Clinical trial NCT02807636
Conditions: Urothelial Carcinoma
Keywords: Urothelial carcinoma Bladder cancer Anti-PD-L1 Transitional carcinoma Tecentriq Atezolizumab IMvigor130
Sponsor: Hoffmann-La Roche
Start date: 2016-06-30; Completion date: 2024-02-12
Enrollment: 1213 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase III, randomised study of atezolizumab alone and in combination with chemotherapy versus chemotherapy alone in participants with untreated advanced urothelial cancer.

Detailed description:

Arms: arm 1: Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). arm 2: Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). arm 3: Eligible participants will receive open-label atezolizumab as monotherapy.
Interventions: intervention 1: Atezolizumab intervention 2: Carboplatin intervention 3: Gemcitabine intervention 4: Placebo intervention 5: Cisplatin
Intervention descriptions: intervention 1: Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression. intervention 2: Carboplatin will be administered at doses to achieve area under the concentration-time curve (AUC) of 4.5 milligram per milliliter into minute (mg/mL\*min) by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity. intervention 3: Gemcitabine will be administered at a dose of 1000 milligrams per square meter (mg/m\^2) by IV infusion on Day 1 and Day 8 of each 21-day cycle, until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity. intervention 4: Placebo matched to atezolizumab will be administered by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression. intervention 5: Cisplatin will be administered at a dose of 70 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.

Protocol documents:
Prot_000.pdf: 



















































































































































































































































































































































































































SAP_001.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Placebo-Controlled Study of 
Atezolizumab (Anti-PD-L1 Antibody) as Monotherapy and in 
Combination With Platinum-Based Chemotherapy in Patients With 
Untreated Locally Advanced or Metastatic Urothelial Carcinoma 
NCT Number: 
NCT02807636 
Document Date: 
SAP Version 3: 15-January-2020 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Atezolizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WO30070
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB 
(ANTIPD-L1 ANTIBODY) AS MONOTHERAPY AND IN 
COMBINATION WITH PLATINUM-BASED CHEMOTHERAPY IN 
PATIENTS WITH UNTREATED LOCALLY ADVANCED OR 
METASTATIC UROTHELIAL CARCINOMA
PROTOCOL NUMBER:
WO30070
STUDY DRUG:
Atezolizumab
VERSION NUMBER:
3
IND NUMBER:
120827
EUDRACT NUMBER:
2016-000250-35
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Ph.D
DATE FINAL:
Version 1: 13 December 2018
DATE (S) AMENDED:
Version 2: 25 February 2019
Version 3: See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
15-Jan-2020 08:31:11
Company Signatory


Atezolizumab —F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WO30070
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
This is Version 3 of the statistical analysis plan for Protocol WO30070. The amendment 
was prepared in response to health authority feedback following the primary PFS/interim 
OS analysis, which used data up to the clinical cut-off date of 31 May 2019. In this 
version, a second interim analysis of OS has been added in order to be able to provide 
updated results on OS earlier than the final analysis. The efficacy boundaries have 
been adjusted accordingly based on the pre-specified O’Brien-Fleming alpha spending 
function. Details are provided in Section 2.5.2.2.
Additional minor changes have been made to improve clarity and consistency.


Atezolizumab —F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WO30070
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 6
2.2
Current Study Design .............................................................. 6
2.3
Initial 2-Arm Study Design (Stage 1, Prior to 
Protocol WO30070, Version 3).............................................. 10
2.4
Determination of Sample Size ............................................... 11
2.4.1
Type I Error Control............................................................... 12
2.4.2
Co-Primary Endpoint: PFS .................................................... 13
2.4.3
Co-Primary Endpoint:  Overall Survival ................................. 14
2.5
Interim and Primary Analysis Timing ..................................... 15
2.5.1
Primary Analysis Timing ........................................................ 16
2.5.2
Interim Analysis Timing.......................................................... 16
2.5.2.1
Ad hoc Interim OS Analysis................................................... 17
2.5.2.2
Interim OS Efficacy Analyses ................................................ 18
3.
STUDY CONDUCT..................................................................................... 21
3.1
Randomization Issues ........................................................... 21
3.2
Independent Review Facility.................................................. 22
3.3
Independent Data Monitoring ................................................ 22
4.
STATISTICAL METHODS .......................................................................... 23
4.1
Analysis Populations ............................................................. 23
4.1.1
ITT Population ....................................................................... 23
4.1.2
PD-L1 IC2/3 Population......................................................... 24
4.1.3
Measurable Disease Population............................................ 24
4.1.4
Duration of Response-Evaluable Population.......................... 24
4.1.5
Pharmacokinetic-Evaluable Population ................................. 24
4.1.6
Safety Population .................................................................. 24
4.1.7
Patient-Reported Outcome Population .................................. 25
4.2
Analysis of Study Conduct..................................................... 25


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4/Statistical Analysis Plan WO30070
4.3
Analysis of Treatment Group Comparability .......................... 25
4.4
Efficacy Analysis.................................................................... 25
4.4.1
Co-primary Efficacy Endpoint PFS ........................................ 25
4.4.2
Co-primary Efficacy Endpoint Overall Survival ...................... 28
4.4.2.1
OS in Arm A vs. Arm C.......................................................... 28
4.4.2.2
OS in Arm B vs. Arm C.......................................................... 29
4.4.2.3
OS in the PD-L1 IC2/3 Population......................................... 30
4.4.3
Secondary Efficacy Endpoints............................................... 30
4.4.3.1
Objective Response Rate...................................................... 30
4.4.3.2
Duration of Response............................................................ 30
4.4.3.3
IRF-assessed PFS Arm A vs. Arm C..................................... 31
4.4.3.4
Timepoint Analysis of Progression-free Survival ................... 31
4.4.3.5
Timepoint Analysis of Overall Survival................................... 31
4.4.3.6
PFS in Arm B vs. Arm C ........................................................ 31
4.4.3.7
Patient-reported Outcomes.................................................... 32
4.4.4
Exploratory Efficacy Endpoints.............................................. 32
4.4.4.1
Disease Control Rate ............................................................ 32
4.4.4.2
Biomarker Analyses............................................................... 32
4.4.4.3
QLQ-C30 Function Scores .................................................... 33
4.4.5
Sensitivity Analyses............................................................... 33
4.4.5.1
Analysis of PFS Accounting for Non-Protocol 
Anti-Cancer Therapy ............................................................. 33
4.4.5.2
Analysis of OS Accounting for Non-Protocol Anti-
Cancer Therapy..................................................................... 34
4.4.5.3
Analysis of OS in Arm B vs. Arm C Accounting 
for Treatment Changes after Protocol Version 6 ................... 34
4.4.5.4
Analyses of Impact of Loss to Follow-Up on OS.................... 34
4.4.6
Subgroup Analyses ............................................................... 35
4.4.6.1
Subgroup Analyses of PFS and OS ...................................... 35
4.4.6.2
Subgroup Analyses by Cisplatin-eligibility and 
Choice of Platinum Therapy .................................................. 35
4.4.6.3
Subgroup Analysis in Patients with a PD-L1 
status of IC0 or IC1 Randomized to Arm B after 
Protocol Version 6 ................................................................. 36
4.5
Pharmacokinetic Analyses..................................................... 36


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5/Statistical Analysis Plan WO30070
4.6
Safety Analyses..................................................................... 36
4.6.1
Exposure to Study Medication............................................... 36
4.6.2
Adverse Events ..................................................................... 37
4.6.3
Laboratory Data..................................................................... 37
4.6.4
Vital Signs.............................................................................. 37
4.6.5
Anti-Therapeutic Antibodies................................................... 37
4.6.6
Subgroup Analyses ............................................................... 37
5.
REFERENCES ........................................................................................... 38
LIST OF TABLES
Table 1
Overall Survival Interim and Final Analysis Characteristics ........ 21
Table 2
Overview of ITT Analysis Population .......................................... 24
Table 3
Baseline Stratification Factors Used in Primary Analysis............ 26
Table 4
Inverse Normal p-Value Combination for PFS Arm A vs. Arm 
C (ITT) ........................................................................................ 27
Table 5
Inverse Normal p-Value Combination for OS Arm A vs. 
Arm C (ITT)................................................................................. 29
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 6
Figure 2
Study Schema for Patients Randomized into Protocol 
WO30070, Version 6................................................................... 10
Figure 3
Study Schema Prior to Protocol Version 3.................................. 11
Figure 4
Progression-Free Survival and Overall Survival Analysis 
Hierarchy, Alpha Allocation and Alpha Recycling ....................... 13
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 39
Appendix 2
Schedule of Assessments........................................................... 53
Appendix 3
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples..................................................................... 61


Atezolizumab —F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan WO30070
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study WO30070 (IMvigor130), “A Phase III, Multicenter, 
Randomized, Placebo-Controlled Study of Atezolizumab (anti-programmed
death-ligand 1 [PD-L1] antibody) as Monotherapy and in Combination with 
Platinum-Based Chemotherapy in Patients with Untreated Locally Advanced or 
Metastatic Urothelial Carcinoma”.
2.
STUDY DESIGN
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  The Protocol Synopsis includes the study 
objectives and endpoints, study design, inclusion and exclusion criteria, medicinal 
product administration, and statistical methods for the primary efficacy analysis and 
planned interim analyses as stated in the protocol.  For details of schedule of 
assessments, see Appendix 2 and Appendix 3.
2.2
CURRENT STUDY DESIGN
IMvigor130 is a Phase III, multicenter, randomized, placebo-controlled, partially blind 
study designed to evaluate the safety and efficacy of atezolizumab given as 
monotherapy or in combination with platinum-based chemotherapy versus placebo in 
combination with platinum-based chemotherapy in patients with locally advanced or 
metastatic urothelial carcinoma who have not received prior systemic therapy 
(see Figure 1).
Figure 1
Study Schema
PDprogressive disease; RECIST Response Evaluation Criteria in Solid Tumors; 
UCurothelial carcinoma.
A total of 1200 patients were planned to be enrolled at approximately 229 sites.
Patients should be considered eligible to receive treatment with platinum-based
chemotherapy (either gemcitabine with cisplatin or gemcitabine with carboplatin) and 


Atezolizumab —F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan WO30070
have measurable disease, defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1.
A total of 1200 patients were planned to be randomized in a 1:1:1 ratio to receive one of 
the following:

Arm A (experimental arm):  blinded atezolizumab in combination with open-label 
platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin)

Arm B (experimental arm): open-label atezolizumab monotherapy

Arm C (control arm):  blinded placebo in combination with open-label 
platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin)
Prior to randomization, the investigator was to select the chemotherapy the patient 
receives (gemcitabine and carboplatin vs. gemcitabine and cisplatin) if randomized to 
Arm A or Arm C.  The Galsky criteria (see Protocol Section 4.2) were to be used to guide 
determination of cisplatin ineligibility.
Randomization was stratified by the following factors:

PD-L1 status (tumor-infiltrating immune cell 0 [IC0] vs. IC1 vs. IC2/3)

Bajorin model risk factor score/liver metastasis (0 vs. 1 vs. 2 or patients with liver 
metastasis)

Investigator-determined chemotherapy (gemcitabine and carboplatin vs. 
gemcitabine and cisplatin)
Treatment with platinum-based chemotherapy can continue until progressive disease 
(PD) per RECIST v1.1 or unacceptable toxicity per investigator discretion.  In the case of 
complete response (CR), only two more cycles of platinum-based chemotherapy may be 
administered after the response confirmation.  In specific circumstances, treatment may 
continue beyond disease progression (see Protocol Section 4.6.2).
An independent data monitoring committee (iDMC) has been convened to help monitor 
patient safety (see Protocol Section 3.1.2).
No crossover will be allowed from the control arm to either experimental arm (Arms A 
and B).
Design Changes
This study was initially implemented with randomization to two treatment arms 
(carboplatin plus gemcitabine with or without atezolizumab) in patients who were 
ineligible for cisplatin-based chemotherapy; details of the original design 
(Protocol Versions 1 and 2) are provided in Section 2.3.  In Protocol WO30070 v3, Arm 
B was added (open-label atezolizumab monotherapy).  In addition, the eligibility criteria 
were expanded to also allow patients who are eligible for cisplatin-based chemotherapy 


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8/Statistical Analysis Plan WO30070
to enter the study.  Protocol WO30070 v3 was implemented while recruitment was 
ongoing.  As a result of this design change, the study consists of two stages:  Patients 
recruited into the study prior to v3 (Stage 1) and patients recruited from Protocol v3 
(Stage 2).  Patients from both stages will be included in the final analysis.
Based on an ad-hoc review of the survival data of all patients randomized in the study up 
to 12 March 2018, the study iDMC recommended closure of Arm B (atezolizumab 
monotherapy) to further accrual of all patients with a PD-L1 expression status of IC0 or 
IC1 (at this point, enrollment into Stage 1 was complete).  The iDMC did not recommend 
a change in therapy for patients already randomized to atezolizumab monotherapy on 
study.
The iDMC recommendation also stated that patients with a PD-L1 expression status of 
IC2/3 could continue to be randomized to Arm A, B, or C and that Arms A and C should 
remain unchanged (open to all patients regardless of PD-L1 status).
This recommendation was implemented in Protocol WO30070 v6.  The study design 
following implementation of Protocol WO30070 v6 is presented below (see Figure 2).
Stratified randomization to the three arms in a 1:1:1 ratio continued regardless of PD-L1 
status.
Prior to randomization, all patients were informed per the consent form that if 
randomized to Arm B (atezolizumab monotherapy) and determined to have a tumor 
PD-L1 expression status of IC0 or IC1, they would receive chemotherapy combined with 
atezolizumab instead of atezolizumab monotherapy.  For patients who are found to have 
a tumor PD-L1 expression status of IC0 or IC1, and are not willing to undergo treatment 
with atezolizumab with chemotherapy, the consent informed these patients to consider 
treatment outside of the trial rather than proceeding with trial enrollment.
For all new patients randomized to Arm B (open-label atezolizumab monotherapy) after 
approval of Protocol WO30070 v6:

The PD-L1 status was unblinded to the investigator and patient at the time of 
randomization.

Patients whose PD-L1 expression status was IC2/3 received atezolizumab 
monotherapy.

Patients with a PD-L1 expression status of IC0 or IC1 received open-label 
atezolizumab plus platinum (carboplatin or cisplatin) and gemcitabine chemotherapy
instead of atezolizumab monotherapy.

If a patient with a PD-L1 expression status of IC0 or IC1 subsequently wished to 
receive standard-of-care chemotherapy instead of atezolizumab plus platinum and 
gemcitabine chemotherapy, he/she was able to receive standard-of-care 
chemotherapy of their choice (provided outside of the protocol) and continue on 
survival follow up.


Atezolizumab —F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan WO30070
For all patients in Arm B currently being treated with open-label atezolizumab 
monotherapy at the time of approval of Protocol WO30070 v6:

Patients to be informed that the iDMC has not recommended any changes to 
therapy for those already randomized to atezolizumab monotherapy.

