Retrospective, Multicenter, Observational Study to Evaluate Current Treatment Patterns and Outcomes in Japanese Patients With Locally Advanced or Metastatic Urothelial Carcinoma Treated With First-line Avelumab Maintenance
Conditions: Urothelial Carcinoma
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Avelumab 
B9991048  NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol version 4.1, 29 Jun 2022 
 
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Study information 
Title 
Retrospective, Multicenter, Observational Study to 
Evaluate Current Treatment patterns and Outcomes in 
Japanese Patients with Locally Advanced or Metastatic 
Urothelial Carcinoma Treated with First-line Avelumab 
Maintenance 
Protocol number 
B9991048 
Protocol version identifier 
Version 4.1 
Date
29 June 2022
Active substance 
Avelumab 
Medicinal product 
Avelumab (BAVENCIO®) 
Research question and 
objectives 
To describe the demographic and baseline disease 
characteristics and treatment outcomes in patients with 
locally advanced or metastatic urothelial carcinoma treated 
with first-line avelumab maintenance. 
Main Author 
 (non-interventional [NI] study lead) 
 
e-mail address :
 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
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the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
PPD
PPD
PPD

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 2 of 3 3  
1.  T A B L E O F C O N T E N T S  
 
1. T A B L E O F C O N T E N T S  ....................................................................................................... 2 
2. LI S T O F A B B R E VI A TI O N S  ................................................................................................ 4 
3. R E S P O N SI B L E P A R TI E S  .................................................................................................... 6 
4. A B S T R A C T  ........................................................................................................................... 6 
5. A M E N D M E N T S A N D U P D A T E S  ....................................................................................... 6 
6. MI L E S T O N E S  ..................................................................................................................... 1 4 
7. R A TI O N A L E A N D B A C K G R O U N D  ................................................................................ 1 5 
8. R E S E A R C H Q U E S TI O N A N D O BJ E C TI V E S  ................................................................. 1 7 
8. 1. Pri mar y o bjecti ve .................................................................................................... 1 7  
8. 2. Sec o n dar y o bjecti ves ............................................................................................... 1 7  
9. R E S E A R C H M E T H O D S  .................................................................................................... 1 8 
9. 1. St u d y desi g n ............................................................................................................ 1 8  
9. 2. E n d p oi nt .................................................................................................................. 1 8  
9. 2. 1. Pri mar y e n d p oi nt ........................................................................................ 1 8  
9. 2. 2. Sec o n dar y e n d p oi nts ................................................................................... 1 9  
9. 2. 3. Defi niti o n of e n d p oi nts ............................................................................... 2 0  
9. 3. Setti n g ...................................................................................................................... 2 1  
9. 3. 1. I n cl usi o n criteria ......................................................................................... 2 1  
9. 3. 2. E xcl usi o n criteria ........................................................................................ 2 2  
9. 4. Varia bles .................................................................................................................. 2 2  
9. 5. Data s o urces  ............................................................................................................ 2 2 
. 2 2 
9. 7. Data ma na g e me nt  .................................................................................................... 2 2 
9. 7. 1. Case re p ort f or ms (e C R Fs)/ Dat a c ollecti o n t o ols ( D C Ts)/ Electr o nic 
data rec or d  ........................................................................................................ 2 2 
9. 7. 2. Rec or d r ete nti o n ........................................................................................... 2 3  
9. 7. 3. Rec or d dis p osal ............................................................................................ 2 3  
9. 8. Data a n al ysis  ........................................................................................................... 2 3 
9. 8. 1. A nal ysis P o p ulati o n .................................................................................... 2 3  
9. 8. 2. A nal ysis Met h o ds ....................................................................................... 2 3  
C CI

