix 1. 
PK, ATA, and biomarker evaluations are no longer required.  
Samples for the following laboratory tests willare to be sent to the study site
's local 
laboratory for analysis: 
•   (…) 
•  EpsteinBarr virus serology 
Screening sample collection only; serology tests to be performed only in 
patients who experience an acute inflammatory event such as systemic 
inflammatory response syndrome while receiving study treatment 
 
A central laboratory will coordinate the sample collection of tissue and blood samples for 
researchrelated testing at central laboratories or at the Sponsor.  Instruction manuals 
and supply kits will be provided for all central laboratory assessments.  Samples for the 
following laboratory tests will be sent to one or several central laboratories or to the 
Sponsor for analysis: 
•  ATA assays (patients assigned to atezolizumab only) 
Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of validated immunoassays.  Accompanying PK samples will be collected 
at the same timepoints. 
•  PK assay (patients assigned to atezolizumab only) 
Blood samples for PK assessments will be obtained according to the schedule 
in Appendix 2. 
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay. 


 
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•  Biomarker assays  
Blood samples will be obtained for biomarker evaluation (including but not 
limited to biomarkers that are related to NSCLC or tumor immune biology) from 
all eligible patients according to the schedule in Appendix 2.  Samples will be 
processed to obtain plasma and serum for the determination of changes in 
bloodbased biomarkers (e.g., ctDNA).  Whole blood samples may be 
processed to obtain their derivatives (e.g., RNA and DNA) and may be 
evaluated for immunerelated, tumor type−related, and other exploratory 
biomarkers (e.g., alterations in gene expression or single nucleotide 
polymorphisms. 
Any remaining samples collected for pharmacokinetics, biomarker assays, and 
ATAs may be used for exploratory biomarker profiling, identification, and 
pharmacodynamic assay development purposes and additional safety 
assessments (e.g., ATA assay) as appropriate. 
•  Blood biomarker samples will no longer be collected, but samples already collected 
will be kept and used per original signed informed consent.   
For patients who consent to the optional collection of samples for the Roche Clinical 
Repository (RCR), any leftover material from samples already collected the above 
sample collection will be stored and used for exploratory analyses as indicated in 
Section 4.5.12. 
SECTION 4.5.7.2:  Optional Tumor Samples at the Time of Radiographic 
Progression 
Patients in both treatment arms willmay undergo an optionalmandatory tumor biopsy to 
obtain a tumor sample, unless not clinically feasible, at the time of radiographic disease 
progression (preferably within 40 days of radiographic progression or prior to start of 
the next anti-cancer treatment, whichever is sooner) if they have provided consent for 
optional biopsy and if clinically feasible. 
The preferred sample types include:  resections, core needle, excisional, incisional, 
punch, or forceps biopsies.  If such specimens are not available, any type of specimens 
(including fine-needle aspiration, cell pellet specimens e.g., from pleural effusion, and 
lavage samples) can also be submitted.   
Acceptable samples include: 
•  Core needle biopsy sample collection for deep tumor tissue; at least three cores, 
embedded into a single paraffin block, should be submitted for evaluation. 
•  Excisional, incisional, punch, or forceps biopsy sample collection for cutaneous, 
subcutaneous, or mucosal lesions 
•  Tumor tissue resection 
 
 


 
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SECTION 4.5.7.3:  Tumor Samples at Other Timepoints 
Patients with additional tissue samples from procedures performed at different times 
during the course of their study participation (during treatment and during survival 
followup) who have signed the RCR optional consent will be requested (but not required) 
to also submit these optional fresh biopsy samples for central testing.  Tumor tissue 
samples collected at the time of clinical events (e.g., clinical response) are preferred.   
SECTION 4.5.9:  Anti-Therapeutic Antibody Testing 
ATA testing will no longer be performed. 
Treatment with atezolizumab may elicit an immune response.  Patients with signs of any 
potential immune response to atezolizumab will be closely monitored.  Validated 
screening and confirmatory assays will be employed to detect ATAs at multiple 
timepoints before, during, and after treatment with atezolizumab (see Appendix 1 and 
Appendix 2 for the schedule).  The immunogenicity evaluation will utilize a riskbased 
immunogenicity strategy (Rosenberg and Worobec 2004; Koren et al. 2008) to 
characterize ATA responses to atezolizumab in support of the clinical development 
program.  This tiered strategy will include an assessment of whether ATA responses 
correlate with relevant clinical endpoints.  Implementation of ATA characterization 
assays will depend on the safety profile and clinical immunogenicity data. 
SECTION 4.5.11:  Patient-Reported Outcomes 
PRO assessments are no longer required, and PRO data will no longer be collected.  
PRO data will be collected via the SILC, EORTC QLQC30, QLQLC13, and EQ5D3L 
questionnaires to more fully characterize the clinical profile of atezolizumab. 
The questionnaires will be translated as required in the local language.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires scheduled for administration during a clinic visit will be completed in their 
entirety by the patient prior to the performance of nonPRO assessments and the 
administration of study treatment. 
Patients will use an electronic PRO (ePRO) device to capture PRO data.  The ePRO 
device and/or instructions for completing the PRO questionnaires electronically will be 
provided by the investigator staff.  The data will be transmitted via a prespecified 
transmission method (e.g., Web or wireless) automatically after entry to a centralized 
database at the ePRO vendor.  The data can be accessed by appropriate study 
personnel securely via the Internet. 
The SILC scale will be used to assess patientreported severity of lung cancer 
symptoms (cough, dyspnea, and chest pain; see Appendix 9).  The SILC scale is a 
nineitem content valid selfreport measure of lung cancer symptoms.  It measures 
severity of cough, dyspnea, and chest pain with a total symptom severity score.  This 


 
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questionnaire will be completed using an ePRO device at the patient’s home on a 
weekly basis, then monthly during survival followup for 6 months following radiographic 
disease progression per RECIST v1.1 (or loss of clinical benefit for atezolizumabtreated 
patients who continue treatment after radiographic disease progression according to 
RECIST v1.1).  For patients who discontinue treatment for any reason other than 
disease progression per RECIST v1.1 or loss of clinical benefit (for atezolizumabtreated 
patients who continue treatment after disease progression according to RECIST v1.1), 
assessment should continue at the same frequency as would have been followed if the 
patient had continued to receive study treatment.  The assessments should be continued 
until disease progression according to RECIST v1.1 (or loss of clinical benefit for 
atezolizumabtreated patients who continue treatment after radiographic disease 
progression according to RECIST v1.1), then follow the survival followup frequency. 
The EORTC QLQC30 (see Appendix 7) is a validated and reliable selfreport measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999) that consists of 30 questions that assess 
five aspects of patient functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, 
and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties).  Scale scores can be obtained for the multiitem scales.  
The EORTC QLQC30 module takes approximately 10 minutes to complete.  This 
questionnaire will be completed on the ePRO tablet at each scheduled study visit during 
study treatment and during survival followup at 3 and 6 months following radiographic 
disease progression per RECIST v1.1 (or loss of clinical benefit for atezolizumabtreated 
patients who continue treatment after disease progression according to RECIST v1.1).  
For patients who discontinue treatment for any reason other than disease progression 
per RECIST v1.1 (or loss of clinical benefit for atezolizumabtreated patients who 
continue treatment after disease progression according to RECIST v1.1), assessment 
should continue at the same frequency as would have been followed if the patient had 
continued to receive study treatment.  The assessments should be continued until 
disease progression according to RECIST v1.1 (or loss of clinical benefit for 
atezolizumabtreated patients who continue treatment after disease progression 
according to RECIST v1.1), then follow the survival followup frequency. 
The EORTC QLQLC13 (see Appendix 8) module incorporates one multiple item scale 
to assess dyspnea and a series of single items assessing pain, coughing, sore mouth, 
dysphagia, peripheral neuropathy, alopecia, and hemoptysis.  The EORTC QLQLC13 
module takes approximately 5 minutes to complete.  This questionnaire will be 
completed on the ePRO tablet at each scheduled study visit during study treatment and 
during survival followup at 3 and 6 months following radiographic disease progression 
per RECIST v1.1 (or loss of clinical benefit for atezolizumabtreated patients who 
continue treatment after disease progression according to RECIST v1.1).  For patients 
who discontinue treatment for any reason other than disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumabtreated patients who continue 


 
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treatment after disease progression according to RECIST v1.1), assessment should 
continue at the same frequency as would have been followed if the patient had 
continued to receive study treatment.  The assessments should be continued until 
disease progression according to RECIST v1.1 (or loss of clinical benefit for 
atezolizumabtreated patients who continue treatment after disease progression 
according to RECIST v1.1), then follow the survival followup frequency. 
The EQ5D3L is a generic, preferencebased health utility measure with questions 
about mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression that is 
used to build a composite of the patient’s health status (see Appendix 10).  The 
EQ5D3L will be utilized in this study for economic modeling.  This questionnaire will be 
completed on the ePRO tablet at each scheduled study visit during study treatment and 
during survival followup at 3 and 6 months following radiographic disease progression 
per RECIST v1.1 (or loss of clinical benefit for atezolizumabtreated patients who 
continue treatment after disease progression according to RECIST v1.1).  For patients 
who discontinue treatment for any reason other than disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumabtreated patients who continue 
treatment after disease progression according to RECIST v1.1), assessment should 
continue at the same frequency as would have been followed if the patient had 
continued to receive study treatment.  The assessments should be continued until 
disease progression according to RECIST v1.1 (or loss of clinical benefit 
atezolizumabtreated patients who continue treatment after disease progression 
according to RECIST v1.1), then follow the survival followup frequency. 
Adverse event reports will not be derived from PRO data by the Sponsor.  However, any 
PRO responses suggestive of a possible adverse event that are identified during site 
review of the PRO data should be reported as outlined in Section 4.5.11. 
SECTION 4.5.12.3:  Sample Collection 
The following sample will be used for identification of genetic (inherited) biomarkers: 
•   Whole blood sample for DNA extraction (6 mL), which may be collected at any time 
during the course of the study (see Appendix 1 and Appendix 2) 
 
SECTION 4.5.13.1:  Screening/Baseline Assessments 
See Appendix 1 of the previous protocol Version 4 for the schedule of screening 
assessments and Appendix 2 for the schedule of PK, ATA, and biomarker sampling. 
SECTION 4.5.13.2:  Assessments during Treatment 
Tumor assessments should occur every 6 weeks (± 7 days) for 12 months48 weeks 
following Cycle 1, Day 1 and every 9 weeks (± 7 days) thereafterafter completion of the 
Week 48 tumor assessment, regardless of treatment delays, until radiographic disease 
progression per RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients 
who continue treatment after disease progression according to RECIST v1.1), 


 
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withdrawal of consent, death, or study termination by the Sponsor, enrollment into an 
extension study, or death, whichever occurs first.  
See Appendix 1 for the schedule of assessments performed during the treatment period 
and Appendix 2 for the schedule of PK, ATA, and biomarker sampling. 
SECTION 4.5.13.3:  Assessments at Treatment Discontinuation Visit 
Patients who discontinue study treatment must be followed according to the followup 
visit schedule for progression and/or survival until death, loss to followup, or withdrawal 
of consent, which will be defined as study discontinuation. 
SECTION 4.5.13.4:  Follow-Up Assessments 
For patients who discontinue study treatment for any reason other than radiographic 
progressive disease per RECIST v1.1, tumor assessments should continue at the same 
frequency as would have been followed if the patient had continued study treatment until 
radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who continue treatment after disease progression 
according to RECIST v1.1), withdrawal of consent, death, or study termination by the 
Sponsor, enrollment into an extension study, or death, whichever occurs first. 
Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 should continue tumor assessments according to the 
protocol schedule of response assessments until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who continue 
treatment after disease progression according to RECIST v1.1), withdrawal of consent, 
death, or study termination by the Sponsor, enrollment into an extension study, or death, 
whichever occurs first. 
Followup data collection will also include PROs (only for the first 6 months after disease 
progression per RECIST v1.1, or loss of clinical benefit for atezolizumabtreated patients 
who continue treatment after disease progression according to RECIST v1.1); SILC will 
be completed monthly using an ePRO device at the patient’s home and EORTC 
QLQ C30, EORTC QLQ C30 LC13, and EQ5D3L will be completed at the site on the 
ePRO tablet at 3 and 6 months after disease progression per RECIST v1.1 (or loss of 
clinical benefit for atezolizumabtreated patients who continue treatment after disease 
progression according to RECIST v1.1).  For patients who discontinue study treatment 
for any reason other than radiographic progressive disease per RECIST v1.1 (or loss of 
clinical benefit for atezolizumabtreated patients who continue treatment after disease 
progression according to RECIST v1.1), PRO assessments should continue at the same 
frequency as would have been followed if the patient had continued study treatment until 
radiographic disease progression (or loss of clinical benefit for atezolizumabtreated 
patients who continue treatment after disease progression according to RECIST v1.1), 
withdrawal of consent, death, or study termination by the Sponsor, whichever occurs 
first. 


 
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Survival followup should continue until death, withdrawal of consent, the patient is lost 
to followup, or study termination by the Sponsor, whichever occurs first.  If the patient 
withdraws from study, the study staff may use a public information source (e.g., county 
records) when permissible, to obtain information about survival status and date only. 
See Appendix 1 and Appendix 2 for assessments to be performed during FollowUp 
visits. 
SECTION 4.6.2:  Study Treatment Discontinuation 
•   Radiographic disease progression per RECIST v1.1 
Exception for atezolizumab treatment:   
Patients must provide written consent to acknowledge deferring any 
standardother treatment options that may exist in favor of continuing 
atezolizumab treatment at the time of initial progression 
Availability of a mandatory biopsy sample collection, unless not clinically 
feasible as assessed by the investigators, at the site of local or metastatic 
progression 
SECTION 4.6.3:  Study and Site Discontinuation 
The study is currently closed to enrollment due to a low number of patients.   
SECTION 5:  Assessment of Safety 
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial carcinoma.  Atezolizumab is not approved and is currently in 
clinical development.  Human experience is currently limited and the entire safety profile 
is not known at this time.  The following information is based on results from nonclinical 
and clinical studies for atezolizumab and published data on similar molecules. 
SECTION 5.1.1:  Risks Associated with Atezolizumab 
Adverse events with potentially immune-mediated causes, including rash, 
hypothyroidism, hepatitis/transaminitis, colitis, pneumonitis, myositis, and myasthenia 
gravis, have been observed in the Phase Ia Study PCD4989g.  A more comprehensive 
list of adverse events observed with atezolizumab is provided in Section 1.6.2.  For 
further details regarding clinical safety, including a detailed description of anticipated 
safety risks for atezolizumab, see the atezolizumab Investigator’s Brochure. 
SECTION 5.1.3.3:  Risks Associated with Erlotinib 
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients 
who had already started switch maintenance treatment with erlotinib under previous 
protocol versions may be allowed to continue treatment with erlotinib upon discussion 
of the risks, potential benefits, and alternative treatment options with the investigator.  


 
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SECTION 5.1.5:  Dose Modification 
SECTION 5.1.5.1:  General Notes Regarding Dose Modification 
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v4.0 
grading system. 
•  For any concomitant conditions already apparent at baseline, the dose 
modifications will apply according to the corresponding shift in toxicity grade, if 
the investigator considers it is appropriate.  For example, if a patient has Grade 1 
asthenia at baseline that increases to Grade 2 during study treatment, this will be 
considered a shift of one grade and treated as Grade 1 toxicity for dose-modification 
purposes. 
•  When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed. 
•  If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one component of chemotherapy, the dose of the other chemotherapy component 
does not require modification and the other chemotherapy component(s) may be 
administered if there is no contraindication.   
•  The investigator may use discretion in modifying or accelerating the 
dose modification guidelines described below depending on the severity of toxicity 
and an assessment of the risk versus benefit for the patient, with the goal of 
maximizing patient compliance and access to supportive care.  
 
SECTION 5.1.6:  Atezolizumab Dose Modifications, Treatment Delays, or 
Treatment Discontinuation 
Management of atezolizumab specific adverse events is present in Section 5.1.7. 
SECTION 5.1.7:  Management of Atezolizumab-Specific Adverse Events 
Discontinuation of atezolizumab may not have an immediate therapeutic effect and, in 
severe cases, immune-mediated toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, mycophenolate, or TNFα inhibitorsor other 
immunosuppressive agents. 
The primary approach to Grade 1 and 2 immune-mediated adverse events is supportive 
and symptomatic care with continued treatment with atezolizumab; for higher-grade 
immune-mediated adverse events, atezolizumab should be withheld and oral/parenteral 
steroids administered.  Recurrent Grade 2 immune-mediated adverse events may also 
mandate withholding atezolizumab or the use of steroids.  Consideration for benefit-risk 
balance should be made by the investigator, with consideration of the totality of 
information as it pertains to the nature of the toxicity and the degree of clinical benefit 
a given patient may be experiencing prior to further administration of atezolizumab.  
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.   


 
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Management of systemic immune activation is presented below.  For the management 
of other adverse events associated with atezolizumab not provided in 
Sections 5.1.7.1−5.1.7.10. Refer toSee the atezolizumab Investigator’s Brochure for 
details on management of gastrointestinal, dermatologic, endocrine, pulmonary toxicity, 
hepatotoxicity, infusion-related reactions, potential pancreatic or eye toxicity, and 
other immune-mediated adverse events.  Guidelines for infusionrelated reactions are 
provided in Section 4.3.2.1 (See Appendix 12 for precautions for anaphylaxis). 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the 
following: 
•  CBC with peripheral smear 
•  PT, PTT, fibrinogen, and D-dimer 
•  Ferritin 
•  Triglycerides 
•  AST, ALT, and total bilirubin 
•  LDH 
•  Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If Systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations. 
SECTION 5.1.7.1:  Pulmonary Events 
Dyspnea, cough, fatigue, hypoxia, and pulmonary infiltrates have been associated with 
the administration of atezolizumab and have primarily been observed in patients with 
underlying NSCLC. 
Mild tomoderate events of pneumonitis have been reported with atezolizumab.  All 
pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension: 
• Measurement of oxygen saturation (i.e., arterial blood gas) 
• Highresolution CT scan of the chest 
• Bronchoscopy with bronchoalveolar lavage and biopsy 
• Pulmonary function tests (diffusion capacity of the lung for carbon monoxide [DL
CO]) 


 
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• Pulmonary function testing with a pulmonary embolism protocol 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study, and 
will also have CT scans of the chest at every tumor assessment. 
Table 12:  Management Guidelines for Pulmonary Events/Pneumonitis 
Table 12 has been removed from the protocol. 
SECTION 5.1.7.2:  Hepatic Events 
Immunemediated 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 transaminase, and liver function will be monitored throughout 
study treatment. 
While in this study, patients presenting 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. 
If LFTs increase, concurrent medications, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate.  Imaging of the liver, gall 
bladder, and biliary tree should be performed to rule out neoplastic or other causes for 
the increased LFTs.  Antinuclear antibody, perinuclear antineutrophil cytoplasmic 
antibody, antiliver kidney microsomal antibodies, and anti−smooth muscle antibody 
tests should be performed if an autoimmune etiology is considered. 
Table 13:  Management Guidelines for Hepatic Events 
Table 13 has been removed from the protocol. 
SECTION 5.1.7.3:  Gastrointestinal Events 
Immunemediated colitis has been associated with the administration of atezolizumab. 
If the event is of significant duration or magnitude or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased Creactive protein or platelet 
count or bandemia), the following is recommended: 
•  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 in order to confirm colitis diagnosis.  If possible, one or two 
biopsy specimens should be snap frozen and stored. 
•  Perform laboratory tests to rule out alternate etiology (i.e., WBCs and stool 
calprotectin) 
 
Table 14:  Management Guidelines for Gastrointestinal Events 
(Diarrhea/Colitis) 
Table 14 has been removed from the protocol. 


 
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SECTION 5.1.7.4:  Endocrine Events 
Thyroid disorders or adrenal insufficiency has been associated with the administration of 
atezolizumab. 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental 
status changes, or constipation should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies as well as for hyponatremia or hyperkalemia.  An 
endocrinologist should be consulted if an endocrinopathy is suspected.  TSH and free 
thyroxine (T4) levels should be obtained to determine if thyroid abnormalities are present.  
TSH, prolactin, and a morning cortisol level will help to differentiate primary adrenal 
insufficiency from primary pituitary insufficiency. 
Table 15:  Management Guidelines for Endocrine Events 
Table 15 has been removed from the protocol. 
SECTION 5.1.7.5:  Ocular Events 
An ophthalmologist should evaluate visual complaints.  Uveitis or episcleritis may be 
treated with topical corticosteroid eye drops.  Atezolizumab should be permanently 
discontinued for immunemediated ocular disease that is unresponsive to local 
immunosuppressive therapy. 
Table 16:  Management Guidelines for Ocular Events 
Table 16 has been removed from the protocol. 
SECTION 5.1.7.6:  InfusionRelated Reactions 
No premedication is indicated for the administration of atezolizumab in Cycle 1.  Patients 
who experience an infusionrelated reaction with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions. 
Table 17:  Management Guidelines for Infusion-Related Reactions 
Table 17 has been removed from the protocol. 
SECTION 5.1.7.7:  Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of other 
immunomodulatory agents.  The differential diagnosis of acute abdominal pain should 
include pancreatitis.  Appropriate workup should include an evaluation for obstruction, 
as well as serum amylase and lipase tests. 
Table 18:  Management Guidelines for Pancreatitis 
Table 18 has been removed from the protocol. 


 
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SECTION 5.1.7.8:  Dermatologic Events 
Treatmentemergent rash has been associated with atezolizumab.  The majority of the 
cases of rash were mild in severity and selflimited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 
be considered unless contraindicated. 
Table 19:  Management Guidelines for Dermatologic Events 
Table 19 has been removed from the protocol. 
SECTION 5.1.7.9:  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 alternate etiologies. 
Table 20:  Management Guidelines for Neurologic Disorders 
Table 20 has been removed from the protocol. 
SECTION 5.1.7.10:  Systemic Immune Activation 
Systemic immune activation (SIA) is a rare condition characterized by an excessive 
immune response.  Given the mechanism of action of atezolizumab, SIA is considered a 
potential risk when given in combination with other immunomodulating agents.  SIA 
should be included in the differential diagnosis for patients who, in the absence of an 
alternate etiology, develop a sepsislike syndrome after administration of atezolizumab. 
Recommendations regarding early identification and management of SIA are provided 
below.  In the event of suspected SIA, the Medical Monitor should be contacted 
immediately for additional guidance. 
Early disease recognition is critical, and the clinician should consider SIA if, in the 
absence of alternate etiologies, the presence of ≥
 2 of the following are present: 
•  Hypotension refractory to aggressive IV fluid challenge 
May/can require vasopressor support 
•  Respiratory distress requiring aggressive supportive care 
Supplemental oxygen, possible intubation 
•  Fever greater than 38.5°C 
•  Acute renal or hepatic failure 
•  Bleeding from coagulopathy 
•  Unexplained laboratory test abnormalities (change from baseline): 
Cytopenias (≥
 Grade 2 in two or more lineages), significant transaminitis, 
coagulopathy, elevated creatinine 
 


 
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Initial evaluation should include CBC with peripheral smear, PT, PTT, fibrinogen, 
Ddimer, ferritin, triglyceride, AST/ALT, total bilirubin, LDH, and a complete neurologic 
and abdominal examination (assess for hepatosplenomegaly). 
If cytopenias (≥
 2 lineages and change from baseline) are present or ferritin 
is ≥
 3000 ng/mL, the following evaluations should also be performed: 
•  Bone marrow biopsy/aspirate (assess for evidence of hemophagocytosis) 
•  sCD25 (soluble IL2 receptor) 
•  Natural killer cell activity 
•  Cytomegalovirus, EpsteinBarr virus and herpessimplex virus evaluation (evaluate 
for reactivated or active disease) 
 
SIA is a clinical syndrome characterized by the following: 
•  Onset greater than 24 hours after exposure to drug  
AND 
•  Progressive clinical deterioration in an acutely ill patient (in the absence of an 
alternate etiology) 
AND 
•  Involving multiple organs (≥
 2)  
AND 
•  Demonstrating specific laboratory test abnormalities 
 
Diagnosis of SIA should only be made in patients who present with a constellation of 
clinical findings as outlined above and who fulfill the following established diagnostic 
criteria in the absence of an alternate etiology. 
The diagnostic criteria and recommended management for systemic immune activation 
are provided in Table 21 below. 
Table 21:  Diagnostic Criteria and Management for Systemic Immune 
Activation 
Table 21 has been removed from the protocol. 
SECTION 5.3.5.8:  Deaths 
For this protocol, mortality is an efficacy endpoint.   
During survival followup, deaths attributed to progression of NSCLC should be recorded 
only on the Survival eCRF. 


 
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SECTION 5.4.3.1:  Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months90 days after 
the last dose of atezolizumab or within 6 months after the last dose of cisplatin. 
SECTION 5.4.3.2:  Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after the last dose of atezolizumab or within 6 months after the last dose of 
gemcitabine, cisplatin, or carboplatin. 
SECTION 6:  Statistical Considerations and Analysis Plan 
The study is currently closed to enrollment due to a low number of patients; therefore, 
formal analysis of efficacy endpoints will not be performed. 
Primary and secondary analyses (PFS, OS) will be performed on all randomized patients 
(i.e., ITT) irrespective of whether the assigned treatment was actually received.  ORR, 
DCR, and TIR analyses will be performed on all randomized patients who have 
measureable disease at baseline.  DOR analyses will be performed on the subset of 
patients who achieve an objective response.  For all efficacy analyses, patients will be 
grouped according to the treatment assigned at randomization. 
For safety analyses, patients will be grouped according to whether any amount of 
atezolizumab was received, including the case when atezolizumab was received in error. 
For TTD analysis, only patients with a nonmissing baseline assessment will be included 
in the analyses.  For change from baseline analysis, only patients with a nonmissing 
baseline assessment and at least one nonmissing post baseline assessment will be 
included in the analyses. 
SECTION 6.1:  Determination of Sample Size 
The study is currently closed to enrollment due to a low number of patients; therefore, 
sample size estimation is no longer applicable.Estimates of the number of events 
required to demonstrate efficacy in terms of PFS (primary PFS analysis as defined in 
Section 6.4.1) and OS are based on the following assumptions: 
•  Twosided significance level of 5% for PFS 
•  97.6% power to detect an HR of 0.6 for PFS, corresponding to an improvement in 
median PFS from 6 months to 10 months 
•  Twosided significance level of 3% for OS 
•  80% power for OS to detect an HR of 0.7, corresponding to an improvement in 
median OS from 11 months to 15.7 months 
•  Event times exponentially distributed 


 
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•  Accrual rampup time of 12 months to reach 20 patients per month thereafter 
•  Dropout rate assumed for both treatment arms 
5% per 12 months for PFS 
5% per 24 months for OS 
 
With these assumptions, approximately 238 PFS events are required.  This number 
of events corresponds to a minimal detectable HR of approximately 0.776.  
Approximately 400 patients will be enrolled in the study.  Primary analysis of PFS (as 
defined in Section 6.4.1 using the U.S. registration censoring rule) will occur when 
approximately 238 PFS events have occurred or after the last patient has been enrolled, 
whichever occurs last.  This is expected at approximately 28 months after the 
first patient is randomized. 
Given this sample size and the assumptions listed above, it is expected that 
approximately 291 deaths will be required for the final OS analysis. 
SECTION 6.2:  Summaries of Conduct of Study 
Subject disposition will be provided in listing format due to the small sample size.  
Summaries will not be provided.Enrollment, study drug administration, and 
discontinuation from the study will be summarized by treatment arm.  The incidence of 
study drug discontinuation for reasons other than disease progression will similarly be 
tabulated.  Protocol deviations, including major deviations of inclusion/exclusion criteria, 
will be summarized in a similar manner by treatment arm. 
SECTION 6.3:  Summaries of Treatment Group Comparability 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, baseline 
disease characteristics, ECOG performance status, and number of prior cancer 
treatments, will be provided in listing formatsummarized by treatment arm.   
Descriptive statistics (mean, median, SD, and range) will be presented for continuous 
data, and frequencies and percentages will be presented for categorical data. 
SECTION 6.4.1:  Primary Efficacy Endpoint 
The primary efficacy analysis is the comparison of PFS between the two treatment arms 
of atezolizumab and gemcitabine
 +
 cisplatin or carboplatin.  The primary endpoint, PFS, 
is defined as the time (in months) between the date of randomization and the date of 
first documented disease progression or death, whichever occurs first.  Disease 
progression will be determined on the basis of investigator assessment per RECIST v1.1.  
Patients who have not experienced disease progression or death at the time of analysis 
will be censored at the time of the last tumor assessment.  Patients with no 
postbaseline tumor assessment will be censored at the randomization date plus 1 day.   
For U.S. registrational purposes, the primary efficacy endpoint of PFS will be defined as 
described above with an additional censoring rule for missed visits.  Data for patients 


 
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with a PFS event who missed two or more scheduled assessments immediately prior to 
the PFS event will be censored at the last tumor assessment prior to the missed visits. 
Type I error control will be applied to this analyses of PFS. 
The null and alternative hypotheses for PFS analysis can be phrased in terms of the 
survival functions SA(t) and S
B(t) in Arm A (atezolizumab) and Arm B (control), 
respectively: 
H0:  S
A(t)
 =
 SB(t) versus H
1:  S
A(t) 
 ≠
 SB(t) 
The stratification factors will be those used during randomization, which include sex 
(male vs. female), ECOG performance status (0 vs.1), presence of liver metastases at 
baseline (yes vs. no), and PDL1 expression by IHC (TC3 and any IC vs. TC0/1/2 and 
IC3).  An unstratified analysis will also be performed.  In case that the numbers of 
patients are too small in some strata, patients in these strata may be pooled for analysis 
according to a prespecified method presented in the statistical analysis plan. 
The HR will be estimated using a stratified Cox regression model including 95% CIs.  
The unstratified HR will also be presented. 
KaplanMeier methodology will be used to estimate the median PFS for each treatment 
arm and to construct survival curves for the visual description of the difference between 
the treatment arms.  The BrookmeyerCrowley methodology will be used to construct the 
95% CI for the median PFS for each treatment arm (Brookmeyer and Crowley 1982). 
The following analyses will be performed for both PFS endpoints described above:  
•  Analyses described in Section 6.7.7 (Analyses at Landmark Timepoints) 
•  Analyses described in Section 6.7.9 (Subgroup Analyses)  
•  Secondary endpoint of PFS by IRF assessment, per RECIST v1.1 in Section 6.4.7.2 
 
SECTION 6.4.2:  Secondary Efficacy Endpoints 
The secondary endpoints include investigatorassessed ORR, DOR, and TIR per 
RECIST v1.1, OS, IRFassessed PFS per RECIST v1.1, and TTD per SILC scale and 
EORTC scale.  The final analyses of ORR, TTD per SILC scale and EORTC scale, DOR, 
and TIR, as well as the first interim analysis of OS, will occur at the time of the final PFS 
analysis.  It is estimated approximately 175 death events (60% of full OS information) 
will be observed.  The second OS interim analysis will be conducted when approximately 
239 death events (82% of full OS information) have occurred.  The final analysis of OS is 
planned when approximately 291 deaths have been observed. 
If the primary endpoint of PFS is statistically significant at a 5% 2sided significance level, 
the secondary endpoints of ORR and TTD (per SILC scale) will be tested simultaneously 
in the ITT population, each at a twosided 1% significance level. 