The option of unblinding the PD-L1 status upon patient and the investigator request 
was introduced.

Patients with PD-L1 expression status of IC2/3 will continue receiving atezolizumab 
monotherapy.

Patients with PD-L1 expression status of IC0 or IC1 are recommended to continue 
with atezolizumab monotherapy, as the iDMC did not recommend a change in 
therapy for patients already randomized to monotherapy on study.
However, if the patient after discussion of benefit-risk with the treating physician 
determines that continuation of atezolizumab monotherapy is not considered 
beneficial, a treatment alternative of atezolizumab plus platinum (cisplatin or 
carboplatin) and gemcitabine chemotherapy will be provided.  These patients 
should then be treated the same as patients in Arms A and C (see Protocol 
Section 4.3.2.2 on duration of chemotherapy).
If the decision is made to unblind the patient and add platinum (cisplatin or 
carboplatin) and gemcitabine chemotherapy to the regimen, it should be added 
before patient has known PD.  Chemotherapy should not be added to Arm B 
patients with documented PD within the study.

Patients also have the option to stop study therapy and receive standard-of-care 
treatment outside of the study by their physician.

All patients (including those who choose to stop atezolizumab monotherapy) are 
requested to continue in the study for survival follow up.






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12/Statistical Analysis Plan WO30070
Simulations were performed to check the expected power of the analyses of co-primary 
endpoints progression-free-survival (PFS) and overall survival (OS) for this sample size 
as described below.
The definitions of the analysis population are provided in Section 4.1.
2.4.1
Type I Error Control
The type I error () for this study is 0.025 (one-sided).  A one-sided test will be used 
because of the enrollment in 2 stages (see Section 2.2), and treatment effects could be 
observed in opposite directions in the 2 stages.
There are two co-primary efficacy endpoints for this study:  PFS by investigator 
assessment per RECIST v1.1 and OS.  To control the overall type I error rate while 
accounting for two co-primary endpoints, will be split between PFS (0.01) and OS 
(0.015) (Figure 4, Bretz et al. 2009).  Because type I error will be controlled 
accounting for two co-primary endpoints, the study will be considered a positive study if 
statistical significance is achieved for either of the co-primary endpoints. 
Formal treatment comparisons of PFS and OS in Arm A versus Arm C will be performed 
in a hierarchical fashion in which may be recycled as follows (Figure 4, 
Burman et al. 2009):
1.
PFS in Arm A versus Arm C of the intent-to-treat (ITT) population will be evaluated 
at 0.01 (one-sided).
2.
If PFS results in Arm A versus Arm C of the ITT population are statistically 
significant at 0.01, then 0.01 will be recycled to OS in Arm A versus Arm C of 
the ITT population, and OS in Arm A versus Arm C of the ITT population will be 
evaluated at 0.025 (one-sided).  If PFS results in Arm A versus Arm C of the ITT 
population are not statistically significant at 0.01, then no recycling of will occur, 
and OS in Arm A versus Arm C of the ITT population will be evaluated at 0.015 
(one-sided).
3.
OS will also be compared between the ITT population of Arm B and Arm C using 
a hierarchical approach as follows:  If the duration of OS is shown to be statistically 
significantly longer in Arm A compared to Arm C at the appropriate level 
(see Step 2 above), then the duration of OS in the ITT population of Arm B and 
Arm C will be compared at the same level.  If the OS results for Arm A versus 
Arm C of the ITT population are not statistically significant, formal treatment 
comparison of OS in the ITT population of Arm B versus Arm C will not be 
performed.
4.
If the comparison in Step 3 above is statistically significant at the appropriate level, 
then OS will be compared between the PD-L1 IC2/3 population of Arm B and Arm C 
at the same level.




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14/Statistical Analysis Plan WO30070
The analysis of the co-primary endpoint of PFS will take place when approximately 
667 PFS events in the ITT population for the comparison of Arm A versus Arm C have 
occurred (75% of 886 randomized patients) on the basis of the following assumptions:

Stratified log-rank test combining data from Stage 1 and Stage 2

0.01 (significance level for combined p-value, one-sided)

Approximately 91% power

Median PFS in the control arm of 6.8 months and estimated median PFS in the 
atezolizumab plus chemotherapy arm of 9.1 months (an increase of 2.3 months, 
corresponding to a hazard ratio [HR] of 0.75)

Dropout rate of 5% annually

No interim analysis of PFS
2.4.3
Co-Primary Endpoint:  Overall Survival
The co-primary endpoint of OS will be compared between Arms A and C, and between 
Arms B and C in a hierarchical fashion as described in Section 2.4.1.
Arm A versus Arm C 
The projected number of patients in the ITT population for the comparison of Arm A 
versus Arm C was 886 patients at the time of implementation of Protocol v3.
The final analysis will take place when approximately 667 OS events in the ITT 
population for the comparison of Arm A versus Arm C of the global enrollment phase of 
the study have occurred (75% of 886 randomized patients) on the basis of the following 
assumptions:

Stratified log-rank test combining data from Stage 1 and Stage 2

0.015 (one-sided) 

Approximately 99% power 

Median OS in the control arm of 12 months and estimated median OS in the 
atezolizumab plus chemotherapy arm of 17.1 months (an increase of 5.1 months, 
corresponding to a HR of 0.70) 

Dropout rate of 5% annually

One interim analysis to be performed at the time of the PFS analysis 
(see Section 2.5.2.2)
Note that the addition of a second interim analysis (see Section 2.5.2) does not result in 
a noticeable reduction of statistical power.


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15/Statistical Analysis Plan WO30070
Arm B versus Arm C 
Prior to the iDMC recommendation to stop further recruitment of patients with PD-L1 
status of IC0 or IC1 to atezolizumab monotherapy (see Section 2.2), the statistical power 
was determined as follows.  The expected number of patients for the comparison of 
Arm B versus Arm C, defined as all patients concurrently randomized during Stage 2 of 
the study, was approximately 628 patients.  The final analysis was planned when 
approximately 471 OS events in the ITT population for Arm B and Arm C in the global 
enrollment phase of the study have occurred (75% of 628 patients) on the basis of the 
following assumptions:

Stratified log-rank test using data from Stage 2 patients only

0.015 (one-sided) 

Approximately 88% power 

Median OS in the control arm of 12 months and estimated median OS in the 
atezolizumab arm of 16.4 months (an increase of 4.4 months, corresponding to a 
HR of 0.73) 

Dropout rate of 5% annually

One interim analysis to be performed at the time of the PFS analysis 
(see Section 2.5.2.2)
In Protocol v6, enrollment into Arm B was modified according to a recommendation from 
the iDMC (see Section 2.2), which was expected to reduce the sample size.  In order to 
ensure sufficient follow-up at the time of the final OS analysis in Arm B versus Arm C, 
the proportion of patients who will have died by the time of the final analysis was kept at 
75% as in the original design.
An additional formal comparison of OS in patients in Arm B versus Arm C with a PD-L1 
status of IC2/3 is included in the testing hierarchy, see Figure 4.  However, this test was 
not taken into account for determining the sample size.
2.5
INTERIM AND PRIMARY ANALYSIS TIMING
Note that the actual enrollment into Stage 1 and 2 was different from the numbers used 
for the projections of the analysis timing in the protocol and in the SAP, Section 2.4, 
which were performed during the early stages of recruitment.  The estimated analysis 
timing for the second interim OS analysis and the final OS analysis that are described in 
this section is based on actual enrollment and updated projections after the final PFS 
analysis/first interim OS analysis.
The definitions of the analysis populations are provided in Section 4.1.


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16/Statistical Analysis Plan WO30070
2.5.1
Primary Analysis Timing
The analysis of the co-primary endpoint of PFS in Arm A versus Arm C will take place 
when approximately 667 PFS events have occurred in the ITT population for 
comparisons of Arm A versus Arm C (in 78% of approximately 852 patients, see 
Section 4.1.1).  Based on the assumptions for median PFS and drop-out rate described 
in Section 2.4.2 and patient accrual, the required number of PFS events is projected to 
occur at Month 35 from the time the first patient was randomized.
The study will be unblinded at the time of the primary PFS analysis.
The final analysis of the co-primary endpoint of OS in Arm A versus Arm C will take 
place when approximately 667 deaths have occurred in the ITT population for Arm A 
versus Arm C (in 78% of approximately 852 patients).  Based on observed survival up to 
the final PFS/interim OS analysis, the required number of events is projected to occur at 
Month 55 from the time the first patient was randomized, i.e., approximately 5 months 
later than according to the projections in the initial SAP.
The final analysis of the co-primary endpoint of OS in Arm B versus Arm C will take 
place at the later of two time points: 
1.
when 75% of the approximately 719 patients in the ITT population for comparisons 
of Arm B versus Arm C have died, i.e., after approximately 539 deaths have been 
reported
2.
at the time of the final analysis of OS in Arm A versus. Arm C; in this scenario, the 
number of deaths reported in the ITT population for Arm B and Arm C is expected to 
be539.
This timing for the final analysis of OS in Arm B versus Arm C may be adjusted under 
certain circumstances, such as
–
the projected cut-off date under the two scenarios above is less than 3 months apart
–
too few patients still at risk in order to meaningfully increase the observed number of 
deaths with longer follow-up.
In these cases, the clinical cut-off date for the analysis of OS in Arm B versus Arm C will 
be the same as that used for the analysis of OS in Arm A versus Arm C.
In addition, OS will be compared in Arm B versus Arm C in the subgroup of patients with 
PD-L1 score of IC 2 or 3 (see Figure 4).  This analysis will be performed at the same 
time as that in the whole ITT for comparisons of Arm B versus Arm C.  The number of 
patients in the PD-L1 IC2/3 population for OS comparisons of Arm B versus Arm C is 
173 patients.
2.5.2
Interim Analysis Timing
There is no interim analysis of PFS.


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17/Statistical Analysis Plan WO30070
2.5.2.1
Ad hoc Interim OS Analysis
An ad hoc OS interim analysis will be performed in order to respond to a request from 
the FDA in June 2018.  The request was for a futility analysis for the comparison of OS 
between Arm B and Arm C to be performed prior to the time of the planned final PFS 
analysis comparing Arm A and Arm C.
The clinical cut-off for this analysis is 16 October 2018.
The analysis will be performed by the independent data coordinating center (iDCC) and 
reviewed by the iDMC (see also Section 3.3).  The Sponsor Study Management Team 
(SMT) will remain blinded to results of the study until the study unblinding at the time of 
the primary PFS analysis.  The analysis population will be the same as the primary 
analysis population for the comparison of Arm B versus Arm C as specified in 
Section 4.1.  The futility criterion will be based on the point estimate of the stratified OS 
HR for OS in Arm B versus Arm C.  The statistical analysis method for calculation of the 
HR, including stratification factors, will be the same as for the primary analysis of OS as 
described in Section 4.4.2.2.
A value for the OS HR of1.60 favoring the chemotherapy control over atezolizumab 
monotherapy will be considered evidence suggestive of futility of treatment with 
atezolizumab monotherapy compared to chemotherapy control.
If the futility criterion is met, the following additional analysis will be performed by the 
iDCC.  The value for the OS HR comparison of Arm B and Arm C will be obtained for the 
subgroup of patients followed for at least one year, i.e., patients randomized up to and 
including 17 October 2017.  The futility criterion described above will be applied to this 
subgroup of patients with the longest follow up.
If the futility criterion is met, the Sponsor Data Review Board (DRB) will work with the 
iDMC and iDCC on further analyses to better understand the data and evaluate changes 
to the study conduct that would be considered, if any.  Additional analyses may be 
performed at Sponsor DRB’s request, regardless of the outcome of the futility analysis, if 
needed as part of the response to FDA’s request for the futility analysis.  The results of 
the futility analyses will be considered advisory by the Sponsor DRB.  The Sponsor DRB 
will decide on actions to be taken by the Sponsor, if any, based on the outcome of these 
analyses.
This analysis was not preplanned in the protocol.  Protocol Section 6.8.2 states that 
optional interim analyses may be performed and that the rationale, timing, and statistical 
details for such an analysis will be documented in the SAP prior to the analysis.  Since 
this interim analysis will not result in early stopping for efficacy, no type I error 
adjustment is required. 


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2.5.2.2
Interim OS Efficacy Analyses
Except for the ad hoc interim OS analysis described above, all efficacy analyses, 
including the interim efficacy analyses of OS will be performed by the Sponsor.
OS comparison of Arm A versus Arm C
A total of three analyses of OS comparing Arm A versus Arm C will be performed (two 
interim analyses and one final analysis; see Table 1).
The first interim analysis of OS in Arm A versus Arm C was performed as planned at the 
time of the primary PFS analysis, regardless of the outcome of the PFS analysis.  At this 
time, the study was unblinded to the Sponsor.  A total of 463 OS events were observed
in Arm A and Arm C (54% of 851 patients). The second interim OS analysis will take 
place after a minimum of approximately 12 months of additional follow-up compared to 
the clinical cut-off date for the primary analysis, which was 31 May 2019.  The projected 
number of events in Arm A and C by this time is approximately 600 (71% of patients). If, 
however, based on subsequent event-tracking, less than 579 events (68% of patients) 
are projected to have occurred by 31 May 2020, the clinical cut-off date for the second 
interim analysis will be delayed until this minimum threshold is met.
According to the type I error allocation between co-primary endpoints PFS and OS 
(see Figure 4), the overall one-sided type I error level for OS will be 0.025 since the PFS 
result was significant.  The methods for the statistical hypothesis test are described in 
Section 4.4.2.  The boundary for statistical significance at the interim and final analyses 
will be determined based on the Lan-DeMets implementation of the O’Brien-Fleming 
alpha spending function to maintain this overall type I error rate.
For example, if 600 deaths have occurred at the time of the second OS interim analysis 
in Arm A versus Arm C, statistical significance will be declared if the one-sided p-value 
is0.016 (Table 1).  This p-value boundary for statistical significance is based on the 
number of projected events; actual boundary p-values will be calculated at the time of 
analysis based on the actual number of events observed in the ITT population for 
comparisons of Arm A versus Arm C.
OS comparison of Arm B versus Arm C
The total number of analyses of OS comparing Arm B versus Arm C will be 3 or 4 (2 or 
3 interim analyses and one final analysis).
The first interim analysis of OS comparing Arm B versus Arm C was performed at the 
time of the primary PFS analysis and the second will be at the same time as the second 
interim OS analysis comparing Arm A versus Arm C.
A third interim analysis of OS in Arm B versus Arm C may be conducted at the time of 
the final analysis of OS in Arm A versus Arm C in case the number of deaths reported at 


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this time has not yet reached 75% of patients in the ITT population for comparisons of 
Arm B versus Arm C, see Section 2.5.1.  The final analysis of OS in Arm B versus Arm C 
would then take place once approximately 75% of patients have died.
A formal comparison of OS in Arm B versus Arm C will only be performed after the OS 
result in Arm A versus Arm C was significant.  If the result for OS in Arm A versus Arm C 
is significant at the interim analysis, but the result in Arm B versus Arm C is not, then the 
study will not be stopped, and OS in Arm B versus Arm C will be tested again at the time 
of the final analysis.
According to the testing hierarchy (see Figure 4), the overall available one-sided type I 
error level for the comparison of OS in Arm B versus Arm C will be the same as above 
for the comparison of OS in Arm A versus Arm C (0.025).  The boundary for statistical 
significance at the interim and final analyses of OS in Arm B versus Arm C will be 
determined based on the Lan-DeMets implementation of the O’Brien-Fleming alpha 
spending function to maintain this overall type I error rate.
The p-value boundaries for statistical significance shown in Table 1 are based on the 
number of projected events; actual boundary p-values will be calculated at the time of 
analysis based on the actual number of events observed in the ITT population for 
comparisons of Arm B versus Arm C.
If a third interim analysis of OS in Arm B versus Arm C is performed at the time of the 
final analysis of OS in Arm A versus Arm C, then the corresponding boundary p-value 
will be determined using the same alpha spending function approach.
As described in Section 2.5.1, the timing of the final analysis of the co-primary endpoint 
of OS in Arm B versus Arm C depends on both the proportion of events observed in 
Arm B versus Arm C as well as that in Arm A versus Arm C.  If the final analysis in 
Arm B versus Arm C is performed at the same time as that in Arm A versus Arm C, then 
it is expected that more than 75% of patients in the ITT population for Arm B versus
Arm C will have died at that time.  In this case, the p-value boundary at the final analysis 
of OS in Arm B versus Arm C will be recalculated taking into account the actual 
information fraction at the respective analysis time points.  The methodology was 
described by Wassmer and Brannath (Wassmer and Brannath 2016, Chapter 3.3).  Of 
note, since the decision on the timing of the final analysis is based on criteria 
independent of the OS results in Arm B versus Arm C, the overall type I error remains 
protected.