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9.8.3. Analysis of Primary Endpoints ...................................................................24 
9.8.4. Analysis of Secondary Endpoints ...............................................................24 
9.9. Quality control .........................................................................................................24 
9.10. Limitations of the research methods .....................................................................24 
9.11. Other aspects .........................................................................................................24 
9.11.1. Report to the chief executive of the study site ..........................................24 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................25 
10.1. Patient information ................................................................................................25 
10.2. Patient consent .......................................................................................................25 
10.2.1. For subjects who are alive and still visit the study site .............................25 
10.2.2. Subjects who are alive and had been transferred to another medical 
facility ..............................................................................................................26 
10.2.3. Subjects who are deceased ........................................................................26 
10.2.4. Response to important findings and other information concerning 
the health of......................................................................................................27 
10.3. Patient withdrawal .................................................................................................27 
10.3.1. Subjects who are alive and still visit the study site, or subjects who 
are alive and had been transferred to another medical facility ........................27 
10.3.2. Subjects who are deceased ........................................................................28 
10.4. Institutional Review Board (IRB)/Independent ethics committee (IEC) ..............28 
10.5. Ethical conduct of the study ..................................................................................28 
10.6. Predictable risks and benefits ................................................................................28 
10.6.1. Risk ...........................................................................................................28 
10.6.2. Benefits .....................................................................................................28 
10.7. Conflicts of interest ...............................................................................................28 
10.8. Registration and publication of study ....................................................................29 
10.9. Secondary use of specimens and information obtained from subjects ..................29 
10.10. Responding to consultations from subjects and other related parties .................29 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................30 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........31 
13. REFERENCES ..................................................................................................................32 
14. LIST OF TABLES .............................................................................................................32 

Avelumab 
B9991048  NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol version 4.1, 29 Jun 2022 
 
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15. LIST OF FIGURES ...........................................................................................................32 
ANNEX 1. IMPLEMENTATION STRUCTURE AND LIST OF STUDY SITES AND 
PRINCIPAL INVESTIGATORS OF THE STUDY ..........................................................33 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................33 
ANNEX 3. ADDITIONAL INFORMATION .........................................................................33 
 
2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AEM 
Adverse Event Monitoring 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BSC 
Best Supportive Care 
Carbo 
Carboplatin 
Cht 
Chemotherapy 
CI 
Confidence interval 
Cis 
Cisplatin 
CR 
Complete response 
CRF 
Case Report Form 
CSA 
Clinical Study agreement 
DCF 
Data Clarification Form 
DCT 
Data Collection Tool 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
GC 
Gemcitabine and Cisplatin 
EU 
European Union 
G-Carbo 
Gemcitabine Carboplatin 
Gem 
Gemcitabine 
IEC 
Independent Ethics Committee 
irAE 
immune-related Adverse Event 
IRB 
Institutional Review Board 
LDH 
High-density lipoprotein 
M-CAVI 
Methotrexate, Carboplatin and Vinblastine 
MVAC 
Methotrexate, Vinblastine, Adriamycin, and Cisplatin 
NA 
Not Applicable 
NI 
Non-Interventional 
NIS 
Non-Interventional Study 
ORR 
Objective Response Rate 
OS 
Overall Survival 

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B9991048  NON-INTERVENTIONAL STUDY PROTOCOL 
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Abbreviation 
Definition 
PAS 
Post Authorization Study 
PD 
Progressive Disease 
PD-L1 
Programmed Death Ligand 1 
PFS 
Progression-Free Survival 
PR 
Partial Response 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation; Stable Disease 
SOC 
Standard of Care 
TNM 
Tumor-Node-Metastasis 
TTF 
Time to Treatment Failure 
UC 
Urothelial Carcinoma 
YRR 
Your Reporting Responsibilities 
1L 
First-Line 
2L 
Second-Line 
 
 

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 6 of 3 3  
3.  R E S P O N SI B L E P A R TI E S  
Pri nci p al I n vesti g at or (s) of t he Pr ot oc ol  
 
 
 
I m ple me nt ati o n str uct ure a n d list of st u d y sites a n d pri nci pal in vesti gat ors i n t his st u d y will be 
pre par e d as A n n e x 1. 
( T his st u d y will be c o n d ucte d as a c o m pa n y-s p o ns ore d cli nical st u d y b y Pfizer) 
 
4.  A B S T R A C T  
N ot a p plica ble 
 
5.  A M E N D M E N T S A N D U P D A T E S  
V ersi o n  Date  
Pr ot oc ol 
secti o n(s) 
c ha n ge d  
S u m mar y of a me n d me nt(s)  
Reas o n  
1. 0  
8 N o v 
2 0 2 1  
N e w  
First e diti o n  
n e w  
2 . 0 
1 8 
Mar 
2 0 2 2 
 