 
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The OS endpoint will be tested next at a twosided significance level depending on the 
outcome of the prior two tests, as follows: 
1.  If both the ORR and the TTD per SILC scale endpoints are statistically significant at 
the 1% significance level, OS will be tested at a 5% significance level. 
2.  Otherwise, if either the ORR or the TTD per SILC scale endpoint is statistically 
significant at a 1% significance level, OS will be tested at a 4% significance level. 
3.  If neither the ORR nor the TTD per SILC scale endpoint is statistically significant at 
the 1% significance level, OS will be tested at a 3% significance level. 
 
SECTION 6.4.2.1:  Objective Response Rate 
An objective response is defined as either an unconfirmed CR or PR, as determined by 
the investigator with use of RECIST v1.1.  Patients not meeting these criteria, including 
patients without any postbaseline tumor assessments, will be considered 
nonresponders. 
ORR is defined as the proportion of patients who had an objective response.  The 
analysis population for ORR will be all randomized patients with measurable disease at 
baseline.  An estimate of ORR and its 95% CI will be calculated using the 
ClopperPearson method for each treatment arm.  CIs for the difference in ORRs 
between the two arms will be determined using the normal approximation to the binomial 
distribution.  The ORR will be compared between the two arms using the stratified 
CochranMantel Haenszel test, stratified by the same factors used in the primary 
efficacy analysis. 
SECTION 6.4.2.2:  Overall Survival 
OS is defined as the time from randomization to death from any cause.  Data for patients 
who are not reported as having died by the date of data cutoff date will be censored at 
the date when they were last known to be alive.  Patients who do not have postbaseline 
information will be censored at the date of randomization plus 1 day. 
OS will be analyzed using the same methods as PFS. 
SECTION 6.4.2.3:  One Year and TwoYear Landmark OverallSurvival 
Analysis 
The 1year and 2year survival rate is defined as the percentage of patients who are still 
alive at 1 year and 2 years after randomization.  The analysis population for the 1year 
and 2year survival rate will be the ITT population.  The KaplanMeier method will be 
used to estimate the 1year and 2year survival rate for each treatment arm, along with 
the 95% CIs with use of Greenwood’s formula.  The difference in 1year and 2year 
survival rates between treatment arms will be assessed using the normal approximation 
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SECTION 6.4.2.1:  PatientReported Outcomes (Symptoms in Lung Cancer 
Scale) 
Only TTD using the SILC scale will be part of the alpha spending. 
TTD with use of the SILC scale is defined as the time from randomization to the 
first documented deterioration of disease symptom in the SILC symptom score (cough, 
dyspnea, or chest pain, whichever occurs first).  In order for the symptom to be 
considered “deteriorated,” the symptom score change from baseline must be held for at 
least two consecutive assessment timepoints or an initial deterioration followed by death 
within 1 week from the last assessment.  Patients will be censored at the last time when 
they completed an assessment for cough, dyspnea, or chest pain if they have not 
deteriorated.  If no postbaseline assessment is performed, patients will be censored at 
the date of randomization plus 1 day.  TTD using the SILC scale will be analyzed using 
the same methods as PFS. 
SECTION 6.4.2.5:  Additional PatientReported Outcomes 
TTD with use of the EORTC is defined as the time from baseline to the first time the 
patient’s score shows a ≥
 10point increase above baseline in any of the following 
EORTC transformed scores for cough, dyspnea (single item), dyspnea (multiitem 
subscale), chest pain, or arm/shoulder pain.  In order for the symptom to be considered 
“deteriorated,” a score increase of ≥
 10 points above baseline must be held for at least 
two consecutive cycles or an initial score increase of ≥
 10 points is followed by death 
within 3 weeks from the last assessment.  A ≥
 10point change in the score is perceived 
by patients as clinically significant (Osoba et al. 1998).  Patients will be censored at the 
last time when they completed an assessment for cough, dyspnea (single item), 
dyspnea (subscale items), chest pain, and arm/shoulder pain if they have not 
deteriorated.  If no postbaseline assessment is performed, patients will be censored at 
the randomization date plus 1 day.  TTD with use of the EORTC scale will be analyzed 
using the same methods as PFS. 
PROs of HRQoL, lung cancer−related symptoms, and health status will be measured 
using the SILC, EORTC QLQC30, and EORTC QLQLC13.  Summary statistics (mean, 
SD, median, 25th and 75th percentiles, range, and change from baseline) of linear 
transformed scores will be reported for all the items and subscales of the SILC, 
EORTC QLQ C30, and the QLQLC13 according to the EORTC scoring manual 
guidelines and the SILC scale symptom scores.  Completion and compliance rates will 
be summarized at each timepoint by treatment arm.  Only patients with a nonmissing 
baseline assessment and at least one nonmissing post baseline assessment will be 
included in the analyses. 
SECTION 6.4.2.6:  Duration of Response 
DOR is defined as the period measured from the date of the first occurrence of a CR or 
PR (whichever status is recorded first) until the first date that progressive disease or 
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the basis of investigator assessment with use of RECIST v1.1.  DOR will be assessed in 
patients who had an objective response during the study as determined by the 
investigator with use of RECIST v1.1.  Patients who have not progressed and who have 
not died by the date of data cutoff for analysis will be censored at the time of last tumor 
assessment date.  If no tumor assessments were performed after the date of the first 
occurrence of a CR or PR, DOR will be censored at the date of the first occurrence of a 
CR or PR plus 1 day. 
DOR analysis is performed on the basis of a nonrandomized subset of patients 
(specifically, patients who achieve an objective response); therefore, formal hypothesis 
testing will not be performed for this endpoint.  DOR will be estimated using 
KaplanMeier methodology.  Comparisons between treatment arms will be made for 
descriptive purposes only. 
SECTION 6.4.2.7:  Time in Response 
The two treatment arms will be compared with respect to TIR.  Nonresponders will be 
considered as having an event and TIR will be defined as date of randomization plus 
1 day; and for responders TIR will be the same as DOR.  The methodologies outlined for 
the primary analysis of PFS will be used for the analyses of TIR. 
SECTION 6.4.2.8:  Independent Review Facility−Assessed PFS per RECIST 
v1.1 
To support the primary analysis of investigatorassessed PFS, the analysis of PFS as 
assessed by the IRF will be performed.  The methodologies outlined for the primary 
analyses of PFS (for both definitions of PFS as described in Section 6.4.1) per the 
investigator will be used for the analyses of PFS based on IRF assessment. 
SECTION 6.5:  Safety Analyses 
Listings of safety data will be provided for the safety population and will include study 
drug exposure, adverse events, and deaths.Safety analyses will be performed on the 
safety population (see Section 6).  Summaries will be presented for the safetyevaluable 
population by treatment arm. 
Study drug exposure, including treatment duration, number of doses, and dose intensity, 
will be summarized for each treatment arm using descriptive statistics. 
All adverse events occurring during or after the first study drug dose will be summarized 
by treatment arm and NCI CTCAE grade.  In addition, serious adverse events, severe 
adverse events (Grade 3, 4, and 5), adverse events of special interest, and adverse 
events leading to study drug discontinuation or interruption will be summarized 
accordingly.  Multiple occurrences of the same event will be counted once at the 
maximum severity.  The proportion of patients experiencing at least one adverse event 
will be reported by toxicity term and treatment arm. 


 
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Deaths reported during the study treatment period and those reported during the 
followup period after treatment completion/discontinuation will be summarized by 
treatment arm. 
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data and changes in vital signs will be summarized by treatment arm.  
Serum levels and incidence of ATA against atezolizumab will be summarized to explore 
the potential relationship of the immunogenicity response with pharmacokinetics, safety, 
and efficacy. 
SECTION 6.6:  Pharmacokinetic Analyses 
The study is currently closed to enrollment due to a low number of patients; therefore, 
samples will no longer be collected, and formal analysis of PK and pharmacodynamics 
samples will not be performed.PK and pharmacodynamic samples will be collected in 
this study as outlined in Appendix 2. 
Atezolizumab serum concentration data (Cmin and C
max) will be tabulated and 
summarized. Descriptive statistics will include means, medians, ranges, and SDs, as 
appropriate.  Additional PK and pharmacodynamic analysis will be conducted based 
upon the availability of data. 
SECTION 6.7:  Exploratory Analyses 
The study is currently closed to enrollment due to low number of patients; therefore, 
formal analysis of exploratory endpoints will not be performed. 
SECTION 6.7.1:  Independent Review Facility−Assessed ORR, DOR, TIR, 
and DCR per RECIST v1.1 
DCR is defined as the rate of patients with complete or partial response as best 
response or stable disease that has been maintained for ≥
 6 weeks as assessed by the 
IRF per RECIST v1.1. 
The methodologies outlined in Sections 6.4.1 and 6.4.2 for primary and secondary 
efficacy endpoint analyses will be used for the analyses of ORR, DOR, TIR, and DCR 
based on IRF assessment. 
SECTION 6.7.2:  Independent Review Facility−Assessed ORR, DOR, TIR, 
DCR, and PFS per Modified RECIST 
IRFassessed ORR, DOR, TIR, DCR, and PFS with use of modified RECIST criteria will 
be limited to the atezolizumab arm only, with no comparison to the control arm.  The 
methods outlined for the primary and secondary efficacy endpoint analyses will be used 
for these analyses. 


 
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SECTION 6.7.3:  InvestigatorAssessed ORR, DOR, TIR, DCR, and PFS per 
Modified RECIST 
Investigatorassessed ORR, DOR, TIR, DCR, and PFS with use of modified RECIST 
criteria will be limited to the atezolizumab arm only, with no comparison to the control 
arm.  The methods outlined for the primary and secondary efficacy endpoint analyses 
will be used for these analyses. 
SECTION 6.7.4:  InvestigatorAssessed DCR per RECIST v1.1 
DCR is defined as the rate of patients with complete or partial response as best 
response or stable disease that has been maintained for ≥
 6 weeks by the investigator 
per RECIST v1.1. 
The methodologies outlined in Section 6.4.2.1 will be used for the analyses of DCR 
based on the investigator assessment. 
SECTION 6.7.5:  Exploratory Biomarker Analysis 
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with study drug response, including efficacy and/or adverse 
events.  The tumor biomarkers include but are not limited to PDL1 and CD8, as defined 
by IHC, qRTPCR, or other methods.  Additional pharmacodynamic analyses will be 
conducted as appropriate. 
SECTION 6.7.6:  EQ5D3L Health Status Data 
The EQ5D3L health status data will be used for obtaining utility measures for economic 
modeling.  Patients without postbaseline assessments will be excluded from this 
analysis.  These analyses will not be analyzed as an endpoint for the Clinical Study 
Report. 
SECTION 6.7.7:  SixMonth and One Year Landmark PFS Analysis 
Sixmonth and 1 year PFS analysis will occur at the time of final PFS analysis. 
The 6month and 1 year PFS rate is defined as the percentage of patients who are still 
progressionfree at 6 months or 1 year after randomization.  The analysis population will 
be the ITT population.  The KaplanMeier method will be used to estimate the 6 month 
and 1year PFS rate for each treatment arm, along with the 95% CIs with use of 
Greenwood’s formula.  The difference in 6 month/1 year PFS rates between treatment 
arms will be assessed using the normal approximation method. 
SECTION 6.7.8:  ThreeYear Landmark OS Analysis 
The methodologies for landmark OS analysis outlined in Section 6.4.2.2 will be used. 
SECTION 6.7.9:  Impact of Demographic and Baseline Characteristics on 
PFS and OS 
To assess the consistency of the study results in subgroups defined by demographic 
(e.g., age, sex, and race/ethnicity) and baseline prognostic characteristics (e.g., PDL1 


 
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tumor expression status, presence of liver metastases at baseline, ECOG performance 
status, prior lines of therapy, smoking history, etc.), the duration of PFS assessed by the 
investigator and OS in these subgroups will be examined.  Summaries of PFS and OS, 
including unstratified HRs estimated from Cox proportional hazards models and 
KaplanMeier estimates of median PFS and OS, will be produced separately for each 
level of the categorical variables. 
SECTION 6.8:  Sensitivity Analyses on the Primary Endpoint 
The study is currently closed to enrollment due to low number of patients; therefore, a 
formal sensitivity analysis of the primary endpoint will not be performed. 
SECTION 6.8.1:  Analysis Accounting for Missing Data 
To support the PFS analyses defined in Section 6.4.1, a sensitivity analysis will be 
performed to evaluate the potential impact of missing scheduled tumor assessments on 
the primary analysis of PFS, as determined by the investigator with use of a PFS event 
imputation rule.  If a patient has missed two or more assessments scheduled 
immediately prior to the date of the PFS event (disease progression or death), the 
patient will be counted as having progressed on the date of the first of these missing 
assessments. 
The imputation rule will be applied to patients in both treatment arms.  Statistical 
methodologies analogous to those used in the primary analysis of PFS as specified in 
Section 6.4.1 will be used for this sensitivity analysis. 
SECTION 6.8.2:  Independent Review Facility−Determined and 
InvestigatorDetermined Concordance Analyses 
Concordance between the IRFdetermined and investigatordetermined assessments 
will be conducted.  Summaries of agreement between the IRFdetermined and the 
investigatordetermined progressive disease status (yes vs. no) and objective response 
(yes vs. no) will be provided by treatment arm. 
Summaries of agreement between the IRFdetermined and the investigatordetermined 
progressive disease dates (PDDIRF and PDD
INV) for patients experiencing progressive 
disease on the basis of both the IRF and the investigator assessments will be provided 
by treatment arm. 
SECTION 6.8.3:  Censoring for NonProtocol AntiCancer Therapy 
PFS data for patients receiving nonprotocol anticancer therapy prior to documented 
disease progression will be censored at the time of the last tumor assessment prior to 
therapy initiation. 
SECTION 6.8.4:  Discontinuation Caused by Toxicity Impact Analysis 
A sensitivity analysis will be performed to assess the impact of discontinuation because 
of toxicity on the primary PFS comparison.  Patients in Study GO29432 who discontinue 
study drug may undergo disease assessments at intervals that are different from those 


 
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mandated during study treatment.  In this analysis, the PFS for any patient who 
discontinued study treatment prior to disease progression because of adverse events 
will be censored at the time of the last tumor assessment prior to study drug 
discontinuation. 
SECTION 6.9:  Handling of Missing Data  
For PFS, patients without a date of disease progression and death will be analyzed as 
censored observations on the date of the last tumor assessment.  If no postbaseline 
tumor assessment is available, PFS will be censored at the date of randomization 
plus 1 day.  In the analysis of PFS for U.S. registrational purposes, data for patients with 
a PFS event who missed two or more scheduled assessments immediately prior to the 
PFS event will be censored at the last tumor assessment prior to the missed visits (see 
Section 6.4.1). 
For objective response, patients without any postbaseline assessment will be 
considered nonresponders. 
For OS, patients who are not reported as having died will be analyzed as censored 
observations on the date when they were last known to be alive.  If no postbaseline 
data are available, OS will be censored at the date of randomization plus 1 day. 
For DOR, patients who have not progressed and who have not died at the time of 
analysis will be censored at the time of last tumor assessment date.  If no tumor 
assessments were performed after the date of the first occurrence of a CR or PR, DOR 
will be censored at the date of the first occurrence of a complete or partial response 
plus 1 day. 
For responders, TIR is censored the same way as DOR.  Nonresponders will be 
considered as having an event at the date of randomization plus 1 day. 
For TTD with use of SILC scale analysis, patients will be censored at the last time when 
they completed an assessment for cough, dyspnea, and chest pain if they have not 
deteriorated.  If no postbaseline assessment is performed, patients will be censored at 
the date of randomization plus 1 day. 
SECTION 6.9.1:  Interim Safety Analyses 
An iDMC will be used to evaluate interim safety on a regular basis.  All 
summaries/analyses by treatment arm for the iDMC’s review will be prepared by an 
external iDCC.  Members of the iDMC will be external to the Sponsor and will follow a 
Charter that outlines their roles and responsibilities.The study is currently closed to 
enrollment due to a low number of patients; therefore, interim safety data will not be 
evaluated by an iDMC. 
SECTION 6.9.2:  Planned Interim Analysis 
No interim analyses are planned for PFS in this study. 


 
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The first OS interim analysis will be conducted at the time of final PFS analysis.  It is 
projected that approximately 175 OS events in the ITT population will have been 
observed at the time of final PFS analysis, but the exact timing of this analysis will 
depend on the actual number of PFS events.  The stopping boundaries are shown in 
Table 31, with the exact boundaries depending on the outcome of the ORR test and TTD 
(SILC) test. 
The second OS interim analysis will be conducted when approximately 82% of the 
information (i.e., approximately 239 OS events in the ITT population) has been observed.  
This is expected at 34 months after the first patient is enrolled, but the exact timing of 
this analysis will depend on the accrual of OS events.  The stopping boundaries are 
shown in Table 31, with the exact boundaries depending on the outcome of the ORR 
test and TTD (SILC) test. 
The final OS analysis will be performed when approximately 291 OS events have 
occurred.  This analysis is expected at 43 months after the first patient is enrolled, but 
the exact timing of this analysis will depend on the accrual of OS events.  The stopping 
boundaries are shown in Table 31, with the exact boundaries depending on the outcome 
of the ORR test and TTD (SILC) test. 
Table 31:  Interim and Final Analysis for Overall Survival 
Table 31 has been removed from the protocol. 
SECTION 6.9.3:  Optional Interim Analysis 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis for the primary endpoint of PFS 
beyond what is specified in Section 6.10.1.  Below are the specifications in place to 
ensure the study continues to meet the highest standards of integrity when an optional 
interim analysis is executed. 
The interim analysis will be conducted by an iDCC and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
Charter. 
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the Statistical Analysis Plan 
(SAP), and the SAP will be submitted to relevant health authorities at least 2 months 
prior to the conduct of the interim analysis.  The iDMC Charter will document potential 
recommendations the iDMC can make to the Sponsor as a result of the analysis 
(e.g., stop the study for positive efficacy, stop the study for futility), and the iDMC Charter 
will also be made available to relevant health authorities. 


 
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SECTION 8.2:  Informed Consent 
The Informed Consent Form will also contain the following additional signature pages: 
•  A signature page for patients to undergo an optional tumor tissue biopsy at the 
time of radiographic disease progression, if clinically feasible.    
 
SECTION 9.4:  Administrative Structure 
Approximately 155 sites globally will participate in the study and approximately 
400 patients will be randomized. 
APPENDIX 1:  Schedule of Assessments 
The appendix has been updated to reflect the changes to the protocol. 
APPENDIX 2:  Schedule of Pharmacokinetic, Biomarker, and 
Anti-Therapeutic Antibody Assessments 
The appendix and all cross references have been removed from the protocol.  
Appendix 7 :  EORTC QLQ-C30 
The appendix and all cross references have been removed from the protocol. 
Appendix 8 :  EORTC QLQ-LC13 
The appendix and all cross references have been removed from the protocol. 
Appendix 9 :  Symptoms in Lung Cancer Scale 
The appendix and all cross references have been removed from the protocol. 
Appendix 10:  EuroQoL 5 Dimension, 3 Level Questionnaire 
The appendix and all cross references have been removed from the protocol. 
Appendix 13:  Preexisting Autoimmune Diseases 
The appendix and all cross references have been removed from the protocol. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol, where appropriate. 
 
 
 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ..........................................51 
PROTOCOL SYNOPSIS 
....................................................................................52 
1.  BACKGROUND..........................................................................................62 
1.1  
 Non-Small  
 
Cell Lung Cancer.................................................62 
1.2    
First-Line Treatment for Non−Small Cell Lung 
Cancer 
...................................................................................63 
1.3    
Targeted Therapy for Non−Small Cell Lung 
Cancer 
...................................................................................67 
1.4    
Maintenance Therapy for Non−Small Cell Lung 
Cancer...................................................................................67 
1.5    
Background on Atezolizumab (MPDL3280A) ........................68 
1.5.1    
Summary of Nonclinical Studies 
............................................68 
1.6  
 Clinical  
 
Experience with Atezolizumab ..................................69 
1.6.1  
 Ongoing  
 
Clinical Studies........................................................69 
1.6.2  
 Clinical Safety........................................................................70 
1.6.2.1   Single-Agent   
Clinical Safety in Patients with 
Non−Small Cell Lung Cancer ................................................70 
1.6.2.2   Single-Agent   
Clinical Safety in Patients with 
Non−Small Cell Lung Cancer in POPLAR 
Study GO28753.....................................................................72 
1.6.2.3   Single-Agent   
Clinical Safety in Patients with 
Non−Small Cell Lung Cancer in 
FIR Study GO28625 
..............................................................73 
1.6.2.4   Immune-Mediated Adverse Events........................................74 
1.6.3  
 Clinical Activity.......................................................................74 
1.6.3.1   
Single-Agent Clinical Activity in Patients with 
Non−Small Cell Lung Cancer in 
Study PCD4989g...................................................................74 
1.6.3.2    Single-Agent Clinical Activity in Patients with 
Non−Small Cell Lung Cancer in 
POPLAR Study GO28753 .....................................................75 
1.6.3.3    Single-Agent Clinical Activity in Patients with 
Non−Small Cell Lung Cancer in 
FIR Study GO28625 
..............................................................77 
1.6.4  
 Clinical  
 
Pharmacokinetics and Immunogenicity.....................78 


 
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1.6.5  
 Rationale  
 
for  
 
Atezolizumab Dosage ......................................78 
1.7    
Study Rationale and Benefit-Risk Assessment......................79 
2.  OBJECTIVES..............................................................................................81 
3.  STUDY  
DESIGN.........................................................................................81 
3.1  
 Description of Study..............................................................81 
3.1.1  
 Independent  
 
Data  
 
Monitoring Committee..............................84 
3.2  
 End  
 
of Study 
..........................................................................84 
3.3  
 Rationale  
 
for Study Design 
....................................................84 
3.3.1    
Rationale for Testing Atezolizumab in 
PD-L1−Selected Patients with Non−Small Cell 
Lung Cancer 
..........................................................................84 
3.3.2    
Rationale for Gemcitabine + Cisplatin or 
Carboplatin as a Comparator.................................................85 
3.3.3    
Rationale for Allowing Patients to Continue 
Atezolizumab Treatment until Loss of Clinical 
Benefit ...................................................................................85 
3.3.4    
Rationale for Collection of Archival and/or Fresh 
Tumor Specimens .................................................................86 
3.3.5    
Rationale for Blood Biomarker Assessments.........................86 
3.3.6    
Rationale for the Collection of Optional Tumor 
Specimens at Radiographic Progression...............................86 
3.4  
 Outcome  
 
Measures ...............................................................87 
4.  MATERIALS  
AND METHODS....................................................................87 
4.1  
 Patients..................................................................................87 
4.1.1  
 Inclusion Criteria....................................................................87 
4.1.2  
 Exclusion Criteria...................................................................90 
4.1.2.1   Cancer-Specific Exclusions ...................................................90 
4.1.2.2   General   
Medical Exclusions ..................................................91 
4.1.2.3   Exclusion   
Criteria Related to Medications .............................92 
4.1.2.4   Exclusion   
Criteria Related to Gemcitabine, 
Cisplatin or Carboplatin .........................................................93 
4.2  
 Method  
 
of  
 
Treatment  
 
Assignment and Blinding 
.....................93 
4.3  
 Study  
 
Treatment 
....................................................................94 
4.3.1  
 Formulation,  
 
Packaging, and Handling..................................94 


 
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4.3.1.1    Atezolizumab (MPDL3280A) ................................................. 94 
4.3.1.2    Gemcitabine + Cisplatin or Carboplatin ................................. 94 
4.3.1.3    Erlotinib.................................................................................. 94 
4.3.2    
Dosage, Administration, and Compliance.............................. 95 
4.3.2.1    Atezolizumab.........................................................................95 
4.3.2.2    Gemcitabine + Cisplatin or Carboplatin ................................. 97 
4.3.2.3    Erlotinib.................................................................................. 99 
4.3.3    
Investigational Medicinal Product Accountability ................... 99 
4.3.4    
Post-Study Access to Atezolizumab 
Investigational Medicinal Product Accountability ................. 100 
4.4    
Concomitant Therapy.......................................................... 100 
4.4.1    
Permitted Therapy............................................................... 100 
4.4.2    
Cautionary Therapy for Atezolizumab-Treated 
Patients................................................................................101 
4.4.3    
Prohibited Therapy.............................................................. 101 
4.5    
Study Assessments............................................................. 102 
4.5.1    
Informed Consent Forms and Pre-
Screening/Screening Log.................................................... 102 
4.5.2    
Medical History and Demographic Data .............................. 103 
4.5.3    
Physical Examinations......................................................... 103 
4.5.4    
Vital Signs............................................................................103 
4.5.5    
Tumor and Response Evaluations....................................... 104 
4.5.6    
Laboratory, Biomarker, and Other Biological 
Samples...............................................................................105 
4.5.7    
Tumor Tissue Samples........................................................ 106 
4.5.7.1    Archival and Freshly Collected Tumor Tissue 
Samples for Screening........................................................ 106 
4.5.7.2    Optional Tumor Samples at the Time of 
Radiographic Progression................................................... 107 
4.5.7.3    Tumor Samples at Other Timepoints................................... 108 
4.5.8    
Use and Storage of Remaining Samples from 
Study-Related Procedures................................................... 108 
4.5.9    
Anti-Therapeutic Antibody Testing....................................... 108 
4.5.10    
Electrocardiograms.............................................................. 108 
4.5.11    
Patient-Reported Outcomes ................................................ 108 


 
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4.5.12    
Samples for Roche Clinical Repository................................ 109 
4.5.12.1    Overview of the Roche Clinical Repository.......................... 109 
4.5.12.2    Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 109 
4.5.12.3    Sample Collection................................................................ 109 
4.5.12.4    Confidentiality......................................................................110 
4.5.12.5    Consent to Participate in the Roche Clinical 
Repository ........................................................................... 111 
4.5.12.6    Withdrawal from the Roche Clinical Repository................... 111 
4.5.12.7    Monitoring and Oversight.....................................................111 
4.5.13    
Timing of Assessments........................................................ 111 
4.5.13.1    Screening/Baseline Assessments ....................................... 111 
4.5.13.2    Assessments during Treatment 
...........................................112 
4.5.13.3    Assessments at Treatment Discontinuation Visit................. 112 
4.5.13.4    Follow-Up Assessments ...................................................... 113 
4.5.13.5    Assessments at Unscheduled Visits 
.................................... 113 
4.6    
Patient, Treatment, Study, and Site 
Discontinuation 
....................................................................113 
4.6.1    
Patient Discontinuation 
........................................................ 113 
4.6.2    
Study Treatment Discontinuation......................................... 114 
4.6.3    
Study and Site Discontinuation............................................ 115 
5.   ASSESSMENT OF SAFETY.....................................................................116 
5.1    
Safety Plan ..........................................................................116 
5.1.1    
Risks Associated with Atezolizumab ...................................116 
5.1.2    
Risks Associated with Gemcitabine 
.....................................117 
5.1.3    
Risks Associated with Platinum-Based 
Chemotherapy 
.....................................................................117 
5.1.3.1    Risks Associated with Cisplatin Chemotherapy................... 117 
5.1.3.2    Risks Associated with Carboplatin Chemotherapy .............. 117 
5.1.3.3    Risks Associated with Erlotinib 
............................................ 118 
5.1.4    
General Plan to Manage Safety Concerns.......................... 118 
5.1.4.1    Monitoring............................................................................118 
5.1.5    
Dose Modification................................................................119 
5.1.5.1    General Notes Regarding Dose Modification....................... 119 


 
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5.1.6    
Atezolizumab Dose Modifications, Treatment 
Delays, or Treatment Discontinuation..................................119 
5.1.7    
Management of Atezolizumab-Specific Adverse 
Events..................................................................................120 
5.1.8  
 Gemcitabine  
 