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OS comparison of Arm B vs. Arm C in PD-L1 IC2/3 population
A formal comparison of OS in Arm B versus Arm C in the PD-L1 IC2/3 population will 
only be performed after the OS result in the ITT population for Arm B versus Arm C was 
significant.
According to the testing hierarchy (see Figure 4), the overall available one-sided type I 
error level for the comparison of OS in Arm B versus Arm C will be the same as above 
for the comparison of OS in the ITT population for Arm B vs. Arm C (0.025).  The 
boundary for statistical significance at the interim and final analyses of OS in the PD-L1 
IC2/3 population for comparisons of Arm B versus Arm C will be determined based on 
the Lan-DeMets implementation of the O’Brien-Fleming alpha spending function to 
maintain this overall type I error rate.
The p-value boundaries for statistical significance shown in Table 1 are based on the 
number of projected events; actual boundary p-values will be calculated at the time of 
analysis based on the actual number of events observed in the PD-L1 IC2/3 population 
for comparisons of Arm B versus Arm C.
If a third interim analysis of OS in the PD-L1 IC2/3 population of Arm B versus Arm C is 
performed at the time of the final analysis of OS in Arm A versus Arm C, then the 
corresponding boundary p-value will be determined using the same alpha spending 
function approach.
As described above for the analysis of OS in the ITT population for Arm B versus Arm C, 
in case the actual number of events observed differs from the projected number, the 
p-value boundary at the time of the final analysis in Arm B versus Arm C in the PD-L1 
IC2/3 population will be determined based on the actual number of events observed 
(Wassmer and Brannath 2016, Chapter 3.3).


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Table 1
Overall Survival Interim and Final Analysis Characteristics
Number of 
Patients
Number of Events
(% Patients)
Information 
Fraction
p-Value 
Boundary
Month 35 – final PFS / first interim OS analysis (PFS event-driven)
First interim OS A vs. C
851
463 (54%)
69%
0.007
First interim OS B vs. C
719
389 (54%)
72%
0.008
First interim OS B vs. C IC2/3
173
75 (43%)
58%
0.003
Month 47 – second interim OS analysis Arm A vs. C (~12 months after first interim OS)
Second interim OS A vs. C
851
600 (71%) a
90%
0.016
Second interim OS B vs. C
719
510 (71%) a
95%
0.019
Second interim OS B vs. C 
IC2/3
173
100 (58%) a
77%
0.010
Month 55 – projected time of final OS analysis Arm A vs. C (OS event-driven)
Final OS A vs. C
851
667 (78%)
100%
0.019
Final OS B vs. C
719
539 (75%) b
100%
0.018
Final OS B vs. C IC2/3
173
130 (75%) b
100%
0.022
AARM A; BArm B; CArm C; OSoverall survival; PFSprogression-free survival.
Month 1month the first patient was randomized.
a Projected number; the actual boundary for statistical significance to be calculated at the time of 
the analysis based on actual number of observed events.
b In case final analysis occurs later ( 75% events/patients, see Section 2.5.1), final boundary for 
statistical significance to be calculated based on actual number of events, see Chapter 3.3 
in Wassmer and Brannath 2016.
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
The randomization scheme was different before and after Protocol v3 (Stage 1 and 2, 
respectively), see Section 2.2 and Section 2.3.
During Stage 1, eligible patients were randomized in a 2:1 ratio to receive either 

atezolizumab in combination with gemcitabine and carboplatin

placebo in combination with gemcitabine and carboplatin
A stratified permuted-block randomization scheme was implemented with the following 
factors:

PD-L1 status (IC0 vs. IC1 vs. IC2/3)

Bajorin model risk factor score/liver metastasis (0 vs. 1 vs. 2 or patients with liver 
metastasis) 

Prior perioperative chemotherapy (neoadjuvant or adjuvant) (yes vs. no)


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Prior perioperative chemotherapy is defined as at least two cycles of 
combination chemotherapy, such as cisplatin/gemcitabine or MVAC 
administered in the neoadjuvant/adjuvant setting or standard radiosensitizing 
chemotherapy (cisplatin or 5FU/mitomycin) if administered concurrently with 
radiotherapy.
During Stage 2, eligible patients were randomized in a 1:1:1 ratio to receive either 

blinded atezolizumab in combination with open-label platinum-based chemotherapy 
(gemcitabine with either cisplatin or carboplatin)

open-label atezolizumab monotherapy

blinded placebo in combination with open-label platinum-based chemotherapy 
(gemcitabine with either cisplatin or carboplatin)
A stratified permuted-block randomization scheme was implemented with the following 
factors:

PD-L1 status (IC0 vs. IC1 vs. IC2/3)

Bajorin model risk factor score/liver metastasis (0 vs. 1 vs. 2 or patients with liver 
metastasis)

Investigator-determined chemotherapy (gemcitabine and carboplatin vs. 
gemcitabine and cisplatin) 
3.2
INDEPENDENT REVIEW FACILITY
The imaging data used for tumor assessment will be collected by the Sponsor to enable 
centralized, independent review of response endpoints by an Independent Review 
Facility (IRF).  The IRF will evaluate tumor assessments for determination of progression 
according to RECIST v1.1.  Investigator tumor assessments will not be reconciled with 
the IRF tumor assessments.  Further details will be included in the IRF Charter.
3.3
INDEPENDENT DATA MONITORING
An iDMC was convened to evaluate safety data during the study.  Members of the iDMC 
are external to the Sponsor and are following a charter that outlines their roles and 
responsibilities.  The iDMC was to conduct its first review of safety data when 
20 patients have completed at least one cycle of study treatment.  The iDMC continued
to evaluate study safety data on a periodic basis, approximately every 3 months until 
1 year after the enrollment of the first patient in Protocol WO30070 v3.  After that period, 
reviews are conducted approximately every 6 months until the time of the analysis of the 
co-primary efficacy endpoint of PFS.  The Sponsor remains blinded to the results until 
the analysis of the co-primary endpoint of PFS occurs.
All summaries and analyses for the iDMC review are prepared by treatment arm by an 
external iDCC.  The safety data include demographic data, adverse events (AEs), 
serious adverse events (SAE), and relevant laboratory data.  Following their data review, 


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the iDMC provides a recommendation to the Sponsor according to the iDMC Charter.  
The final decision on any changes to the protocol rests with the Sponsor.
Any outcomes of these safety reviews that affect study conduct are to be communicated 
in a timely manner to the investigators for notification of the Institutional Review 
Boards/Ethics Committees (IRBs/ECs).
The FDA requested an unplanned ad hoc OS interim analysis to be performed prior to 
the final PFS analysis. The Sponsor will remain blinded to the result. The analysis will be 
performed by the iDCC and reviewed by the iDMC, see Section 2.5.2.1 for details.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
The study population consists of two enrollment stages, see Section 2:

Stage 1:  This study was initially implemented with two treatment arms (carboplatin 
plus gemcitabine with or without atezolizumab, Arm A and Arm C) in patients who 
are ineligible for cisplatin-based therapy.

Stage 2:  In Protocol WO30070 v3, a third treatment arm was added (atezolizumab 
monotherapy, Arm B).  In addition, the eligibility criteria were expanded to also allow 
patients who are eligible for cisplatin-based chemotherapy to enter the study.
At the time Protocol v3 was submitted, enrollment was ongoing, and therefore the actual 
number of patients randomized in each stage is different from the estimates provided in 
Protocol v3.
4.1.1
ITT Population
For the comparison of efficacy in Arm A versus Arm C, the ITT population is defined as 
all patients randomized to Arm A or Arm C in Stages 1 and 2, whether or not the 
assigned study treatment was received.
For the comparison of efficacy in Arm B versus Arm C, the ITT population includes only 
patients concurrently enrolled in Stage 2 and only those who had been randomized at 
the time of approval of Protocol WO30070 v6.
The table below summarizes the approximate numbers of patients per enrollment stage 
and arm and the resulting approximate size of the ITT populations.


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Table 2
Overview of ITT Analysis Population
Arm A
Arm B
Arm C
Total
ITT 
A vs. C
ITT 
B vs. C
Only ITT 
A vs. C
ITT A vs. C 
and B vs. C
Total Randomized
1213
447
361
404
Stage 1 (2:1 ratio A:C)
129
86
-
43
Stage 2 (1:1:1 ratio A:B:C)
1084
361
361
361
Before Protocol V6
1078
359
359
359
Protocol V6
6
2
2
2
ITT A vs. C
852
447
404
ITT B vs. C
719
-
359
359
ITTintent-to-treat.
AARM A; BArm B; CArm C.
Table shows rounded estimates based on enrollment and randomization ratio.
4.1.2
PD-L1 IC2/3 Population 
The PD-L1 IC2/3 population for the comparison of Arm B versus Arm C is defined as all 
patients randomized in Stage 2 with a PD-L1 status of IC2/3.  This includes patients who 
were randomized to Arm B or Arm C after implementing the iDMC recommendation in 
Protocol WO30070 v6.
4.1.3
Measurable Disease Population
The measurable disease populations are defined as patients in the respective ITT 
populations with at least one measurable lesion according to RECIST v1.1 based on 
investigator assessment.
4.1.4
Duration of Response-evaluable Population
The duration of response (DOR)-evaluable population is defined as patients with an 
objective response.
4.1.5
Pharmacokinetic-Evaluable Population 
The pharmacokinetic (PK)-evaluable population is defined as all patients dosed with 
atezolizumab who have at least one post-baseline PK result.
4.1.6
Safety Population
The safety population is defined as patients who received any amount of any component 
of study treatment.  Patients will be analyzed according to the treatment received.  In 
particular, patients randomized to Arm B after approval of Protocol WO30070 v6 who 
received open-label atezolizumab and chemotherapy will be pooled with patients in 
Arm A for safety analyses.


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4.1.7
Patient-Reported Outcome Population
The patient reported outcome (PRO)-evaluable population is defined as patients in the 
respective ITT populations for comparisons of Arm A versus Arm C and Arm B versus
Arm C who have a baseline and at least one post-baseline assessment.
4.2
ANALYSIS OF STUDY CONDUCT
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and reasons for discontinuation from the study will be summarized overall and 
by treatment arm for the ITT populations for comparisons of Arm A versus Arm C, Arm B 
versus. Arm C, and the PD-L1 IC2/3 population for the comparison of Arm B versus 
Arm C.  Study treatment administration and reasons for discontinuation from study 
treatment will be summarized for the safety population.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic characteristics (e.g., age, sex, and race/ethnicity), baseline disease 
characteristics (e.g., Eastern Cooperative Oncology Group [ECOG] performance status, 
hemoglobin, time from prior chemotherapy) and stratification factors (Bajorin model risk 
factor score/liver metastasis, investigator choice of chemotherapy, and PD-L1 
immunohistochemistry [IHC] IC status) will be summarized by treatment arm for the ITT 
populations and for subpopulations as appropriate, see Section 4.4.6.
Baseline values are the last available data obtained prior to the patient receiving the first 
dose of any component of the study treatment on Cycle 1, Day 1 (or at screening, for 
patients who were not treated), unless otherwise noted.  Descriptive statistics (mean, 
median, standard deviation, minimum, and maximum) will be presented for continuous 
variables, and frequencies and percentages will be presented for categorical variables.
4.4
EFFICACY ANALYSIS
Patients will be grouped for efficacy analyses according to the treatment assigned at 
randomization, whether or not the assigned treatment was received.
4.4.1
Co-primary Efficacy Endpoint PFS
PFS is defined as the time from randomization to the first documented disease 
progression as determined by the investigator with the use of RECIST v1.1, or death 
from any cause, whichever occurs first.
Data for patients who are alive and have not experienced disease progression at the 
time of analysis will be censored at the date of the last tumor assessment at which they 
were known to be progression free.  Data for patients with no post-baseline tumor 
assessment will be censored at the date of randomization plus 1 day.  The primary 
analysis of PFS will be analyzed in the ITT population for comparisons of Arm A versus
Arm C.