Re visi o n fr o m A d vis or’s re vie w a n d Pfi zer 
re vie w as f oll o ws 
9. 2. E n d p oi nt 9. 2. 1. Pri mar y e n d p oi nt 
4)  
C o nfir me d date of ur ot h elial 
carci n o ma  
1 3) 
Site of metastasis ( Yes [ visceral/ n o n 
visceral]/ N o)   
1 4) 
Rec urre n ce ( Yes/ N o), if yes, 
rec urre nce c o nfir me d dat e 
 
9. 2. E n d p oi nt 9. 2. 2. Sec o n dar y e n d p oi nt 
- r w P F S fr o m c h e m ot hera p y (r w P F S-c） 
- C ha n ges i n s u m of t he l o n gest dia meters  
U p date d 
descri pti o n 
i n 
acc or d a nce 
wit h t he 
c ollecti o n 
ite ms 
3 . 0 
7  
A pril 
2 0 2 2 
R e vise 
9. 2. E n d p oi nt  9. 2. 1 Pri m ar y E n d p oi nt   
6) T u m or- n o de- metastasis ( T N M) 
classificati o n  
➞ 
6) T u m or- n o de- metastasis( T N M) 
classificati o n (t he 8t h e diti o n of A merica n 
J oi nt C o m mittee o n Ca ncer/ U ni o n f or 
U p date d 
descri pti o n 
i n 
acc or d a nce 
wit h t he 
c ollecti o n 
ite ms 
P P D

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International Cancer Control) 
 
8) Number of Cht cycles received in 1L 
→ 
8)Start date and end date of administration, 
Number of Cht cycles received in 1L 
 
9.2 Endpoint 9.2.2 Secondary Endpoint 
 
Changes in sum of the longest diameters*  
The following data will be collected: 
1) 
sum of the longest diameters, site  
(bladder, urethra or upper tract), histology 
(Urothelial carcinoma/ adenocarcinoma/ 
squamous cell carcinoma/ small cell 
carcinoma/ others [details])   
Data collection scope: At the start of 1L cht/ 
every 2 cycles from the start of 1L cht/ 
immediately before the first avelumab 
administration/ every 12 weeks from the start 
of avelumab treatment/ at the time of PD 
judgment 
 
Changes in sum of the target lesion 
diameters*  
The following data will be collected: 
1) 
sum of the target lesion diameters, site  
(bladder / urethra / upper tract / others 
[details]) 
Data collection points: At the start of 1L cht / 
immediately before the first avelumab 
administration/ after the start of avelumab 
treatment/ at the time of PD judgment 
 
1)Medication for UC after avelumab 
maintenance therapy (drug classification, type 
of treatment, start date of treatment, end date 
of treatment) 
 
1)Medication for UC after avelumab 
maintenance therapy (drug name, start date of 
treatment, end date of treatment) 
 
2) Data collection points: At the start of 1L 

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B9991048  NON-INTERVENTIONAL STUDY PROTOCOL 
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cht/ immediately before the first avelumab 
administration/ every 12 weeks from the start 
of avelumab treatment/ at the time of PD 
judgment 
 
2) Data collection scope: At the start of 1L cht 
/ immediately before the first avelumab 
administration/ after the start of avelumab 
treatment/ at the time of PD judgment  
 
ANNEX 
CRM Department 2, Clinical Research 
Promotion Center, EP-CRSU Co., Ltd. 
 
CR Department2, Clinical Research Center, 
Real World Evidence Business Headquarters, 
EPS Co., Ltd. 
 
DS Department 2, Data Solution Center, EP-
CRSU Co., Ltd. 
 
CR Data Science Department, Clinical 
Research Center, Real World Evidence 
Business Headquarters, EPS Co., Ltd. 
4.0 
28 
April 
2022 
Revise 
8.2. Secondary objectives 
2) 
To describe clinical usage of 
corticosteroid for immune-related adverse 
events (irAEs) observed during avelumab 
therapy and within 90 calendar days after the 
last administration of avelumab therapy. 
 
2) 
To describe clinical usage of 
corticosteroid for immune-related adverse 
events (irAEs) observed during avelumab 
therapy and after the last administration of 
avelumab therapy. 
 