+ Cisplatin or Carboplatin Dose 
Modification and Management of Specific 
Adverse Events...................................................................121 
5.1.8.1   Hematologic Toxicity...........................................................121 
5.1.8.2    Dose Modifications Guidelines of 
Non-Hematological Toxicity 
.................................................122 
5.1.9  
 Platinum  
 
Chemotherapy Dose Modification and 
Management of Specific Adverse Events ............................123 
5.1.9.1   Cisplatin...............................................................................123 
5.1.9.2   Carboplatin..........................................................................125 
5.2  
 Safety  
 
Parameters and Definitions......................................127 
5.2.1  
 Adverse Events ...................................................................128 
5.2.2   
Serious Adverse Events (Immediately Reportable 
to the Sponsor)....................................................................128 
5.2.3    
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)..................................................129 
5.3    
Methods and Timing for Capturing and 
Assessing Safety Parameters..............................................130 
5.3.1  
 Adverse  
 
Event Reporting Period .........................................130 
5.3.2  
 Eliciting  
 
Adverse Event Information.....................................130 
5.3.3    
Assessment of Severity of Adverse Events .........................130 
5.3.4    
Assessment of Causality of Adverse Events .......................131 
5.3.5    
Procedures for Recording Adverse Events..........................132 
5.3.5.1   Infusion-Related Reactions..................................................132 
5.3.5.2   Diagnosis   
versus Signs and Symptoms...............................132 
5.3.5.3    Adverse Events That Are Secondary to Other 
Events..................................................................................132 
5.3.5.4    Persistent or Recurrent Adverse Events..............................133 
5.3.5.5   Abnormal   
Laboratory Values ...............................................133 
5.3.5.6   Abnormal   
Vital Sign Values .................................................134 
5.3.5.7   Abnormal   
Liver Function Tests 
............................................134 
5.3.5.8   
Deaths .................................................................................135 


 
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5.3.5.9   Preexisting   
Medical Conditions............................................ 135 
5.3.5.10    Worsening of Non−Small Cell Lung Cancer........................ 135 
5.3.5.11   Hospitalization   
or   
Prolonged Hospitalization........................ 136 
5.3.5.12    Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 136 
5.3.5.13   Patient-Reported Outcome Data ......................................... 136 
5.4  
 Immediate  
 
Reporting Requirements from 
Investigator to Sponsor........................................................ 137 
5.4.1  
 Emergency  
 
Medical Contacts 
.............................................. 137 
5.4.2  
 Reporting  
 
Requirements for Serious Adverse 
Events and Adverse Events of Special Interest 
................... 138 
5.4.2.1    Events That Occur prior to Study Drug Initiation.................. 138 
5.4.2.2    Events That Occur after Study Drug Initiation...................... 138 
5.4.3  
 Reporting  
 
Requirements for Pregnancies............................ 138 
5.4.3.1    Pregnancies in Female Patients 
.......................................... 138 
5.4.3.2    Pregnancies in Female Partners of Male Patients............... 139 
5.4.3.3   Abortions .............................................................................139 
5.4.3.4   Congenital   
Anomalies/Birth Defects .................................... 139 
5.5  
 Follow-Up  
 
of  
 
Patients  
 
after Adverse Events ........................ 140 
5.5.1  
 Investigator Follow-Up 
.........................................................140 
5.5.2  
 Sponsor  
 
Follow-Up.............................................................. 140 
5.6  
 Post-Study  
 
Adverse Events 
................................................. 140 
5.7    
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 140 
6.  STATISTICAL  
CONSIDERATIONS AND ANALYSIS PLAN..................... 141 
6.1  
 Determination  
 
of  
 
Sample Size ............................................. 141 
6.2    
Summaries of Conduct of Study 
..........................................141 
6.3    
Summaries of Treatment Group Comparability ................... 141 
6.4  
 Efficacy  
 
Analyses................................................................ 141 
6.5  
 Safety  
 
Analyses................................................................... 141 
6.6  
 Pharmacokinetic Analyses...................................................142 
6.7  
 Exploratory  
 
Analyses........................................................... 142 
6.8    
Sensitivity Analyses on the Primary Endpoint...................... 142 


 
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6.9  
 Interim  
 
Analysis................................................................... 142 
6.9.1  
 Interim  
 
Safety Analyses 
....................................................... 142 
7.  DATA  
COLLECTION  
AND MANAGEMENT .............................................142 
7.1  
 Data  
 
Quality  
 
Assurance 
....................................................... 142 
7.2  
 Electronic  
 
Case  
 
Report Forms............................................. 142 
7.3  
 Electronic  
 
Patient  
 
Reported Outcome Data 
......................... 143 
7.4    
Source Data Documentation................................................ 143 
7.5    
Use of Computerized Systems ............................................ 144 
7.6  
 Retention  
 
of Records 
........................................................... 144 
8.  ETHICAL  
CONSIDERATIONS.................................................................. 144 
8.1    
Compliance with Laws and Regulations ..............................144 
8.2  
 Informed  
 
Consent................................................................ 145 
8.3    
Institutional Review Board or Ethics Committee 
.................. 146 
8.4  
 Confidentiality...................................................................... 146 
8.5  
 Financial  
 
Disclosure............................................................ 147 
9.   STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 147 
9.1  
 Study  
 
Documentation.......................................................... 147 
9.2  
 Protocol  
 
Deviations.............................................................. 147 
9.3  
 Site  
 
Inspections................................................................... 147 
9.4  
 Administrative Structure....................................................... 148 
9.5    
Publication of Data and Protection of Trade 
Secrets................................................................................ 148 
9.6  
 Protocol  
 
Amendments......................................................... 149 
10. REFERENCES .........................................................................................150 
 
 
LIST OF TABLES 
Table 1    
Randomized Phase III Trials in Patients with Previously 
Untreated Non−Small Cell Lung Cancer..................................... 65 
Table 2    
Study PCD4989g:  Adverse Events with Frequency  ≥ 10% 
of Patients for All Grades ............................................................ 71 
Table 3    
Adverse Events Reported in at Least 10% of Patients in 
POPLAR Study GO28753........................................................... 72 


 
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Table 4    
Adverse Events Reported in FIR Study GO28625 
...................... 73 
Table 5    
Patients with Non−Small Cell Lung Cancer in Study 
PCD4989g:  Objective Response Rate by Tumor PD-L1 
Expression and Best Overall Response Rate (per RECIST 
Version 1.1).................................................................................75 
Table 6    
Efficacy Results in Study GO28753 (POPLAR):  
Intent-to-Treat Population ........................................................... 76 
Table 7    
Study GO28753 (POPLAR) Efficacy Results by Combination 
PD-L1 Diagnostic Subgroups with Complementary 
Comparison Subgroupings:  Intent-to-Treat Population 
.............. 77 
Table 8    
Efficacy Results for Study GO28625 (FIR):  
Efficacy-Evaluable Patients by PD-L1 Diagnostic Subgroups..... 78 
Table 9    
Administration of First and Subsequent Infusions 
of Atezolizumab .......................................................................... 96 
Table 10    Gemcitabine + Cisplatin or Carboplatin Regimen ....................... 97 
Table 11    Vital Sign Measurements at Cycle 1 and All Subsequent 
Cycles.......................................................................................104 
Table 12    Dose Modification Guidelines for Hematological Toxicities on 
Day 1 of Gemcitabine + Cisplatin or Carboplatin ...................... 121 
Table 13    Dose Modification Guidelines for Hematological Toxicities on 
Day 8 of Gemcitabine............................................................... 122 
Table 14    Gemcitabine Dose Modification Guidelines for 
Non-Hematological Toxicities.................................................... 123 
Table 15    Cisplatin Dose Modification for Hematologic Toxicities............. 124 
Table 16    Cisplatin Dose Modification for Non-Hematologic Toxicities 
(Excluding Neurotoxicity).......................................................... 124 
Table 17    Cisplatin Dose Modification for Associated Neurotoxicity ......... 125 
Table 18    Carboplatin Dose Modification for Hematologic Toxicities ........ 125 
Table 19    Carboplatin Dose Modification on the Basis of 
Non-Hematologic Toxicities in the Preceding Cycle.................. 127 
Table 20    Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ....................................... 131 
 
 
LIST OF FIGURES 
Figure 1    Study Schema............................................................................. 82 
Figure 2    Criteria for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size (Atezolizumab Arm) ........ 115 
 
 
LIST OF APPENDICES 
Appendix 1   Schedule of Assessments......................................................... 154 


 
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Appendix 2   American Joint Committee on Cancer Non−Small Cell Lung 
Cancer Staging, 7th Edition ......................................................156 
Appendix 3   Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication..............................................158 
Appendix 4   Modified Response Evaluation Criteria in Solid Tumors...........170 
Appendix 5   Anti−PD-L1 Immunohistochemistry...........................................177 
Appendix 6   Eastern Cooperative Oncology Group Performance Status 
Scale 
.........................................................................................178 
Appendix 7   Anaphylaxis Precautions...........................................................179 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
OF ATEZOLIZUMAB (ANTI−PD-L1 ANTIBODY) 
COMPARED WITH GEMCITABINE +
 CISPLATIN OR 
CARBOPLATIN FOR PD-L1−SELECTED, 
CHEMOTHERAPY NAIVE PATIENTS WITH STAGE 
IV SQUAMOUS NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER:  GO29432 
VERSION NUMBER:   5 
EUDRACT NUMBER:   2014-003106-33 
IND NUMBER:   
117296 
TEST PRODUCT:   
Atezolizumab (MPDL3280A, RO5541267) 
MEDICAL MONITOR: 
, M.D., Ph.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 to 
the Sponsor or their designee.  Contact details will be provided to the investigator prior 
to study start.   
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
52/Protocol GO29432, Version 5 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY OF 
ATEZOLIZUMAB (ANTI−PD-L1 ANTIBODY) COMPARED WITH 
GEMCITABINE +
 CISPLATIN OR CARBOPLATIN FOR 
PD-L1−SELECTED, CHEMOTHERAPY NAIVE PATIENTS WITH 
STAGE IV SQUAMOUS NON−SMALL CELL LUNG CANCER 
PROTOCOL NUMBER:   GO29432 
VERSION NUMBER:   
5 
EUDRACT NUMBER:   2014-003106-33 
IND NUMBER:   
117296 
TEST PRODUCT:   
Atezolizumab (MPDL3280A, RO5541267) 
PHASE: 
III 
INDICATION:   
Non−Small Cell Lung Cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
The study is currently closed to enrollment due to a low number of patients; therefore, the 
objectives of this study are no longer applicable and formal analyses of efficacy or safety will 
not be performed. 
Study Design 
Description of Study 
This is a randomized, Phase III, multicenter, open-label study designed to evaluate and 
compare the safety and efficacy of atezolizumab with gemcitabine
 +
 cisplatin or carboplatin in 
programmed death−ligand 1 (PD-L1)−selected patients who are chemotherapy-naïve and have 
Stage IV squamous non−small cell lung cancer (NSCLC).   
At screening, tumor specimens from each potentially eligible patient will be tested for PD-L1 
expression by a central laboratory.  Only patients who are PD-L1−selected (tumor cell [TC]3 or 
tumor-infiltrating immune cell [IC]3) will be enrolled.  Patients will be randomized 1:1 to receive 
either atezolizumab alone or gemcitabine
 +
 cisplatin or carboplatin, stratified by sex (male vs. 
female), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs.1), presence 
of liver metastases at baseline (yes vs. no), and PD-L1 tumor tissue expression by 
immunohistochemistry (IHC; TC3 and any IC vs. TC0/1/2 and IC3). 
Given the toxicities associated with platinum-based chemotherapies (neutropenia, anemia) and 
the requirement for pre-medications, this will be an open-label study.  No crossover will be 
allowed from the control arm (gemcitabine +
 cisplatin or carboplatin) to the experimental arm 
(atezolizumab).  Approximately 400 patients will be randomized. 
Atezolizumab (fixed dose of 1200 mg) will be administered intravenously on Day 1 of each 
21-day cycle.  Atezolizumab treatment may continue as long as patients are experiencing 
clinical benefit as assessed by the investigator (i.e., in the absence of unacceptable toxicity or 
symptomatic deterioration attributed to disease progression after an integrated assessment of 
radiographic data, biopsy results [if available], and clinical status) or until unacceptable toxicity 
or death. 
During treatment, patients who are treated with atezolizumab and who show evidence of clinical 
benefit will be permitted to continue atezolizumab treatment at any timepoint after Response 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
53/Protocol GO29432, Version 5 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria for progressive disease are met if 
they meet all of the following criteria: 
•   Evidence of clinical benefit as assessed by the investigator 
•   Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease 
•   Patients must provide written consent to acknowledge deferring other treatment options in 
favor of continuing treatment with atezolizumab at the time of initial progression. 
 
Patients in both treatment arms may undergo an optional tumor tissue biopsy at the time of 
radiographic disease progression if clinically feasible.  To do this, patients must sign a 
separate consent.  These data will be used to explore if the radiographic findings are consistent 
with the presence of tumor or if the appearance of progression was pseudoprogression.  In 
addition, these data will be analyzed for the association between changes in tumor tissue and 
clinical outcome and to understand further the potential mechanisms of resistance and 
progression to atezolizumab when compared to such mechanisms after treatment with 
chemotherapy.  This exploratory biomarker evaluation will not be used for any treatment-related 
decisions.   
Patients randomized to receive gemcitabine +
 cisplatin or carboplatin (per investigator’s choice) 
will receive chemotherapy intravenously on Day 1 (for cisplatin or carboplatin) and on Days 1 
and 8 (for gemcitabine) of each 21-day cycle for four or six cycles, as per local standard-of-care.  
The intended number of cycles planned for the platinum-based chemotherapy will be specified 
by the investigator prior to study randomization.  Treatment with gemcitabine
 +
 cisplatin or 
carboplatin will discontinue early if RECIST v1.1 criteria for progressive disease are met or if 
patient experiences unacceptable toxicity.   
All patients will undergo tumor assessments at baseline and every 6 weeks thereafter, 
regardless of dose delays, for the first 48 weeks following Cycle 1, Day 1 regardless of 
treatment delays.  After 48 weeks, tumor assessments will be required every 9 weeks after 
completion of the Week 48 tumor assessment, regardless of treatment delays, until disease 
progression per RECIST v1.1 (for patients in both treatment arms) or loss of clinical benefit (for 
atezolizumab-treated patients who continue treatment after disease progression according to 
RECIST v1.1), consent withdrawal, enrollment into an extension study, or death, whichever 
occurs first.  Patients who discontinue treatment for reasons other than disease progression 
(e.g., toxicity) will continue scheduled tumor assessments until disease progression, withdrawal 
of consent, death, or are eligible to roll over to an extension study, whichever occurs first.  In 
the absence of disease progression, tumor assessments should continue regardless of whether 
patients start a new anti-cancer therapy, unless consent is withdrawn. 
Number of Patients 
The study is currently closed to enrollment due to a low number of patients. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
•   Signed Informed Consent Form 
•   Male or female, 18 years of age or older 
•   Histologically or cytologically confirmed Stage (IV) squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 7th
edition) 
•   Patients with a history of treated asymptomatic CNS metastases are eligible, provided they 
meet all of the following criteria: 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, 
pons, medulla, or spinal cord) 
No ongoing requirement for corticosteroids as therapy for CNS disease 
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
randomization 


 
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54/Protocol GO29432, Version 5 
No evidence of interim progression between the completion of CNS-directed therapy 
and the screening radiographic study 
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, these 
patients may then be eligible without the need for an additional brain scan prior to 
randomization, if all other criteria are met. 
•   Tumor PD-L1 expression (TC3 or IC3), as determined by an IHC assay performed by a 
central laboratory on previously obtained archival tumor tissue or tissue obtained from a 
biopsy at screening 
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in paraffin 
block (preferred) or a minimum of 15 unstained, freshly cut, serial sections from an 
FFPE tumor specimen is required for participation in this study.  This specimen must 
be accompanied by the associated pathology report. 
If fewer than 15 slides are available at baseline (but no fewer than 10), the patient 
may still be eligible, upon discussion with the Medical Monitor. 
For freshly collected specimens, resections, core needle biopsies, excisional, 
incisional, punch, or forceps biopsies are acceptable. 
Fine-needle aspiration, brushing, cell pellet from pleural effusion, and lavage samples 
are not acceptable. 
Tumor tissue from bone metastases is not acceptable. 
For core needle biopsy specimens, preferably, at least three cores embedded in a 
single paraffin block, should be submitted for evaluation. 
For patients whose initial archival tumor tissue sample is PD-L1 negative, a biopsy can 
be performed at screening to submit fresh tissue for the purposes of testing PD-L1 
status.  A positive test result in any tumor tissue sample will satisfy this eligibility 
criterion. 
For samples not meeting minimum requirements for size/slide number, contact the 
Medical Monitor to determine if patient is eligible for study participation. 
•   No prior treatment for Stage IV squamous NSCLC unless patient had a previously detected 
sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma 
kinase (ALK) fusion oncogene. 
Patients having previously detected sensitizing EGFR mutation must have been 
previously treated with an EGFR tyrosine kinase inhibitor (TKI; erlotinib, gefitinib, etc.) 
and experienced disease progression (during or after treatment) or intolerance to 
treatment with an EGFR TKI.  However, given that testing for EGFR mutations is not 
considered standard in this patient population due to its extremely low frequency, 
patients with an unknown status will not be required to be tested at screening. 
Patients having a previously detected ALK fusion oncogene must have been 
previously treated with crizotinib or another ALK inhibitor and experienced disease 
progression (during or after treatment) or intolerance to treatment with the ALK 
inhibitor.  However, given that testing to detect ALK fusion oncogenes is not 
considered standard in this patient population due to its extremely low frequency, 
patients with an unknown status will not be required to be tested at screening. 
•   Patients who have received prior neo-adjuvant, adjuvant chemotherapy, or 
chemoradiotherapy with curative intent for non-metastatic disease must have experienced a 
treatment-free interval of at least 6 months from randomization since the last chemotherapy 
or chemoradiotherapy cycle. 
•   Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can only be considered measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of measurable disease. 


 
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55/Protocol GO29432, Version 5 
•   ECOG performance status of 0 or 1 
•   Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to the first study treatment: 
ANC ≥
 1500 cells/μL without granulocyte colony-stimulating factor support 
Lymphocyte count ≥
 500 cells/μL 
Platelet count ≥
 100,000 cells/μL without transfusion 
Hemoglobin ≥
 9.0 g/dL 
Patients may be transfused to meet this criterion. 
INR or aPTT ≤
 1.5 times the upper limit of normal (ULN) 
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation must have an INR or aPTT within 
therapeutic limits for at least 1 week prior to randomization.  
AST and ALT ≤
 2.5
 ×
 ULN 
If patient has liver metastases, AST and/or ALT ≤
 5
 ×
 ULN 
Alkaline phosphatase ≤
 2.5
 ×
 ULN 
If patient has liver or bone metastases, alkaline phosphatase ≤
 5
 ×
 ULN 
Serum bilirubin ≤
 1.5
 ×
 ULN 
Patients with known Gilbert disease who have serum bilirubin level ≤
 3
 ×
 ULN may 
be enrolled. 
Calculated creatinine clearance (CrCl) ≥
 45 mL/min 
If using cisplatin, calculated CrCl must be ≥
 60 mL/min  
•   For female patients of childbearing potential and male patients with partners of childbearing 
potential, agreement (by patient and/or partner) to use a highly effective form(s) of 
contraception during study treatment that results in a low failure rate of
 <
 1% per year when 
used consistently and correctly.  Female patients treated with atezolizumab should continue 
contraception use for 5 months after the last dose.  Female patients treated with cisplatin 
should continue contraception use for 6 months after the last dose.  Male patients treated 
with gemcitabine, cisplatin, or carboplatin should continue contraception use for 6 months 
after the last dose.  Such methods include combined (estrogen and progestogen containing) 
hormonal contraception, progestogen-only hormonal contraception associated with 
inhibition of ovulation together with another additional barrier method always containing a 
spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral 
tubal occlusion or vasectomized partner (on the understanding that this is the only one 
partner during the entire study duration), and sexual abstinence. 
Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drug.  The same rules are valid for male 
patients involved in this clinical trial if they have a partner of childbirth potential.  Male 
patients must always use a condom. 
•   Women who are not postmenopausal (≥
 12 months of non−therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Specific Exclusions 
•   Active or untreated CNS metastases as determined by computed tomography (CT) or 
magnetic resonance imaging evaluation during screening and prior radiographic 
assessments 
•   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 randomization 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
56/Protocol GO29432, Version 5 
• Leptomeningeal  
disease  
•   Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
•   Uncontrolled tumor-related pain  
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to randomization.  
There is no required minimum recovery period. 
Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy, if 
appropriate, prior to enrollment. 
•   Uncontrolled or symptomatic hypercalcemia (>
 1.5 mmol/L ionized calcium or 
calcium >
 12 mg/dL or corrected serum calcium >
 ULN) 
Patients who are receiving denosumab prior to randomization must be willing and 
eligible to discontinue its use and replace it with a bisphosphonate instead while in the 
study. 
•   Malignancies other than NSCLC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival 
>
 90%) treated with expected curative outcome (such as adequately treated carcinoma in 
situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated 
surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent) 
 
General Medical Exclusions 
•   Women who are pregnant, lactating, or intending to become pregnant during the study 
•   History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
•   Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation 
•   History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid-replacement hormone may be eligible for this study. 
Patients with controlled Type I diabetes mellitus on a stable insulin regimen are 
eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
Rash must cover less than 10% of body surface area 
Disease is well controlled at baseline and only requiring low potency topical 
steroids 
No acute exacerbations of underlying condition within the last 12 months 
requiring treatment with either PUVA [psoralen plus ultraviolet A radiation], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or high potency 
or oral steroids. 
•   Prior allogeneic bone marrow transplantation or prior solid organ transplantation 


 
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57/Protocol GO29432, Version 5 
•   History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia 
(i.e., bronchiolitis obliterans), idiopathic pneumonitis or evidence of active pneumonitis on 
screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
•   Positive HIV test 
•   Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening).  
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.  HBV 
DNA test must be performed in these patients prior to randomization. 
•   Patients with active hepatitis C 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA. 
•   Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to randomization, unstable 
arrhythmias, or unstable angina 
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or left ventricular ejection fraction <
 50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation with a 
cardiologist if appropriate. 
• Active  
tuberculosis  
•   Severe infections within 4 weeks prior to randomization including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
•   Major surgical procedure other than for diagnosis within 28 days prior to randomization or 
anticipation of need for a major surgical procedure during the course of the study 
•   Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications 
 
Exclusion Criteria Related to Medications 
•   Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy 
within 3 weeks prior to initiation of study treatment; the following exceptions are allowed: 
TKIs approved for treatment of NSCLC discontinued >
 7 days prior to randomization; 
the baseline scan must be obtained after discontinuation of prior TKIs. 
•   Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 28 days prior to randomization 
•   Received therapeutic oral or intravenous antibiotics within 2 weeks prior to randomization 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
•   Administration of a live, attenuated vaccine within 4 weeks prior to randomization or 
anticipation that such a live attenuated vaccine will be required during the study 
Influenza vaccination should be given during influenza season.  Patients must not 
receive live, attenuated influenza vaccine (e.g., FluMist
®) within 4 weeks prior to 
randomization or at any time during the study. 


 
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•   Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, 
and anti−PD-L1 therapeutic antibodies 
Patients who have had prior anti−cytotoxic T lymphocyte−associated 
antigen 4 (CTLA-4) treatment may be enrolled, provided the following requirements 
are met: 
Minimum of 6 weeks from the last dose of anti−CTLA-4 
No history of severe immune related adverse effects from anti−CTLA-4 (National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
Grades 3 and 4) 
•   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 
randomization 
Prior treatment with cancer vaccines is allowed. 
•   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 [anti-TNF] agents) within 2 weeks 
prior to randomization 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in 
the study after discussion with and approval by the Medical Monitor. 
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and 
low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed. 
 
Exclusion Criteria Related to Gemcitabine, Cisplatin or Carboplatin 
•   History of allergic reactions to cisplatin, carboplatin, or other platinum-containing 
compounds 
•   Patients with hearing impairment (cisplatin) 
•   CrCl < 60 mL/min (cisplatin) 
•   Grade ≥
 2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria (cisplatin) 
•   Known hypersensitivity to gemcitabine 
•   History of radiation therapy within 7 days prior to initiating gemcitabine 
 
Length of Study 
The study is currently closed to enrollment due to a low number of patients. 
End of Study 
The study is currently closed to enrollment due to a low number of patients. 
Outcome Measures 
The study is currently closed to enrollment due to a low number of patients; therefore, the outcome 
measures of this study are no longer applicable and formal analyses of efficacy or safety will not be 
performed. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Atezolizumab, at a dose of 1200 mg, will be administered by intravenous infusion every 21 days. 
Comparator 
The comparator arm includes gemcitabine+
 cisplatin or carboplatin to be administered every 
21 days for four or six cycles in accordance with the local standard-of-care or at the suggested 
doses and/or infusion times indicated in the table below. 
 


 
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Table: Gemcitabine +
 Cisplatin or Carboplatin Regimen 
Chemotherapy 
Dose/Route 
Treatment 
(Four or Six Cycles) 
Gemcitabine  
 1250  
 
mg/m2 IV    
Over 30 minutes on Days 1 and 8 q21d 
Cisplatin 
75 mg/m2 IV  
Over 1−2 hours on Day 1 q21d 
Gemcitabine  
 1000  
 
mg/m2 IV    
Over 30 minutes on Days 1 and 8 q21d 
Carboplatin 
AUC 5 IV 
Over ~30–60 minutes on Day 1 q21d 
AUC =
 area under the concentration curve; IV
 =
 intravenous; q21d
 =
 every 21 days. 
 
Erlotinib 
Erlotinib is considered an Investigational Medicinal Product and will be provided by the 
Sponsor if required by local health authority regulations.  Switch maintenance treatment to 
erlotinib is no longer permitted for patients randomized to Arm B.  However, patients who had 
already started switch maintenance treatment with erlotinib under previous protocol versions 
may be allowed to continue treatment with erlotinib upon discussion of the risks, potential 
benefits, and alternative treatment options with the Investigator. 
Statistical Methods 
Primary Analysis 
The study is currently closed to enrollment due to a low number of patients; therefore, formal 
analysis of efficacy endpoints will not be performed. 
Determination of Sample Size 
The study is currently closed to enrollment due to a low number of patients; therefore, formal 
analysis of efficacy endpoints will not be performed. 
Interim Analyses 
The study is currently closed to enrollment due to a low number of patients; therefore, 
interim safety data will not be evaluated by an independent Data Monitoring Committee.