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For U.S. registrational purposes, the primary analysis of PFS will be defined as 
described above, with an additional censoring rule for missed visits.  Data for patients 
with a PFS event who missed two or more consecutive scheduled assessments 
immediately prior to the PFS event will be censored at the last tumor assessment prior to 
the missed visits.
Stratification Factors
The stratification factors will be obtained from the values entered in the Interactive 
Voice/Web Response System (IxRS) at the time of randomization.  As stated in the 
protocol, to avoid small or zero cell sizes for some of the strata, the stratification factors 
for Stage 1 and Stage 2 may be combined.  For analysis purposes, the stratification 
factors will be as described below, see Table 3. Specifically, ‘prior perioperative 
chemotherapy’ will not be included as a stratification factor in the analyses; the 
stratification factor of ‘investigator choice of chemotherapy’ does not apply in Stage 1 
because all patients receive carboplatin plus gemcitabine. 
Table 3
Baseline Stratification Factors Used in Primary Analysis
Stratification 
Factor a
Randomization
Analysis
Stage 1
Stage 2
Stage 1
Stage 2
Prior perioperative 
chemotherapy
Yes
No
-
-
-
Investigator choice 
of chemotherapy a
-
-
Cis/Gem
Carbo/ 
Gem
-
-
Cis/Gem
Carbo/ 
Gem
PD-L1 Status
IC0
IC1
IC2/3
IC0
IC1
IC2/3
IC0
IC1
IC2/3
IC0
IC1
IC2/3
Bajorin score/liver 
metastases b
0
1
2
0
1
2
0
1
2
0
1
2
ICtumor-infiltrating immune cell; PD-L1programmed death-ligand 1.
a Cis/Gem cisplatingemcitabine vs. Carbo/Gem carboplatingemcitabine; all Stage 1 patients 
were treated with carboplatingemcitabine.
b Bajorin model risk factor score/ presence of liver metastases (0score 0 and no liver metastases 
vs. 1score 1 and no liver metastases vs. 2score 2 and/or liver metastases.
P-value Combination
The analysis will be performed in the ITT Population for Arm A versus Arm C. Treatment 
comparisons will be based on the stratified log-rank test at the one-sided level of 
significance of 0.01, see in Section 2.4.1.  The stratification factors will be as described 
above.
A possible effect of study stage will be taken into account as follows:  The null 
hypothesis will first be tested in each of the two stages separately, and both one-sided 
p-values will be calculated (p1 and p2 for Stage 1 and 2, respectively).  A combined 


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p-value will be calculated using the inverse normal approximation (Wassmer 2006) for 
the combined test statistic:
z Stage 1+2 w1 Φ-1(1-p1) + w2 Φ-1(1-p2) 
Here w1 and w2 are the pre-specified weights, where w12 + w221.  The weights were 
determined prior to unblinding and were based on the projected number of events at the 
time of the analysis.  If d1 and d2 are the projected number of events in Stage 1 and 
Stage 2, then: 
w1( d1 / (d1d2 )) ½  ,     w2( 1w12) ½ 
The weights were determined using the following assumptions:

Number of PFS events triggering final analysis: 667

Estimated number of patients in ITT population for Arm A versus Arm C: N852 

Of those, approximately 129 were randomized 2:1 to Arm A and Arm C during 
Stage 1 over a duration of 14 months between July 2016 and August 2017

The remaining approximately 723 patients were randomized 1:1 to Arm A and 
Arm C during Stage 2 over a duration of 19 months between January 2017 and 
July 2018

Median duration of PFS 6.8 months in Arm C and 9.1 months in Arm A

Dropout rate of 5% annually
Using simulations, the projected number of PFS events at the time of the final analysis is 
approximately 112 and 555 in Stage 1 and 2, respectively (17% and 83%, respectively, 
of 667 total events).  The resulting values for the weights to be used in the inverse 
normal p-value combination are:
w1(112 / 667) ½  0.410,     w2(1w12) ½ 0.912
The values to be used for the primary PFS analysis are summarized in the table below.
Table 4
Inverse Normal p-Value Combination for PFS Arm A vs. Arm C 
(ITT)
Stage 1
Stage 2
Combined
Number of Patients
129
723
852
Number of Events
112
555
667
Weights
0.410
0.912
-
p-value
p1
p2
1 Φ [ 0.410 Φ-1(1-p1) + 0.912 Φ-1(1-p2) ]
ITTintent-to-treat; PFSprogression-free survival.
Table shows estimates based on enrollment rates, randomization ratio, median PFS of 6.8 
and 9.1 months in Arm A and C, respectively, 5% drop-out annually.


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PFS Hazard Ratio
The HR, λA/λC, where λA and λC represent the hazard of a PFS event in Arm A and 
Arm C, respectively, will be estimated using a stratified Cox regression model on pooled 
data from Stage 1 and 2.  The stratification variables will be those used for the stratified 
log-rank testenrollment stage.  The 95% CI for the HR will be provided.  Results from 
analyses stratified only by enrollment stage or unstratified will also be provided.  HR1 
indicates treatment benefit in favor of atezolizumab plus chemotherapy.
Kaplan-Meier methodology will be used to construct PFS-event-free curves for both 
treatment arms and to estimate median PFS for both treatment arms.  The 
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
PFS.
4.4.2
Co-primary Efficacy Endpoint Overall Survival
4.4.2.1
OS in Arm A vs. Arm C
OS is defined as the time from randomization to death from any cause.  Data for patients 
who are not reported as having died at the time of analysis will be censored at the date 
last known to be alive.  Data for patients who do not have post-baseline information will 
be censored at the date of randomization plus 1 day.
The statistical methods for the comparison of OS in Arm A versus Arm C and the 
stratification factors will be the same as those described for PFS in Section 4.4.1.
The corresponding weights for the inverse normal p-value combination were determined 
using the following assumptions:

Number of deaths triggering final analysis: 667

Estimated number of patients in ITT population for Arm A versus Arm C: N852 

Of those, approximately 129 were randomized 2:1 to Arm A and Arm C during 
Stage 1 over a duration of 14 months between July 2016 and August 2017

The remaining approximately 723 patients were randomized 1:1 to Arm A and 
Arm C during Stage 2 over a duration of 19 months between January 2017 and 
July 2018

Median duration of OS 12 months in Arm C and 17.1 months in Arm A

Dropout rate of 5% annually
Using simulations, the projected number of deaths at the time of the interim and final 
analysis was determined as above for PFS.  The resulting weights for the first interim 
and final OS analysis were calculated prior to unblinding of the study Table 5. The 
weights to be used for the second interim OS analysis will be the same as those that 
were pre-specified for the first interim analysis, summarized in the table below. They 
were not recalculated based on projected events at the second interim OS because the 


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Sponsor was already unblinded at the time the second interim analysis was added to 
this SAP.
Table 5
Inverse Normal p-Value Combination for OS Arm A vs. Arm C (ITT)
Stage 1
Stage 2
Combined
Number of Patients
129
723
852
Interim Analysis OS A vs. C
Number of Events
89
413
502
Weights
0.420
0.908
-
Final Analysis OS A vs. C
Number of Events
104
563
667
Weights
0.394
0.919
-
ITTintent-to-treat; OSoverall survival.
AARM A; BArm B; CArm C.
Table shows estimates based on enrollment rates, randomization ratio, median OS of 12 and 
17.1 months in Arm A and Arm C, respectively, 5% drop-out annually.
OS Hazard Ratio Arm A vs. Arm C
The HR, λA/λC, where λA and λC represent the hazard of death in Arm A and Arm C, 
respectively, and the 95% CI will be determined using the same methods as described 
for PFS above. 
Kaplan-Meier methodology will be used to construct survival curves for both treatment 
arms and to estimate median OS for both treatment arms.  The Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median OS.
The duration of survival follow-up will be summarized for all patients in the analysis using 
descriptive statistics (median, range).  Duration of survival follow-up is defined as the 
survival time for all patients in the analysis (whether patient is alive or has died).
4.4.2.2
OS in Arm B vs. Arm C
The ITT population for Arm B versus Arm C does not include Stage 1 patients.  
Therefore, for the analyses of OS in Arm B versus Arm C, stratification factors will be 
those used for randomization in Stage 2.  The values for the stratification factors will be 
obtained from those entered in the IxRS at the time of randomization. Treatment 
comparisons will be based on the stratified log-rank test.  Otherwise, the same methods 
will be used as for analyses of OS in Arm A versus Arm C.
For the primary analysis of OS in the ITT population for Arm B versus Arm C, all 
available data for these patients (before and after implementation of the iDMC 
recommendation in Protocol WO30070 v6) will be included.


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The duration of follow-up in this population will be summarized as described above in 
Section 4.4.2.1.
4.4.2.3
OS in the PD-L1 IC2/3 Population
The analysis of OS in the PD-L1 IC2/3 population for Arm B versus Arm C will use the 
same methods as that for the ITT population for Arm B versus Arm C, except that PD-L1 
status will not be one of the stratification factors.  The analysis will include all available 
data for these patients (before and after implementation of the iDMC recommendation in 
Protocol WO30070 v6).
The duration of follow-up in this population will be summarized as described above in 
Section 4.4.2.1.
4.4.3
Secondary Efficacy Endpoints
4.4.3.1
Objective Response Rate
Objective response rate (ORR) is defined as the proportion of patients with a confirmed 
objective response, either CR or partial response (PR), observed on two consecutive 
assessments ≥ 28 days apart with the use of RECIST v1.1, based on investigator 
assessment.  Patients without any post-baseline tumor assessments will be considered 
non-responders.  The analysis population for ORR will be all randomized patients with 
measurable disease at baseline.
ORR will be compared between treatment arms (A vs. C and B vs. C) using the stratified 
Cochran Mantel-Haenszel test.  The 95% CI for the difference in ORRs between the two 
treatment arms will be computed using the normal approximation to the binomial 
distribution.  An estimate of ORR and its 95% CI will be calculated for each treatment 
arm using the Clopper-Pearson method.
In order to characterize responders, descriptive statistics (e.g., median, range) will be 
provided for time from randomization to response for patients with an objective response.
4.4.3.2
Duration of Response
DOR is defined, for patients with a confirmed objective response, as the time from the 
first documented objective response to documented disease progression with the use of 
RECIST v1.1, as determined by the investigator, or death from any cause, whichever 
occurs first.  Data for patients who are alive and who have not experienced disease 
progression at the time of analysis will be censored at the date of the last tumor 
assessment at which they were known to be progression free.  Because the 
determination of DOR is based on a non-randomized subset of patients, formal 
hypothesis testing will not be performed.
Median DOR and corresponding 95% CIs will be estimated using Kaplan-Meier 
methodology for each treatment arm.


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4.4.3.3
IRF-assessed PFS Arm A vs. Arm C
IRF-PFS is defined as the time from randomization to the first documented disease 
progression as assessed by an IRF using RECIST v1.1, or death from any cause, 
whichever occurs first.  Data for patients who have not experienced disease progression 
or death will be censored at the last tumor assessment.  Data for patients with no 
post-baseline tumor assessment will be censored at the date of randomization plus 
1 day.
As for investigator-assessed (INV)-PFS, an analysis of IRF-PFS will also be performed 
with the additional censoring rule for missed visits (see Section 4.4.1).  Data for patients 
with an IRF-PFS event who missed two or more scheduled assessments immediately 
prior to the event will be censored at the last tumor assessment prior to the missed visits.
The same methods as described above for INV-PFS will be used to determine the HR 
and 95% CI, median duration of IRF-PFS and 95% CI, and Kaplan Meier plots.
Analyses will be performed to evaluate the concordance between the two methods in 
patients who have a post-baseline assessment by both investigator as well as by IRF.
Sensitivity analyses for IRF-PFS are described in Section 4.4.5.1.
4.4.3.4
Timepoint Analysis of Progression-free Survival
The INV-PFS and IRF-PFS rates at 6 month intervals (e.g., 6 months, 1 year, etc.) in 
Arms A and C will be estimated by use of Kaplan-Meier methodology for each treatment 
arm, along with 95% CIs calculated by use of the standard error derived from 
Greenwood’s formula.  The 95% CI for the difference in PFS rates between Arms A and 
C will be estimated by use of the normal approximation method.
4.4.3.5
Timepoint Analysis of Overall Survival
The OS rates at 1, 2, and 3 years will be estimated by use of Kaplan-Meier methodology
for each treatment arm, along with 95% CIs calculated by use of the standard error 
derived from Greenwood’s formula.  The 95% CI for the difference in OS rates between 
Arms A and C or Arms B and C, respectively, will be estimated by use of the normal 
approximation method.
4.4.3.6
PFS in Arm B vs. Arm C
The HR for INV-PFS and IRF-PFS in the ITT population for Arm B versus Arm C and 95% 
CI will be estimated using a stratified Cox regression model with the stratification factors 
used for randomization in Stage 2. 
Kaplan-Meier methodology will be used to construct PFS-event-free curves for both 
treatment arms and to estimate median PFS for both treatment arms.  The 
Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
PFS.


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4.4.3.7
Patient-reported Outcomes
The European Organisation for Research and Treatment of Cancer (EORTC) 
Quality-of-Life Questionnaire Core 30 (QLQ-C30) data will be scored according to the 
EORTC scoring manual (Fayers 2001).  For all questionnaire subscales, if more than 50% 
of the constituent items are completed, a prorated score will be computed consistent 
with the scoring manuals and validation papers.  For subscales with less than 50% of the 
items completed, the subscale will be considered as missing.
Completion analysis will be performed in the ITT population for the overall EORTC 
QLQ-C30 questionnaire.  Completion rates will be summarized by number and 
proportion of patients among those expected to complete the QLQ-C30 at each time 
point.
Time to deterioration in global health status in the ITT population will be compared 
between treatment groups (Arm A vs. Arm C and Arm B vs. Arm C) as a secondary 
efficacy endpoint with use of the log rank test (descriptive, two-sided).  Deterioration in 
global health status is defined as a change from baseline of at least 10-points.  Data for 
patients without a post-baseline assessment will be censored at the date of 
randomization plus 1 day.  The HR will be estimated using a stratified Cox proportional 
hazards model and its 95% CI will be provided.  The stratification factors will be the 
same as those used for the OS analysis comparing Arm A versus Arm C (pooled 
Stage 1 and Stage 2) and Arm B versus Arm C, respectively (see Section 4.4.2).
Kaplan-Meier methodology will be used to estimate the median time to deterioration in 
health status, and Kaplan-Meier curves will be produced.
Time to deterioration of the physical function score on the EORTC QLQ-C30 will be 
analyzed in the ITT population using the same methodology as for time to deterioration 
in global health status.  Deterioration in physical function score is defined as a change 
from baseline of at least 10 points.
4.4.4
Exploratory Efficacy Endpoints
4.4.4.1
Disease Control Rate
Disease control rate (DCR) is defined as the proportion of patients with either confirmed 
objective response (CR or PR), or stable disease (SD) maintained for6 months, as 
determined by the investigator on the basis of RECIST v1.1.  The analysis methods for 
DCR will be the same as those for ORR.
4.4.4.2
Biomarker Analyses
Per protocol, the exploratory biomarker objectives of the study are to investigate:

Relationship between tumor tissue PD-L1 expression and measures of efficacy

Predictive, prognostic, and pharmacodynamics (PD) exploratory biomarkers in 
archival and/or fresh tumor tissue and blood and their association with disease 
status and/or response to study treatment.