9.2.1. Primary endpoint 
12) 
Treatment of primary lesion (Yes 
[Surgery/ Radiation therapy /Others]/ No), 
date of treatment. (Collect treatment data for 
primary tumor at the most recent after the 
start of primary anticancer chemotherapy) 
 
12) 
Treatment of primary lesion (Yes 
Updated 
description 
in 
accordance 
with the 
collection 
items 

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 9 of 3 3  
[ S ur ger y/ Ra diati o n t hera p y / Ot hers]/ N o), 
date of treat me nt.  
 
9. 7. D at a m a n a ge me nt  
I n v esti gat ors will fill o ut electr o nic case 
re p ort f or ms (e C R Fs) bas e d o n t he me dical 
c harts b y electr o nic dat a ca pt ure ( E D C). Aft er 
t he c o m pleti o n, e C R Fs are tra nsferre d t o a 
si n gle electr o nic d ata bas e. O nl y t he de-
i de ntifie d a n d a n o n y mize d data are i ncl u de d. 
W he n recei vi n g a q u er y fr o m t he data 
ma na ger o n t he c o m plete d e C R F (ie, data 
clarificati o n f or m [ D C F]), i n vesti gat ors will 
rec o nfir m t he i nf or mati o n o n s o urce 
d oc u me nts, fill o ut t he D C F as re q uire d, a n d 
s u b mit t he D C F. 
 
I n v esti gat ors will fill o ut electr o nic case 
re p ort f or ms (e C R Fs) bas e d o n t he me dical 
c harts b y electr o nic dat a ca pt ure ( E D C). Aft er 
t he c o m pleti o n, e C R Fs are tra nsferre d t o a 
si n gle electr o nic d ata bas e. O nl y t he de-
i de ntifie d a n d pse u d o n y mize d data are 
i ncl u de d. W he n recei vi n g a q uer y fr o m t he 
data ma na g er o n t he c o m plete d e C R F (ie, d ata 
clarificati o n f or m [ D C F]), i n vesti gat ors will 
rec o nfir m t he i nf or mati o n o n s o urce 
d oc u me nts, fill o ut t he D C F as re q uire d, a n d 
su b mit t he D C F.  
 
1 0. 2. 1. F or s u bjects w h o are ali ve a n d still 
visit t he st u d y site  
1 1)  
Ha n dli n g of pers o n al i nf or mati o n 
(i ncl u di n g pr ocess of a n o n y mizati o n, w he n 
a n pse u d o n y mizati o n is c o n d ucte d); 
1 1)  
Ha n dli n g of pers o n al i nf or mati o n 
(i ncl u di n g pr ocess of ps e u d o n y mizati o n, 
w he n a n pse u d o n y mizati o n is c o n d ucte d);  
4 .1  
2 9  
J u ne 
2 0 2 2 
R e vise 
M ai n A ut h or  
 
 
 
 
U p date d 
descri pti o n 
i n 
acc or d a nce 
wit h t he 
c ollecti o n 
ite ms 
P P D

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 1 0  of 3 3  
 
 
 
e-mail a d dress :  
 
 
9. 2. 1. P rim ar y e n d p oi nt 
3)  Me dical hist or y/c o m or bi dit y ( re nal 
d ysf u ncti o n/ he patic 
d ysf u ncti o n/ i nterstitial l u n g 
disease/a ut oi m m u ne disease/ ot hers) *  
 
3) Me dical hist or y/c o m or bi dit y  (i nterstitial 
l u n g disease/c hr o nic o bstr ucti ve 
p ul m o nar y disease /a ut oi m m u ne 
disease/cere br o v asc ular 
disease/car di o vasc ular 
disease/ dia betes/ ot hers) *  
 
7) C ht  re gi me ns  recei ve d  i n  1 L  ( Cis plati n  
[ Cis]/ Ge mcita bi ne  [ G e m], Car b o plati n 
[Car b o]/ Ge m, 
Cis/ Car b o/ Ge m, 
Met h otre xate,  Vi n blasti ne,  A dria m y ci n,  
a n d  Cis plati n  [ M V A C]  re gi me ns,  d ose 
de nse- M V A C, ot hers) 
 