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation
 Definition
 
ALK 
anaplastic lymphoma kinase 
ASCO    
American Society of Clinical Oncology 
ATA  
 anti-therapeutic  
 
antibody  
 
AUC 
area under the concentration-time curve 
BSC 
best supportive care 
CR
 complete
 
response
 
CRC  
 colorectal  
 
cancer  
 
CrCl  
 creatinine  
 
clearance  
 
CRF 
Case Report Form 
CT
 computed
 
tomography
 
CTLA-4   
cytotoxic T lymphocyte−associated antigen 4 
Ctrough 
trough concentration 
DLT  
 dose-limiting  
 
toxicity  
 
EC
 Ethics
 
Committee
 
ECOG    
Eastern Cooperative Oncology Group 
eCRF    
electronic Case Report Form 
EDC 
electronic data capture 
EGFR    
epidermal growth factor receptor 
ePRO  
 electronic  
 
PRO  
 
FDA 
U.S. Food and Drug Administration 
FFPE    
formalin fixed paraffin embedded 
GFR 
glomerular filtration rate 
HBcAb    
hepatitis B core antibody 
HBsAg    
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV  
 hepatitis  
 
C  
 
virus  
 
HIPAA    
Health Insurance Portability and Accountability Act 
HR
 hazard
 
ratio
 
IC 
tumor-infiltrating immune cell 
ICH 
International Conference on Harmonisation 
iDMC    
independent Data Monitoring Committee 
IHC  
 immunohistochemistry  
 
IMP  
 Investigational  
 
Medicinal  
 
Product  
 
IND 
Investigational New Drug application 
IRB 
Institutional Review Board 


 
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Abbreviation 
Definition 
ITT 
intent to treat 
IV 
intravenous 
IxRS   
interactive Web/voice response system 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN    
National Comprehensive Cancer Network 
NCI CTCAE    National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
next-generation sequencing 
NSCLC    
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD
 progressive
 
disease
 
PD-1   
programmed death−1 
PD-L1    
programmed death−ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PRO   
patient-reported outcome 
q21d   
every 21 days 
RCC 
renal cell carcinoma 
RCR 
Roche Clinical Repository 
RECIST    
Response Evaluation Criteria in Solid Tumors 
SD
 stable
 
disease
 
TC 
tumor cell 
TKI 
tyrosine kinase inhibitor 
TNF 
tumor necrosis factor 
UBC 
urothelial bladder cancer 
ULN 
upper limit of normal 
 


 
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1.    
BACKGROUND 
1.1    
NON-SMALL CELL LUNG CANCER 
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most 
common cancer in both men and women and accounted for approximately 13% of all 
new cancers in 2008 (Jemal et al. 2011).  In 2012, it was estimated that there would be 
226,160 new cases of lung cancer and 160,340 lung cancer deaths in the United States 
alone (Siegel et al. 2012).  Similar data from Europe estimate that there were 
288,000 new cases of lung cancer and 253,000 deaths in 2008 (GLOBOCAN 2008). 
Non−small cell lung cancer (NSCLC) is the predominant subtype of lung cancer, 
accounting for approximately 85% of all cases (Molina et al. 2008; Howlader et al. 2014).  
NSCLC can be divided into two major histologic types:  adenocarcinoma and squamous 
cell carcinoma (Travis et al. 2011).  Adenocarcinoma histology accounts for more than 
half of all NSCLC, while squamous cell histology accounts for approximately 25% 
(Langer et al. 2010) of NSCLC.  The remaining cases of NSCLC are represented by 
large cell carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly 
differentiated histology. 
The overall 5-year survival rate for advanced disease is 2%–4%, depending on 
geographic location (Cetin et al. 2011).  Poor prognostic factors for survival in patients 
with NSCLC include advanced stage of disease at the time of initial diagnosis, poor 
performance status, and a history of unintentional weight loss.  More than half of the 
patients with NSCLC are diagnosed with distant disease, which directly contributes to 
poor survival prospects. 
There are recognized differences in disease characteristics between adenocarcinoma 
and squamous NSCLC.  First, squamous tumors are commonly present in the central 
airways and typically remain localized in the bronchial epithelium (Hirsch et al. 2008), 
whereas non-squamous tumors are more commonly located in the lung parenchyma 
distal to the central airways.  Evaluation of NSCLC tumor tissue will reveal cytological 
differences between the squamous cell type (keratinization, intracellular bridges, and 
central necrosis) and adenocarcinoma (glandular architecture).  In cases where the 
tumor sample is poorly differentiated or there is limited tissue available, 
immunohistochemical markers may support the histologic diagnosis.  Thyroid 
transcription factor−1 is infrequently expressed in squamous cells and strongly 
expressed in adenocarcinoma.  In contrast, p63, CK5/6, and 34βE12 are strongly 
expressed in squamous cell carcinoma and less frequently in adenocarcinoma 
(Travis et al. 2011). 
Genetic changes that have prognostic and/or predictive significance in NSCLC include 
mutations in the epidermal growth factor receptor (EGFR), the rearrangement in the 
anaplastic lymphoma kinase (ALK) gene, and mutations in the GTPase Kras (K-ras) 
gene.  The rates of these mutations differ between squamous cell carcinoma and 


 
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adenocarcinoma.  For example, EGFR kinase domain mutations have been reported in 
10%–40% of patients with adenocarcinoma NSCLC but are infrequently observed in 
squamous NSCLC (Herbst et al. 2008).  The ALK fusion oncogene, recognized as a 
driver of lung tumorigenesis, is very rare in the squamous histology but observed in 
approximately 7% of patients with adenocarcinoma (Herbst et al. 2008; 
Langer et al. 2010).  In addition, K-ras mutations are very rare in squamous NSCLC, 
while they can be observed in up to 30% of cases of adenocarcinoma NSCLC 
(Travis et al. 2011). 
1.2    
FIRST-LINE TREATMENT FOR NON−SMALL CELL LUNG 
CANCER 
Patients with previously untreated NSCLC that does not harbor a driver mutation that 
confers sensitivity to a targeted agent are typically treated with chemotherapy.  The 
first evidence that chemotherapy produced a significant survival benefit in patients with 
advanced NSCLC came in 1995; a meta-analysis showed that platinum-based doublet 
chemotherapy conferred a 2-month improvement in median survival over best supportive 
care (BSC) (NSCLC Collaborative Group 1995).  More recently, the European Big Lung 
Trial demonstrated the potential benefits of chemotherapy.  In this trial, 725 patients with 
advanced NSCLC were randomly assigned to BSC plus cisplatin-based chemotherapy 
or BSC alone (Spiro et al. 2004).  Patients allocated to chemotherapy had a significantly 
longer median survival than did those managed with BSC (8 vs. 5.7 months).   
The benefit conferred by platinum-based chemotherapy regimens appears to have 
reached a plateau in overall response rate (approximately 15%−22%) and median 
survival (7−10 months).  More recently, the addition of bevacizumab to carboplatin and 
paclitaxel resulted in an increase in response rate from 15% to 35% and an increase in 
median overall survival (OS) from 10 to 12 months (see Table 1). 
Despite the limited survival benefit conferred by cytotoxic chemotherapy, platinum-based 
regimens remain the standard first-line option for most patients with locally advanced 
and metastatic NSCLC not harboring an activating EGFR mutation or ALK gene 
rearrangement.  In particular, for newly diagnosed advanced stage non-squamous 
NSCLC, standard of care is a platinum doublet with either cisplatin or carboplatin and a 
taxane or pemetrexed, with or without bevacizumab.  However, well-designed clinical 
trials conducted over the last decade have clearly demonstrated that bevacizumab and 
pemetrexed are not appropriate agents for the treatment of patients with squamous cell 
carcinoma of the lung (Johnson et al. 2004; Scagliotti et al. 2008; Sandler et al. 2009). 
The combination of gemcitabine and a platinum analog (either carboplatin or cisplatin) 
has demonstrated efficacy as first-line treatment for NSCLC and, as a result, is often a 
reference arm in clinical trials evaluating new therapeutics (Schiller et al. 2002; 
Treat et al. 2010).  The median duration of progression-free survival (PFS) and OS in 
patients with squamous NSCLC is approximately 5.1−5.5 months and 10.3−10.8 months, 
respectively (see Table 1). 


 
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Overall, these regimens are associated with substantial toxicities (such as febrile 
neutropenia, myelosuppression, nausea, alopecia, nephropathy, and neuropathy) and 
are generally poorly tolerated by elderly and poor−performance status patients.  
Therefore, novel therapies that deliver an improved therapeutic index are urgently 
needed for squamous NSCLC.


 
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Table 1   Randomized Phase III Trials in Patients with Previously Untreated Non−Small Cell Lung Cancer 
First-Line Therapy Regimen 
ORR 
(%) 
Median PFS 
(months) 
Median OS 
(months) 
OS HR 
(95% CI) 
Chemotherapy a 
  Cisplatin and paclitaxel (n
 =
 288)
 21
 
3.4
 
7.8
 
 
  Cisplatin and gemcitabine (n
 =
 288)
 22
 
4.2
 
8.1
 
 
  Cisplatin and docetaxel (n
 =
 289)
 17
 
3.7
 
7.4
 
 
  Carboplatin and paclitaxel (n
 =
 290)
 17
 
3.1
 
8.1
 
 
Chemotherapy +
 biologic b 
  Carboplatin and paclitaxel (n
 =
 444)
 15
 
4.5
 
10.3
 
  Carboplatin, paclitaxel, and bevacizumab (n
 =
 434)
 35
 
6.5
 
12.3
 
0.79 
0.67−0.92 
Chemotherapy c  
  Cisplatin and pemetrexed, overall (n
  =
 839
 )
 31
 
4.8
 
10.3
 
  Cisplatin and gemcitabine, overall (n
 =
 830)
 28
 
5.1
 
10.3
 
0.94 
0.84−1.05 
  Cisplatin and pemetrexed, non-squamous 
NR 
5.3 
11.8 
  Cisplatin and gemcitabine, non-squamous 
NR 
4.7 
10.4 
0.81 
0.70−0.94 
  Cisplatin and pemetrexed, squamous 
NR 
4.4 
9.4 
  Cisplatin and gemcitabine, squamous 
NR 
5.5 
10.8 
1.23 
1.00−1.51 
Chemotherapy  d 
  Carboplatin and nab-paclitaxel, overall (n
 =
 521)
 33
 
6.3
 
12.1
 
  Carboplatin and paclitaxel, overall (n
 =
 531)
 25
 
5.8
 
11.2
 
0.922 
0.797−1.066 
  Carboplatin and nab-paclitaxel, non-squamous (n
 =
 221)  
 26  
    6.9  
    
13.1  
 
  Carboplatin and paclitaxel, non-squamous (n
 =
 292)
 25
  6.5
   13.0
 
0.950 
NR 
  Carboplatin and nab-paclitaxel, squamous (n
 =
 300)
 41
  5.6
   10.7
 
  Carboplatin and paclitaxel, squamous (n
 =
 229) 
24
 5.7
   9.5
 
0.890 
0.719−1.101 


 
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Table 1   Randomized Phase III Trials in Patients with Previously Untreated Non−Small Cell Lung C (cont.)    
First-Line Therapy Regimen 
ORR 
(%) 
Median PFS 
(months) 
Median OS 
(months) 
OS HR 
(95% CI) 
Phase III trials e 
  Cisplatin and vinorelbine (n
 =
 568)
 29
 
4.8
 
10.1
 
  Cisplatin, vinorelbine, and cetuximab (n
 =
 557)
 36
 
4.8
 
11.3
 
0.871 
0.762−0.996 
HR =
 hazard ratio; NR
 =
 not reported; ORR
 =
 objective response rate; OS
 =
 overall survival; PFS
 =
 progression-free survival. 
a Schiller JH, Harrington D, Belani CP, et al. Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for 
advanced non–small-cell lung cancer. N Engl J Med 2002;346:92−8. 
b Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non−small cell lung cancer. N Engl J Med 
2006;355:2542−50. 
c  Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in 
chemotherapy-naive patients with advanced-stage non−small cell lung cancer. J Clin Oncol 2008;26:3543−51. 
d Socinski MA, Bondarenki I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel 
plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial.  J of Clin Oncol 
2012;30:2055−62. 
e Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an 
open-label randomised Phase III trial. Lancet 2009;373:1525−31. 


 
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1.3    
TARGETED THERAPY FOR NON−SMALL CELL LUNG 
CANCER 
Genotype-directed therapy has the potential to dramatically improve the balance of 
benefit and toxicity for selected patients with NSCLC (mainly non-squamous histology) 
characterized by alterations of driver oncogenes, including sensitizing EGFR mutations 
and ALK rearrangements.  However, these mutations are more prevalent in 
adenocarcinoma NSCLC and are very rare in squamous NSCLC.  Randomized Phase III 
trials of gefitinib (IPASS), erlotinib (EURTAC), and afatinib (Lux-Lung 3) showed 
significant improvement of PFS and objective response rate (ORR) compared with 
platinum doublet chemotherapy (Fukuoka et al. 2011; Rosell et al. 2012; 
Yang et al. 2012; respectively).  Similarly, the ALK inhibitor crizotinib has demonstrated 
efficacy in patients with NSCLC positive for ALK rearrangement as defined by 
fluorescence in situ hybridization (Crino et al. 2011; Camidge et al. 2012; 
Shaw et al. 2012; Shaw and Engelman 2014; Xalkori® U.S. Package Insert). 
Despite current progress in treatment of patients with EGFR mutations and ALK 
rearrangements, survival rates for advanced disease remain low and acquired 
resistance to targeted agents is a major clinical problem.  Therefore, alternative 
treatment options that yield durable responses and enhance OS remain an important 
focus of research.  Against this background, immunotherapeutic agents, such as cancer 
vaccines and antibodies that modulate immune cell activity, offer an alternative 
treatment approach that could potentially improve the prognosis of patients with this 
disease. Therefore, patients with EGFR mutations or ALK mutations who have been 
treated with and whose disease progressed on an appropriate tyrosine kinase inhibitor 
(TKI) will be eligible for this trial. 
1.4    
MAINTENANCE THERAPY FOR NON−SMALL CELL LUNG 
CANCER 
National Comprehensive Cancer Network (NCCN) guidelines on chemotherapy for 
Stage IV NSCLC recommend that cytotoxic regimens consisting of two drugs should be 
given for no more than six cycles.  The guidelines also recommend stopping first-line 
cytotoxic chemotherapy at disease progression.  When the study was started, switch 
maintenance with erlotinib in unselected patients could be considered for patients with 
stable disease or continued response to therapy after four to six cycles of chemotherapy 
(NCCN Guidelines 2014).  This recommendation was based onthe Sequential Tarceva 
Unresectable NSCLC study (SATURN).  In the SATURN study, the median PFS in 
patients receiving maintenance therapy with erlotinib was significantly longer than in 
patients receiving placebo (12.3 vs. 11.1 weeks; hazard ratio [HR] 0.71, 95% CI: 
0.62−0.81; p
 <
 0.0001).  Maintenance treatment with erlotinib also yielded a statistically 
significant yet clinically modest improvement in OS (12.0 vs. 11.0 months; HR 0.81, 95% 
CI: 0.70−0.95; p
 =
 0.0088).  A statistically significant improvement in PFS and OS was 
observed in patients with EGFR−wild-type and EGFR−mutation-positive tumors 
(Cappuzzo et al. 2010).  This Phase III trial resulted in regulatory approval by the U.S. 


 
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Food and Drug Administration (FDA) and European Medicines Agency for erlotinib in 
unselected NSCLC, as maintenance therapy of patients with locally advanced or 
metastatic NSCLC whose disease has not progressed after four cycles of platinum-
based first-line chemotherapy.  However, recent data from Study BO25460, a 
randomized, double-blind, placebo-controlled Phase III study, have demonstrated that 
patients with advanced or recurrent (Stage IIIB) or metastatic (Stage IV) NSCLC 
whose tumor did not harbor an EGFR-activating mutation did not achieve benefit from 
first-line maintenance therapy with erlotinib compared with placebo.  OS was not 
superior in patients randomized to receive maintenance erlotinib followed by 
chemotherapy or best supportive care upon disease progression compared with patients 
randomized to receive maintenance placebo followed by erlotinib upon disease 
progression (HR
 =
 1.02, 95% CI, 0.85−1.22, p
 =
 0.82).  In the maintenance phase, 
patients who received erlotinib also did not have superior PFS compared with patients 
who received placebo (HR =
 0.94, 95% CI, 0.80−1.11, p
 =
 0.48).  This change in the 
benefit-risk assessment of erlotinib as switch maintenance therapy in patients whose 
tumors do not harbor an activating EGFR mutation has led to the removal of this 
treatment option from this protocol.  Patients already receiving the switch maintenance 
therapy with erlotinib, permitted under previous protocol versions, may be allowed to 
continue to receive treatment with erlotinib upon discussion of the risks, potential 
benefits, and alternative treatment options with the investigator. 
1.5    
BACKGROUND ON ATEZOLIZUMAB (MPDL3280A) 
Atezolizumab (MPDL3280A) is a humanized IgG1 monoclonal antibody consisting of 
two heavy chains (448 amino acids) and two light chains (214 amino acids) and is 
produced in Chinese hamster ovary cells.  Atezolizumab was engineered to eliminate 
Fc-effector function via a single amino acid substitution at position 298 on the heavy 
chain, which results in a non-glycosylated antibody that has minimal binding to 
Fc receptors and prevents Fc-effector function at expected concentrations in humans.  
Atezolizumab targets human programmed death−ligand 1 (PD-L1) and inhibits its 
interaction with its receptors, programmed death−1 (PD-1) and B7.1 (CD80, B7-1).  
Both of these interactions are reported to provide inhibitory signals to T cells. 
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans.  Atezolizumab is approved in the United States 
for the treatment of locally advanced or metastatic urothelial cancer. 
1.5.1    
Summary of Nonclinical Studies 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose.  Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab. 


 
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The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid in 
projecting the appropriate starting dose in humans.  Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.  
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway 
and supported entry into clinical trials in patients. 
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies. 
1.6    
CLINICAL EXPERIENCE WITH ATEZOLIZUMAB 
Refer to the Atezolizumab Investigator’s Brochure for details on all clinical studies 
conducted to date. 
1.6.1    
Ongoing Clinical Studies 
Atezolizumab is currently being tested in multiple Phase I, II, and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  The single-agent safety 
and efficacy data are summarized below from the following three studies: 
•   Study PCD4989g:  A Phase Ia, multicenter, first-in-human, open-label, 
dose-escalation study evaluating the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of 
biologic activity of atezolizumab administered as a single agent by IV infusion 
every 21 days (q21d) to patients with locally advanced or metastatic solid 
malignancies or hematologic malignancies. 
•   Study GO28753 (POPLAR):  A randomized, Phase II, open-label study assessing 
the clinical benefit of atezolizumab as a single agent versus docetaxel in PD-L1 
unselected patients with locally advanced or metastatic NSCLC that has progressed 
during or following treatment with a platinum-containing regimen. 
Study GO28625 (FIR):  A Phase II study assessing the clinical benefit of atezolizumab 
as a single agent in patients with locally advanced or metastatic NSCLC representing all 
lines of therapy (previously untreated to heavily pre-treated patients with exposure to 
multiple prior regimens). 


 
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1.6.2    
Clinical Safety 
1.6.2.1    Single-Agent Clinical Safety in Patients with Non−Small Cell 
Lung Cancer 
Study PCD4989g is a Phase Ia dose escalation and expansion study, in which 
atezolizumab is being used as a single agent in patients with locally advanced or 
metastatic solid tumors or hematologic malignancies, and provides the majority of data 
(with 558 safety evaluable patients as of the data cutoff date of 11 May 2015) for the 
safety profile of atezolizumab as monotherapy. 
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined. 
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications.  The most common cancer types for these patients include NSCLC, 
urothelial bladder cancer (UBC), melanoma, and renal cell carcinoma (RCC).  Safety 
data for NSCLC are also derived from Studies GO28753 (POPLAR) and GO28625 
(FIR). 
Single-Agent Clinical Safety in Patients with NSCLC in Study PCD4989g 
Of the 558 patients in Study PCD4989g, 520 (93.2%) patients experienced at least one 
adverse event, including 376 patients (67.4%) who experienced one treatment-related 
adverse event.  Commonly reported events (reported in ≥
 10% of all patients) included 
fatigue, decreased appetite, nausea, pyrexia, constipation, and cough (see Table 2). 


 
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Table 2   Study PCD4989g:  Adverse Events with Frequency 
 ≥
 10% of 
Patients for All Grades 
Preferred Term 
All Grades 
n (%) 
All Grades 
Related 
n (%) 
Grade 3−4 
n (%) 
Grade 3−4 
Related 
n (%) 
Any adverse event   
520 (93.2)   
376 (67.4)   
239 (42.8)   
66 (11.8) 
Fatigue 
192 (34.4)   
115 (20.6)   
13 (2.3)   
6 (1.1) 
Decreased Appetite   
142 (25.4)   
62 (11.1)   
4 (0.7)   
0 (0.0) 
Nausea 
136 (24.4)   
65 (11.6)   
5 (0.9)   
2 (0.4) 
Pyrexia 
117 (21.0)   
63 (11.3)   
2 (0.4)   
0 (0.0) 
Constipation 
116 (20.8)   
8 (1.4)   
2 (0.4)   
0 (0.0) 
Cough 
113 (20.3)   
11 (2.0)   
1 (0.2)   
1 (0.2) 
Dyspnea 
112 (20.1)   
18 (3.2)   
18 (3.2)   
4 (0.7) 
Diarrhea 
110 (19.7)   
53 (9.5)   
2 (0.4)   
1 (0.2) 
Anemia 
104 (18.6)   
26 (4.7)   
23 (4.1)   
5 (0.9) 
Vomiting 
96 (17.2)   
28 (5.0)   
3 (0.5)   
2 (0.4) 
Asthenia 
88 (15.8)   
53 (9.5)   
8 (1.4)   
4 (0.7) 
Back Pain 
85 (15.2)   
9 (1.6)   
8 (1.4)   
1 (0.2) 
Headache 
83 (14.9)   
32 (5.7)   
2 (0.4)   
1 (0.2) 
Arthralgia 
79 (14.2)   
35 (6.3)   
2 (0.4)   
0 (0.0) 
Pruritus 
75 (13.4)   
55 (9.9)   
0 (0.0)   
0 (0.0) 
Rash 
73 (13.1)   
53 (9.5)   
0 (0.0)   
0 (0.0) 
Abdominal Pain   
63 (11.3)   
12 (2.2)   
8 (1.4)   
0 (0.0) 
Insomnia 
62 (11.1)   
7 (1.3)   
1 (0.2)   
0 (0.0) 
Peripheral edema   
59 (10.6)   
7 (1.3) 
⎯ 
⎯ 
Chills 
57 (10.2)   
31 (5.6)   
0 (0.0)   
0 (0.0) 
Note:  “⎯“ refers to missing Common Terminology Criteria grade. 
 
Grade 3−4 adverse events (on the basis of National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 [NCI CTCAE v4.0]) were reported 
in 239 patients (42.8%), of which 66 (11.8%) were considered related.  Grade 3 and 4 
adverse events considered related by the investigator included dyspnea, pneumonitis, 
increased ALT, increased AST, increased gamma-glutamyl transferase (GGT), 
lymphocyte count decreased, cardiac tamponade, asthenia, autoimmune hepatitis, 
pneumonia, influenza, and hypoxia. 
Refer to the Atezolizumab Investigator’s Brochure for details on the adverse events 
observed in patients treated with atezolizumab. 


 
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1.6.2.2    Single-Agent Clinical Safety in Patients with Non−Small Cell 
Lung Cancer in POPLAR Study GO28753 
The Phase II Study GO28753 interim analysis, as of the 30 January 2015 data cutoff 
date, included data from 142 patients treated with atezolizumab as a fixed dose of 
1200 mg IV every 3 weeks and 135 patients treated with docetaxel 75 mg/m2 IV every 
3 weeks.  The frequency of patients in Study GO28753 who reported any adverse event 
regardless of attribution was 96.5% for the atezolizumab arm and 95.6% for the 
docetaxel arm.  A higher number of Grade ≥
 3 adverse events were observed in the 
docetaxel arm (55.6% vs. 43.0%), explained primarily by the difference in adverse 
events due to bone marrow suppression.  Adverse events reported in at least 10% of 
patients in either treatment arm are listed in Table 3. 
Table 3   Adverse Events Reported in at Least 10% of Patients in 
POPLAR Study GO28753 
 
No. of Patients (%) 
MedDRA Preferred Term 
Atezolizumab 
(n
 =
 142) 
Docetaxel 
(n
 =
 135) 
Fatigue 
54 (38.0)   
54 (40.0) 
Decreased appetite 
49 (34.5)   
29 (21.5) 
Dyspnoea 
39 (27.5)   
26 (19.3) 
Cough 
35 (24.6)   
33 (24.4) 
Nausea 
31 (21.8)   
45 (33.3) 
Constipation 
28 (19.7)   
32 (23.7) 
Pyrexia 
24 (16.9)   
17 (12.6) 
Diarrhoea 
24 (16.9)   
38 (28.1) 
Arthralgia 
22 (15.5) 
12 (8.9) 
Anemia 
21 (14.8)   
27 (20.0) 
Insomnia 
19 (13.4) 
11 (8.1) 
Musculoskeletal pain   
18 (12.7) 
7 (5.2) 
Vomiting 
17 (12.0)   
19 (14.1) 
Back Pain 
16 (11.3) 
10 (7.4) 
Asthenia 
15 (10.6)   
22 (16.3) 
Pneumonia 
15 (10.6) 
4 (3.0) 
Rash 
15 (10.6)   
16 (11.9) 
Myalgia 
8 (5.6) 
18 (13.3) 
Alopecia 
3 (2.1) 
52 (38.5) 
Neuropathy peripheral   
2 (1.4) 
16 (11.9) 
Neutropenia 
2 (1.4) 
17 (12.6) 
 


 
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For additional information, refer to the Atezolizumab Investigator’s Brochure. 
1.6.2.3    Single-Agent Clinical Safety in Patients with Non−Small Cell 
Lung Cancer in FIR Study GO28625 
As of the 23 October 2014 data cutoff date, the clinical database included preliminary 
safety data from 137 safety-evaluable patients in Study GO28625 with a median 
treatment duration of 88 days.  Table 4 shows the overall safety findings in 
Study GO28625, which were consistent with those observed in Study PCD4989g 
(overall and NSCLC populations), as well as with the atezolizumab arm in 
Study GO28753. 
Table 4   Adverse Events Reported in FIR Study GO28625 
 
No. of Patients (%) 
Parameter 
Cohort 1 
(n
 =
 31) 
Cohort 2 
(n
 =
 93) 
Cohort 3 
(n
 =
 13) 
All Patients 
(n
 =
 137) 
Any adverse event 
31 (100.0%)   93 (100.0%)   13 (100.0%)  137 (100.0%) 
Grade 3−5 adverse event a   
15 (48.4%)   54 (58.1%)   
8 (61.5%)   77 (56.2%) 
Related adverse event 
23 (74.2%)   60 (64.5%)   
9 (69.2%)   92 (67.2%) 
Adverse event leading to 
withdrawal from treatment 
4 (12.9%)   
8 (8.6%)   
2 (15.4%)   14 (10.2%) 
Serious adverse event 
15 (48.4%)   45 (48.4%)   
7 (53.8%)   67 (48.9%) 
Related serious adverse event   
2 (6.5%)   
9 (9.7%)   
1 (7.7%)   
12 (8.8%) 
Grade 5 adverse event  a 
3 (9.7%)   13 (14.0%)   
4 (30.8%)   20 (14.6%) 
NSCL non−small cell lung cancer. 
a Deaths due to progression of NSCLC during the protocol-specified adverse event reporting period 
were captured as adverse events. 
 
The most frequently observed adverse events (occurring in ≥
 10% of treated patients) of 
the 137 patients (100.0%) reporting any adverse event included fatigue, dyspnea, 
cough, nausea, and decreased appetite.  In 43.8% of patients, the adverse events were 
Grade 1 or 2 in severity.  In 12 patients (8.8%), the serious adverse event reported was 
considered by the investigator as related to atezolizumab (diarrhea in 2 patients and 
1 patient each for lower gastrointestinal hemorrhage, rectal hemorrhage, 
Guillain-Barré syndrome, monoparesis, pleural effusion, pneumonitis, cardiac 
tamponade, elevated AST and ALT, diabetes mellitus, and muscular weakness). 
Overall, there were 54 patient deaths (39.4%) reported.  Disease progression was the 
cause of death in 46 patients.  The remaining 9 deaths were reported due to the 
following in 1 patient each:  cardiac tamponade, cardiac arrest, disseminated 
intravascular coagulation, pericardial effusion, respiratory disorder, death due to 
euthanasia, pericarditis constrictive, pneumonia, and death not otherwise specified. 


 
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1.6.2.4    Immune-Mediated Adverse Events 
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
atezolizumab clinical program.  These include potential dermatologic, hepatic, endocrine, 
gastrointestinal, and respiratory events. 
See the Atezolizumab Investigator’s Brochure for details regarding immune-mediated 
adverse events observed in patients treated with atezolizumab.  Guidelines for the 
management of potential immune-mediated adverse events are described in 
Section 5.1.7. 
1.6.3    
Clinical Activity 
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)−based responses (i.e., RECIST, Version 1.1 responses), have been observed 
in patients with different tumor types, including NSCLC, RCC, melanoma, gastric cancer, 
UBC, colorectal cancer (CRC), head and neck cancer, breast cancer, and sarcoma 
treated with atezolizumab in Study PCD4989g.  
See the Atezolizumab Investigator’s Brochure for details on clinical activity in all patients 
treated to date, regardless of tumor type. 
1.6.3.1    Single-Agent Clinical Activity in Patients with Non−Small Cell 
Lung Cancer in Study PCD4989g 
As of the clinical data cutoff date of 2 December 2014, the safety and efficacy evaluable 
population included 88 patients with locally advanced or metastatic NSCLC enrolled into 
Study PCD4989g who had received their first dose of atezolizumab by 21 October 2013 
and were evaluable for efficacy.  The median age was 60.5 years (range from 24 to 
84 years); the group represented a heavily pre-treated patient population in that 97.7% 
of the patients had received ≥
 2 prior systemic therapies and 77.3% had received 
≥
 4 prior systemic therapies.  RECIST responses (confirmed) were observed in a total of 
20 patients, inclusive of squamous and non-squamous histologies and across all 
treatment cohorts (treatment dose levels: 1 to 20 mg/kg). 
Preliminary results suggest that PD-L1 expression 
in tumor tissue 
is likely to be 
associated with response to atezolizumab.  A prototype immunohistochemistry (IHC) 
assay has been used that measures specific PD-L1 signals in tumor-infiltrating immune 
cells (ICs) and tumor cells (TCs).  PD-L1 staining categories in ICs are defined as IC0, 
IC1, IC2, and IC3, and are defined in TCs as TC0, TC1, TC2, and TC3.  Table 5 
summarizes the ORR by PD-L1 tumor expression in patients with NSCLC. 
An ORR of 50.0% (11 of 22 patients, 95% CI: 28.2%−71.8%) was observed in patients 
with high levels of PD-L1 staining in TCs or ICs (TC3 or IC3 group) compared with an 
ORR of 15.5% (9 of 58 patients, 95% CI: 7.4%−27.4%) in patients with low or no PD-L1 
staining in TCs and ICs (TC0/1/2 and IC0/1/2). 


 
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As of the 2 December 2014 cutoff date, 8 of 20 patients have continued to respond after 
7+
 to 27+ weeks.  The median duration of response is 17 months. 
Refer to the atezolizumab Investigator’s Brochure for details on the clinical activity of 
atezolizumab in patients with NSCLC treated to date. 
Table 5   Patients with Non−Small Cell Lung Cancer in Study PCD4989g:  
Objective Response Rate by Tumor PD-L1 Expression and Best 
Overall Response Rate (per RECIST Version 1.1) 
PD-L1 IHC 
Expression Category 
ORR 
(n
 =
 88) 
PR   
SD 
TC3 or IC3 
50% (11 of 22) 
95% CI: 28.2%−71.8% 
50% 
(11 of 22) 
18.2% 
(4 of 22) 
TC3 or IC2/3 
31.6% (12 of 38) 
95% CI: 17.5%−48.6% 
31.6% 
(12 of 38) 
28.9% 
(11 of 38) 
TC0/1/2 and IC0/1/2    
12.1% (7 of 58) 
95% CI: 5.7%−22.5% 
12.1% 
(7 of 58) 
36.2% 
(21 of 58) 
TC0/1/2 and IC0/1    
14.3% (6 of 42) 
95% CI: 6.4%−27.7% 
14.3% 
(6 of 42) 
33.3% 
(14 of 42) 
IC
 =
 tumor-infiltrating immune cells; IHC
 =
 immunohistochemistry; 
NSCLC =
 non−small cell lung cancer; ORR
 =
 objective response rate; 
PD-L1 =
 programmed death−ligand 1; PR
 =
 partial response;  
RECIST =
 Response Evaluation Criteria in Solid Tumors: SD
 =
 stable disease; 
TC =
 tumor cell. 
Notes:  This table is based on a data cutoff date of 21 April 2014 of patients with 
NSCLC dosed by 21 October 2013.  Objective response is per RECIST v1.1. 
 