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Exploratory biomarker analyses will be performed to examine the relationship between 
tumor tissue PD-L1 expression and measures of efficacy.
Additionally, predictive, prognostic and pharmacodynamics exploratory biomarkers in 
archival and/or fresh tumor tissue and/or blood will be examined for their association 
with disease status and/or clinical outcomes.
The tumor biomarkers include but are not limited to tissue tumor mutational burden
(tTMB) using the cut-offs of10 mutations/MB and16 mutations/MB separately (given 
data availability), CD103, and CD8, as defined by IHC, quantitative reverse 
transcriptase−polymerase chain reaction (qRT−PCR), or other methods.  Additional PD
analyses of predictive, prognostic, and exploratory biomarkers in archival and/or fresh 
tumor tissue and blood and their association with disease status, mechanisms of 
resistance, and/or response to study treatment will be conducted as appropriate. These 
exploratory analyses may be provided in a separate report.
4.4.4.3
QLQ-C30 Function Scores
Disease and treatment burden as measured by global health status, physical function, 
and other EORTC QLQ-C30 scales will be analyzed in the PRO-evaluable population. 
Data will be summarized descriptively as absolute mean scores and for single scores as 
percent of patients per category at each timepoint and at time to treatment 
discontinuation due to adverse events, clinical progression and radiographic progression 
(per protocol definition).
The number and proportion of patients with a clinically meaningful change, defined as 
a10-point change of the score, for global health status and physical function will be 
summarized by treatment arm at each timepoint and at time to treatment discontinuation 
due to adverse events, clinical progression and radiographic progression (per protocol 
definition). The 95% CI around the proportion will be calculated using the 
Clopper-Pearson method for each treatment arm.
Repeated measures mixed-effects model will be used for comparing the global health 
status and physical function scores between treatment arms. The model will include a 
term for intercept, a term for linear time trend, a term for treatment group, and a term for 
treatment-by-time interaction. Time points following treatment discontinuation for any 
reason at the patient level or timepoints with less than 20% patients who completed 
these scales, where all subsequent time points also have less than 20% completion will 
be excluded.
4.4.5
Sensitivity Analyses
4.4.5.1
Analysis of PFS Accounting for Non-Protocol Anti-Cancer 
Therapy
The impact of non-protocol anti-cancer therapy on INV-PFS and IRF-PFS (Arms A vs. C) 
will be assessed depending on the number of patients who receive non-protocol therapy 


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before a PFS event.  If5% of patients received non-protocol therapy before a PFS 
event in Arms A or C, a sensitivity analysis will be performed for the comparisons 
between treatment arms in which patients who receive non-protocol therapy before a 
PFS event will be censored at the last tumor assessment date before receipt of 
non-protocol therapy.
4.4.5.2
Analysis of OS Accounting for Non-Protocol Anti-Cancer 
Therapy
The impact of subsequent non-protocol anti-cancer therapy on OS (Arms A vs. C and 
Arms B vs. C) will be assessed depending on the number of patients who receive 
non-protocol anti-cancer therapy.  If more than 10% of patients in the control arm have 
received a non-protocol anti-cancer (immune-) therapy that is considered to have an 
effect on their OS, the following analyses may be performed to compare treatment arms:

OS in patients who switched will be discounted according to a range of possible 
effects on OS of subsequent non-protocol therapy.

Additional sensitivity analyses may be conducted if deemed necessary.
4.4.5.3
Analysis of OS in Arm B vs. Arm C Accounting for Treatment 
Changes after Protocol Version 6
All patients in Arm B who were being treated with open-label atezolizumab monotherapy 
at the time of approval of Protocol v6 had the option of requesting unblinding of their 
PD-L1 status (see Section 2.2).  If they were IC0 or 1, then a treatment alternative of 
atezolizumab plus platinum (cisplatin or carboplatin) and gemcitabine chemotherapy was 
provided if this was considered in the patient’s best interest.
If a substantial number of such treatment switches occurred, additional sensitivity 
analyses may be performed to account for this using the same approach as described in 
Section 4.4.5.2.
A sensitivity analysis will also be performed on patients randomized to Arm B or Arm C 
prior to implementation of Protocol v6 that will include their data only up to the time of 
implementation of the iDMC recommendation.
4.4.5.4
Analyses of Impact of Loss to Follow-Up on OS
The impact of loss to follow-up on OS will be assessed depending on the number of 
patients who are lost to follow-up.  For each comparison (Arms A vs. C; Arms B vs. C),
if5% of patients are lost to follow-up for OS in any treatment arm, a sensitivity analysis 
will be performed for the comparisons between treatment arms in which patients who are 
lost to follow-up will be considered as having died at the last date they were known to be 
alive.


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4.4.6
Subgroup Analyses
4.4.6.1
Subgroup Analyses of PFS and OS
Subgroup analyses will assess the consistency of the study results for the duration of 
INV-PFS (Arms A vs. C) and OS (Arms A vs. C and Arms B vs. C) across subgroups of 
the ITT populations.  Subgroups will be defined by 

Demographics (e.g., age, sex, and race/ethnicity)

Baseline characteristics, e.g.,
–
ECOG performance status 
–
Time from prior chemotherapy 

Stratification factors: 
–
Bajorin model risk factor score/liver metastasis 
–
Investigator choice of chemotherapy 
–
PD-L1 IHC IC status

Enrollment stage
Summaries of INV-PFS and OS, including HRs estimated from Cox proportional hazards 
models and Kaplan-Meier estimates of median INV-PFS and OS, will be produced 
separately for each level of the categorical variables and displayed in a Forest plot.
Analyses including Stage 1 and 2 data will be stratified by enrollment stage.  Analyses 
including only one enrollment stage will be unstratified.
Kaplan-Meier plots will be produced for selected subgroups.
Additional subgroup analyses may be conducted as appropriate.
4.4.6.2
Subgroup Analyses by Cisplatin-eligibility and Choice of 
Platinum Therapy
The determination of cisplatin eligibility of patients was to be made prior to 
randomization according to the Galsky criteria as defined in Protocol Section 4.2.  
Patients who met at least one of the following criteria were considered ineligible for 
cisplatin and should be treated with carboplatin plus gemcitabine if randomized to Arm A 
or Arm C; however, the final decision was made by the investigator:

Impaired renal function (GFR30 but60 mL/min); GFR was to be assessed by 
direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if 
not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)

NCI CTCAE v4.0 Grade2 audiometric hearing loss of 25 decibels at two 
contiguous frequencies

NCI CTCAE v4.0 Grade2 peripheral neuropathy (i.e., sensory alteration or 
paresthesia, including tingling)

ECOG performance status of 2


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During the study, patients were allowed to switch from cisplatin to carboplatin 
chemotherapy if they became ineligible for cisplatin due to toxicity, or from carboplatin to 
cisplatin chemotherapy in the event that patient became eligible to receive cisplatin.
Subgroups will be defined based on cisplatin-eligibility per Galsky criteria and actual 
investigator choice of chemotherapy.  Summaries will be provided by subgroup in the 
ITT populations for comparisons of Arm A versus Arm C and Arm B versus Arm C, 
including key demographic and baseline characteristics.  Data on patients switching from 
cisplatin to carboplatin or vice versa will also be summarized.
Efficacy analyses, including of INV-PFS (Arm A vs. Arm C) and OS (Arm A vs. Arm C 
and Arm B vs. Arm C) will be performed in these subgroups using the same methods as 
those described in Section 4.4.6.1. Because these analyses will be based on a 
non-randomized subset of patients, formal hypothesis testing will not be performed.
4.4.6.3
Subgroup Analysis in Patients with a PD-L1 status of IC0 or IC1 
Randomized to Arm B after Protocol Version 6
Efficacy data for patients with a PD-L1 status of IC0 or IC1 randomized to Arm B after 
implementation of the iDMC recommendation in Protocol WO30070 v6 will not be 
included in any formal efficacy analyses.  Since this subgroup includes10 patients, 
descriptive listings will be provided.
4.5
PHARMACOKINETIC ANALYSES
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized.  Descriptive statistics will include means, medians, ranges, SDs, and %CV, 
as appropriate.  Additional PK analyses may be conducted if deemed appropriate.
4.6
SAFETY ANALYSES
Unless specified otherwise, safety analyses described below will be conducted for the 
safety population (see Section 4.1.6).  The safety-evaluable population is defined as 
patients who received any amount of any component of the study treatments.  Patients 
will be analyzed according to the treatment received.  In particular, patients randomized 
to the monotherapy arm after approval of Protocol WO30070 v6, who received 
combination open-label atezolizumab and chemotherapy will be pooled with patients in 
Arm A for safety analyses. For the analyses of safety, data from patients enrolled before 
and after Protocol WO30070 v3, will be pooled by treatment arm.
4.6.1
Exposure to Study Medication
Study drug exposure, including treatment duration, number of cycles, and dose intensity, 
will be summarized for each treatment arm and for each study drug with descriptive 
statistics.


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4.6.2
Adverse Events
Verbatim description of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms.  AEs will be graded by the investigator according 
to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v4.0.  Treatment-emergent AEs will be summarized by mapped term, 
appropriate thesaurus level, NCI CTCAE grade and treatment arm.  Multiple 
occurrences of the same event will be counted once at the maximum grade.  All reported 
AEs, SAEs, Grade 5 AEs, treatment-related AEs (as assessed by the investigator), 
severe AEs (Grade3), adverse events of special interest (AESIs), AEs leading to study 
drug discontinuation, and AEs leading to interruption or reduction will be summarized.
All listings of AEs will include all AEs with onset on or after the first study drug treatment 
up to the data cut-off date.
All deaths and causes of death will be summarized by treatment arm overall as well as, 
during the study treatment period and those reported during the follow-up period after 
treatment discontinuation.
4.6.3
Laboratory Data
Laboratory data will be summarized by treatment arm.  Laboratory data will be graded 
according to NCI CTCAE and will be summarized descriptively with shift tables from 
baseline to worst value post-baseline.
4.6.4
Vital Signs
Changes from baseline in selected vital signs will be summarized by treatment arm.  
ECOG performance status will also be summarized over time.
4.6.5
Anti-Therapeutic Antibodies
Incidence of anti-therapeutic antibodies (ATAs) against atezolizumab will be summarized.  
The analyses of pharmacokinetics, key efficacy, and safety by ATA status may be 
conducted to explore the potential impact of immunogenicity.
4.6.6
Subgroup Analyses
Analyses of safety in selected subgroups, e.g., by cisplatin-eligibility and investigator 
choice of chemotherapy (see Section 4.4.6.2), will be provided.


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5.
REFERENCES
Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med 2009;28:586-604.
Burman CF, Sonesson C, Guilbaud O, et al. A recycling framework for the construction 
of bonferroni-based multiple tests. Stat Med 2009;28:739-61.
Wassmer G. Planning and analyzing adaptive group sequential survival trials. Biom J 
2006;48:714-29.
Wassmer G and Brannath W. (2016). Group Sequential and Confirmatory Adaptive 
Designs in Clinical Trials. Springer.
Fayers PM. Interpreting quality of life data: population-based reference data for the 
EORTC QLQ-C30. Eur J Cancer 2001;37:13314.


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Appendix 1 Protocol Synopsis
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB 
(ANTIPD-L1 ANTIBODY) AS MONOTHERAPY AND IN 
COMBINATION WITH PLATINUM-BASED CHEMOTHERAPY 
IN PATIENTS WITH UNTREATED LOCALLY ADVANCED OR 
METASTATIC UROTHELIAL CARCINOMA
PROTOCOL NUMBER:
WO30070
VERSION NUMBER:
8
EUDRACT NUMBER:
2016-000250-35
IND NUMBER:
120827
TEST PRODUCT:
Atezolizumab (RO5541267), gemcitabine, carboplatin, cisplatin
PHASE:
Phase III
INDICATION:
Urothelial cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This is a Phase III, multicenter, randomized, placebo-controlled, partially blind study designed to 
evaluate the efficacy of atezolizumab given as monotherapy or in combination with 
platinum-based chemotherapy versus placebo in combination with platinum-based 
chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who have not 
received prior systemic therapy.
Efficacy Objectives
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus 
platinum-based chemotherapy compared with placebo plus platinum-based chemotherapy on 
the basis of the following endpoints:

Co-primary endpoints of progression-free survival (PFS) and overall survival (OS)
PFS is defined as the time from randomization to the first documented disease 
progression as determined by the investigator with use of Response Evaluation Criteria 
in Solid Tumors Version 1 (RECIST v1.1), or death due to any cause, whichever occurs 
first.
OS is defined as the time from randomization to death due to any cause.
In addition, a primary efficacy objective is to evaluate the efficacy of atezolizumab monotherapy 
compared with placebo plus platinum-based chemotherapy on the basis of OS, as defined 
above.
The secondary efficacy objectives for this study are to evaluate the efficacy of atezolizumab 
given as either monotherapy or in combination with platinum-based chemotherapy compared 
with placebo in combination with platinum-based chemotherapy on the basis of the following 
endpoints:


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
Objective response rate (ORR), defined as the proportion of patients with a confirmed 
objective response, either complete response (CR) or partial response (PR), observed on 
two assessments 28 days apart per RECIST v1.1, based on investigator assessment

Duration of response (DOR), defined for patients with an objective response as the time 
from the first documented objective response to documented disease progression per 
RECIST v1.1, based on investigator assessment, or death due to any cause, whichever 
occurs first

IRF-PFS, defined as the time from randomization to the first documented disease 
progression as determined by blinded independent central review with use of RECIST v1.1, 
or death due to any cause, whichever occurs first

Investigator-assessed (INV-PFS) in patients treated with atezolizumab monotherapy 
compared with patients treated with placebo plus platinum-based chemotherapy

OS rate at 1 year

PFS rate at 1 year

Time to deterioration in global health status as measured by the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 
(QLQ-C30)

Time to deterioration in physical function as measured by the EORTC QLQ-C30
Exploratory Efficacy Objectives
The exploratory efficacy objectives for this study are to evaluate the efficacy of atezolizumab 
given as either monotherapy or in combination with platinum-based chemotherapy compared 
with placebo in combination with platinum-based chemotherapy on the basis of the following 
endpoints:

Disease control rate (DCR), defined as the proportion of patients with confirmed CR or PR 
as best response, or stable disease maintained for 6 months, per RECIST v1.1

Relationship between tumor tissue programmed deathligand 1 (PD-L1) expression and 
measures of efficacy

Predictive, prognostic, and pharmacodynamic exploratory biomarkers in archival and/or 
fresh tumor tissue and blood and their association with disease status and/or response to 
study treatment

Disease and treatment burden as measured by the symptom (e.g., pain, fatigue) and 
function scores from the QLQ-C30
An additional exploratory objective is to characterize patients who are able to continue 
treatment past progression by RECIST v1.1 as permitted per protocol and to describe clinical 
outcomes by treatment arm using modified RECIST, such as ORR, DOR, DCR, and PFS.
Health Economics Objective
Health status will be measured using the EuroQol 5-Dimension, 5-Level version (EQ-5D-5L) 
questionnaire to be included in health economic modeling.  As such, data from the EQ-ED-5L 
will not be reported in the Clinical Study Report.
Safety Objectives
The safety objectives for this study are to evaluate the safety and tolerability of atezolizumab 
given as either monotherapy or in combination with platinum-based chemotherapy compared 
with placebo plus platinum-based chemotherapy on the basis of the following:

Incidence, nature, and severity of adverse events graded according to National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0

Changes in vital signs, and clinical laboratory results


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Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the pharmacokinetics of 
atezolizumab when administered as monotherapy or in combination with platinum-based 
chemotherapy in patients who are treatment-naive:

PK parameters for atezolizumab include maximum serum concentration and minimum 
serum concentration when appropriate, as data allow.
Immunogenicity Objective
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab 
as monotherapy and in combination with platinum-based chemotherapy on the basis of the 
following endpoint:

Incidence of anti-therapeutic antibodies (ATAs) during the study relative to the prevalence 
of ATAs at baseline
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
detectable ATAs on the basis of the following endpoint:

Correlation between ATA status and efficacy, safety, and PK endpoints
Study Design
Description of Study
This is a Phase III, multicenter, randomized, placebo-controlled, partially blind study 
(IMvigor130) designed to evaluate the safety and efficacy of atezolizumab given as 
monotherapy or in combination with platinum-based chemotherapy versus placebo in 
combination with platinum-based chemotherapy in patients with locally advanced or metastatic 
urothelial carcinoma who have not received prior systemic therapy.
Treatment with platinum-based chemotherapy can continue until progressive disease (PD) per 
RECIST v1.1 or unacceptable toxicity per investigator discretion.  In the case of CR, only two 
more cycles of platinum-based chemotherapy will be administered after the response 
confirmation.  In specific circumstances, treatment may continue beyond disease progression.
No crossover will be allowed from the control arm to either experimental arm (Arms A and B).
Patients should be considered eligible to receive treatment with platinum-based chemotherapy 
(either gemcitabine with cisplatin or gemcitabine with carboplatin) and have measurable disease, 
defined by RECIST v1.1.
Note, the study was initially implemented with randomization to two treatment arms (carboplatin 
plus gemcitabine with or without atezolizumab) in patients who were ineligible for cisplatin-
based chemotherapy.  In Protocol WO30070, Version 3, a third treatment arm was added 
(open-label atezolizumab monotherapy).  In addition, the eligibility criteria were expanded to 
also allow patients who are eligible for cisplatin-based chemotherapy to enter the study.  
Protocol WO30070, Version 3 was implemented while recruitment was ongoing.  Patients 
recruited into the study prior to Version 3 will be included in the final analysis.
Tumor specimens from eligible patients will be prospectively tested for PD-L1 
immunohistochemistry (IHC) expression by a central laboratory prior to randomization.  The IHC 
scores will have three categories (tumor-infiltrating immune cell [IC]0, IC1, IC2/3).  Sponsor, 
patients, and investigators will be blinded to the PD-L1 expression status, but the Sponsor will 
be able to view aggregate PD-L1 expression data.  An exception is the case for any new 
patients enrolled in Arm B, in which PD-L1 status will be unblinded to the patient and 
investigator at the time of randomization.  However, the Sponsor will not be able to review these 
scores (see below for further information regarding Protocol Version 6 update based on iDMC 
recommendation).  The study will enroll all eligible patients whose tissue is evaluable for 
expression testing, regardless of PD-L1 expression status.
This study will enroll approximately 1200 patients at approximately 229 sites globally.  
Following implementation of Protocol WO30070, Version 3, patients will be randomized in a 
1:1:1 ratio to receive one of the following: 

Arm A (experimental arm):  blinded atezolizumab in combination with open-label 
platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin)


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42/Statistical Analysis Plan WO30070

Arm B (experimental arm): open-label atezolizumab monotherapy

Arm C (control arm):  blinded placebo in combination with open-label platinum-based 
chemotherapy (gemcitabine with either cisplatin or carboplatin)
Based on an ad-hoc review of survival data of all patients randomized in the study up to 
12 March 2018, the study iDMC recommended closure of Arm B (atezolizumab monotherapy) to 
further accrual of all patients with a PD-L1 expression status of IC0 or IC1.  The iDMC did not 
recommend a change in therapy for patients already randomized to monotherapy on study.
The iDMC recommendation also stated that patients with a PD-L1 expression status of IC2/3 
can continue to be randomized to Arm A, B, or C and that Arms A and C should remain 
unchanged (open to all patients regardless of PD-L1 status). 
Randomization to the three arms in a 1:1:1 ratio will continue regardless of PD-L1 status.
Prior to randomization, all patients will be informed per the consent form that if randomized to 
Arm B (atezolizumab monotherapy) and are determined to have a tumor PD-L1 expression 
status of IC0 or IC1, they will receive chemotherapy combined with atezolizumab instead of 
atezolizumab monotherapy.  The consent will also inform patients who are randomized to Arm B, 
are found to have with a tumor PD-L1 expression status of IC0 or IC1, and who are not willing to 
undergo treatment with atezolizumab with chemotherapy should consider treatment outside of 
the trial rather than proceeding with trial enrollment. 
For all new patients randomized to Arm B (open-label atezolizumab monotherapy) after 
approval of Protocol WO30070, Version 6:

The PD-L1 status will be unblinded to the investigator and patient at the time of 
randomization.

Patients whose PD-L1 expression status of IC2/3 will receive atezolizumab monotherapy.

Patients with a PD-L1 expression status of IC0 or IC1 will receive open-label atezolizumab 
plus platinum (carboplatin or cisplatin) and gemcitabine chemotherapy instead of 
atezolizumab monotherapy.
If a patient with a PD-L1 expression status of IC0 or IC1 subsequently wished to receive 
standard-of-care chemotherapy instead of atezolizumab plus platinum and gemcitabine 
chemotherapy will be able to receive standard-of-care chemotherapy of their choice (to be 
provided outside of the protocol) and continue on survival follow up.
For all patients in Arm B who are currently being treated with open-label atezolizumab 
monotherapy at the time of approval of Protocol WO30070, Version 6:

Patients will be informed that the iDMC has not recommended any changes to therapy for 
those already randomized to atezolizumab monotherapy.

PD-L1 status may be unblinded to the patient and the investigator upon request. 

Patients with PD-L1 expression status of IC2/3 will continue receiving atezolizumab 
monotherapy.

Patients with PD-L1 expression status of IC0 or IC1 are recommended to continue with 
atezolizumab monotherapy, as the iDMC did not recommend a change in therapy for 
patients already randomized to monotherapy on study. 
However, if the patient after discussion of benefit-risk with the treating physician 
determines that continuation of atezolizumab monotherapy is not considered beneficial, 
a treatment alternative of atezolizumab plus platinum (cisplatin or carboplatin) and 
gemcitabine chemotherapy will be provided.  These patients should then be treated the 
same as patients in Arms A and C. 
If the decision is made to unblind the patient and add platinum (cisplatin or carboplatin) 
and gemcitabine chemotherapy to the regimen, it must be added before the patient 
has known progressive disease.  Chemotherapy cannot be added to patients in Arm B 
with documented progressive disease within the study.

Patients will also have the option to stop study therapy and receive standard-of-care 
treatment outside of the study by their physician.


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43/Statistical Analysis Plan WO30070

All patients (including those who choose to stop atezolizumab monotherapy) are requested 
to continue in the study for survival follow up.
Prior to randomization, the investigator will select which chemotherapy the patient should 
receive (gemcitabine and carboplatin vs. gemcitabine and cisplatin) if the patient is randomized 
to Arm A or Arm C.  The Galsky criteria should be used to guide determination of cisplatin 
ineligibility.  The criteria to determine ineligibility for cisplatin should be the same as the criteria 
used in the initial implementation of the study.
Randomization will be stratified by the following factors:

PD-L1 status (IC0 vs. IC1 vs. IC2/3)

Bajorin model risk factor score/liver metastasis (0 vs. 1 vs. 2 or patients with liver 
metastasis) 

Investigator-determined chemotherapy (gemcitabine and carboplatin vs. gemcitabine and 
cisplatin)
Gemcitabine will be administered at a dose of 1000 mg/m2 by intravenous (IV) infusion on 
Day 1 and Day 8 of each 21-day cycle.
Carboplatin will be administered at area under the concentrationtime curve (AUC) 4.5 by IV 
infusion on Day 1 of each 21-day cycle.
Cisplatin will be administered at a dose of 70 mg/m2 by IV infusion on Day 1 of each 21-day
cycle.  Split dosing of cisplatin is not permitted.
All visits and infusions may be administered with a window of 3 days, except for the Day 8 
visit.  The Day 8 dose of gemcitabine may be given no earlier than Day 7 but may be given up 
to Day 11 (1 to 3) of a cycle.
Gemcitabine and platinum chemotherapy (carboplatin or cisplatin) will be administered until 
investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.
For patients who receive chemotherapy and who have a CR, only two more cycles of 
chemotherapy will be administered after the response confirmation.
For patients who receive chemotherapy and who have a PR or stable disease, 
chemotherapy administration may be discontinued after completion of six cycles, if 
necessary, to comply with institutional guidelines.
If the initial protocol doses of chemotherapy agents differ from institutional guidelines or local 
label, the initial doses may be modified to achieve compliance.
Atezolizumab will be administered at a fixed dose of 1200 mg by IV infusion on Day 1 of each 
21-day cycle until investigator-assessed disease progression per RECIST v1.1. 
Placebo for atezolizumab (Arm C) will be administered by IV infusion on Day 1 of each 21-day 
cycle until investigator-assessed disease progression per RECIST v1.1.  In specific 
circumstances, treatment may continue beyond disease progression.  No crossover will be 
allowed from the control arm to either experimental arm (Arms A and B).
Patients will undergo scheduled tumor assessment at baseline and every 9 weeks (from 
initiation of the first dose) thereafter for 54 weeks after randomization.  After 54 weeks, patients 
will undergo tumor assessment every 12 weeks until disease progression per RECIST v1.1, 
death, study termination by the Sponsor, or withdrawal of consent, whichever occurs first.  
Patients must discontinue treatment at the first occurrence of radiographic progression, per 
RECIST v1.1, with the following exception:  Patients who have achieved a PR or CR of target 
lesions and who develop new lesions (3) that are amenable to surgery or ablative techniques 
(e.g., radiotherapy, radiofrequency ablation) may continue to receive study treatment if they 
demonstrate no further progression of disease at the next imaging assessment and continue to 
demonstrate clinical benefit per investigator.  Because gemcitabine is not indicated for use in 
combination with radiation therapy and has been shown to cause excess toxicity (mucositis, 
pneumonitis) as well as radiation recall when administered in close proximity to radiation 
therapy, patients who continue treatment with gemcitabine should not receive radiation to ports 
that include a significant proportion of lung or mucosal surface (esophagus, intestine).  In the 
absence of disease progression, tumor assessments should continue, regardless of whether 


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44/Statistical Analysis Plan WO30070
patients start new anti-cancer therapy, until death, loss of follow-up, withdrawal of consent, or 
study termination by the Sponsor, whichever occurs first.  Follow-up data capture, including 
subsequent anti-cancer therapies (including targeted therapies and immunotherapies), will 
continue for each patient until death, loss of follow-up, withdrawal of consent, or study 
termination by the Sponsor, whichever occurs first.
Patients are required to undergo tumor biopsy sample collection, if clinically feasible as 
assessed by investigators, at the first evidence of radiographic disease progression.  These 
data will be used to confirm that radiographic findings are consistent with the presence of tumor.  
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 to treatment.
All primary imaging data used for tumor assessment will be collected by the Sponsor to enable 
a centralized independent review.
Safety assessments will include the incidence, nature, and severity of adverse events, vital 
signs and laboratory abnormalities graded per the NCI CTCAE v4.0. Laboratory safety 
assessments will include the regular monitoring of hematology and blood chemistry.  Serum 
samples will be collected to monitor atezolizumab pharmacokinetics and to detect the presence 
of antibodies to atezolizumab.  Patient samples, including archival tumor tissues, as well as 
serum, plasma, and blood, will be collected for future exploratory biomarker assessments.
An external independent Data Monitoring Committee (iDMC) will evaluate safety data according 
to policies and procedures detailed in an iDMC Charter.
After approximately 1200 patients have been randomized, enrollment in sites will be closed. 
Number of Patients
Approximately 229 sites globally will participate in the study, and approximately 1200 patients
will be randomized.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Considered to be eligible to receive platinum-based chemotherapy, in the investigator’s 
judgment

Eastern Cooperative Oncology Group (ECOG) performance status of 2 

Able to comply with the study protocol, in the investigator’s judgment

Histologically documented, locally advanced (T4b, any N; or any T, N 23) or metastatic 
urothelial carcinoma (M1, Stage IV) (also termed TCC or UCC of the urinary tract; including 
renal pelvis, ureters, urinary bladder, and urethra)
Patients with mixed histologies are required to have a dominant transitional cell pattern.
Locally advanced bladder cancer must be inoperable on the basis of involvement of 
pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis 
(N2N3).

Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin 
blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology 
report, for central testing and determined to be evaluable for tumor PD-L1 expression prior 
to study enrollment; patients who have fewer than 15 unstained slides available at baseline 
(but no fewer than 10) may be eligible following discussion with the Medical Monitor.
Tumor tissue should be of good quality based on total and viable tumor content.  Fine-
needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and 
lavage samples are not acceptable.  For core-needle biopsy specimens, at least three 
cores should be submitted for evaluation.
Transurethral Resection of Bladder Tumor (TURBT) specimens must contain a muscle 
invasive component (i.e., T2 or greater) of the bladder tumor as verified by local
pathology review.  If the TURBT specimens do not contain a muscle invasive 


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component, then specimens obtained at the time of cystectomy/nephroureterectomy 
(i.e., pT2 or greater) or metastatic spread (i.e., sample from a metastatic lesion) will be 
required prior to randomization.  An archival specimen, if available, should also be 
submitted.
Patients who do not have tissue specimens that meet eligibility requirements may 
undergo a biopsy during the screening period.  Acceptable samples include core needle 
biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, or 
forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable.
Patients who have additional tissue samples from procedures performed at different 
times during the course of their urothelial carcinoma may also submit these samples for 
central testing.  Tissue samples that are obtained at multiple times for individual 
patients may contribute to an improved understanding of the dynamics of PD-L1 
expression and relationship with intervening anti-cancer therapy.  In situations where 
multiple specimens were received from different sites or at different times, the highest
score will be used for stratification and for subsequent analyses.

No prior chemotherapy for inoperable, locally advanced, or metastatic urothelial carcinoma
For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation 
for urothelial carcinoma, a treatment-free interval 12 months between the last 
treatment administration and the date of recurrence is required in order to be 
considered treatment naive in the metastatic setting.
Prior local intravesical chemotherapy or immunotherapy is allowed if completed at least 
4 weeks prior to the initiation of study treatment.

Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions should not be counted as target lesions unless there has 
been demonstrated progression in the lesion since radiotherapy and no other lesions 
are available for selection as target lesions.

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 28 days prior to the first study treatment:
ANC 1500 cells/L (without granulocyte colony-stimulating factor support within 
2 weeks prior to Cycle 1, Day 1)
WBC counts 2500 cells/L 
Lymphocyte count 300 cells/L
Platelet count 100,000 cells/L (without transfusion within 2 weeks prior to 
Cycle 1, Day 1)
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
Patients with a solitary kidney or chronic kidney disease with low erythropoietin 
production may use erythropoietin-stimulating agents.
AST, ALT, and alkaline phosphatase 2.5the upper limit of normal (ULN), with the 
following exceptions:
Patients with documented liver metastases:  AST and/or ALT 5ULN
Patients with documented liver or bone metastases:  alkaline phosphatase 
5 ULN
Serum bilirubin 1.5 ULN
Patients with known Gilbert disease who have serum bilirubin level 3ULN may 
be enrolled.