7) C ht  re gi me ns  recei ve d  i n  1 L  ( Cis plati n  
[ Cis]/ Ge mcita bi ne  [ G e m], Car b o plati n 
[Car b o]/ Ge m,  Met h otre xate,  Vi n blasti ne,  
A dria m yci n,
 a n d
 Cis plati n
 [ M V A C]
 
re gi mens, d ose de ns e- M V A C, ot hers) 
 
1 0) Best  res p o nse  t o  1 L  C ht  ( c o m plete 
res p o nse [ C R], partial  res p o nse  [ P R], 
sta ble disease [ S D], P D) 
 
1 0) Best o verall  res p o ns e t o 1 L C ht (c o m plete 
res p o nse [ C R], partial  res p o nse  [ P R], 
sta ble disease [ S D], P D) 
 
1 1) 
Site ( bla d der, uret hra or u p per tract ) 
a n d hist ol o g y ( Ur ot helial carci n o ma/ 
a de n ocarci n o ma/ s q ua m o us cell carci n o ma/ 
s mall cell carci n o ma/ ot h ers [ details])  of t he 
pri mar y t u m or at t he ti me of i nitial dia g n osis.  
P P D
P P D

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 
11) 
Site (bladder, urethra, renal pelvis or 
ureter) and histology (Urothelial carcinoma/ 
adenocarcinoma/ squamous cell carcinoma/ 
small cell carcinoma/others [details])  of the 
primary tumor at the time of initial diagnosis. 
 
none 
 
12) 
Histological atypia 
13) 
Histological depth of tumor invasion 
 
12) Treatment of primary lesion (Yes [Surgery/ 
Radiation therapy /Others]/ No), date of 
treatment. 
 
14) Definitive treatment of primary lesion (Yes 
[Surgery/ Others]/ No), date of treatment. 
 
13) Site of metastasis (Yes [visceral/ non 
visceral]/ No)  
 
15) Site of distant metastasis (Yes [visceral/ 
non visceral]/ No)  
 
14) Recurrence (Yes/No), if yes, recurrence 
confirmed date 
 
16) Local 
recurrence 
(Yes/No), 
if 
yes, 
recurrence confirmed date 
 
15) Bajorin risk classification (0/1/2)  
Risk factor 
 
Karnofsky performance status <80% 
(>ECOG 2) 
 
17) Bajorin risk classification (0/1/2)  
Risk factor 
 
Karnofsky performance status <80% 
 
9.2.2. Secondary endpoints 
Efficacy endpoint 
 
Changes in sum of the target lesion 
diameters*  
The following data will be collected: 

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1) sum of the target lesion diameters, 
site (bladder / urethra / upper tract 
/ others [details]) 
Data collection scope: At the start of 
1L cht / immediately before the first 
avelumab administration/ after the 
start of avelumab treatment/ at the 
time of PD judgment 
* The tumor is evaluated based on 
medical information. 
 
(deleted) 
 
Safety endpoints 
 
Corticosteroid therapy for immune-related 
adverse events (irAEs)  
The following data will be collected:  
3) Dose of corticosteroid 
 
3) Starting dose of corticosteroid 
 
 
Hematological test (after the start of 1L 
Cht) 
1) Red blood cell count/ hemoglobin/ 
hematocrit/ white blood cell count 
(neutrophils, 
eosinophils, 
basophils, 
monocytes, 
lymphocytes)/ platelet count/ C-
reactive protein (CRP)/ AST/ ALT/ 
LDH 
Data collection scope: At the start 
of 1L cht / immediately before the 
first avelumab administration/ after 
the start of avelumab treatment/ at 
the time of PD judgment 
 
1) Red blood cell count/ hemoglobin/ 
hematocrit/ white blood cell count 
(neutrophils, 
eosinophils, 
basophils, 
monocytes, 
lymphocytes)/ platelet count/ C-
reactive 
protein 
(CRP)/ 
total 
protein/ albumin/ AST/ ALT/ 
LDH/ BUN/ creatinine/ Na/ K/ Cl 
Data collection scope: At the start 