1.6.3.2    Single-Agent Clinical Activity in Patients with Non−Small Cell 
Lung Cancer in POPLAR Study GO28753 
The interim OS analysis in Study GO28753 (POPLAR) was conducted when 
approximately 150 deaths (30 January 2015) were observed.  Demographic 
characteristics were comparable between treatment arms in the intent-to-treat (ITT) 
population.  The median age was 62 years (range: 42−82 years for the atezolizumab 
arm, range: 36−84 years for the docetaxel arm), and the majority of patients had one 
prior therapy (64.6% for atezolizumab and 67.1% for docetaxel), non-squamous 
histology (66.0% for atezolizumab and 66.4% for docetaxel), and Eastern Cooperative 
Oncology Group (ECOG) performance status of 1 (66.4% for atezolizumab and 67.8% 
for docetaxel).  More females were enrolled in the docetaxel arm (46.9% vs. 35.4%). 
Key efficacy results for the ITT population and the PD-L1−selected subgroup categories, 
are shown in the next sections.  For this interim dataset, median follow-up was 
approximately 12 months in both arms.  The ORR and PFS data are expected to be 
mature given the length of follow-up and the number of PFS events observed 
(119 of 144 events and 111 of 143 events in the atezolizumab and docetaxel arm, 


 
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respectively).  The OS data are not yet mature, with 71 events of 144 patients and 
80 events out of 143 patients in the atezolizumab and docetaxel arms, respectively, 
having occurred.  Follow-up is ongoing. 
Efficacy results for the ITT population are shown in Table 6.  PFS and ORR for the 
atezolizumab arm were similar to those for the docetaxel arm.  An initial indication of OS 
benefit in the atezolizumab arm was observed, with a stratified HR of 
0.78 (95% CI: 0.59, 1.03). 
Table 6   Efficacy Results in Study GO28753 (POPLAR):  Intent-to-Treat 
Population 
Efficacy Endpoint 
Atezolizumab 
(n
 =
 144) 
Docetaxel 
(n
 =
 143) 
Overall survival 
 
 
     No. of deaths (%) 
71 (49.3)   
80 (55.9) 
     Median (months) 
     95% CI 
11.4 
9.7, NE  
9.5 
8.6, 12.5  
     Stratified hazard ratio 
     95% CI 
0.78 
0.59, 1.03 
 
Progression-free survival 
 
 
     No. of events (%) 
119 (82.6)   
111 (77.6) 
     Median (months) 
     95% CI 
2.8 
2.1, 4.1 
3.4 
2.8, 4.1 
     Stratified hazard ratio 
     95% CI 
0.96 
0.76, 1.20 
 
Objective response rate 
(confirmed) 
14.6%   
15.4% 
NE =
 not estimable. 
 
The efficacy results for combined PD-L1 selected subgroups at different combinations of 
TC and IC cutoff are provided in Table 7, and include the complementary groups 
corresponding to each of the PD-L1 selected subgroups for comparison.  Benefit with 
respect to OS appears to extend to the TC2/3 or IC2/3 subgroup, as well as to the 
TC1/2/3 or IC1/2/3 subgroup.  For PFS, there appears to be a numerically graded 
benefit with increasing TC and IC PD-L1 expression.  


 
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Table 7   Study GO28753 (POPLAR) Efficacy Results by Combination 
PD-L1 Diagnostic Subgroups with Complementary Comparison 
Subgroupings:  Intent-to-Treat Population 
HR (95% CI) 
Diagnostic 
Subgroup 
OS 
PFS 
Atezolizumab/ 
Docetaxel ORR 
(%) 
Total No. of 
Patients 
(Atezolizumab/ 
Docetaxel) 
TC3 or IC3   
0.47 (0.20, 1.11)  0.56 (0.28, 1.11)   
37.5/13.0   
47 (24/23) 
TC3 or IC2/3   0.52 (0.28, 0.95)  0.64 (0.38, 1.08)   
25/16.2   
77 (40/37) 
TC2/3 or IC2/3   0.56 (0.33, 0.95)  0.70 (0.45, 1.08)   
22.0/14.5   
105 (50/55) 
HR =
 hazard ratio; IC
 =
 tumor-infiltrating immune cell; ORR
 =
 objective response rate; OS
 =
 overall 
survival; PFS
 =
 progression-free survival; TC
 =
 tumor cell. 
Notes:  The HRs for OS and PFS are unstratified values.  The ORRs are for confirmed 
responses. 
 
1.6.3.3    Single-Agent Clinical Activity in Patients with Non−Small Cell 
Lung Cancer in FIR Study GO28625 
Key efficacy data from NSCLC patients enrolled in Study GO28625 are summarized in 
Table 8.  Among the 71 efficacy-evaluable patients in Cohort 2, the ORR was 
17% (95% CI: 8.18, 25.62).  The median duration of response was not reached.  As of 
the data cutoff date, the median PFS for all Cohort 2 efficacy-evaluable patients 
was 2.7 months (95% CI: 1.4, 3.1), and the 24-week PFS was 34.91% (95% CI: 
23.46, 46.36). 
Analyses of the PD-L1−selected subgroups revealed that the TC3 or IC3 subgroups 
showed the highest ORR (27%), with reductions in ORR with the inclusion of the 
IC2 and TC2 subgroups.  For the TC3 or IC3 subgroup of Cohort 2, the median duration 
of response was not reached, the median PFS was 3.1 months (95% CI: 1.6, 15.3), and 
the 24-week PFS was 49.23% (95% CI: 29.76, 68.70). 


 
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Table 8   Efficacy Results for Study GO28625 (FIR):  Efficacy-Evaluable 
Patients by PD-L1 Diagnostic Subgroups 
Efficacy Endpoint 
Efficacy 
Evaluable 
(i.e., TC2/3 or IC2/3) 
(n
 =
 71) 
TC3 or IC3 
(n
 =
 26) 
TC3 or IC2/3 
(n
 =
 63) 
ORR 
17% (12 of 71)   
27% (7 of 26)   
18% (11 of 63) 
Median DOR (months) (95% CI)   
NE (10.4, NE)   
NE (10.4, NE)   
NE (10.4, NE) 
Median PFS (months) (95% CI)   
2.7 (1.4, 3.1)   
3.1 (1.6, 15.3)   
2.7 (1.4, 4.5) 
24-week PFS (%) (95% CI)   
34.91 (23.46, 46.36)   49.23 (29.76, 68.70)  34.49 (22.31, 46.67) 
1 year OS (%) (95% CI) 
NA 
NA 
NA 
DOR =
 duration of response; IC
 =
 tumor-infiltrating immune cell; NA
 =
 not applicable; NE
 =
 not 
estimable; ORR
 =
 objective response rate; OS
 =
 overall survival; PD-L1
 =
 programmed−death 
ligand 1; PFS
 =
 progression-free survival; TC
 =
 tumor cell. 
a Data for the PD-L1 subgroup of TC2/3 or IC2/3 are currently not available for Study PCD4989g. 
b Only Cohort 2 patients. 
 
1.6.4    
Clinical Pharmacokinetics and Immunogenicity 
On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab appeared 
to show linear pharmacokinetics at doses ≥
 1 mg/kg.  For the 1-mg/kg and 20-mg/kg 
dose groups, the mean apparent clearance and the mean volume of distribution at 
steady state had a range of 3.11−4.14 mL/kg and 48.1−67.0 mL/kg, respectively, which 
is consistent with the expected profile of an IgG1 antibody in humans. 
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses from 10 to 20 mg/kg.  
Patients dosed at the 10-, 15-, and 20-mg/kg dose levels have maintained the expected 
target trough levels of drug despite the detection of ATAs.  To date, no clear relationship 
between the detection of ATAs and adverse events or infusion reactions has been 
observed. 
1.6.5    
Rationale for Atezolizumab Dosage 
The fixed dose of 1200 mg (equivalent to an average body weight−based dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below. 
The target exposure for atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed atezolizumab interim pharmacokinetics in humans, and other factors.  The 
target trough concentration (C
trough) was projected to be 6 mg/mL on the basis of several 


 
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assumptions, including the following:  1) 95% tumor-receptor saturation is needed for 
efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue 
distribution data in tumor-bearing mice. 
The atezolizumab dose is also informed by available clinical activity, safety, 
pharmacokinetics, and immunogenicity data.  Anti-tumor activity has been observed 
across doses from 1 mg/kg to 20 mg/kg.  The MTD of atezolizumab was not reached, 
and no DLTs have been observed at any dose in Study PCD4989g.  Currently available 
PK and ATA data suggest that the 15-mg/kg atezolizumab q21d regimen (or fixed-dose 
equivalent) for Phase II and Phase III studies would be sufficient to both maintain 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 q21d regimen (or fixed-dose equivalent).  From inspection of 
available observed Ctrough data, moving further to the 20-mg/kg atezolizumab 
q21dregimen does not appear to be warranted to maintain targeted Ctrough levels relative 
to the proposed 15-mg/kg atezolizumab q21d level. 
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in 
exposure following a fixed dose or a dose adjusted for weight.  Therefore, a fixed dose 
of 1200 mg has been selected (equivalent to an average body weight−based dose of 
15 mg/kg).  Selection of an every-21-day dosing interval is supported by this preliminary 
pharmacokinetics evaluation. 
See the Atezolizumab Investigator’s Brochure for details regarding nonclinical and 
clinical pharmacology of atezolizumab. 
1.7    
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with Stage IV cancer (Hodi et al. 2010; 
Kantoff et al. 2010; Chen et al. 2012). 
PD-L1 is an extracellular protein that downregulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1.  PD-1 is an 
inhibitory receptor expressed on T cells following T-cell activation, which is sustained in 
states of chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; 
Keir et al. 2008).  Ligation of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of 
T cells.  B7.1 is a molecule expressed on antigen-presenting cells and activated T cells.  
PD-L1 binding to B7.1 on T cells and antigen-presenting cells can mediate 
downregulation of immune responses, including inhibition of T-cell activation and 
cytokine production (Butte et al. 2007; Yang et al. 2011). 


 
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Overexpression of PD-L1 on TCs has been reported to impede anti-tumor immunity, 
resulting in immune evasion (Blank and Mackensen 2007).  Therefore, interruption of the 
PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific 
T-cell immunity. 
PD-L1 expression is prevalent in many human tumors, and elevated PD-L1 expression 
is associated with a poor prognosis in patients with NSCLC (Mu et al. 2011). 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies and who have failed standard-of-care therapies.  In Study 
PCD4989g, a Phase Ia, dose-escalation and expansion study, objective responses with 
atezolizumab monotherapy were observed in a broad range of malignancies, including 
NSCLC, RCC, melanoma, UBC, CRC, head and neck cancer, gastric cancer, breast 
cancer, and sarcoma.  In addition, in the NSCLC cohort, patients with NSCLC who have 
a high level of PD-L1 expression in TCs or ICs (TC3 or IC3) were more likely to respond 
to atezolizumab than those with low or no PD-L1 expression in TCs or ICs (TC0/1/2 and 
IC0/1/2; see also Sections 1.6.3.1 and 3.3.1). 
On the basis of these observations, Study GO29432 is designed to evaluate if this 
anti-tumor effect observed in atezolizumab-treated patients would translate into 
prolonged PFS and OS compared with gemcitabine
 +
 cisplatin or carboplatin in patients 
with squamous NSCLC whose tumors show high levels of PD-L1 expression.  A PD-L1 
IHC assay will be used to identify patients by their tumor PD-L1 expression (see 
Appendix 5). 
Study GO29432 will enroll patients with Stage IV squamous NSCLC who are naive to 
chemotherapy treatment and for whom the experimental arm can represent a valuable 
treatment option and can offer a reasonable benefit-risk balance.  Patients whose 
tumors are known to harbor sensitizing EGFR mutations or ALK rearrangements must 
have experienced disease progression during or after treatment with an EGFR tyrosine 
kinase or ALK inhibitor, respectively (see specific inclusion criteria in Section 4.1.1), 
before they can enroll in the study.  For these patients, atezolizumab can provide a 
potential clinical benefit compared with a standard platinum-based chemotherapy. 
In order to account for the possibility of pseudoprogression/tumor-immune infiltration 
(i.e., radiographic increase in tumor volume caused by the influx of immune cells; 
Hales et al. 2010) and the potential for delayed anti-tumor activity, this trial will allow 
patients treated with atezolizumab to receive treatment beyond the initial apparent 
radiographic progression (see Section 3.3.3 and Section 4.6.2) with use of modified 
RECIST criteria (in addition to RECIST v1.1) to evaluate clinical benefit.  As it is not yet 
possible to reliably differentiate pseudoprogression/tumor-immune infiltration from true 
tumor progression, the risk exists that some patients who are not responding to 
treatment but yet continuing to receive atezolizumab may experience further progression 
of NSCLC and delay treatment with subsequent therapies for which they are eligible.  


 
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Investigators should make every effort to fully inform patients of this risk.  Investigators 
should make a careful assessment of the potential benefit of continuing treatment with 
atezolizumab, considering radiographic data and the clinical status of the patient.  If, 
after an integrated assessment of radiographic data and clinical status, the decision is 
made to continue treatment with atezolizumab following apparent radiographic 
progression, patients for whom alternative approved anti-cancer therapies exist must 
provide written consent at that time to acknowledge deferring these treatment options in 
favor of continuing study treatment.  
Atezolizumab has been generally well tolerated (see Section 1.6.2).  Adverse events 
with potentially immune-mediated causes consistent with an immunotherapeutic agent, 
including rash, hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis 
have been observed in Study PCD4989g.  To date, these events have been 
manageable with treatment. 
In summary, treatment with atezolizumab offers the potential for clinical benefit in 
chemotherapy naive, squamous Stage IV NSCLC patients with high PD-L1 expression.  
Because most atezolizumab-related toxicities observed to date have been mild and 
transient in nature and do not overlap with those of chemotherapy, patients who do not 
respond to study treatment are considered likely to be able to subsequently receive 
standard therapies for which they would otherwise have been eligible.  Patients will be 
fully informed of the risk of continuing study treatment in spite of apparent radiographic 
progression, and investigators should make a careful assessment of the potential benefit 
of doing so, considering radiographic data, biopsy results, and the clinical status of the 
patient. 
2.    
OBJECTIVES 
The study is currently closed to enrollment due to a low number of patients; therefore, 
the objectives of this study are no longer applicable and formal analyses of efficacy or 
safety will not be performed. 
3.    
STUDY DESIGN 
3.1    
DESCRIPTION OF STUDY 
This is a randomized, Phase III, multicenter, open-label study designed to evaluate and 
compare the safety and efficacy of atezolizumab with gemcitabine
 +
 cisplatin or 
carboplatin in PD-L1−selected patients who are chemotherapy-naive and have Stage IV 
squamous NSCLC.  Figure 1 illustrates the study design.  The schedule of assessments 
is provided in Appendix 1. 


 
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Figure 1  Study Schema  
 
AUC =
 area under the concentration−time curve; ECOG PS
 =
 Eastern Cooperative Oncology 
Group performance status; IV =
 intravenous; NSCLC
 =
 non−small cell lung cancer; 
PD-L1 =
 programmed death−ligand 1; q21d
 =
 every 21 days; RECIST
 =
 Response Evaluation 
Criteria in Solid Tumors. 
 
At screening, tumor specimens from each potentially eligible patient will be tested for 
PD-L1 expression by a central laboratory using an IHC assay (see Appendix 5).  Only 
patients who are PD-L1−selected (TC3 or IC3) will be enrolled.  Patients will be 
randomized 1:1 to receive either atezolizumab alone or gemcitabine
 +
 cisplatin or 
carboplatin, stratified by sex (male vs. female), ECOG performance status (0 vs.1), 
presence of liver metastases at baseline (yes vs. no), and by PD-L1 tumor tissue 
expression by IHC (TC3 and any IC vs. TC0/1/2 and IC3). 
Given the toxicities associated with platinum-based chemotherapies (neutropenia, 
anemia) and the requirement for pre-medications, this will be an open-label study.  No 
crossover will be allowed from the control arm (gemcitabine
 +
 cisplatin or carboplatin) to 
the experimental arm (atezolizumab).  Approximately 400 patients will be randomized. 
Atezolizumab (fixed dose of 1200 mg) will be administered intravenously on Day 1 of 
each 21-day cycle.  Atezolizumab treatment may continue as long as patients are 
experiencing clinical benefit as assessed by the investigator (i.e., in the absence of 
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an integrated assessment of radiographic data, biopsy results [if available], and clinical 
status) or until unacceptable toxicity or death. 
During treatment, patients who are treated with atezolizumab and who show evidence of 
clinical benefit will be permitted to continue atezolizumab treatment at any timepoint after 
RECIST v1.1 criteria for progressive disease are met if they meet all of the following 
criteria: 
•   Evidence of clinical benefit as assessed by the investigator 
•   Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease 
•   No decline in ECOG performance status that can be attributed to disease 
progression 
•   Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
•   Patients must provide written consent to acknowledge deferring other treatment 
options in favor of continuing treatment with atezolizumab at the time of initial 
progression. 
 
Patients in both treatment arms may undergo an optional tumor tissue biopsy at the time 
of radiographic disease progression if clinically feasible.  To do this, patients must sign 
a separate consent.  These data will be used to explore if the radiographic findings are 
consistent with the presence of tumor or if the appearance of progression was 
pseudoprogression.  In addition, these data will be analyzed for the association between 
changes in tumor tissue and clinical outcome and to understand further the potential 
mechanisms of resistance and progression to atezolizumab when compared to such 
mechanisms after treatment with chemotherapy.  This exploratory biomarker evaluation 
will not be used for any treatment-related decisions.   
Patients randomized to receive gemcitabine +
 cisplatin or carboplatin (per investigator’s 
choice) will receive chemotherapy intravenously on Day 1 (for cisplatin or carboplatin) 
and on Days 1 and 8 (for gemcitabine) of each 21-day cycle for four or six cycles, as per 
local standard-of-care (see Section 4.3.2.2 for treatment administration details).  The 
intended number of cycles planned for the platinum-based chemotherapy will be 
specified by the investigator prior to study randomization.  Treatment with 
gemcitabine
 +
 cisplatin or carboplatin will discontinue early if RECIST v1.1 criteria for 
progressive disease are met or if patient experiences unacceptable toxicity.   
All patients will undergo tumor assessments at baseline and every 6 weeks thereafter, 
regardless of dose delays, for the first 48 weeks following Cycle 1, Day 1 regardless of 
treatment delays.  After 48 weeks, tumor assessments will be required every 9 weeks 
after completion of the Week 48 tumor assessment, regardless of treatment delays, until 
disease progression per RECIST v1.1 (for patients in both treatment arms) or loss of 


 
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clinical benefit (for atezolizumab-treated patients who continue treatment after disease 
progression according to RECIST v1.1), consent withdrawal, enrollment into an 
extension study, or death, whichever occurs first.  Patients who discontinue treatment 
for reasons other than disease progression (e.g., toxicity) will continue scheduled tumor 
assessments until disease progression, withdrawal of consent, death, or are eligible to 
roll over to an extension study, whichever occurs first.  In the absence of disease 
progression, tumor assessments should continue regardless of whether patients start a 
new anti-cancer therapy, unless consent is withdrawn. 
3.1.1    
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) was in place to evaluate the 
safety data during the study on a periodic basis.  However, as of 20 April 2016 the 
study was closed to enrollment due to a low number of patients; therefore, an iDMC 
will no longer be used to evaluate safety data.  
3.2    
END OF STUDY 
The study is currently closed to enrollment due to a low number of patients.  
The end of study will be when all enrolled patients have discontinued study treatment  
or all patients have been enrolled into an extension study.  Patients already enrolled 
will remain on study and will be allowed to continue study treatment until 
radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who continue treatment beyond disease progression 
according to RECIST v1.1), withdrawal of consent, enrollment into an extension study, 
or death, whichever occurs first.  In addition, the Sponsor may decide to terminate the 
study at any time  
If the Sponsor decides to end the study, patients still receiving study treatment may be 
offered enrollment in an extension study if, in the opinion of the investigator and in 
consultation with the Medical Monitor, the patient would potentially benefit from 
continuing therapy. 
3.3    
RATIONALE FOR STUDY DESIGN 
This Phase III study design is based on the assumption that in patients with Stage IV 
squamous NSCLC, who are chemotherapy naive and whose tumors are selected for 
high levels of PD-L1 expression, treatment with atezolizumab may prolong PFS 
compared with treatment with gemcitabine
 +
 cisplatin or carboplatin. 
3.3.1    
Rationale for Testing Atezolizumab in PD-L1−Selected Patients 
with Non−Small Cell Lung Cancer 
Despite recent improvements in treatment, the prognosis for patients with advanced 
NSCLC remains dismal, with a median OS of approximately 12.5 months 
(Sandler et al. 2006).  Patients who receive second-line treatment for their disease have 


 
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an even more limited prognosis, with a median survival duration of 
approximately 8−9 months (Stinchcombe et al. 2008).  Approved therapies are 
associated with significant toxicities (e.g., neuropathy, febrile neutropenia, 
myelosuppression, and alopecia) that negatively impact quality of life.  Therefore, there 
is a continuing need for more efficacious, better tolerated treatments. 
Inhibition of PD-L1/PD-1 signaling has been shown to produce durable responses in 
some patients, and expression of PD-L1 by TCs in several tumor types 
(including NSCLC) correlates with response to therapy (Topalian et al. 2012). 
Data from Phase Ia Study PCD4989g suggest that tumor PD-L1 status as determined by 
IHC in patients with NSCLC correlates with response to atezolizumab (see 
Section 1.6.3). 
Patients whose tumors were characterized as high TCs or ICs exhibited an ORR of 
50% (TC3 or IC3 group; 11 of 22, 95% CI: 28.2%−71.8%) compared with an ORR of 
12.1% in patients whose tumors expressed low or no PD-L1 staining in TCs and ICs 
(TC0/1/2 and IC0/1/2 group; 7 of 58, 95% CI: 5.7%−22.5%). 
These data provide a rationale for evaluating the efficacy of atezolizumab in patients 
with Stage IV squamous NSCLC selected on the basis of tumor PD-L1 expression. 
3.3.2    
Rationale for Gemcitabine
 +
 Cisplatin or Carboplatin as a 
Comparator 
In the first-line treatment setting for non-squamous NSCLC that does not harbor a driver 
mutation, standard of care is a platinum doublet with either cisplatin or carboplatin and a 
taxane or pemetrexed, with or without bevacizumab.  However, well-designed clinical 
studies conducted over the last decade have clearly demonstrated that bevacizumab 
and pemetrexed are not appropriate agents for the treatment of patients with squamous 
cell carcinoma of the lung (Johnson et al. 2004; Scagliotti et al 2008; Sandler et al. 2009).  
The combination of gemcitabine and a platinum analog (either carboplatin or cisplatin) 
has demonstrated efficacy as first-line treatment for NSCLC and, as a result, is often a 
reference arm in clinical trials evaluating new therapeutics (Schiller et al. 2002; 
Scagliotti et al. 2008; Treat et al. 2010).  The control group in this study will receive 
gemcitabine
 +
 cisplatin or carboplatin, which is a standard of care regimen for patients 
with squamous NSCLC.  This control group will be instrumental in assessing the relative 
benefit and safety of atezolizumab compared with chemotherapy in the front-line 
treatment setting. 
3.3.3    
Rationale for Allowing Patients to Continue Atezolizumab 
Treatment until Loss of Clinical Benefit 
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure (see Section 1.7).  Because of 


 
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the potential for pseudoprogression/tumor immune infiltration, this study will allow 
patients randomized to receive atezolizumab to continue to receive study treatment after 
apparent radiographic progression, provided the benefit-risk ratio is judged to be 
favorable.  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 (see Section 3.1). 
3.3.4    
Rationale for Collection of Archival and/or Fresh Tumor 
Specimens 
Published results suggest that the expression of PD-L1 in tumors correlates with 
response to anti−PD-1 therapy (Topalian et al. 2012).  This correlation is also observed 
with atezolizumab in preliminary data from Study PCD4989g.  In this study, archival 
and/or fresh tumor specimens from patients will be prospectively tested for PD-L1 
expression by a central laboratory during the screening period.  Only patients with 
PD-L1−selected tumors (defined by expression of PD-L1 in TCs or ICs) will be enrolled. 
In addition to the assessment of PD-L1 status, other exploratory markers, such as 
potential predictive and prognostic markers related to the clinical benefit of atezolizumab, 
tumor immunobiology, mechanisms of resistance, or tumor type, may also be analyzed.  
DNA and/or RNA extraction may be performed to enable next-generation sequencing (NGS) 
to identify somatic mutations to increase understanding of disease pathobiology. 
3.3.5    
Rationale for Blood Biomarker Assessments 
An exploratory objective of this study is to evaluate surrogate biomarkers (that may 
include circulating tumor DNA) in blood samples.  The evaluation of blood biomarkers 
may provide evidence for biologic activity of atezolizumab in patients with NSCLC and 
may allow for the development of blood-based biomarkers to help predict which patients 
may benefit from atezolizumab. 
In addition, potential correlations of these biomarkers with the safety and activity of 
atezolizumab will be explored. 
3.3.6    
Rationale for the Collection of Optional Tumor Specimens at 
Radiographic Progression 
Anti-tumor immune responses such as those associated with atezolizumab may result in 
objective responses that are delayed and 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 immune infiltration of the tumor with a 
concomitant increase in tumor size.  In addition, lesions that would otherwise be 
undetectable with conventional imaging (i.e., micrometastatic disease) may increase in 
size as a result of these processes and be recorded as new lesions (Hales et al. 2010). 
Patients in both treatment arms may undergo an optional tumor biopsy at the time of 
radiographic disease progression if clinically feasible.  To do this, patients must sign a 


 
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separate consent.  These data will be used to evaluate the utility of the biopsy in 
distinguishing pseudoprogression/tumor immune infiltration from true progression.  In 
addition, mechanisms relating to progression, resistance, predictive, prognostic, and 
pharmacodynamic relationships in tumor biomarkers (including but not limited to PD-L1, 
CD8, mutation status, and others) and their efficacy will be evaluated.  DNA and/or RNA 
extraction may be performed to enable NGS to identify somatic mutations that are 
associated with disease progression or acquired resistance to atezolizumab and to 
increase understanding of disease pathobiology. 
3.4    
OUTCOME MEASURES 
The study is currently closed to enrollment due to a low number of patients; therefore, 
the outcome measures of this study are no longer applicable and formal analyses of 
efficacy or safety will not be performed. 
4.    
MATERIALS AND METHODS  
4.1    
PATIENTS 
PD-L1−selected chemotherapy naive patients with Stage IV squamous non−small cell 
lung cancer will be enrolled in this study. 
4.1.1    
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
•   Signed Informed Consent Form 
•   Male or female, 18 years of age or older 
•   Histologically or cytologically confirmed Stage IV squamous NSCLC (per the Union 
Internationale contre le Cancer/American Joint Committee on Cancer staging 
system, 7th edition; Detterbeck et al. 2009; see Appendix 2) 
•   Patients with a history of treated asymptomatic CNS metastases are eligible, 
provided they meet all of the following criteria: 
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla, or spinal cord) 
No ongoing requirement for corticosteroids as therapy for CNS disease 
No stereotactic radiation within 7 days or whole-brain radiation within 14 days 
prior to randomization 
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study 
Patients with new asymptomatic CNS metastases detected at the 
screening scan must receive radiation therapy and/or surgery for CNS 
metastases.  Following treatment, these patients may then be eligible 
without the need for an additional brain scan prior to randomization, if all 
other criteria are met. 


 
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•   Tumor PD-L1 expression (TC3 or IC3), as determined by an IHC assay performed 
by a central laboratory on previously obtained archival tumor tissue or tissue 
obtained from a biopsy at screening 
A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in 
paraffin block (preferred) or a minimum of 15 unstained, freshly cut, serial 
sections from an FFPE tumor specimen is required for participation in this study.  
This specimen must be accompanied by the associated pathology report. 
If fewer than 15 slides are available at baseline (but no fewer than 10), the 
patient may still be eligible, upon discussion with the Medical Monitor. 
For freshly collected specimens, resections, core needle biopsies, excisional, 
incisional, punch, or forceps biopsies are acceptable. 
Fine-needle aspiration, brushing, cell pellet from pleural effusion, and lavage 
samples are not acceptable. 
Tumor tissue from bone metastases is not acceptable. 
For core needle biopsy specimens, preferably, at least three cores embedded 
in a single paraffin block, should be submitted for evaluation. 
For patients whose initial archival tumor tissue sample is PD-L1 negative, a 
biopsy can be performed at screening to submit fresh tissue for the purposes of 
testing PD-L1 status.  A positive test result in any tumor tissue sample will 
satisfy this eligibility criterion. 
For samples not meeting minimum requirements for size/slide number, contact 
the Medical Monitor to determine if patient is eligible for study participation. 
•   No prior treatment for Stage IV squamous NSCLC unless patient had a previously 
detected sensitizing EGFR mutation or ALK fusion oncogene. 
Patients having previously detected sensitizing EGFR mutation must have 
been previously treated with an EGFR TKI (erlotinib, gefitinib, etc.) and 
experienced disease progression (during or after treatment) or intolerance to 
treatment with an EGFR TKI.  However, given that testing for EGFR mutations 
is not considered standard in this patient population due to its extremely low 
frequency, patients with an unknown status will not be required to be tested at 
screening. 
Patients having a previously detected ALK fusion oncogene must have been 
previously treated with crizotinib or another ALK inhibitor and experienced 
disease progression (during or after treatment) or intolerance to treatment with 
the ALK inhibitor.  However, given that testing to detect ALK fusion oncogenes 
is not considered standard in this patient population due to its extremely low 
frequency, patients with an unknown status will not be required to be tested at 
screening. 
•   Patients who have received prior neo-adjuvant, adjuvant chemotherapy, or 
chemoradiotherapy with curative intent for non-metastatic disease must have 
experienced a treatment-free interval of at least 6 months from randomization since 
the last chemotherapy or chemoradiotherapy cycle. 