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46/Statistical Analysis Plan WO30070
PTT/aPTT 1.5 ULN 
PT 1.5 ULN or INR 1.7
This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation should be on a stable dose.
Calculated creatinine clearance 30 mL/min (Cockcroft-Gault formula)
Serum calcium 3 mmol/L
For patients with serum albumin 40 g/L, corrected serum calcium must be ULN 

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the treatment period and for at least 6 months after the last dose of 
carboplatin, cisplatin, or gemcitabine or for 5 months after the last dose of atezolizumab
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, established and proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical study and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for at least 6 months after the last dose 
of gemcitabine and/or carboplatin, and/or cisplatin.  Men must refrain from donating 
sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical study and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-Specific Exclusions

Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 
3 weeks prior to initiation of study treatment; the following exceptions are allowed:
Palliative radiotherapy for bone metastases or soft tissue lesions should be 
completed 7 days prior to baseline imaging.
Hormone-replacement therapy or oral contraceptives

Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 28 days prior to enrollment

Active or untreated CNS metastases as determined by computed tomography (CT) or 
magnetic resonance imaging evaluation during screening and prior radiographic 
assessments
Patients with treated asymptomatic CNS metastases are eligible, provided they meet all 
of the following criteria:
Evaluable or measurable disease outside the CNS


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No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus 
(optic nerves and chiasm)
No history of intracranial or spinal cord hemorrhage
No ongoing requirement for corticosteroid as therapy for CNS disease; 
anti-convulsants at a stable dose are allowed
No evidence of significant vasogenic edema
No stereotactic radiation, whole-brain radiation or neurosurgical resection within 
4 weeks prior to Cycle 1, Day 1
Radiographic demonstration of interim stability (i.e., no progression) between the 
completion of CNS-directed therapy and the screening radiographic study
Screening CNS radiographic study 4 weeks since completion of radiotherapy or 
surgical resection and 2 weeks since discontinuation of corticosteroids

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled tumor-related pain
Patients who require pain medication must be on a stable regimen at study entry.
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment.
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 hypercalcemia defined as any one or more of the following criteria:
1.5 mmol/L ionized calcium 
Serum calcium 3 mmol/L 
Corrected serum calcium ULN (if serum albumin 40 g/L)
Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or 
denosumab
Patients who are receiving bisphosphonate therapy or denosumab specifically to 
prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible.

Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1
Patients with localized prostate cancer (defined as Stage pT2c, Gleason score 7, 
and prostate-specific antigen (PSA) at prostate cancer diagnosis 20 ng/mL) treated 
with curative intent and without PSA recurrence are eligible.
Patients with pre-existing low-risk prostate cancer (defined as Stage cT1/T2a, Gleason 
score 6 and PSA 10 ng/mL) who are treatment-naive and undergoing active 
surveillance are eligible.
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death 5% at 5 years) are eligible provided they meet all of the following 
criteria:
Malignancy treated with expected curative intent (e.g., adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any 
disease-specific tumor markers


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General Medical Exclusions

Life expectancy of 12 weeks

Pregnant or lactating, or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study drug.

Serum albumin 25 g/L
Exclusion Criteria Related to Atezolizumab

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation

History of autoimmune disease including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid-replacement hormone may be eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis) 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 (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids)

Patients with prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class III or greater), myocardial infarction within 3 months prior to randomization, unstable 
arrhythmias, or unstable angina

Known left ventricular ejection fraction (LVEF) 40%
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF 40%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.  Patients with a history of clinically significant cardiac disease (including 
anatomic abnormality, coronary disease, congestive heart failure, abnormal LVEF, 
arrhythmia, or abnormal ECG) will be required to undergo a screening echocardiogram.

Positive test for HIV

Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at 
screening) or hepatitis C 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as having a negative HBsAg test and a positive antibody to hepatitis B core antigen 
[anti-HBc] antibody test) are eligible.  A negative HBV DNA test must be obtained in 
these patients prior to Cycle 1, Day 1.


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Patients who test positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.

Active tuberculosis

Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia

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 chronic obstructive pulmonary disease or for dental extraction) are eligible.

Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a 
major surgical procedure during the course of the study other than for diagnosis.

Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 
Influenza vaccination should be given during influenza season only (approximately 
October through May in the Northern Hemisphere and approximately April through 
September in the Southern Hemisphere).  
Patients must agree not to receive live, attenuated influenza vaccine within 28 days 
prior to initiation of study treatment, during treatment, or within 5 months after the last 
dose of atezolizumab. 

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications

Prior treatment with CD137 agonists, antiCTLA-4, antiprogrammed death-1 (PD-1), or 
antiPD-L1 therapeutic antibody or pathway-targeting agents

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 shorter, prior to 
Cycle 1, Day 1.

Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks 
prior to Cycle 1, Day 1 or anticipated requirement for systemic immunosuppressive 
medications during the study
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, physiologic replacement doses of glucocorticoids 
(i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed.
End of Study 
The end of this study is defined as the date when the required number of deaths has been 
observed for the final analysis of OS in the global (main) study’s intent-to-treat (ITT) population.  
Additionally, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the global (main) study, from randomization of the first patient to the end of 
the study, is expected to be approximately 44 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are atezolizumab, placebo, 
gemcitabine, carboplatin, and cisplatin.  
Test Products (Investigational Drugs)
Atezolizumab
The dose level of atezolizumab in this study is 1200 mg administered by IV infusion every 
3 weeks (q3w).  Administration of atezolizumab and placebo will be performed in a setting with 


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50/Statistical Analysis Plan WO30070
emergency medical facilities and staff who are trained to monitor for and respond to medical 
emergencies.
Gemcitabine
Gemcitabine will be administered according to the local prescribing information.  The starting 
dose of gemcitabine will be 1000 mg/m2, administered by IV infusion on Day 1 and Day 8 of 
each 21-day cycle.  The Day 8 dose of gemcitabine may be given no earlier than Day 7 but may 
be given up to Day 11 (1 to 3) of a cycle.  A change of body weight 5% compared to 
previous measured weight requires that the dose be re-calculated.
Carboplatin
Carboplatin will be administered according to the local prescribing information.  The starting 
dose of carboplatin will be calculated to achieve an AUC of 4.5, administered by IV infusion on 
Day 1 of each 21-day cycle.  If institutional guidelines conflict with protocol carboplatin dosing, 
carboplatin may be administered at a maximum starting AUC of 5.0.  A change of body weight 
5% compared to previous measured weight requires that the dose be re-calculated.
Cisplatin
Cisplatin will be administered according to the local prescribing information. The starting dose of 
cisplatin will be 70 mg/m2, administered by IV infusion on Day 1 of each 21-day cycle.  Split 
dosing of cisplatin is not permitted.  A change of body weight 5% compared to previous 
measured weight requires that the dose be re-calculated.
Comparator
Placebo
The placebo will be identical in appearance to atezolizumab and comprise the same excipients 
but without atezolizumab drug product.  It should be handled, stored, and used in the same 
manner as atezolizumab (by IV infusion q3w).
Duration of Chemotherapy Treatment
Gemcitabine and platinum chemotherapy (carboplatin or cisplatin) will be administered until 
investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity. 
For patients in the combination arms who receive chemotherapy (Arms A and C) and who have 
a CR, only two more cycles of chemotherapy will be administered after the response 
confirmation. 
For patients in the combination arms who receive chemotherapy and who have a PR or stable 
disease, chemotherapy administration may be discontinued after completion of six cycles, if 
necessary, to comply with institutional guidelines.
Non-Investigational Medicinal Products
None
Statistical Methods
Primary Analysis
The efficacy analyses for PFS and OS will be performed on all randomized patients (ITT 
population) for the respective treatment arm comparison according to the analysis hierarchy.  
Patients will be grouped according to the treatment assigned at randomization.  Analysis of 
secondary and exploratory efficacy endpoints will be performed for randomized patients in the 
ITT population.
Co-Primary Efficacy Endpoints
The co-primary efficacy endpoints are PFS as assessed by the investigator using RECIST v1.1 
and OS.  Because type I error will be controlled accounting for two co-primary endpoints, the 
study will be considered a positive study if statistical significance is achieved for either of the 
co-primary endpoints.
PFS is defined as the time from randomization to the first documented disease progression as 
assessed by the investigator using RECIST v1.1, or death from any cause, whichever occurs 
first.  Data for patients who have not experienced disease progression or death will be censored 
at the last tumor assessment.  Data for patients with no post-baseline tumor assessment will be 
censored at the date of randomization plus 1 day.


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For U.S. registration purposes, the co-primary efficacy endpoint of PFS will be defined as 
described above with an additional censoring rule for missed visits.  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. 
OS is defined as the time from randomization to death due to any cause.  Data for patients who 
are not reported as having died at the date of analysis will be censored at the date when they 
were last known to be alive.  Data for patients who do not have post-baseline information will be 
censored at the date of randomization plus 1 day.
The following analyses will be performed for both PFS and for OS.  PFS and OS will be 
compared between treatment arms with the use of the stratified log-rank test.  For the 
comparisons of Arm A versus Arm C, a possible effect of study stage will be taken into account.
The HR for PFS and OS will be estimated using a stratified Cox regression model.  The 95% CI 
for the HR will be provided.  The stratification factors will be the same as the randomization 
stratification factors, with values as recorded in the IxRS. Results from an unstratified analysis 
will also be presented.  Kaplan-Meier methodology will be used to estimate median PFS and 
OS for each treatment arm, and Kaplan-Meier plots will be constructed to provide a visual 
description of the difference between the treatment and control arms.  The Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median PFS and OS for each 
treatment arm.
For the primary analysis of OS in the ITT population for Arm B versus Arm C, all available data 
for these patients (before and after implementation of the iDMC recommendation in Protocol 
WO30070, Version 6) will be included. 
However, if a substantial number of patients with a PD-L1 expression status of IC0 or IC1 
randomized to Arm B prior to implementation of Protocol WO30070, Version 6 choose to switch 
to the combination of atezolizumab and chemotherapy, an additional analysis may be 
performed to account for treatment switching.  A sensitivity analysis will also be performed on 
patients randomized to Arm B or Arm C prior to implementation of Protocol WO30070, 
Version 6 that will include their data only up to the time of implementation of the iDMC 
recommendation. 
The analysis of OS in the PD-L1 IC2/3 population for Arm B versus Arm C will use the same 
methods as that for the ITT population for Arm B versus Arm C, except that PD-L1 status will 
not be one of the stratification factors.  The analysis will include all available data for these 
patients (before and after implementation of the iDMC recommendation of Protocol WO30070, 
Version 6).
Determination of Sample Size
A total of approximately 1200 patients will be randomized to the study (Stage 1 and Stage 2 
combined).    
Enrollment of approximately 1200 patients is based on the following assumptions:  
approximately 258 patients are projected to be enrolled in Stage 1 and allocated 2:1 to Arm A 
(atezolizumab in combination with platinum therapy) or Arm C (placebo in combination with 
platinum therapy).  Approximately 942 patients are projected to be enrolled in Stage 2 and 
allocated 1:1:1 to Arm A, Arm B (atezolizumab monotherapy), or Arm C.
Simulations were performed to check the expected power of the analyses of co-primary 
endpoints PFS and OS for this sample size.
Interim Analyses
There are no interim analyses planned for PFS in this study.  
A total of three efficacy analyses of OS are planned (two interim analyses and the final analysis).  
The final analysis of OS in Arm A versus Arm C will be performed when approximately 667 OS 
events in Arm A and Arm C of the ITT population have occurred. Based on observed survival up 
to the final PFS/interim OS analysis, the required number of events is projected to occur at 
Month 55 from the time the first patient was randomized.
The interim and final analyses of OS in Arms A versus C and Arms B versus C will be 
performed according to the analysis hierarchy.
The first interim OS analysis will be conducted by the Sponsor at the time of the final PFS 
analysis.  


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The second interim OS analysis will take place after approximately 12 months of additional
follow-up compared with the clinical cut-off date for the primary analysis, or when at least 
579 patients (68%) have died in Arm A and C, whichever is later.
Because the patient populations enrolled during Stage 1 and Stage 2 are considered 
independent, standard methods of group sequential designs apply.  
If the required number of OS events in Arm B versus Arm C has not been reached at the time of 
the second interim or final OS analysis in Arm A versus Arm C, then two further interim 
analyses for the comparison of Arm B versus Arm C may be performed at the time of these 
analyses.   
To control type I error for OS, the stopping boundaries for the OS interim and final analyses are 
to be computed for the appropriate alpha level with use of the Lan-DeMets implementation of 
the O’Brien-Fleming use function.


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53/Statistical Analysis Plan WO30070
Appendix 2 Schedule of Assessments
Assessment Window (Days) b
Screening a
Treatment Cycles (Each cycle21 days)
Treat. Discon.
(30 Days) c
90 Day 
Follow-Up
Survival 
Follow-Up d
–28 
to –1
–7 
to 1
Platinum/Gem + Atezolizumab 
or Platinum/Gem + Placebo
Atezolizumab/
Placebo 
Monotherapy
Day 1
Day 8 gg
Day 15
Day 1
Informed consent a
x
Medical, surgical, and cancer 
histories, including demographic 
information e
x
x
Cancer 
treatment
Age-adjusted Charlson comorbidity 
index
x
HIV, HBV, HCV serology f
x
TB test g
x
Concomitant medications h
x
x
x
x
x
Screening CT/MRI 
(chest/abdomen/pelvis/head) i
x
Tumor assessment j
x
Every 9 weeks (3 business days) for 54 weeks and every 12 weeks (6 business days) 
thereafter until disease progression, death, or loss of follow-up
Complete physical examination k
x
x
Limited physical examination l
x m
x m
x
ECOG performance status
x
x m
x m
x
Vital signs n
x
x
x
x
12-lead ECG o
x
x


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Appendix 2 Schedule of Assessments (cont.)
Assessment Window (Days) b
Screening a
Treatment Cycles (Each cycle21 days)
Treat. Discon.
(30 Days) c
90 Day 
Follow-Up
Survival 
Follow-Up d
–28 
to –1
–7 
to 1
Platinum/Gem + Atezolizumab 
or Platinum/Gem + Placebo
Atezolizumab/
Placebo 
Monotherapy
Day 1
Day 8gg
Day 15
Day 1
Echocardiogram o
x
Weight p, q
x
x
x
Height
x
Hematology r
x
x
x
x r
x
x
x
Serum chemistry s
x
x
x
x
x
Serum pregnancy test t
x
x t
x t
x t
Coagulation panel (PTT/aPTT, INR)
x
x
Urinalysis u
x
x
x
x
x
TSH, free T3, free T4 v
x
x v
x v
x
x
Serum ferritin
x
x v
x v
x
x
Optional blood sample for RBR 
DNA w
x
Blood samples for 
pharmacodynamics biomarkers x
x
x
CRP
x y
x k
x y
x
Autoantibody testing y
x
x
x
Serum sample for PK sampling z
x
x
x
x z