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 1 3  of 3 3  
of 1 L c ht / i m me diatel y bef ore t h e 
first  a vel u ma b  a d mi nistrati o n/  at 
t he  start  of  f o urt h c ycle  of 
a vel u ma b treat me nt/ at t he ti m e of 
P D  j u d g me nt  (at  t he  latest  test  
d uri n g  t he  o bser vati o n  peri o d  f or  
t h ose
 c o nti n ui n g
 a vel u ma b
 
treat me nt
 wit h o ut
 disease
 
pr o gressi o n) 
 
9. 2. 3. Defi niti o n of e n d p oi nts 
9. 2. 3. 1. Ti me t o tre at me nt f ail ure ( T T F) 
o n t he last visit date d uri n g t he st u d y peri o d.  
 
o n t he last o bser vati o n date d uri n g t he st u d y 
peri o d.  
 
9. 2. 3. 2. r w P F S 
or at t heir last visit date d uri n g t he st u d y 
peri o d  
 
or at t heir last o bser v ati o n date d uri n g t he 
st u d y peri o d 
 
9. 2. 3. 4. r w P F S-c 
or at t heir last visit date d uri n g t he st u d y 
p eri o d 
 
or at t heir last o bser v ati o n date d uri n g t he 
st u d y peri o d 
 
A N N E X  
Rese arc h S p o ns or  
Res p o nsi ble P art y 
 
 
 
 
 
 
Me d ical Writi n g 
 
 
 
P P D
P P D
P P D

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 1 4  of 3 3  
 
 
 
 
 
 
 
 
6.  MI L E S T O N E S  
Milest o ne  
Pl a n ne d d ate  
Patie nt e nr oll me nt peri o d *  
* P atie nts w h o were recei ve d a vel u ma b 
mai nte na nce t hera p y d uri n g t he peri o d 
fr o m 2 4 Fe br uar y 2 0 2 1 t o 3 0 
N o ve m ber 2 0 2 1. 
F r o m 2 4 Fe br uar y 2 0 2 1 t o 3 0 N o ve m ber 2 0 2 1 . 
2 4 Fe br u ar y 2 0 2 1 is la u nc h da y of a vel u ma b a n d 
3 0  N o ve m ber 2 0 2 1  is  t he  date  t he  e x pecte d  
n u m ber of patie nts w h o were recei v e d a vel u ma b 
mai nte na nce t hera p y  will be a p pr o xi matel y  
 
patie nts i n t otal.  
O bser vati o n peri o d  
Fr o m i n de x date  (the dat e of first prescri pti o n f or 
a vel u ma b  bet wee n  2 4  Fe br u ar y 2 0 2 1  [ la u n c h 
date ] a n d 3 0 N o ve m ber 2 0 2 1) t o 3 0 J u ne 2 0 2 2. 
Patie nts will be f oll o we d fr o m i n de x date t o 3 0 
J u ne 2 0 2 2. 
It is ass u me d t hat t he p eri o d patie nts w h o will be 
f oll o we d  is at least 7 m o nt hs (3 0 N o ve m ber 2 0 2 1 
t o 3 0 J u ne 2 0 2 2) t o e val uate pri mar y e n d p oi nt of 
t his st u d y. 
S t u d y peri o d 
Fr o m  t he  a p pr o val  of  t he  I nstit uti o nal  Re vie w  
B oar d t o 3 0 A pr il 2 0 2 3 (fi nal re p ort pre parati o n)  
Start of data c ollecti o n  
0 1 J ul y  2 0 2 2   
It is ass u me d t hat d ata c ollecti o n will start t he da y 
after t he c o m pleti o n of o bser vati o n peri o d.  
E n d of data c ollecti o n  
3 0 N o v e m ber 2 0 2 2   
It is ass u me d t hat it will ta ke 5 m o nt hs fr o m start 
of data c ollecti o n t o e n d of data c ollecti o n.  
A nal ytical dataset l oc k  
3 1 Ja n uar y 2 0 2 3   
It is ass u me d t hat a nal yti cal datas et l oc k will ta ke 
2 m o nt hs fr o m e n d of dat a c ollecti o n . 
Fi nal st u d y re p ort  
3 0 A pr il 2 0 2 3   
It  is  ass u me d  t hat  it  will  ta ke  3  m o nt hs  fr o m  
a nal ytical dataset l oc k t o t he date f or a p pr o v al of 
fi nal st u d y re p ort. 
 