 
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•   Measurable disease, as defined by RECIST v1.1 
Previously irradiated lesions can only be considered measurable disease if 
disease progression has been unequivocally documented at that site since 
radiation and the previously irradiated lesion is not the only site of measurable 
disease. 
•   ECOG performance status of 0 or 1 (see Appendix 6) 
•   Adequate hematologic and end-organ function, defined by the following laboratory 
test results obtained within 14 days prior to the first study treatment: 
ANC ≥
 1500 cells/μL without granulocyte colony-stimulating factor support 
Lymphocyte count ≥
 500 cells/μL 
Platelet count ≥
 100,000 cells/μL without transfusion 
Hemoglobin ≥
 9.0 g/dL 
Patients may be transfused to meet this criterion. 
INR or aPTT ≤
 1.5 times the upper limit of normal (ULN) 
This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation must have 
an INR or aPTT within therapeutic limits for at least 1 week prior to 
randomization. 
AST and ALT ≤
 2.5
 ×
 ULN 
If patient has liver metastases, AST and/or ALT ≤
 5
 ×
 ULN 
Alkaline phosphatase ≤
 2.5
 ×
 ULN 
If patient has liver or bone metastases, alkaline phosphatase ≤
 5
 ×
 ULN 
Serum bilirubin ≤
 1.5
 ×
 ULN 
Patients with known Gilbert disease who have serum bilirubin level 
≤
 3
 ×
 ULN may be enrolled. 
Calculated creatinine clearance (CrCl) ≥
 45 mL/min 
If using cisplatin, calculated CrCl must be ≥
 60 mL/min 
•   For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement (by patient and/or partner) to use a highly 
effective form(s) of contraception during study treatment that results in a low failure 
rate of
 <
 1% per year when used consistently and correctly.  Female patients treated 
with atezolizumab should continue contraception use for 5 months after the last 
dose.  Female patients treated with cisplatin should continue contraception use for 
6 months after the last dose.  Male patients treated with gemcitabine, cisplatin, or 
carboplatin should continue contraception use for 6 months after the last dose.  
Such methods include combined (estrogen and progestogen containing) hormonal 
contraception, progestogen-only hormonal contraception associated with inhibition 
of ovulation together with another additional barrier method always containing a 
spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 


 
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bilateral tubal occlusion or vasectomized partner (on the understanding that this is 
the only one partner during the entire study duration), and sexual abstinence. 
Oral contraception should always be combined with an additional contraceptive 
method because of a potential interaction with the study drug.  The same rules are 
valid for male patients involved in this study if they have a partner of childbirth 
potential.  Male patients must always use a condom. 
•   Women who are not postmenopausal (≥
 12 months of non−therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug. 
4.1.2    
Exclusion Criteria 
Patients who meet any of the criteria in the following sections will be excluded from 
study entry. 
4.1.2.1    Cancer-Specific Exclusions 
•   Active or untreated CNS metastases as determined by CT or magnetic resonance 
imaging (MRI) evaluation during screening and prior radiographic assessments 
•   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 randomization 
• Leptomeningeal  
disease  
•   Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
•   Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated 
prior to randomization.  There is no required minimum recovery period. 
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy, if appropriate, prior to enrollment. 
•   Uncontrolled or symptomatic hypercalcemia (>
 1.5 mmol/L ionized calcium or 
calcium >
 12 mg/dL or corrected serum calcium >
 ULN) 
Patients who are receiving denosumab prior to randomization must be willing 
and eligible to discontinue its use and replace it with a bisphosphonate instead 
while in the study. 
•   Malignancies other than NSCLC within 5 years prior to randomization, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 
5-year OS >
 90%) treated with expected curative outcome (such as adequately 
treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized 


 
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prostate cancer treated surgically with curative intent, ductal carcinoma in situ 
treated surgically with curative intent) 
4.1.2.2    General Medical Exclusions 
•   Women who are pregnant, lactating, or intending to become pregnant during the 
study 
•   History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
•   Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
•   History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis  
Patients with a history of autoimmune-related hypothyroidism on a stable dose 
of thyroid-replacement hormone may be eligible for this study. 
Patients with controlled Type I diabetes mellitus on a stable insulin regimen are 
eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
Rash must cover less than 10% of body surface area (BSA) 
Disease is well controlled at baseline and only requiring low potency topical 
steroids 
No acute exacerbations of underlying condition within the last 12 months 
requiring treatment with either PUVA [psoralen plus ultraviolet A radiation], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or high 
potency or oral steroids. 
•   Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
•   History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing 
pneumonia (i.e., bronchiolitis obliterans), idiopathic pneumonitis or evidence of 
active pneumonitis on screening chest CT scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
•   Positive HIV test 
•   Patients with active hepatitis B (chronic or acute; defined as having a positive 
hepatitis B surface antigen [HBsAg] test at screening).  
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of 
HBsAg) are eligible.  HBV DNA test must be performed in these patients prior 
to randomization. 


 
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•   Patients with active hepatitis C 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
•   Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to 
randomization, unstable arrhythmias, or unstable angina 
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or left ventricular ejection fraction <
 50% must be on 
a stable medical regimen that is optimized in the opinion of the treating 
physician, in consultation with a cardiologist if appropriate. 
• Active  
tuberculosis  
•   Severe infections within 4 weeks prior to randomization including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
•   Major surgical procedure other than for diagnosis within 28 days prior to 
randomization or anticipation of need for a major surgical procedure during the 
course of the study 
•   Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications 
4.1.2.3    Exclusion Criteria Related to Medications 
•   Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy 
within 3 weeks prior to initiation of study treatment; the following exceptions are 
allowed: 
TKIs approved for treatment of NSCLC discontinued >
 7 days prior to 
randomization; the baseline scan must be obtained after discontinuation of prior 
TKIs. 
•   Treatment with any other investigational agent or participation in another clinical trial 
with therapeutic intent within 28 days prior to randomization 
•   Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
•   Administration of a live, attenuated vaccine within 4 weeks prior to randomization or 
anticipation that such a live attenuated vaccine will be required during the study 
Influenza vaccination should be given during influenza season.  Patients must 
not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks 
prior to randomization or at any time during the study. 


 
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•   Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
anti−PD-1, and anti−PD-L1 therapeutic antibodies 
Patients who have had prior anti−cytotoxic T lymphocyte−associated antigen 4 
(CTLA-4) treatment may be enrolled, provided the following requirements are 
met: 
Last dose of anti−CTLA-4 at least 6 weeks prior to randomization 
No history of severe immune related adverse effects from anti−CTLA-4 
(CTCAE Grade 3 and 4) 
•   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 randomization 
Prior treatment with cancer vaccines is allowed. 
•   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 [anti-TNF] agents) within 2 weeks prior to randomization 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled in the study after discussion with and approval by the Medical Monitor. 
The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical 
insufficiency are allowed. 
4.1.2.4    Exclusion Criteria Related to Gemcitabine, Cisplatin or 
Carboplatin 
•   History of allergic reactions to cisplatin, carboplatin, or other platinum-containing 
compounds 
•   Patients with hearing impairment (cisplatin) 
• CrCl  <
 60mL/min (cisplatin) 
• Grade  ≥
 2 peripheral neuropathy as defined by NCI CTCAE v4.0 criteria (cisplatin) 
•   Known hypersensitivity to gemcitabine 
•   History of radiation therapy within 7 days prior to initiating gemcitabine 
4.2    
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study. 
After written informed consent has been obtained and eligibility has been established 
(including determination of tumor PD-L1 status by central testing), personnel at the study 
site will enter demographic and baseline characteristics in the interactive Web/voice 
response system (IxRS).  For patients who are eligible for enrollment, the study site will 


 
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obtain the patient’s randomization number and treatment assignment from the IxRS.  
Randomization to one of two treatment arms will occur in a 1:1 ratio. 
Permuted-block randomization will be applied to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified by the following criteria: 
•   Sex (male vs. female) 
•   ECOG performance status (0 vs. 1) 
•   Presence of liver metastases at baseline (yes vs. no) 
•   Tumor tissue PD-L1 expression by IHC (TC3 and any IC vs. TC0/1/2 and IC3) 
 
Patients should receive their first dose of study treatment on the day of randomization if 
possible.  If this is not possible, the first dose should occur within 5 days after 
randomization. 
4.3    
STUDY TREATMENT 
4.3.1    
Formulation, Packaging, and Handling 
4.3.1.1    Atezolizumab (MPDL3280A) 
The atezolizumab (MPDL3280A) drug product is provided as a sterile liquid in a 
single-use, 20-mL glass vial.  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.   
For further details on the formulation and handling of atezolizumab, see the Pharmacy 
Manual and Investigator’s Brochure. 
Atezolizumab (MPDL3280A) will be supplied by the Sponsor. 
4.3.1.2    Gemcitabine
 +
 Cisplatin or Carboplatin 
The comparator study drugs, gemcitabine +
 cisplatin or carboplatin (based on 
investigator’s choice), will be used in commercially available formulations.  They will be 
provided by the Sponsor if they are considered Investigational Medical Products (IMPs) 
by local regulations (see Section 4.3.4). 
For information on the formulation, packaging, and handling of gemcitabine, cisplatin 
and carboplatin see the local prescribing information for each drug. 
4.3.1.3    Erlotinib 
Switch maintenance to erlotinib is no longer permitted for patients randomized to Arm B.  
However, patients who had already started switch maintenance treatment with erlotinib 
under previous protocol versions may be allowed to continue treatment with erlotinib 
upon discussion of the risks, potential benefits, and alternative treatment options with 
the investigator.  


 
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Erlotinib will be provided by the Sponsor if required by local health authority regulations.  
For information on the formulation, packaging, and handling of erlotinib, see the local 
prescribing information. 
4.3.2    
Dosage, Administration, and Compliance 
4.3.2.1    Atezolizumab 
Patients who are randomized to be treated with atezolizumab will receive 1200 mg 
atezolizumab administered by IV infusion q21d in a monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.  
Atezolizumab infusions will be administered per the instructions outlined in Table 9. 


 
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Table 9   Administration of First and Subsequent Infusions 
of Atezolizumab 
First Infusion 
Subsequent Infusions 
•   No pre-medication is allowed. 
•   Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion. 
•  Infuse atezolizumab (1200 mg in a 250 mL 
0.9% NaCl intravenous infusion bag) over 
60 (±
 15) minutes 
•  If clinically indicated, record patient’s vital 
signs (heart rate, respiratory rate, blood 
pressure, and temperature) during the 
infusion at 15, 30, 45, and 60 minutes 
(±
 5-minute windows are allowed for all 
timepoints). 
•  If clinically indicated, record patient’s 
vital signs (heart rate, respiratory rate, blood 
pressure, and temperature) at 
30 (±
 10) minutes after the infusion. 
•   Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
•  If patient experienced infusion-related 
reaction during any previous infusion, 
pre-medication with antihistamines may 
be administered for Cycles ≥
 2 at the 
discretion of the treating physician. 
•   Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion. 
•  If the patient tolerated the first infusion 
well without infusion-associated adverse 
events, the second infusion may be 
delivered over 30 (±
 10) minutes. 
•  If no reaction occurs, continue 
subsequent infusions over 
30 (±
 10) minutes 
Continue to record vital signs within 
60 minutes before starting infusion and 
during and after the infusion if clinically 
indicated. 
•  If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be delivered 
over 60 (±
 15) minutes. 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion if 
clinically indicated or if patient 
experienced symptoms during the 
previous infusion.  
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) 30 (± 10) minutes after 
the infusion, if clinically indicated or if 
patient experienced symptoms during 
previous infusion. 
NaCl =
 sodium chloride. 
 
Dose modifications to atezolizumab are not permitted.  Guidelines for treatment 
interruption or discontinuation and the management of specific adverse events are 
provided in Sections 5.1.6 and 5.1.7. 
See the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 


 
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4.3.2.2    Gemcitabine
 +
 Cisplatin or Carboplatin 
Each study site will administer gemcitabine +
 cisplatin or carboplatin according to local 
practice.  The selected chemotherapy combination should remain the same for all cycles 
(i.e., patients who start on gemcitabine
 +
 cisplatin remain on this combination and not 
switch to gemcitabine
 +
 carboplatin during treatment and vice versa).  Treatment can be 
given for four or six cycles as per local standard of care.  The intended number of cycles 
of carboplatin or cisplatin will be specified by the investigator prior to study 
randomization.  
Patients should receive anti-emetic and IV hydration for platinum-based treatments 
according to the local standard-of-care and manufacturer’s instruction.  Table 10 lists the 
suggested doses and infusion times for gemcitabine
 +
 cisplatin or carboplatin.  
Gemcitabine +
 cisplatin or carboplatin may be administered in accordance with the local 
standard-of-care in lieu of the suggested doses and/or infusion times in Table 10.  If 
there is a significant difference between the protocol guidelines and institutional standard 
of care, call the Medical Monitor to discuss. 
Table 10  Gemcitabine +
 Cisplatin or Carboplatin Regimen 
Chemotherapy 
Dose/Route 
Treatment 
(Four or Six Cycles) 
Gemcitabine  
 1250  
 
mg/m2 IV    
Over 30 minutes on Days 1 and 8 q21d 
Cisplatin 
75 mg/m2 IV  
Over 1−2hours on Day 1 q21d 
Gemcitabine  
 1000  
 
mg/m2 IV    
Over 30 minutes on Days 1 and 8 q21d 
Carboplatin 
AUC 5 IV 
Over ~30–60 minutes on Day 1 q21d 
AUC =
 area under the concentration curve; IV
 =
 intravenous; q21d
 =
 every 21 days. 
 
The guidelines for dose modification and treatment interruption or discontinuation for 
gemcitabine
 +
 cisplatin or carboplatin are provided in Section 5.1.8. 
4.3.2.2.1    Gemcitabine 
Institutions should follow their standard administration regimens for gemcitabine.  
In general, gemcitabine will be administered intravenously at a dose of 1250 mg/m
2 (in 
combination with cisplatin) 1000 mg/m2 (in combination with carboplatin) or over 30 minutes 
on Days 1 and 8 of each 21 day cycle followed by cisplatin or carboplatin at 
approximately 30 minutes after the completion of the gemcitabine infusion on Day 1 only. 
Gemcitabine injection must be diluted prior to infusion.  The recommended diluent for 
reconstitution of gemcitabine is 0.9% sodium chloride injection without preservatives.  
The administration of gemcitabine should be done in accordance with local practice and 
manufacturers’ instructions; sites should follow their institutional standard-of-care for 


 
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determining the gemcitabine dose for obese patients and for dose adjustment in the 
event of patient weight changes. 
4.3.2.2.2    Cisplatin/Carboplatin 
Each site will choose to treat a given patient with either cisplatin or carboplatin according 
to local practice. 
Cisplatin 
Cisplatin should be administered by IV infusion approximately 30 minutes after 
completion of the gemcitabine infusion at a dose of 75 mg/m² over 1–2 hours or per 
standard-of-care at the institution.  Patients must receive adequate anti-emetic treatment 
and appropriate hydration prior to and/or after receiving cisplatin. 
Refer to local clinical practice guidelines for further details. 
Carboplatin 
Carboplatin should be administered by IV infusion, immediately after the completion of 
the gemcitabine administration over 30−60 minutes to achieve an initial target area under 
the concentration−time curve (AUC) of 5 mg/mL/min (Calvert formula dosing) with 
standard anti-emetics per local practice guidelines. 
The carboplatin dose of AUC 5 will be calculated using the Calvert formula 
(Calvert et al. 1989): 
Calvert Formula 
Total dose (mg) =
 (target AUC)
 ×
 (glomerular filtration rate [GFR]
 +
 25) 
NOTE:  The GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min. 
For the purposes of this protocol, the GFR is considered to be equivalent to the CrCl.  
The CrCl is calculated by institutional guidelines or by the method of Cockcroft and Gault 
(1976) using the following formula: 
(140−age) (wt) 
CrCl =
  
72
 ×
 Scr 
(×
 0.85 if female) 
 
Where:  CrCl =
 creatinine clearance in mL/min 
   age
 =
 patient
's age in years  
    wt
 =
 patient’s weight in kg 
    Scr
 =
 serum creatinine in mg/dL 
 
NOTE:  For patients with an abnormally low serum creatinine level, estimate GFR using 
a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 125 mL/min. 


 
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If a patient’s GFR is estimated on the basis of serum creatinine measurements by the 
isotope dilution mass spectroscopy method, the FDA recommends that physicians 
consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential 
toxicity caused by overdosing.  On the basis of the Calvert formula described in the 
carboplatin label, the maximum doses can be calculated as follows: 
Maximum carboplatin dose (mg) =
 target AUC (mg
 • min/mL) ×
 (GFR
 +
 25 mL/min) 
 
The maximum dose is based on a GFR estimate that is capped at 150 mL/min for 
patients with normal renal function.  No higher estimated GFR values should be used. 
For a target AUC =
 6, the maximum dose is 6
 ×
 150
 =
 900 mg. 
For a target AUC =
 5, the maximum dose is 5
 ×
 150
 =
 750 mg. 
For a target AUC =
 4, the maximum dose is 4
 ×
 150
 =
 600 mg. 
 
See the FDA’s communication regarding carboplatin dosing for more details at 
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm. 
4.3.2.3    Erlotinib 
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients 
who had already started switch maintenance treatment with erlotinib under previous 
protocol versions may be allowed to continue treatment with erlotinib upon discussion 
of the risks, potential benefits, and alternative treatment options with the investigator. 
4.3.3    
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (atezolizumab, gemcitabine, cisplatin 
carboplatin, and erlotinib) will be provided by the Sponsor where required by local 
health authority regulations.  The study site will acknowledge receipt of the IMPs with 
use of the IxRS to confirm the shipment condition and content.  Any damaged shipments 
will be replaced. 
IMPs 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 IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 


 
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4.3.4    
Post-Study Access to Atezolizumab Investigational Medicinal 
Product Accountability 
The Sponsor will evaluate the appropriateness of continuing to provide atezolizumab to 
patients assigned to this treatment in accordance with the Roche Global Policy on 
Continued Access to Investigational Medicinal Product, available at the following Web 
site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4    
CONCOMITANT THERAPY 
4.4.1    
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening until the treatment discontinuation visit.  All such medications 
should be reported to the investigator.  
Premedication with antihistamines may be administered for any atezolizumab infusions 
after Cycle 1. 
The following therapies should continue while patients are in the study: 
•   Oral contraceptives 
•   Hormone-replacement therapy 
•   Prophylactic or therapeutic anticoagulation therapy (such as low−molecular weight 
heparin or warfarin at a stable dose level) 
•   Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain only after the induction phase with chemotherapy is complete) provided 
it does not interfere with the assessment of tumor target lesions (e.g., if the lesion to 
be irradiated is not the only site of disease as that would render the patient not 
evaluable for response by tumor assessments according to RECIST v1.1) 
It is not a requirement to withhold atezolizumab during palliative radiotherapy. 
•   Inactive influenza vaccinations 
•   Megestrol administered as an appetite stimulant  
•   Inhaled corticosteroids for chronic obstructive pulmonary disease 
•   Mineralocorticoids (e.g., fludrocortisone)  
•   Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency 
 
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, as per local standards.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or famotidine or another H2 receptor antagonist as per standard 
practice (for sites outside the United States, equivalent medications may be substituted 


 
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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 7). 
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients 
who had already started switch maintenance treatment with erlotinib under previous 
protocol versions may be allowed to continue treatment with erlotinib upon discussion 
of the risks, potential benefits, and alternative treatment options with the investigator.  
4.4.2    
Cautionary Therapy for Atezolizumab-Treated Patients 
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations where 
systemic corticosteroids or TNF-α inhibitors would be routinely administered, alternatives, 
including antihistamines, should be considered first by the treating physician.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors may be 
administered at the discretion of the treating physician except in the case of patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance; see Section 5.1.7). 
Systemic corticosteroids are recommended, with caution at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with 
atezolizumab therapy.  Guidelines for the management of immune-mediated adverse 
events are provided in Section 6 (Guidance for the Investigator) of the atezolizumab 
Investigator’s Brochure. 
4.4.3    
Prohibited Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority−approved or experimental, is prohibited for various time periods prior to 
starting study treatment depending on the anti-cancer agent (see Section 4.1.2) and 
during study treatment until disease progression is documented and patient has 
discontinued study treatment.  This includes but is not limited to chemotherapy, 
hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal 
therapy (unless otherwise noted). 
The following medications are prohibited while in the study, unless otherwise noted: 
•   Denosumab; patients who are receiving denosumab prior to enrollment must be 
willing and eligible to receive a bisphosphonate instead while in the study.  
•   Any live, attenuated vaccine (e.g., FluMist
®) within 4 weeks prior to randomization, 
during treatment, or within 90 days following the last atezolizumab dose (for patients 
randomized to atezolizumab). 
•   Use of steroids to pre-medicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in 


 
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such patients, non-contrast CT of the chest and non-contrast CT or MRIs of the 
abdomen and pelvis should be performed. 
 
The concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, their use for patients in the study is allowed at the discretion of 
the investigator, provided that there are no known interactions with any study 
treatment.  As noted above, herbal therapies intended for the treatment of cancer are 
prohibited.  
4.5    
STUDY ASSESSMENTS 
See Appendix 1 for the schedules of assessments to be performed during the study.  
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient. 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits rescheduled accordingly. 
4.5.1    
Informed Consent Forms and Pre-Screening/Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations and may be obtained more 
than 28 days before initiation of study treatment. 
Prior to signing the main consent form for the study, patients will specifically allow for the 
collection and testing of archival or fresh tumor tissue by signing the pre-screening 
consent form. 
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 randomization.  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. 
Patients who are treated with atezolizumab and who show apparent radiographic 
progression at a tumor response evaluation must sign consent at that time to 
acknowledge deferring other treatment options in favor of continuing atezolizumab. 


 
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Patients in both treatment arms may undergo an optional tumor biopsy at the time of 
radiographic disease progression if clinically feasible.  To do this, patients must sign a 
separate consent.   
4.5.2    
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, non-NSCLC cancer 
history (including prior cancer therapies and procedures), reproductive status, smoking 
history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, 
over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used 
by the patient within 7 days prior to the screening visit. 
NSCLC cancer history will include prior cancer therapies and procedures. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3    
Physical Examinations 
A complete physical examination, according to local practice, should be performed at 
screening.  Any abnormality identified at screening should be recorded on the General 
Medical History and Baseline Conditions electronic Case Report Form (eCRF). 
At subsequent visits, 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.  Vital 
signs will be measured and recorded as described in Table 11. 


 
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Table 11  Vital Sign Measurements at Cycle 1 and All Subsequent Cycles 
 
Cycle 1 
Treatment Arm 
Timepoints 
Arm A  
Within 60 minutes prior to atezolizumab infusion  
During the infusion (every 15 [±
 5] minutes) and within 30 (±
 10) minutes after 
atezolizumab infusion if clinically indicated 
Arm B 
Within 60 minutes prior to gemcitabine infusion 
As clinically indicated prior, during, or after carboplatin or cisplatin infusion 
 
Subsequent Cycles 
Treatment Arm 
Timepoints 
Arms A and B 
Within 60 minutes prior to infusion 
During the infusion  if clinically indicated or if symptoms occurred during the 
prior infusion 
Within 30 (±
 10) minutes after infusion if clinically indicated or if symptoms 
occurred during the prior infusion 
 
For patients in the atezolizumab arm, see Table 9 in Section 4.3.2.1. 
4.5.5    
Tumor and Response Evaluations 
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRIs of the chest and abdomen.  A CT scan of the pelvis is required 
at screening and as clinically indicated or as per local standard-of-care at subsequent 
response evaluations.  A spiral CT scan of the chest may be obtained but is not a 
requirement. 
A CT (with contrast) or MRI scan of the head must be done at screening to evaluate 
CNS metastasis in all patients.  An MRI scan of the brain is required to confirm or refute 
the diagnosis of CNS metastases at baseline in the event of an equivocal scan.  Patients 
with active or untreated CNS metastases are not eligible for this study (see 
Section 4.1.2.1 for CNS-related exclusions). 
If a CT scan for tumor assessment is performed in a positron emission tomography/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast 
diagnostic CT scan. 
Bone scans and CT scans of the neck should also be performed if clinically indicated.  At 
the investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used. 


 
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Tumor assessments performed as standard-of-care prior to obtaining informed consent 
and within 28 days of Cycle 1, Day 1 may be used rather than repeating tests. 
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  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).  Response will be assessed by the investigator with use of 
RECIST v1.1 and modified RECIST (see Appendix 3 and Appendix 4).  Assessments 
should be performed by the same evaluator, if possible, to ensure internal consistency 
across visits.  Results must be reviewed by the investigator before dosing at the next 
cycle. 
Tumor assessments will be performed every 6 weeks (±
 7 days) for 48 weeks following 
Cycle 1, Day 1 and then every 9 weeks (±
 7 days) thereafter, regardless of treatment 
delays, until radiographic disease progression per RECIST v1.1 (for patients in both 
treatment arms) or loss of clinical benefit (for atezolizumab-treated patients who 
continue treatment beyond disease progression according to RECIST v1.1), withdrawal 
of consent, enrollment into an extension study, or death, whichever occurs first.  At the 
investigator’s discretion, CT scans should be repeated at any time if progressive disease 
is suspected. 
Patients treated with atezolizumab continuing to experience clinical benefit, despite 
evidence of radiographic progression per RECIST v1.1, will continue tumor assessments 
as per the schedule listed above.   
4.5.6    
Laboratory, Biomarker, and Other Biological Samples 
The schedule of laboratory assessments should be performed according to Appendix 1. 
PK, ATA, and biomarker evaluations are no longer required.  
Samples for the following laboratory tests are to be sent to the study site
's local 
laboratory for analysis: 
•   Hematology (CBC, including RBC count, hemoglobin, hematocrit,   WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count) 
•   Serum chemistries (glucose, BUN or urea, creatinine, sodium, potassium, 
magnesium, chloride, bicarbonate, calcium, phosphorus, total bilirubin, ALT, AST, 
alkaline phosphatase, LDH, total protein, and albumin) 
•   Coagulation (INR or aPTT) 


 
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•   Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; urine pregnancy tests will be performed on Day 1 of each 
cycle during treatment prior to administration of study treatment.  A serum 
pregnancy test must be performed if the urine pregnancy test result is positive.  
Childbearing potential is defined as not having undergone surgical sterilization, 
hysterectomy, and/or bilateral oophorectomy or not being postmenopausal 
(≥
 12 months of amenorrhea).  
•   Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood); dipstick 
permitted 
•   Thyroid function testing (thyroid-stimulating hormone, free T3, free T4) 
•   HIV testing 
All patients will be tested for HIV prior to the inclusion into the study and 
HIV-positive patients will be excluded from the clinical study. 
•   HBV serology:  HBsAg, antibodies against HBsAg, total HBcAb 
HBV DNA test must be performed prior to randomization if patient has negative 
serology for HBsAg and positive serology for HBcAb.  
•   HCV:  hepatitis C virus antibody (anti-HCV) 
HCV RNA should be obtained prior to randomization if patient tests positive for 
anti-HCV 
•  Blood biomarker samples will no longer be collected, but samples already collected 
will be kept and used per original signed informed consent.   
•   For patients who consent to the optional collection of samples for the Roche Clinical 
Repository (RCR), any leftover material from samples already collected will be 
stored and used for exploratory analyses as indicated in Section 4.5.12. 
 