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Appendix 2 Schedule of Assessments (cont.)
Assessment Window (Days) b
Screening a
Treatment Cycles (Each cycle21 days)
Treat. Discon.
(30 Days) c
90 Day 
Follow-Up
Survival 
Follow-Up d
–28 
to –1
–7 
to 1
Platinum/Gem + Atezolizumab 
or Platinum/Gem + Placebo
Atezolizumab/
Placebo 
Monotherapy
Day 1
Day 8 gg
Day 15
Day 1
Serum sample for ATA aa
x aa
x aa
x
x aa
Archival and/or fresh FFPE tumor 
tissue specimen or 15 unstained 
slides for eligibility bb
x
PROs (EORTC QLQ-C30 and 
EQ-5D-5L) cc
x
x
x
x
Fresh biopsy at the time of 
radiographic progression dd
x
Optional RBR tumor biopsy 
samples ee
x
Atezolizumab/placebo infusion ff
x
x
Gemcitabine infusion p
x
x
Carboplatin or cisplatin infusion q
x
Adverse events gg
x
x
x
x
x
x
x
x
x


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Appendix 2 Schedule of Assessments (cont.)
anti-HBc antibody against hepatitis B core antigen; ATAanti-therapeutic antibody; AUCarea under the concentrationtime curve; 
CRPC-reactive protein; ECOG Eastern Cooperative Oncology Group;  eCRFelectronic Case Report Form; EORTCEuropean Organisation 
for Research and Treatment of Cancer; ePRO electronic patient-reported outcome; EQ-5D-5LEuro QoL 5-Dimensions 5-Level; FFPE formalin 
fixed paraffin embedded; Gem gemcitabine; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis C virus; 
IGRAinterferon-gamma release assay; IVintravenous; LVEF = left ventricular ejection fraction; PDprogressive disease; PD-L1programmed 
death-ligand 1; PKpharmacokinetic; Platinum cisplatin or carboplatin; PRO patient-reported outcome; QLQ-C30Quality-of-life Questionnaire 
Core 30; RBRResearch Biosample Repository; RECIST Response Evaluation Criteria in Solid Tumors; TBtuberculosis; TBNKT, B, and 
natural killer; TSHthyroid-stimulating hormone.
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted. 
a Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur 
outside the 28-day screening period.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and 
within 28 days prior to study entry (except where otherwise specified) may be used for screening assessments rather than repeating such tests. 
If re-screening is required, then HBV, HCV, HIV, CRP, and autoantibody testing from the initial screening may be acceptable for screening 
assessment if performed60 days from Cycle 1 Day 1.  
b The first dosing day (Cycle 1, Day 1) should occur within 5 days from date of randomization.  All visits and infusions may be administered with a 
window of 3 days, except for the Day 8 visit.  Day 8 dose of gemcitabine may be given no earlier than Day 7 but may be given up to Day 11 
(1 to 3) of a cycle.  Blood counts for gemcitabine dosing should be obtained within 1 day prior to Day 1 and Day 8 of each cycle of therapy.
c Patients will be asked to return to the clinic not more than 30 days after the last treatment for a treatment discontinuation visit.
d Starting from the treatment discontinuation visit, survival follow-up information will be collected via telephone calls, patient medical records, 
and/or clinic visits approximately every 3 months (30 days) until death, loss to follow-up, or study termination by the Sponsor.  All patients will 
be followed for survival and new anti-cancer therapy (including targeted therapy and immunotherapy) information unless the patient requests to 
be withdrawn from follow-up; this request must be documented in the source documents and signed by the investigator.  If the patient 
withdraws from the study, the study staff may use a public information source (e.g., county records) to obtain information about survival status 
only. 
e Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment.  Demographic information includes age, sex, and self-reported 
race/ethnicity.  Reproductive status and smoking history should also be captured.
f
All patients will be tested for HIV locally prior to the inclusion into the study, and HIV-positive patients will be excluded from the clinical study.  
HBsAg, anti-HBc antibody and anti-HBs antibody should be collected during screening and tested locally.  In patients who have positive 
serology for the anti-HBc antibody, HBV DNA should be collected and tested prior to Cycle 1, Day 1.  
g All patients will have tuberculin (PPD) skin test or IGRA performed locally prior to inclusion into the study, and patients with active TB will be 
excluded from the clinical study.
h Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 


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Appendix 2 Schedule of Assessments (cont.)
used within the 7 days prior to initiation of study drug should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.
i
All patients will have imaging during screening to establish measurable lesions per RECIST v1.1  Screening assessments must include 
CT scans (with oral or IV contrast unless contraindicated) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis and head.  
In patients for whom CT scans with contrast are contraindicated (e.g., patients with contrast allergy or impaired renal clearance), MRIs of the 
chest, abdomen, and pelvis with a non-contrast spiral CT scan of the chest may be used.  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. For further information see section 4.5.5.
j
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 measurable and evaluable lesions should be assessed and documented at the screening visit. The same 
radiographic procedure must be used throughout the study for each patient.  Results must be reviewed by the investigator before dosing at the 
next cycle.  Tumor assessments will be performed at baseline, every 9 weeks (approximately every three cycles) following randomization for 
54 weeks, and every 12 weeks thereafter, with additional scans as clinically indicated.  Assessments will continue until disease progression or 
loss of clinical benefit (whichever comes later).  Tumor assessments should continue regardless of whether patients start new anti-cancer 
therapy in the absence of disease progression unless they withdraw consent.  Patients who discontinue study treatment for reasons other than 
disease progression (e.g., toxicity), should continue to undergo scheduled tumor assessments as if they were on the protocol schedule until the 
patient dies, experiences disease progression per RECIST v1.1, withdraws consent, or until the study closes, whichever occurs first.  If an
optional biopsy is to be performed at approximately the same timepoint of a tumor assessment or as a result of the radiographic determination 
(e.g., response or progression), samples should be acquired after all imaging scans have been performed, if at all possible. Investigators may 
perform additional scans or more-frequent assessments if clinically indicated.  After the first five cycles, one of three cycles may be delayed by 
1 week (28 days instead of 21 days for one cycle) to allow for vacations.
k Complete physical exam includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological,
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on 
the Adverse Event eCRF.
l
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
m ECOG performance status, limited physical examination, local laboratory assessments, and CRP assessment may be obtained 96 hours 
before Day 1 of each cycle (note:  CRP at Cycle 3 and every other cycle thereafter; see footnote x).
n Vital signs include heart rate, respiratory rate, blood pressures, and temperature.  For the first atezolizumab infusion, the patient’s vital signs 
should be determined within 60 minutes before, during (every 15 [5] minutes), and 30 (10) minutes and 2 hours (15 minutes) after the 
infusion.  For subsequent atezolizumab infusions, vital signs will be collected within 60 minutes before the infusion.  Vital signs need to be 
collected during the infusion and 30 (10) minutes after the infusion only if clinically indicated. Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed to contact their study physician if they develop such symptoms. 


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Appendix 2 Schedule of Assessments (cont.)
o Twelve-lead ECGs are required as part of the screening assessment, at the end of treatment visit, and when clinically indicated.  ECGs will be 
reviewed by the investigator to determine patient eligibility at screening.  Patients with a history of clinically significant cardiac disease (including 
anatomic abnormality, coronary disease, congestive heart failure, abnormal LVEF, arrhythmia, or abnormal ECG) will be required to undergo a 
screening echocardiogram.  However a baseline evaluation of LVEF should be considered for all patients, especially in those with cardiac risk 
factors and/or history of coronary artery disease.
p Gemcitabine will be administered at a dose of 1000 mg/m2 by IV infusion on Day 1 and Day 8 of each 21-day cycle, until PD or unacceptable 
toxicity.  Weight will be measured for dose calculations (baseline weight should be used to calculate dose unless there is a greater than 5% 
weight change).  Day 8 gemcitabine should not be administered any earlier than Day 7, but can be administered up to Day 11.  Dose 
modifications of gemcitabine for hematologic toxicity are allowed and will be based on blood counts obtained within 1 day prior to Day 1 and 
Day 8 of each cycle of therapy.
q For patients receiving carboplatin-based chemotherapy: carboplatin will be administered at AUC 4.5 by IV infusion on Day 1 of each 21-day cycle, until PD 
or unacceptable toxicity.  If institutional guidelines conflict with protocol carboplatin dosing, carboplatin may be administered at a maximum starting dose of 
AUC of 5.
Weight will be measured for dose calculations (baseline weight should be used to calculate dose unless there is a greater than 5% weight 
change).  For patients receiving cisplatin-based chemotherapy:  Cisplatin will be administered at a dose of 70 mg/m2 by IV infusion on Day 1 of 
each 21-day cycle, until PD or unacceptable toxicity.  Weight will be measured for dose calculations (baseline weight should be used to 
calculate dose unless there is a greater than 5% weight change).
r
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, 
eosinophils, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated. During 
chemotherapy plus atezolizumab/placebo the assessment at Day 15 is required at C1 and C2, thereafter at investigator discretion.
s Serum chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, 
total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, total protein, and albumin.  In countries where serum bicarbonate is not 
considered a standard chemistry measurement (e.g., Japan), serum bicarbonate is not required as a laboratory study in the screening or on-
study serum measurements.
t
Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and 
documented as negative within 7 days prior to Cycle 1, Day 1, every two cycles during the study treatment, and as clinically indicated 
thereafter.  In countries where urine pregnancy testing is considered a standard, urine pregnancy testing may substitute for serum pregnancy 
testing.
u Urine dipstick includes specific gravity, pH, glucose, protein, ketones, and blood.  Urine dipstick and 24-hr urine collection may be performed up 
to 7 days before Cycle 1, Day 1.  Screening urine tests performed up to 7 days before Cycle 1, Day 1 do not need to be repeated for Cycle 1.
v TSH, free T3, free T4, and serum ferritin should be evaluated every two cycles (starting at Cycle 2).
w Blood for DNA isolation will be collected from patients who have consented to optional RBR sampling at baseline, after the patient is 


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Appendix 2 Schedule of Assessments (cont.)
randomized to the study but before study treatment.  If, however, the RBR genetic blood sample is not collected during the scheduled visit, it may 
be collected as soon as possible (after randomization) during the conduct of the clinical study.
x See Appendix 2 for details of the pharmacodynamic sampling schedule.
y Includes anti-nuclear antibody, antidouble-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear antineutrophil 
cytoplasmic antibody.  Baseline auto-antibody testing to be collected at screening or on Cycle 1, Day 1 prior to the first dose of study drug.  
If re-screening is required, auto-antibody testing may be performed within 60 days prior to Cycle 1, Day 1.  Baseline CRP testing can be 
collected up to 7 days prior to Cycle 1, Day 1.  CRP and autoantibody testing to be performed on Day 1 of Cycle 3 and every other cycle 
thereafter. 
z See Appendix 2 for details of the PK sampling schedule.
aa Additional ATA samples may be collected in patients with signs and symptoms of infusion-related reactions if clinically indicated.  See 
Appendix 2 for details of the ATA sampling schedule.
bb 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).  Fine-needle aspiration, brushing, cell pellets from pleural effusion, bone metastases, and lavage 
samples are not acceptable.  For core-needle biopsy specimens, at least three cores should be submitted for evaluation.  After signing the 
Informed Consent Form, retrieval and submission of archival tumor sample can occur outside the 28-day screening period.
cc The PRO questionnaires (EORTC QLQ-C30 and EQ-5D-5L) will be completed by patients on Day 1 of each cycle and at the end-of-treatment 
visit and will also be completed by patients at any visits after disease progression and/or when OS is evaluated.  All PRO questionnaires are 
required to be completed prior to the administration of study treatment and/or prior to any other study assessment(s) to ensure that the validity 
of the instruments is not compromised and to ensure that data quality meets regulatory requirements.
dd Tumor specimens are required at the time of disease progression per RECIST v1.1, unless the location of the tumor renders the biopsy 
medically unsafe or infeasible per investigator decision.  Tumor biopsy samples will be collected by core needle or excisional/punch biopsy if 
deemed feasible per investigator discretion.  Preferably, growing lesions should be selected. 
ee Optional tumor biopsies may be obtained at other timepoints at the investigator’s discretion if patient has provided RBR consent.  Tumor biopsy 
samples will be collected by core needle or excisional/punch biopsy if deemed feasible per investigator discretion.  Preferably, growing lesions 
should be selected. 
ff The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the first infusion is tolerated without infusion-associated adverse 
events, the second infusion may be delivered over 30 (10) minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may 
be delivered over 30 (10) minutes. 
gg 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.  After initiation of study drug, all serious adverse events and adverse events of special interest will be reported 
until 90 days after the last dose of study drug or initiation of another anti-cancer therapy, whichever occurs first.  All other adverse events will be 
reported until 30 days after the last dose of study drug or until the initiation of another anti-cancer therapy, whichever occurs first.  After this 


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Appendix 2 Schedule of Assessments (cont.)
period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study 
drug treatment.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow 
all serious adverse events considered to be related to study drug or study-related procedures until a final outcome can be reported. During the 
chemotherapy plus atezolizumab/placebo period, adverse events are to be collected at Day 15 if a clinic visit is made.
hh Day 8 visit not required once gemcitabine dosing has been discontinued or if gemcitabine is not being administered for that particular cycle.


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Appendix 3 Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples
Visit
Timepoint
Sample Type
Cycle 1, Day 1
Predose
Serum atezolizumab ATA
Serum atezolizumab pharmacokinetics
Plasma PD biomarker
Serum PD biomarker
Blood PBMC
30 (10) minutes after 
end of atezolizumab 
infusion
Serum atezolizumab pharmacokinetics
Cycle 3, Day 1
Predose
Plasma PD biomarker
Serum PD biomarker
Blood PBMC
Cycles 2, 3, and 4, 
Day 1
Predose
Serum atezolizumab ATA
Serum atezolizumab pharmacokinetics
Cycle 8, and every 
eighth cycle 
thereafter, Day 1
Predose
Serum atezolizumab ATA
Serum atezolizumab pharmacokinetics
Radiographic 
Progression
At Visit
Plasma PD biomarker
Serum PD biomarker
Treatment 
discontinuation visit a
At visit
Serum atezolizumab ATA
Serum atezolizumab pharmacokinetics
120 (30) days after 
last dose of 
atezolizumab/placebo
At visit
Serum atezolizumab ATA
Serum atezolizumab pharmacokinetics
ATAanti-therapeutic antibody; NAnot applicable; PBMCperipheral blood 
mononuclear cell; PDpharmacodynamic.
Notes:  Except for Day 1 of Cycle 1, all other predose visits and assessments during the 
treatment period should be performed within 3 days of the scheduled date.  Study 
assessments may be delayed or moved ahead of the window to accommodate holidays, 
vacations, and unforeseen delays.  Additional ATA samples may be collected in patients 
with signs and symptoms of infusion-related reactions if clinically indicated.
a Patients who discontinue study drug will return to the clinic for a treatment 
discontinuation visit 30 days after the last dose of study drug.