 
P P D
P P D
C CI

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 1 5  of 3 3  
7.  R A TI O N A L E A N D B A C K G R O U N D  
Bla d der ca ncer  acc o u nts f or a p pr o xi mat el y 9 0 % of Ur ot helial carci n o ma ( U C). A p pr o xi matel y 
5 5 0, 0 0 0  cases  of  bla d d er  ca n cer  are  ne wl y  dia g n ose d  w orl d wi de  eac h  year 1.  Eac h  year,  
2 0 0, 0 0 0 cases of deat h ar e ca us e d b y bla d d er ca ncer. Bla d der ca n cer i nci de nce a n d d eat h rates 
ha ve n ot c ha n ge d b y 2 5 a n n uals 2. Acc or di n g t o t h e ca ncer statistical f orecast i n 2 0 2 1 c o n d ucte d 
b y t he Nati o nal C a n cer Ce nter Ja p a n, t he esti mate d n u m ber of bla d d er ca ncers a n d deat hs i n 
2 0 2 1 i n Ja pa n w ere 2 4, 3 0 0 a n d 9, 7 0 0, res pecti vel y 3. Patie nts wit h metastatic U C ha v e a dis mal 
pr o g n osis wit h a 5 -year s ur vi val rate of o nl y 5 %. Plati n u m -base d p ol yc he m ot hera p y re gi me n 
is c urre ntl y t h e first-li ne ( 1 L) st a n dar d of care ( S O C) f or p atie nts wit h a d va nce d/ metastati c 
disease, b ut des pite hi g h i nitial res p o nse rat es, d ura ble a n d c o m plete res p o nses f oll o wi n g 1 L 
c he m ot hera p y ( C ht) are u nc o m m o n, a n d m ost patie nts will ulti matel y  e x perie n ce disease 
pr o gressi o n wit hi n 9 m o nt hs after i nitiati o n of treat me nt 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
A ve l u ma b  ( M S B 0 0 1 0 7 1 8 C,  B A V E N CI O ®)  is  a  h u ma n  i m m u n o gl o b uli n  G 1  m o n ocl o nal  
a nti b o d y directe d a g ai nst t he pr o gra m me d d eat h li ga n d 1 ( P D -L 1) .  I n J a p a n, C ht is t he 1 L 
S O C  rec o m me n de d  i n  g ui deli nes  f or l ocall y  a d va nce d  or metastatic U C;  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 1 6  of 3 3  
 
 
 
 
A ve l u ma b i n c o m bi nati o n wit h best s u p p orti ve care ( B S C) as a mai nte na nce treat me nt ha d 
bee n e val uat e d vers us B S C al o ne i n a P hase 3 ra n d o mize d trial (J A V E LI N Bla d der 1 0 0) i n 
patie nts wit h l ocall y a d va nce d or m etastatic U C w h o ha d n ot pr o gress e d wit h 1 L pla ti n u m-
base d  C ht.  T he  J A V E LI N  Bla d der  1 0 0  st u d y  has  de m o nstrate d  a  si g nifica nt  7. 1 - m o nt hs 
i m pr o ve me nt  i n  me dia n  O S  wit h  A vel u ma b + B S C  as  1 L  mai nte na nce  vers us  B S C  al o ne  
( me dia n O S , 2 1. 4 m o nt hs vs 1 4. 3 m o nt hs), wit h a 3 1 % re d ucti o n of t he deat h ris k i n t he o verall 
p o p ulati o n ( hazar d rati o = 0. 6 9 ( 9 5 % c o nfi de nce i nter val  [ CI], 0. 5 6, 0. 8 6), p = 0. 0 0 1)  8. T he 
res ults of Ja pa n ese su b gr o u p a nal ysis i n t he J A V E LI N Bla d der 1 0 0 w ere g e nerall y c o nsiste nt 
wit h t h ose i n t he o verall p o p ulati o n 9. 
 