See the laboratory manual for additional details on laboratory assessments and sample 
handling. 
4.5.7    
Tumor Tissue Samples 
A central laboratory will coordinate the sample collection of tissue samples for 
research-related testing at central laboratories or at the Sponsor.  Instruction manuals 
and supply kits will be provided for all central laboratory assessments. 
See the laboratory manual for additional details on tissue sample handling. 
4.5.7.1    Archival and Freshly Collected Tumor Tissue Samples for 
Screening 
Representative tumor specimens in paraffin blocks (preferred) or at least 15 serial-cut, 
unstained slides with an associated pathology report must be submitted 
for determination of PD-L1 status to ensure patient meets eligibility criteria prior to 
randomization.  In addition, exploratory biomarkers (including but not limited to markers 


 
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related to immune or NSCLC biology, such as T-cell markers or non-inherited 
biomarkers identified through NGS on extracted DNA and/or RNA) may be evaluated. 
Tumor tissue should be of good quality based on total and viable tumor content (sites 
will be informed if the quality of the submitted specimen is inadequate to determine 
tumor PD-L1 status). 
An archival tumor specimen should be submitted if available.  If an archival specimen is 
not available, the patient may still be eligible, with the assumption that the patient is 
willing to consent to and undergo a pre-treatment biopsy or resection of the tumor.  For 
freshly collected biopsy specimens, acceptable samples include: 
•   Core needle biopsy sample collection for deep tumor tissue; at least three cores, 
embedded into a single paraffin block, should be submitted for evaluation. 
•   Excisional, incisional, punch, or forceps biopsy sample collection for cutaneous, 
subcutaneous, or mucosal lesions 
 
Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples 
are not acceptable. 
For archival samples, the remaining tumor tissue block for all patients enrolled will be 
returned to the site upon request or 18 months after final closure of the study database, 
whichever is sooner.  Tissue samples from patients who are deemed ineligible to enroll 
in the study will be returned no later than 6 weeks after eligibility determination. 
4.5.7.2   
Optional Tumor Samples at the Time of Radiographic 
Progression 
Patients in both treatment arms may undergo an optional tumor biopsy to obtain a tumor 
sample at the time of radiographic disease progression (preferably within 40 days of 
radiographic progression or prior to start of the next anti-cancer treatment, whichever 
is sooner) if they have provided consent for optional biopsy and if clinically feasible. 
The preferred sample types include:  resections, core needle, excisional, incisional, punch, or 
forceps biopsies.  If such specimens are not available, any type of specimens (including fine-needle 
aspiration, cell pellet specimens e.g., from pleural effusion, and lavage samples) can also be 
submitted.   
The status of immune-related, tumor type−related and other exploratory biomarkers 
(including but not limited to T-cell markers and non-inherited biomarkers identified 
through NGS on extracted DNA and/or RNA) in tumor tissue samples may be evaluated. 
NGS may be performed by Foundation Medicine.  If performed by Foundation Medicine, 
the investigator can obtain results from the samples collected at the time of disease 
progression in the form of an NGS report, which is available upon request directly from 
Foundation Medicine.  The investigator may share and discuss the results with the 


 
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patient, unless the patient chooses otherwise.  The Foundation Medicine NGS assay 
has not been cleared or approved by the FDA; results from these investigational tests 
should not be used to guide future treatment decisions. 
4.5.7.3    Tumor Samples at Other Timepoints 
If a patient undergoes a medically indicated procedure (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) any time during the course of the study 
that has the likelihood of yielding tumor tissue, any remaining samples or a portion of the 
sample not necessary for medical diagnosis (leftover tumor tissue) may be obtained 
for exploratory analysis. 
Patients with additional tissue samples from procedures performed at different times 
during the course of their study participation (during treatment) who have signed the 
RCR optional consent will be requested (but not required) to also submit these optional 
fresh biopsy samples for central testing.  Tumor tissue samples collected at the time of 
clinical events (e.g., clinical response) are preferred.  Tissue samples obtained at 
multiple times from individual patients will greatly contribute to an improved 
understanding of the dynamics of PD-L1 expression and relationship with intervening 
anti-cancer therapy. 
4.5.8    
Use and Storage of Remaining Samples from Study-Related 
Procedures 
The remainder of samples obtained for study-related procedures (including blood 
samples and tumor tissues) will be destroyed no later than 5 years after the end of the 
study or earlier depending on local regulations.  If the patient provides optional consent 
for storing samples in the RCR for future research (see Section 4.5.12), the samples will 
be destroyed no later than 15 years after the date of final closure of the clinical database. 
4.5.9    
Anti-Therapeutic Antibody Testing 
ATA testing will no longer be performed. 
4.5.10    
Electrocardiograms 
A twelve-lead ECG is required at screening and when clinically indicated.  ECGs for 
each patient should be obtained from the same machine wherever possible.  Lead 
placement should be as consistent as possible.  ECG recordings must be performed 
after the patient has been resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient
's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.11    
Patient-Reported Outcomes 
PRO assessments are no longer required, and PRO data will no longer be collected.  


 
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4.5.12    
Samples for Roche Clinical Repository 
4.5.12.1    Overview of the Roche Clinical Repository 
The RCR 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 and analysis of RCR 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 RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR 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 
4.5.12.2    Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site
's institutional review board/ethics committee (IRB/EC) and, 
if applicable, an appropriate regulatory body.  If a site has not been granted approval for 
RCR sampling, this section of the protocol (Section 4.5.12.1) will not be applicable at 
that site. 
4.5.12.3    Sample Collection 
The following samples may be collected for patients who have signed the RCR optional 
consent: 
•   Optional fresh biopsy samples 
•   Leftover tumor tissue samples 
•   Remaining fluids (serum, plasma, blood cell derivatives) after study-related tests 
have been performed  
•   Remaining FFPE tissue (with the exception of archival FFPE blocks, which will be 
returned to sites) after study-related tests have been performed 
 
The following sample will be used for identification of genetic (inherited) biomarkers: 
•   Whole blood sample for DNA extraction (6 mL), which may be collected at any time 
during the course of the study 
 


 
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For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Laboratory Manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 4.5.12.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.12.4    Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche
's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR 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. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 


 
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4.5.12.5    Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  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 RCR 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 by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant
's death or loss of competence, the participant
's 
specimens and data will continue to be used as part of the RCR research. 
4.5.12.6    Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient
's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR 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 Study GO29432 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient
's withdrawal from the RCR does not constitute withdrawal from 
Study GO29432. 
4.5.12.7    Monitoring and Oversight 
RCR 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.  Monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RCR for the purposes of verifying 
the data provided to Roche.  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 RCR samples. 
4.5.13    
Timing of Assessments 
4.5.13.1    Screening/Baseline Assessments 
Screening tests and evaluations will be performed within 28 days prior to Cycle 1, Day 1.  
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within 28 days prior to Cycle 1, Day 1 may be used; such tests do not need 
to be repeated for screening. 


 
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See Appendix 1 of the previous protocol Version 4 for the schedule of screening 
assessments. 
4.5.13.2    Assessments during Treatment 
All treatment visits must occur within ±
 3 days from the scheduled date unless otherwise 
noted (see Appendix 1).  All assessments will be performed on the day of the specified 
visit unless a time window is specified.  Assessments scheduled on the day of study 
treatment administration (Day 1) of each cycle should be performed prior to study 
treatment infusion unless otherwise noted. 
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing and visits continuing on a 21-day schedule.  If treatment was 
postponed for fewer than 3 days, the patient can resume the original schedule. 
After completion of the induction phase (for patients in the control arm) or after five 
cycles (for patients in the atezolizumab arm), one of three cycles may be delayed by 
1 week (28 days instead of 21 days for one cycle) to allow for vacations/holidays.  
Following the delay, the next cycle must be delivered 21 days from the previous dose 
administration.  Two consecutive 28-day cycles are not permitted. 
If a dose modification is required due to toxicity, refer to Section 5.1.6. 
Tumor assessments should occur every 6 weeks (± 7 days) for 48 weeks following 
Cycle 1, Day 1 and every 9 weeks (± 7 days) after completion of the Week 48 tumor 
assessment, regardless of treatment delays, until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who continue 
treatment after disease progression according to RECIST v1.1), withdrawal of consent, 
enrollment into an extension study, or death, whichever occurs first.  
The following assessments may be performed ≤
 96 hours before Day 1 of each cycle (for 
Cycle 1, Day 1, the following Day 1 procedures should occur after randomization but 
before study treatment is administered):  
•   ECOG performance status 
•   Limited physical examination 
•   Local laboratory tests 
 
See Appendix 1 for the schedule of assessments performed. 
4.5.13.3    Assessments at Treatment Discontinuation Visit 
Patients who discontinue study treatment will return to the clinic for a treatment 
discontinuation visit within 30 days after the last dose of study treatment.  The visit at 
which a response assessment shows radiographic progressive disease according to 
RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who continue 


 
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treatment after disease progression according to RECIST v1.1) may be used as the 
treatment discontinuation visit. 
See Appendix 1 for assessments to be performed at the treatment discontinuation visit. 
4.5.13.4    Follow-Up Assessments 
After the Treatment Discontinuation Visit, adverse events should be followed as outlined 
in Section 5.3. 
For patients who discontinue study treatment for any reason other than radiographic 
progressive disease per RECIST v1.1, tumor assessments should continue at the same 
frequency as would have been followed if the patient had continued study treatment until 
radiographic disease progression per RECIST v1.1 (or loss of clinical benefit for 
atezolizumab-treated patients who continue treatment after disease progression 
according to RECIST v1.1), withdrawal of consent, enrollment into an extension study, 
or death, whichever occurs first. 
Patients who start a new anti-cancer therapy in the absence of radiographic disease 
progression per RECIST v1.1 should continue tumor assessments according to the 
protocol schedule of response assessments until radiographic disease progression per 
RECIST v1.1 (or loss of clinical benefit for atezolizumab-treated patients who continue 
treatment after disease progression according to RECIST v1.1), withdrawal of consent, 
enrollment into an extension study, or death, whichever occurs first. 
Ongoing or new serious adverse events, adverse events of special interest or adverse 
events thought to be related to study treatment will be followed until the event has 
resolved to the baseline grade, the event is assessed by the investigator as stable, new 
anti-tumor treatment is initiated, the patient is lost to follow-up, the patient withdraws 
consent, or it has been determined that the study treatment or participation is not the 
cause of the adverse events. 
4.5.13.5    Assessments at Unscheduled Visits 
Assessments for unscheduled visits related to a patient’s underlying NSCLC, study 
treatment, or adverse events should be performed as clinically indicated and entered 
into Unscheduled Visit eCRFs. 
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 


 
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•   Investigator or Sponsor determines it is in the best interest of the patient 
•   Patient non-compliance 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2    
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
•   Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status. 
•   Intolerable toxicity related to atezolizumab, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event 
•   Intolerable toxicity related to study treatment 
•   Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment 
•   Use of another non-protocol anti-cancer therapy (see Section 4.4.3) 
•   Pregnancy 
•   Radiographic disease progression per RECIST v1.1 
Exception for atezolizumab treatment:  patients randomized to atezolizumab 
treatment will be permitted to continue study treatment after RECIST v1.1 criteria for 
progressive disease are met if they meet all of the following criteria (see Figure 2 for 
schematic representation): 
Evidence of clinical benefit as assessed by the investigator 
Absence of symptoms and signs (including worsening of laboratory values 
[e.g., new or worsening hypercalcemia]) indicating unequivocal progression of 
disease 
No decline in ECOG performance status that can be attributed to disease 
progression  
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be readily managed and stabilized by protocol-allowed 
medical interventions prior to repeat dosing 
Patients must provide written consent to acknowledge deferring other treatment 
options in favor of continuing atezolizumab treatment at the time of initial 
progression 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 


 
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Figure 2  Criteria for Continuing Atezolizumab in the Presence of 
Increased Radiographic Tumor Size (Atezolizumab Arm) 
  
ECOG PS =
 Eastern Cooperative Oncology Group performance status; RECIST = Response 
Evaluation Criteria in Solid Tumors. 
 
4.6.3    
Study and Site Discontinuation 
The study is currently closed to enrollment due to a low number of patients.   
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 


 
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•   Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
•   No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
5.    
ASSESSMENT OF SAFETY  
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial carcinoma.  The following information is based on results from 
nonclinical and clinical studies for atezolizumab and published data on similar molecules. 
5.1    
SAFETY PLAN 
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Sections 4.1.1 and 4.1.2) and 
close monitoring (as indicated below and in Section 4.5).  See Section 5.3 for complete 
details regarding safety reporting for this study. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment/medicine to manage 
potentially serious reactions.  All serious adverse events and adverse events of special 
interest will be recorded during the trial and for up to 90 days after the last dose of study 
treatment or initiation of new anti-cancer therapy, whichever occurs first. All other 
adverse events will be recorded during the trial and for up to 30 days after the last dose 
of study treatment or until the initiation of another anti-cancer therapy, whichever occurs 
first. 
Investigators are instructed to report all serious adverse events and adverse events of 
special interest considered related to study treatment regardless of time after study.  The 
potential safety issues anticipated in this trial, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections. 
5.1.1    
Risks Associated with Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy 
may increase the risk of immune-mediated adverse events, specifically the induction or 
enhancement of autoimmune conditions.  Adverse events with potentially 
immune-mediated causes, including rash, hypothyroidism, hepatitis/transaminitis, colitis, 
pneumonitis, myositis, and myasthenia gravis, have been observed in the Phase Ia 
Study PCD4989g.  For further details regarding clinical safety, including a detailed 
description of anticipated safety risks for atezolizumab, see the atezolizumab 
Investigator’s Brochure. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications (Di Giacomo et al. 2010).  
Suggested workup and management guidelines for suspected immune-mediated 


 
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adverse events are provided in Section 5.1.7 and in Section 6 (Guidance for the 
Investigator) of the Atezolizumab Investigator’s Brochure. 
5.1.2    
Risks Associated with Gemcitabine 
Infusion times of gemcitabine longer than 60 minutes and more frequent than weekly 
dosing have been shown to increase toxicity. 
Pulmonary toxicity has been reported with the use of gemcitabine.  In cases of severe 
lung toxicity, gemcitabine therapy should be discontinued immediately and appropriate 
supportive care measures instituted. 
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia has been 
reported with gemcitabine as a single agent or in combination with other cytotoxic drugs.  
Monitoring for myelosuppression should occur prior to each cycle. 
Hemolytic-uremic syndrome and/or renal failure have been reported following one or 
more doses of gemcitabine.  Renal failure leading to death or requiring dialysis, despite 
discontinuation of therapy, has been rarely reported.  The majority of the cases of renal 
failure leading to death were due to hemolytic-uremic syndrome. 
Serious hepatotoxicity, including liver failure and death, has been reported very rarely in 
patients receiving gemcitabine alone or in combination with other potentially hepatotoxic 
drugs. 
Use caution in patients with pre-existing renal impairment or hepatic insufficiency. 
For more details regarding the safety profile of gemcitabine, see the gemcitabine 
prescribing information. 
5.1.3    
Risks Associated with Platinum-Based Chemotherapy 
5.1.3.1    Risks Associated with Cisplatin Chemotherapy 
Cisplatin is known to cause myelosuppression, ototoxicity, and nephrotoxicity.  
Cisplatin-based chemotherapy is considered to be moderately emetogenic.  Patients will 
be monitored for cisplatin-related adverse events. 
For more details regarding the safety profile of cisplatin, see the carboplatin prescribing 
information. 
5.1.3.2    Risks Associated with Carboplatin Chemotherapy 
Carboplatin is known to cause bone marrow suppression including myelosuppression, 
anemia, and thrombocytopenia.  Carboplatin-based chemotherapy is considered to be 
moderately emetogenic.  Patients will be monitored for carboplatin-related adverse 
events. 


 
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For more details regarding the safety profile of carboplatin, see the carboplatin 
prescribing information. 
5.1.3.3    Risks Associated with Erlotinib 
Switch maintenance treatment with erlotinib is no longer permitted.  However, patients 
who had already started switch maintenance treatment with erlotinib under previous 
protocol versions may be allowed to continue treatment with erlotinib upon discussion 
of the risks, potential benefits, and alternative treatment options with the investigator.  
The most commonly reported adverse drug reactions with erlotinib were rash and 
diarrhea.  Most were Grade 1 or 2 in severity and were manageable without intervention.  
In general, rash manifests as a mild or moderate erythematous and papulopustular rash 
and may occur or worsen in sun-exposed areas.  For patients who are exposed to the 
sun, protective clothing and/or the use of sunscreen (e.g., mineral-containing) may be 
advisable. 
For more details regarding the safety profile of erlotinib, refer to the erlotinib prescribing 
information. 
5.1.4    
General Plan to Manage Safety Concerns 
5.1.4.1    Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and 
non−serious adverse events defined and graded according to NCI CTCAE v4.0.  
Patients will be assessed for safety (including laboratory values) according to 
the schedule in Appendix 1.  Laboratory values must be reviewed prior to each infusion. 
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts 
(see Appendix 1 for the list and timing of study assessments). 
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection. 
All serious adverse events and protocol-defined events of special interest 
(see Section 5.2.2 and Section 5.2.3, respectively) will be reported in an expedited 
fashion (see Section 5.4.2).  In addition, the Medical Monitor will review and evaluate 
observed adverse events on a regular basis. 
Patients will be followed for serious adverse events and adverse events of special 
interest for 90 days following their last dose of study drug or initiation of new anti-cancer 
therapy, whichever occurs first.  For all other adverse events, patients will be followed for 
30 days after their last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first.  Investigators are instructed to report all serious adverse events 
and adverse events of special interest considered related to study treatment regardless 
of time after study. 


 
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Patients who have an ongoing study treatment−related adverse event upon study 
completion or at discontinuation from the study will be followed until the event has 
resolved to baseline grade, the event is assessed by the investigator as stable, new 
anti-cancer treatment is initiated, the patient is lost to follow-up, the patient withdraws 
consent, or it has been determined that study treatment or participation is not the cause 
of the adverse event. 
5.1.5   
Dose Modification 
5.1.5.1   General Notes Regarding Dose Modification 
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF.  
The severity of adverse events will be graded according to the NCI CTCAE v4.0 
grading system. 
•  For any concomitant conditions already apparent at baseline, the dose 
modifications will apply according to the corresponding shift in toxicity grade, if 
the investigator considers it is appropriate.  For example, if a patient has Grade 1 
asthenia at baseline that increases to Grade 2 during study treatment, this will be 
considered a shift of one grade and treated as Grade 1 toxicity for dose-modification 
purposes. 
•  When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed. 
•  If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one component of chemotherapy, the dose of the other chemotherapy component 
does not require modification and the other chemotherapy component(s) may be 
administered if there is no contraindication.   
•  The investigator may use discretion in modifying or accelerating the 
dose modification guidelines described below depending on the severity of toxicity 
and an assessment of the risk versus benefit for the patient, with the goal of 
maximizing patient compliance and access to supportive care.  
 
5.1.6    
Atezolizumab Dose Modifications, Treatment Delays, or 
Treatment Discontinuation 
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 105 days beyond the last dose if they experience an 
adverse event that requires a dose to be withheld.  If atezolizumab is withheld because 
of adverse events for >
 105 days beyond the last dose, then the patient will be 
discontinued from atezolizumab treatment and will be followed for safety and efficacy as 
specified in Section 5.5. 
If a patient must be tapered off steroids used to treat adverse events, atezolizumab may 
be withheld for additional time >
 105 days from the last dose until steroids are 
discontinued or reduced to prednisone dose (or dose equivalent) ≤
 10 mg/day.  The 


 
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acceptable length of interruption will depend on agreement between the investigator and 
the Medical Monitor. 
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed with Medical Monitor approval.  The acceptable length of interruption will depend 
on agreement between the investigator and the Medical Monitor. 
5.1.7    
Management of Atezolizumab-Specific Adverse Events 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to determine a possible immunogenic etiology. 
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect and, in severe cases, immune-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The primary approach to Grade 1 and 2 immune-mediated adverse events is supportive 
and symptomatic care with continued treatment with atezolizumab; for higher-grade 
immune-mediated adverse events, atezolizumab should be withheld and oral/parenteral 
steroids administered.  Recurrent Grade 2 immune-mediated adverse events may also 
mandate withholding atezolizumab or the use of steroids.  Consideration for benefit-risk 
balance should be made by the investigator, with consideration of the totality of 
information as it pertains to the nature of the toxicity and the degree of clinical benefit 
a given patient may be experiencing prior to further administration of     
atezolizumab. Atezolizumab should be permanently discontinued in patients with  
life-threatening immune-mediated adverse events. 
Management of systemic immune activation is presented below.  See the atezolizumab 
Investigator’s Brochure for details on management of gastrointestinal, dermatologic, 
endocrine, pulmonary toxicity, hepatotoxicity, infusion-related reactions, potential 
pancreatic or eye toxicity, and other immune-mediated adverse events.  See Appendix 7 
for precautions for anaphylaxis. 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the 
following: 
•  CBC with peripheral smear 


 
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•  PT, PTT, fibrinogen, and D-dimer 
•  Ferritin 
•  Triglycerides 
•  AST, ALT, and total bilirubin 
•  LDH 
•  Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If Systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations. 
5.1.8    
Gemcitabine
 +
 Cisplatin or Carboplatin Dose Modification and 
Management of Specific Adverse Events 
Dose modification guidelines for gemcitabine +
 cisplatin or carboplatin are described in 
Table 12, Table 13, and Table 14.  Additionally, manufacturer’s instructions as well as 
local hospital or clinical practice should also be followed. 
5.1.8.1    Hematologic Toxicity 
Dose adjustments for hematologic toxicity may be required for gemcitabine and for 
cisplatin or carboplatin.  Gemcitabine dosage adjustments for hematologic toxicity are 
based on the granulocyte and platelet counts taken on Days 1 and 8 of therapy.  Patient 
receiving gemcitabine should be monitored prior to each dose with a CBC, including 
differential and platelet counts.  If bone marrow suppression is detected, therapy should 
be modified or suspended according to the guidelines in Table 12.  For cisplatin or 
carboplatin dosage adjustment, see also Section 5.1.9 and the manufacturer’s 
prescribing information. 
Table 12  Dose Modification Guidelines for Hematological Toxicities on 
Day 1 of Gemcitabine + Cisplatin or Carboplatin 
Absolute Granulocyte Count 
(×
 106/L) 
 
Platelet Count 
(×
 106/L) 
Gemcitabine/Cisplatin or 
Carboplatin 
% of full dose 
≥
 1500
 and
 
≥
 100,000
 100%
 
less than 1,500    
or    Less than100,000 
Withhold 
 


 
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Table 13  Dose Modification Guidelines for Hematological Toxicities on 
Day 8 of Gemcitabine 
Absolute Granulocyte Count 
(×
 106/L) 
 Platelet  
 
Count  
 
(×
 106/L) 
Gemcitabine 
% of full dose 
≥
 1000
 and
 
≥
 100,000
 100%
 
500-999
 or
 
50,000−99,999
 75%
 
<
 500
 or
 
<
 50,000
 Withhold
 
 
5.1.8.2    Dose Modifications Guidelines of Non-Hematological Toxicity 
In general, for severe (Grade 3 or 4) non-hematological toxicity, and nausea/vomiting, 
therapy with gemcitabine should be held or dose reduced by 50% depending on the 
judgment of the investigator. 
Permanently discontinue gemcitabine for any of the following: 
•   Unexplained dyspnea or other evidence of severe pulmonary toxicity 
•   Severe hepatic toxicity 
• Hemolytic-uremic  
syndrome  
• Capillary-leak  
syndrome  
•   Posterior reversible encephalopathy syndrome 
Table 14 summarizes dose modifications guidelines for non-hematologic toxicities based 
on grade and severity. 


 
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Table 14  Gemcitabine Dose Modification Guidelines for 
Non-Hematological Toxicities 
 
Grade 2 
Grade 3 
Grade 4 
First appearance   Interrupt treatment until 
resolved to Grade 0−1 
then continue at same 
dose with prophylaxis 
where possible  
Interrupt treatment until 
resolved to Grade 0−1, 
then continue at 75% of 
original dose with 
prophylaxis where 
possible 
Discontinue treatment 
unless investigator 
considers it to be in the 
best interest of the patient 
to continue at 50% of 
original dose, once 
toxicity has resolved to 
Grade 0−1 (after approval 
by the Sponsor) 
Second 
appearance of 
same toxicity  
Interrupt treatment until 
resolved to Grade 0−1, 
then continue at 75% of 
original dose 
Interrupt treatment until 
resolved to Grade 0−1, 
then continue at 50% of 
original dose  
 
Third appearance 
of same toxicity  
Interrupt treatment until 
resolved to Grade 0−1, 
then continue at 50% of 
original dose 
Discontinue treatment 
permanently  
 
Fourth 
appearance of 
same toxicity 
Discontinue treatment 
permanently  
 
 
 
5.1.9    
Platinum Chemotherapy Dose Modification and Management of 
Specific Adverse Events 
5.1.9.1    Cisplatin 
Treatment with cisplatin should be discontinued if a patient experiences any hematologic 
or non-hematologic Grade 3 or 4 toxicity after two dose reductions (except alopecia, 
which does not warrant treatment discontinuation) or immediately if a Grade 3 or 4 
neurotoxicity is observed. 
Hematologic Toxicity 
Treatment can be delayed for up to 3 weeks until the Day 1 ANC is ≥
 1500/mm3 and the 
platelet count is >
 100,000
 mm3.  However, if the counts have not recovered in 3 weeks, 
the patient’s chemotherapy will be dose reduced, held until adequate neutrophil recovery, 
or discontinued, according to physician judgment and local standard practice. 
The cisplatin doses may be either administered at full dose (in the absence of toxicity) or 
at a reduced dose, as described in Table 15. 


 
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Table 15  Cisplatin Dose Modification for Hematologic Toxicities 
Toxicity a Cisplatin
 Dose
ANC <
 500/mm3 and platelets ≥
 50,000/mm3 
75% of previous dose 
Platelets <
 50,000/mm3, regardless of ANC 
75% of previous dose 
Platelets <
 50,000/mm3 with Grade ≥
 2 bleeding, regardless of ANC   50% of previous dose 
ANC <
 1000/mm3 plus fever of ≥
 38.5°C 
75% of previous dose 
a Nadir prior cycle. 
 
Non-Hematologic Toxicity 
If a patient develops a Grade ≥
 3 non-hematologic toxicity (excluding alopecia, which 
does not warrant treatment discontinuation, and neurotoxicity), cisplatin should be 
withheld until resolution to less than or equal to the patient’s pre-treatment value.  
Treatment should be resumed according to the guidelines in Table 16. 
Table 16  Cisplatin Dose Modification for Non-Hematologic Toxicities 
(Excluding Neurotoxicity) 
Toxicity
 Cisplatin
 
Dose
Any Grade 3 or 4 toxicity (except alopecia) 
75% of previous dose 
Any diarrhea requiring hospitalization (irrespective of 
grade) or Grade 3 or 4 diarrhea that occurs on adequate 
anti-diarrhea medication 
75% of previous dose 
 
Nephrotoxicity 
Impairment of renal function has been reported with cisplatin as single agent or in 
combination with other cytotoxic agents.  CrCl must be ≥
 60 mL/min prior to the start of 
any cycle of cisplatin.  If there is a drop in CrCl between cycles, but the CrCl is still 
≥
 60 mL/min at the time of the next cycle, the treating physician should use his/her 
clinical judgment regarding continuing cisplatin, dose reduction, or delaying the cycle.  If 
a patient’s CrCl value has not returned to ≥
 60 mL/min within 42 days following last study 
drug administration, the patient must be discontinued from study treatment. 
Ototoxicity 
Ototoxicity has been observed with cisplatin as single agent or in combination with other 
cytotoxic agents.  If the patient develops ototoxicity, subsequent doses of cisplatin  
should not be given until an audiometric analysis indicates that auditory acuity is within  
normal limits (http://www.drugs.com/pro/platinol.html). 


 
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Neurotoxicity 
In the event of neurotoxicity, the recommended dose adjustment for cisplatin is 
documented in Table 17.  Patients should discontinue therapy if Grade 3 or 4 
neurotoxicity is observed. 
Table 17  Cisplatin Dose Modification for Associated Neurotoxicity 
Toxicity
 Cisplatin
 
Dose
 
Grade 0–1 neurotoxicity    100% of previous dose 
Grade 2 neurotoxicity    
50% of previous dose 
Grade 3 or 4 neurotoxicity   Permanent discontinuation 
 
5.1.9.2    Carboplatin 
Hematologic Toxicity 
At the start of each cycle, the ANC must be ≥
 1500/mm3 and the platelet count must be 
≥
 100,000/mm3.  Treatment should be delayed for up to 42 days to allow sufficient time 
for recovery.  Growth factors may be used in accordance with American Society of 
Clinical Oncology (ASCO) and NCCN guidelines (Smith et al. 2006; NCCN 2012).  Upon 
recovery, dose adjustments at the start of a subsequent cycle will be made on the basis 
of the lowest platelet and neutrophil values from the previous cycle (see Table 18). 
Table 18  Carboplatin Dose Modification for Hematologic Toxicities 
Toxicity a Carboplatin
 Dose
ANC <
 500/mm3 and platelets ≥
 50,000/mm3 
75% of previous dose 
Platelets <
 50,000/mm3, regardless of ANC 
75% of previous dose 
Platelets <
 50,000/mm3 with Grade ≥
 2 bleeding, regardless of ANC   50% of previous dose 
ANC <
 1000/mm3 plus fever of ≥
 38.5°C 
75% of previous dose 
a Nadir prior cycle. 
 
All dose reductions for the first episode of neutropenic fever or thrombocytopenia 
(platelet count <
 25,000 or <
 50,000 with bleeding or that requires transfusion) are 
permanent.  If a second episode of neutropenic fever or thrombocytopenia requiring 
dose reduction occurs, the dose of carboplatin or cisplatin will be reduced according to 
physician judgment and local standard practice.  Colony-stimulating factors, such as 
granulocyte colony-stimulating factor, may be used instead of dose reduction for 
neutropenic fever or Grade 4 neutropenia, according to the local standard practice and 
ASCO guideline.  Patients who require a third dose reduction will immediately 
discontinue chemotherapy. 
In the event that dose adjustments are needed for both ANC and platelets, patients are 
to receive the lower dose. 


 
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Treatment should be delayed for up to 3 weeks until the Day 1 ANC is ≥
 1500/mm3 and 
the platelet count is ≥
 100,000/mm3.  However, if the counts have not recovered in 
3 weeks, the patient’s chemotherapy will be dose-reduced, held until adequate 
neutrophil recovery, or discontinued, according to physician judgment and local standard 
practice.  If chemotherapy is held longer than 42 days, all study treatment should be 
discontinued. 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed.  Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity. 
If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower 
limits for treatment as outlined.  The treatment schedule will then proceed in the usual 
sequence. 
No dose reductions will be made for anemia.  Patients should be supported per the 
treating physician’s institution’s guidelines. 
Non-Hematologic Toxicity 
For Grade 3 or 4 non-hematologic toxicities, treatment should be delayed until resolution 
to less than or equal to the patient’s baseline value.  Dose reductions at the start of the 
subsequent cycle will be made on the basis of non-hematologic toxicities from the dose 
administered in the preceding cycle.  Table 19 provides the relevant dose adjustments 
for non-hematologic toxicities. 


 
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Table 19  Carboplatin Dose Modification on the Basis of Non-Hematologic 
Toxicities in the Preceding Cycle 
Toxicity 
Adjusted Carboplatin 
Dose as % of 
Previous Dose a 
Diarrhea 
Grade 3 or 4 b 100%  
 
Oral mucositis 
Grade 3 or 4 
75% 
Nausea/vomiting 
Grade 3 or 4 
75% 
Neurotoxicity (motor or sensory)   Grade 2  100%
 
 
Grade 3 or 4 
75% 
Transaminase elevation    
Grade 3 
75% 
 Grade
 4
 
Discontinue
 
Other 
Grade 3 or 4 
75% 
AUC =
 area under the concentration curve. 
a If deemed appropriate by the treating physician, adjust carboplatin dose 
to the specified percentage of the previous AUC. 
b Or any grade of diarrhea requiring hospitalization. 
 
Nausea and/or vomiting should be controlled with adequate anti-emetics.  If 
Grade 3 or 4 nausea/vomiting occurs in spite of anti-emetics, the dose should be 
reduced by 25% for the next cycle.  If tolerated, the dose should be increased back to 
100% as soon as possible. 
If, on Day 1 of any treatment cycle, the patient has oral mucositis, the treatment should 
be withheld until the oral mucositis is cleared.  If the oral mucositis has not cleared in 
3 weeks, the patient’s chemotherapy will be discontinued.  If acute Grade 3 oral 
mucositis occurs at any time, the dose should be given at a 75% dose when the oral 
mucositis is completely cleared.  This is a permanent dose reduction. 
Other Toxicities 
For any Grade 3 or 4 toxicity not mentioned above, carboplatin should be withheld until 
the patient recovers completely or to Grade 1 toxicity.  The treatment should then be 
resumed at 50% dose (permanent dose reduction).  If recovery to Grade 1 toxicity does 
not occur within 3 weeks, the patient’s chemotherapy will be discontinued.  For Grade 1 
and 2 toxicities, no dose reduction should be made. 
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. 


 
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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1    
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
•   Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
•   Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
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) 
 


 
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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
criteria; see Section 5.3.3; the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3    
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported immediately by the 
investigator to the Sponsor (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include: 
•   The following confirmed treatment-emergent autoimmune conditions: 
Pneumonitis 
Hypoxia or dyspnea Grade ≥
 3 
Colitis 
Endocrinopathies: diabetes mellitus, pancreatitis, or adrenal insufficiency 
Vasculitis 
Hepatitis 
Transaminitis:  Grade ≥
 2 (AST or ALT >
 3
 ×
 ULN and bilirubin >
 2
 ×
 ULN) OR 
AST/ALT >
 10
 ×
 ULN 
Systemic lupus erythematosus 
Guillain-Barré syndrome 
Skin reactions:  vitiligo, pemphigoid 
•   Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response system, or infusion-reaction syndromes 
•   Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.7) 
•   Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 


 
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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 to 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 serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  
All other adverse events, regardless of relationship to study drug, will be reported until 
30 days after the last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first. Investigators are instructed to report all serious adverse events 
and adverse events of special interest considered related to study treatment regardless 
of time after study (see 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 20 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 20  Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE 
Grade
 Severity
 
1    Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2    Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3    Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of 
daily living b, c 
4    Life-threatening consequences or urgent intervention indicated d 
5    Death related to adverse event d 
NCI CTCAE =
 National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of 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 or 
not 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: 
•   Temporal relationship of event onset to the initiation of study drug 
•   Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
•   Known association of the event with the study drug or with similar treatments 
•   Known association of the event with the disease under study 
•   Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
•   Presence of non−treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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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; colloquialisms and abbreviations should be avoided. 
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. 
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. 


 
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•   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 intensity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated by 
changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5    Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
•   Is accompanied by clinical symptoms 
•   Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
•   Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
•   Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5
 ×
 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 


 
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descriptor indicating if 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6    Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
•   Is accompanied by clinical symptoms 
•   Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
•   Results in a medical intervention or a change in concomitant therapy 
•   Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7    Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (>
 3
 ×
 baseline value) in combination with either 
an elevated total bilirubin (>
 2
 ×
 ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
•   Treatment-emergent ALT or AST >
 3
 ×
 baseline value in combination with total 
bilirubin >
 2
 ×
 ULN (of which ≥ 35% is direct bilirubin) 


 
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•   Treatment-emergent ALT or AST >
 3
 ×
 baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8    Deaths 
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1) that are attributed by the investigator solely to progression of NSCLC 
should be recorded only on the Study Completion/Early Discontinuation eCRF.  All other 
on-study deaths, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).   
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  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. 
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" or “worsened headache”). 
5.3.5.10    Worsening of Non−Small Cell Lung Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 criteria.  In rare cases, the determination of 


 
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clinical progression will be on the basis of 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 caused by 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. 
The following hospitalization scenarios are not considered to be adverse events: 
•   Hospitalization for respite care 
•   Planned hospitalization required by the protocol (e.g., for study drug administration 
or to perform an efficacy measurement for the study) 
•   Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
•   Hospitalization caused solely by progression of the underlying cancer 
5.3.5.12    Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.   
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF. 
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded in the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.13    Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data, 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. 


 
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5.4    
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
•   Serious adverse events (see Section 5.2.2 for further details) 
•   Adverse events of special interest (see Section 5.2.3 for further details) 
•   Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
•   New signs or symptoms or a change in the diagnosis 
•   Significant new diagnostic test results 
•   Change in causality on the basis of new information 
•   Change in the event’s outcome, including recovery 
•   Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1    
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites 
Medical Monitor: 
, M.D., Ph.D. 
E-Mail: 
 
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 
Monitor, 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 contact information will be distributed to all investigators. 


 
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5.4.2    
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1    Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained, but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to Roche or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and e-mailing the form with use of the fax number or e-mail address 
provided to investigators. 
5.4.2.2    Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study treatment or initiation of 
new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of 
relationship to study treatment, will be reported until 30 days after the last dose of study 
drug or initiation of new anti-cancer therapy, whichever occurs first.  Investigators are 
instructed to report all serious adverse events and adverse events of special interest 
considered related to study treatment regardless of time after study.  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 Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and e-mailing the form with use of 
the fax number or e-mail address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3    
Reporting Requirements for Pregnancies 
5.4.3.1    Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of atezolizumab or within 6 months after the last dose of cisplatin.  A Pregnancy 
Report eCRF should be completed by the investigator immediately (i.e., no more than 
24 hours after learning of the pregnancy) and submitted via the EDC system.  A 
pregnancy report will automatically be generated and sent to Roche Safety Risk 
Management.  Pregnancies 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 


 
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continue until the 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 the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and e-mailing the form with use of the fax number or 
e-mail address provided to investigators.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
5.4.3.2    Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
6 months after the last dose of gemcitabine, cisplatin, or carboplatin.  A Pregnancy 
Report eCRF should be completed by the investigator immediately (i.e., no more than 24 
hours after learning of the pregnancy) and submitted via the EDC system.  Attempts 
should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  Once the authorization has been 
signed, the investigator will update the Pregnancy Report eCRF with additional 
information on the course and outcome of the pregnancy.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus to support an informed 
decision in cooperation with the treating physician and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3    Abortions 
Any 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). 
5.4.3.4    Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 


 
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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 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.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
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    
POST-STUDY ADVERSE EVENTS 
Investigators are instructed to report all serious adverse events or adverse events of 
special interest that occur after the end of the adverse event reporting period (defined as 
90 days after the last dose of study drug for serious adverse events and adverse events 
of special interest, and 30 days after the last dose of study drug for all other adverse 
events or initiation of new anti-cancer therapy, whichever occurs first), if the event is 
believed to be related to prior study drug treatment. 
The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and e-mailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form with use of the fax number or e-mail address provided 
to investigators. 
5.7    
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 


 
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communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the atezolizumab Investigator
's Brochure 
as a reference. 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator
's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6.    
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The study is currently closed to enrollment due to a low number of patients; therefore, 
formal analysis of efficacy endpoints will not be performed. 
The safety population will include all randomized patients who received any amount of 
study treatment.  Patients who are randomized into the study but did not receive any 
amount of study drug will not be included in the safety population.   
6.1    
DETERMINATION OF SAMPLE SIZE 
The study is currently closed to enrollment due to a low number of patients; therefore, 
sample size estimation is no longer applicable. 
6.2    
SUMMARIES OF CONDUCT OF STUDY 
Subject disposition will be provided in listing format due to the small sample size.  
Summaries will not be provided. 
6.3    
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, baseline 
disease characteristics, ECOG performance status, and number of prior cancer 
treatments, will be provided in listing format.  Baseline measurements are the last 
available data obtained prior to patients receiving the first dose of study drug.   
6.4    
EFFICACY ANALYSES 
The study is currently closed to enrollment due to low number of patients; therefore, 
formal analysis of efficacy endpoints will not be performed.  
6.5    
SAFETY ANALYSES 
Listings of safety data will be provided for the safety population and will include study 
drug exposure, adverse events, and deaths. 


 
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Verbatim description of adverse events will be mapped to thesaurus terms and graded 
according to NCI CTCAE v4.0.   
6.6    
PHARMACOKINETIC ANALYSES 
The study is currently closed to enrollment due to a low number of patients; therefore, 
samples will no longer be collected, and formal analysis of PK and pharmacodynamics 
samples will not be performed. 
6.7    
EXPLORATORY ANALYSES 
The study is currently closed to enrollment due to low number of patients; therefore, 
formal analysis of exploratory endpoints will not be performed. 
6.8    
SENSITIVITY ANALYSES ON THE PRIMARY ENDPOINT 
The study is currently closed to enrollment due to low number of patients; therefore, a 
formal sensitivity analysis of the primary endpoint will not be performed. 
6.9    
INTERIM ANALYSIS 
6.9.1    
Interim Safety Analyses 
The study is currently closed to enrollment due to a low number of patients; therefore, 
interim safety data will not be evaluated by an iDMC. 
7.    
DATA COLLECTION AND MANAGEMENT 
7.1    
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC with use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2    
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 


 
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All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3    
ELECTRONIC PATIENT REPORTED OUTCOME DATA 
Patient-reported data will be collected electronically with use of electronic devices 
provided by an electronic PRO (ePRO) vendor.  The electronic device is designed for 
entry of data in a way that is attributable, secure, and accurate, in compliance with the 
FDA regulations for electronic records (21 Code of Federal Regulations, Part 11).  The 
data will be transmitted to a centralized database at the ePRO vendor.  The data from 
the ePRO devices are available for view access only via secure access to a Web portal 
provided by the ePRO vendor.  Only identified and trained users may view the data, and 
their actions become part of the audit trail.  The Sponsor will have view access only.  
Regular data transfers will occur from the centralized database at the vendor to the 
database at the Sponsor. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The Sponsor will receive all data entered by patients on 
the e-diary and tablet device and all study documentation. 
Details regarding patient reported data and the electronic device is available in the Study 
Reference Manual.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures. 
7.4    
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 


 
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entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.5    
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. 
7.6    
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at least 
15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8.    
ETHICAL CONSIDERATIONS 
8.1    
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
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and applicable local, state, and federal laws.  Studies conducted in the European Union 
(E.U.) or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.2    
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form 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. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining samples for optional exploratory research.  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 and for any reason.  A 
separate, specific signature will be required to document a patient
's agreement to allow 
the collection of optional samples and any remaining specimens to be used for 
exploratory research.  Patients who decline to participate will not provide a separate 
signature. 
The Informed Consent Form will also contain the following additional signature pages: 
•   A signature page for patients receiving atezolizumab who wish, if approved by the 
treating physician, to continue treatment beyond initial radiographic disease 
progression and meet criteria specified in Section 4.6.2.  This separate consent is to 
be signed after initial radiographic disease progression has occurred and patients 
have discussed other available treatment options and the potential risks of 
continuing treatment. 
•  A signature page for patients to undergo an optional tumor tissue biopsy at the 
time of radiographic disease progression, if clinically feasible.    
 
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. 


 
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Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3    
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC and 
archived in the site’s study file. 
8.4    
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 


 
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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other 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 (i.e., last patient last visit). 
9.    
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1    
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2    
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
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. 


 
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9.4    
ADMINISTRATIVE STRUCTURE 
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.   
Randomization will occur through an IxRS.  Central facilities will be used for certain 
study assessments throughout the study (e.g., specified laboratory tests, PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
9.5    
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
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. 


 
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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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Shaw AT, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl 
J Med; 2014;370:2537−9. 
Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed 
or docetaxel in patients with advanced ALK-positive non-small cell lung cancer 
(NSCLC). European Society of Medical Oncology Meeting 2012:abstract LBA1 PR. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 
2012;62:10−29. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice 
guideline. J Clin Oncol 2006;24:3187−205. 
Spiro SG, Rudd RM, Souhami RL, et al. Chemotherapy versus supportive care in 
advanced non-small cell lung cancer: improved survival without detriment to quality 
of life. Thorax 2004;59:828–36. 
Stinchcombe TE, Socinski MA. Considerations for second-line therapy of non-small cell 
lung cancer. Oncologist 2008;13:28−36. 


 
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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. 
Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung 
cancer/american thoracic society/european respiratory society international 
multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 
2011;6:244–85. 
Treat J, Edelman MJ, Belani CP, et al. A retrospective analysis of outcomes across 
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small cell lung cancer. Lung Cancer 2010;70:340–6. 
XALKORI® (crizotinib) U.S. Package Insert, Pfizer. 
Yang J, Riella LV, Chock S. The novel costimulatory programmed death ligand 1/B7.1 
pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 
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Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and 
epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet 
Oncol 2012;13:539−48. 


 
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Appendix 1   
Schedule of Assessments 
All Treatment 
Cycles a 
Treatment 
Discontinuation 
Visit 
Procedure 
Every 21 days 
(± 3 Days) 
b 
≤
 30 Days after 
Last Dose 
Vital signs c 
x
 c 
x
 c 
Weight 
x 
x 
Limited physical examination d 
x 
x 
ECOG performance status 
x 
x 
12-lead ECG 
x e 
x e 
Hematology f 
x 
x 
Serum chemistry g 
x 
x 
Coagulation test (INR or aPTT)  
 
x 
Pregnancy test  (women of childbearing potential 
ONLY) 
x h 
x
 h 
TSH, free T3, free T4 i 
x j 
x
 j 
Urinalysis k 
x
 k 
x
 k 
Study treatment administration  
x l 
 
Tumor response assessment m 
x
 n 
x 
Informed consent to continue treatment beyond 
radiographic progression (atezolizumab patients 
only) 
At time of 
radiographic 
progression  
 
Optional tumor biopsy at radiographic progression 
(separate consent required)
o 
At time of radiographic progression 
Adverse events 
x 
x p 
Concomitant medications 
x 
x 
Optional RCR Blood (for DNA extraction) 
RCR consent required 
At any time 
during the study 
 
CT =
 computerized tomography; ECOG
 =
 Eastern Cooperative Oncology Group; 
FFPE =
 formalin fixed paraffin embedded; ICF
 =
 Informed Consent Form; IV
 =
 intravenous; 
MRI =
 magnetic resonance imaging; NSCLC =
 non−small cell lung cancer; 
TSH =
 thyroid-stimulating hormone. 
a Assessments should be performed before study drug infusion unless otherwise noted. 
b  Except for Cycle 1, which must be performed within 5 days after the patient is randomized.  
In addition, ECOG performance status, limited physical examination, and local laboratory 
tests may be performed ≤ 96 hours before Day 1 of each cycle as specified in Section 
4.5.13.2. 
c Vital signs include pulse rate, respiratory rate, blood pressure, and temperature.  For both 
study treatment arms, the patient’s vital signs should be recorded within 60 minutes before 
infusion, and 30 (±
 10) minutes after the infusion if clinically indicated.  For the second 
atezolizumab infusion and beyond in both arms, vital signs will be collected within 


 
 
Appendix 1   
Schedule of Assessments (cont.)   
Atezolizumab—F. Hoffmann-La Roche Ltd 
155/Protocol GO29432, Version 5 
60 minutes prior to the infusion and should be collected during the infusion and 
30 (±
 10) minutes after the infusion, if clinically indicated or if symptoms occurred in the prior 
infusion. 
d Symptom-directed physical examinations; see Section 4.5.3 for details.  
e ECG recordings will be obtained when clinically indicated. 
f  Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count 
with differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other 
cells), and platelet count.   
g  Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, 
bicarbonate, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, 
LDH, total protein, and albumin.   
h Urine pregnancy tests; if a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
i    Total T3 will be tested only at sites where free T3 is not performed. 
j  Thyroid function testing (TSH, free T3, free T4) every fourth cycle after Cycle 1, Day 1. 
k  Urinalysis by dipstick (specific gravity, pH, glucose, protein, ketones, and blood). Urinalysis 
will be obtained during study treatment when clinically indicated. 
l  If the first infusion is well tolerated, all subsequent infusions may be delivered over 
30 (± 10) minutes until disease progression per RECIST v1.1 or loss of clinical benefit.  For 
gemcitabine + cisplatin/carboplatin, study drug will be administered according to the local 
prescribing information, including premedication with steroids (see Section 4.3.2.2.2). 
m Perform every 6 weeks (±
 7 days; approximately every two cycles) for 48 weeks following 
Cycle 1, Day 1, regardless of treatment delays, and then every 9 weeks (±
 7 days) after 
completion of the Week 48 tumor assessment, regardless of treatment delays, until 
radiographic disease progression, (or loss of clinical benefit for atezolizumab-treated 
patients who continue treatment after disease progression according to RECIST v1.1), 
withdrawal of consent, death, or are eligible to roll over to an extension study, whichever 
occurs first.  CT scans may be repeated at any time if progressive disease is suspected.  
See Section 4.5.5  for details. 
n  CT scans (with oral/IV contrast unless contraindicated) or MRI of the chest and abdomen.  A 
CT scan of the pelvis is required as clinically indicated or as per local standard-of-care at 
subsequent response evaluations.  A CT (with contrast) or MRI scan of the head must be 
done at screening to evaluate CNS metastasis in all patients.  See Section 4.5.5 for details. 
o Optional tumor biopsy at radiographic disease progression, if clinically feasible, preferably 
within 40 days of radiographic progression or prior to start of the next anti-cancer 
therapy, whichever occurs is sooner. 
p   All serious adverse events and adverse events of special interest, regardless of relationship 
to study drug, will be reported until 90 days after the last dose of study drug or initiation of 
new anti-cancer therapy, whichever occurs first.  All other adverse events, regardless of 
relationship to study drug, will be reported until 30 days after the last dose of study drug or 
initiation of new anti-cancer therapy, whichever occurs first.  After this period, the 
investigator should report any serious adverse events or adverse events of special interest 
believed to be related to prior study drug treatment. 
 
 


 
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Appendix 2   
American Joint Committee on Cancer 
Non−Small Cell Lung Cancer Staging, 7th Edition 
 
 


 
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Appendix 2   
American Joint Committee on Cancer 
Non−Small Cell Lung Cancer Staging, 7th Edition (cont.) 
 
 
 
Reference:  Lung. In: Edge S, Byrd DR, Compton CC, et al, editors. AJCC Cancer Staging 
Manual, Seventh Edition. Chicago: Springer, 2010:267–70. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows. 
a.  Measurable Tumor Lesions 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
•   10 mm by 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) 
•   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 Non-Target Lesions” for information on lymph node 
measurement. 
b.  Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <
 10 mm or 
pathological lymph nodes with ≥
 10 to <
 15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
                                            
 
1  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228−47. 
2  For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
 
c.  Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions: 
•   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 non-measurable. 
 
Cystic lesions: 
•   Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
•   Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
•   Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
a.  Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
b.  Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and ≥
 10 mm in diameter as assessed using calipers (e.g., skin nodules). 
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 on the basis of 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 non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or two 
organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will be 
recorded as non-measurable lesions (even if the size is >
 10 mm by CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs but, additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥
 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm
 ×
 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis ≥
 10 mm 
but <
 15 mm) should be considered non-target lesions.  Nodes that have a short axis 
<
 10 mm are considered non-pathological and should not be recorded or followed. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
a.  Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
•   Complete response (CR):  disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <
 10 mm. 
•   Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters 
•   Progressive disease (PD):  at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum during the 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 during the study 
 
b.  Special Notes on the Assessment of Target Lesions 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the  


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
baseline examination), even if the nodes regress to <
 10 mm during the 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 in the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF as follows: 
•   If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
•   If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but 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. 
c.  Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol. 
 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
•   CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level) 
All lymph nodes must be non-pathological in size (<
 10 mm short axis). 
•   Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or (if 
applicable) maintenance of tumor marker level above the normal limits 
•   PD:  unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
 
d.  Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease; that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from “trace” to 
“large” or an increase in lymphangitic disease from localized to widespread or may be 
described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 
point.  Although it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
e.  New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
“new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
a.  Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
Table 1  Timepoint Response:  Patients with Target Lesions (with or 
without Non-Target Lesions) 
Target Lesions    
Non-Target Lesions    
New Lesions    
Overall Response 
CR
 CR
 
No
 
CR
 
CR
 Non-CR/non-PD
 
No
   PR
 
CR
 Not
 
evaluated
 
No
  PR
 
PR 
Non-PD or not all 
evaluated 
No
 PR
 
SD 
Non-PD or not 
all evaluated 
No
 SD
 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any
 Any
 
Yes
 
PD
 
CR =
 complete response; NE
 =
 not evaluable; PD
 =
 progressive disease; PR
 =
 partial response; 
SD =
 stable disease. 
 
Table 2  Timepoint Response:  Patients with Non-Target Lesions Only 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR
 No
 
CR
 
Non-CR/non-PD
 No
 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any
 Yes
 
PD
 
CR =
 complete response; NE
 =
 not evaluable; PD
 =
 progressive disease. 
a  “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
b.  Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen  


 
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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 non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint. 


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
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. 
 
c.  Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (<
 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective  


 
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Appendix 3   
Response Evaluation Criteria in Solid Tumors:  Modified Excerpt 
from Original Publication (cont.) 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1−3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.


 
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Appendix 4   
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 Response Evaluation Criteria in Solid Tumors (RECIST) is derived from 
RECIST, Version 1.1 (v1.1) conventions3 and immune-related response criteria
4 (irRC).  
When not otherwise specified, RECIST v1.1 conventions will apply. 
Modified RECIST and RECIST v1.1:  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 
RECIST =
 Response Evaluation Criteria in Solid Tumors. 
 
A.  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 
performed, as clinically indicated for suspicion of progression.   
                                            
 
3  Eisenhauer et al. Eur J Cancer 2009;45: 228−47; Topalian et al. N Engl J Med 
2012;366:2443−54; and Wolchok et al., Clin Can Res 2009;15:7412−20. 
4  Wolchok et al. Clin Can Res 2009;15:7412−20; Nishino et al J Immunother Can 2014;2:17; 
Nishino et al. Clin Can Res 2013;19:3936−43. 


 
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Appendix 4   
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
A.1     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. 
A.2     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. 
A.3    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. 


 
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Appendix 4   
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
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. 
B.  TUMOR RESPONSE EVALUATION 
B.1 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  


 
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Appendix 4   
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
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, 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. 
New Lesions 
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will also be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST, (e.g., non−lymph node lesions must be ≥
 10mm; see note for new 
lymph node lesions below).  Up to a maximum of five new lesions total (and a maximum 
of two lesions per organ), all with measurements at all timepoints, can be included in the 
tumor response evaluation.  New lesion types that would not qualify as target lesions per 
RECIST cannot be included in the tumor response evaluation. 
New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent timepoint will be measured from that point on and contribute to the sum  


 
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Appendix 4   
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
of longest diameters (SLD), if the maximum number of 5 measurable new lesions being 
followed has not been reached.  
B.2 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 selected at 
baseline and up to five new measurable lesions (with a maximum of two new lesions per 
organ) that have emerged after baseline will contribute to the sum of the diameters at 
tumor assessment.  Hence, each net percentage change in tumor burden per 
assessment with use of modified RECIST accounts for the size and growth kinetics of 
both old and new lesions as they appear. 
Note:  In the case of new lymph nodes, RECIST v1.1 criteria for measurability 
(equivalent to baseline target lesion selection) will be followed.  That is, if at first 
appearance the short axis of a new lymph node lesion ≥
 15 mm, it will be considered a 
measureable new lesion and will be tracked and included in the SLD.  Thereafter, the 
lymph node lesion will be measured at subsequent timepoints and measurements will be 
included in the SLD, even if the short axis diameter decreases to <
 15 mm (or even 
<
 10 mm).  However, if it subsequently decreases to <
 10 mm, and all other lesions are 
no longer detectable (or have also decreased to a short axis diameter of <
 10 mm if 
lymph nodes), then a response assessment of CR may be assigned. 
If at first appearance the short axis of a new lymph node is ≥
 10 mm and <
 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion. It 
will not be included in the SLD unless it subsequently becomes measurable (short axis 
diameter ≥
 15 mm). 
The appearance of new lymph nodes with diameter <
 10 mm should not be considered 
pathological and not considered a new lesion. 


 
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Appendix 4   
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
B.3 RESPONSE CRITERIA 
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. 
Complete Response (CR):  Disappearance of all target and non-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 in 
the study. 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and selected new measurable lesions, taking as reference the smallest sum 
during the study (nadir SLD; this includes the baseline sum if that is the smallest during 
the 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. 
Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is 
considered 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 convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This 
would only 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  


 
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Appendix 4   
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
those gave a sum of 80 mm, the patient will be assigned PD status, regardless of the 
contribution of the missing lesion. 
Table 1  Modified RECIST Timepoint Response Definitions 
% Change in Sum of the Diameters a 
Non-Target Lesion 
Response 
Assessment 
Overall Modified RECIST 
Timepoint Response 
−
 100% from baseline b CR
    
CR
 
−
 100% from baseline b 
Non-CR or not all 
evaluated 
PR 
≤
  −
 30% from baseline 
Any 
PR 
>
  −
 30% to <
 +
 20%
 Any
    SD
 
Not all evaluated 
Any 
NE 
≥
  +
 20%from nadir SLD 
Any 
PD 
CR =
 complete response; NE
 =
 not evaluable; PD
 =
 progressive disease; PR
 =
 partial response; 
RECIST =
 Response Evaluation Criteria in Solid Tumors; SD
 =
 stable disease; SLD
 =
 sum of the 
longest diameter. 
a Percent change in sum of the diameters (including measurable new lesions when present). 
b  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. 
 


 
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Appendix 5   
Anti−PD-L1 Immunohistochemistry 
OVERVIEW 
The Ventana anti−programmed death ligand−1 (PD-L1) (SP142) rabbit monoclonal 
primary antibody immunohistochemistry (IHC) assay will be used to determine PD-L1 
IHC status.  The anti−PD-L1 (SP142) rabbit monoclonal antibody IHC assay is currently 
being developed by Ventana Medical Systems as a companion diagnostic to 
atezolizumab.  For Study GO29432, the anti−PD-L1 (SP142) IHC assay will be used for 
investigational purposes only. 
The Ventana anti−PD-L1 (SP142) rabbit monoclonal primary antibody is intended for 
laboratory use in the semi-quantitative immunohistochemical assessment of the PD-L1 
protein in formalin-fixed, paraffin-embedded non−small cell lung cancer (NSCLC) tissue 
stained on a Ventana BenchMark ULTRA automated slide stainer.  It is indicated as an 
aid in the selection of patients with NSCLC with locally advanced or metastatic disease 
who might benefit from treatment with atezolizumab. 
This assay is for investigational use only.  The performance characteristics of this 
product have not been established. 
DEVICE DESCRIPTION 
The Ventana anti−PD-L1 (SP142) rabbit monoclonal primary antibody is a pre-dilute, 
ready-to-use antibody product optimized for use with the Ventana Medical Systems 
OptiView DAB IHC Detection Kit and the OptiView Amplification Kit on Ventana Medical 
Systems automated BenchMark ULTRA platforms.  One 5-mL dispenser of anti−PD-L1 
(SP142) rabbit monoclonal primary antibody contains approximately 36 μg of rabbit 
monoclonal antibody directed against the PD-L1 protein and contains sufficient reagent 
for 50 tests.  The reagents and the IHC procedure are optimized for use on the 
BenchMark ULTRA automated slide stainer, utilizing Ventana System Software (VSS).  
SCORING SYSTEM 
PD-L1 staining with anti−PD-L1 (SP142) rabbit monoclonal primary antibody in NSCLC 
can be observed in both tumor cells and tumor-infiltrating immune cells. 


 
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Appendix 6   
Eastern Cooperative Oncology Group Performance Status Scale 
Grade
 Description
 
0    Fully active, able to carry on all pre-disease 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 7   
Anaphylaxis Precautions 
EQUIPMENT NEEDED 
• Tourniquet  
• Oxygen  
•   Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice 
• Antihistamines  
• Corticosteroids  
•   Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study drug infusion, 
the following procedures should be performed: 
4.  Stop the study drug infusion. 
5.  Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug.  Do not obstruct arterial flow in the limb. 
6. Maintain an adequate airway. 
7. Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
8. Continue to observe the patient and document observations