  
T he  pres e nt  st u d y,  B 9 9 9 1 0 4 8,  ai ms  t o  e val uat e  t he  de m o gra p hic  a n d  baseli ne  diseas e  
c haracteristics a n d c urre nt treat me nt o utc o mes i n patie nts wit h l ocall y a d va nce d or metastati c 
U C treate d wit h a vel u ma b t h ose w h o ha d bee n prescri be d A v el u ma b i n a peri o d of 9 m o nt hs 
after l a u nc h, a n d ha d a f oll o w -u p d urati o n of 7 m o nt hs. I n
 
 
 
 
 
C CI
C CI
C CI

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8. RESEARCH QUESTION AND OBJECTIVES 
To describe the demographic and baseline characteristics and treatment outcomes in patients 
with locally advanced or metastatic UC treated with avelumab as 1L maintenance therapy. 
8.1. Primary objective 
To describe the demographic and baseline disease characteristics of patients with locally 
advanced or metastatic UCtreated with avelumab as 1L maintenance therapy in a real-world 
clinical setting. 
8.2. Secondary objectives 
1) To evaluate the effectiveness of 1L avelumab maintenance therapy for patients with  
locally advanced or metastatic UC treated in Japan. 
2) To describe clinical usage of corticosteroid for immune-related adverse events (irAEs) 
observed during avelumab therapy and after the last administration of avelumab therapy.  
3) To describe premedication and treatment for infusion-related reaction of avelumab. 
4) To describe the patterns of subsequent UC therapy. 
 
 

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9. RESEARCH METHODS 
9.1. Study design 
This study is a multicenter, non-interventional, retrospective, medical chart review of locally 
advanced or metastatic UC patients who were prescribed avelumab as 1L maintenance therapy 
between 24 February 2021 and 30 November 2021 in Japan. All decisions regarding clinical 
management and treatment of the participating patients were made by the investigator as part 
of standard care in a real-world clinical setting and were not contingent upon the patient’s 
participation in the study. Data will be collected if available per study site. 
 
Index date: The date of first prescription for avelumab between 24 February 2021 (launch 
date of avelumab) and 30 November 2021 
 
Observation period: Patients will be followed from index date to 30 Jun 2022 
9.2. Endpoint 
9.2.1. Primary endpoint 
Patient characteristics at baseline (at the initiation of 1L Cht and the initiation of avelumab 
maintenance therapy) 
The following baseline (at the initiation of 1L Cht and the initiation of avelumab maintenance 
therapy) patient background will be collected. The latest data before the start of 1L Cht and 
before the start of avelumab administration will be collected, respectively. 
1) Age* 
2) Sex* 
3) Medical history/comorbidity (interstitial lung disease/chronic obstructive pulmonary 
disease/autoimmune disease/cerebrovascular disease/cardiovascular 
disease/diabetes/others) * 
If these diseases are cured by the start of avelumab administration, they are treated as a 
medical history, and if they continue after avelumab administration, they are treated as 
comorbidity. 
4) Confirmed date of urothelial carcinoma 
5) Eastern Cooperative Oncology Group (ECOG)  
6)  Tumor-node-metastasis (TNM) classification  
7) Cht regimens received in 1L (Cisplatin [Cis]/ Gemcitabine [Gem], Carboplatin 
[Carbo]/Gem, Methotrexate, Vinblastine, Adriamycin, and Cisplatin [MVAC] regimens, 
dose dense-MVAC, others) 
8) Start date and end date of administration, Number of Cht cycles received in 1L 
9) Duration between the end date of 1L Cht and the start date of avelumab 
10) Best overall response to 1L Cht (complete response [CR], partial response [PR], stable 
disease [SD], PD) 
11) Site (bladder, urethra, renal pelvis or ureter) and histology (Urothelial carcinoma/ 
adenocarcinoma/ squamous cell carcinoma/ small cell carcinoma/others [details])  of the 
primary tumor at the time of initial diagnosis. 
12) Histological atypia 
13) Histological depth of tumor invasion 
14) Definitive treatment of primary lesion (Yes [Surgery/ Others]/ No), date of treatment. 

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15) Site of distant metastasis (Yes [visceral/ non visceral]/ No)  
Visceral: Having to do with the viscera, which are the soft internal organs of the body, 
including the lungs, the heart, and the organs of the digestive, excretory, reproductive, and 
circulatory systems (Classified as "visceral" if it has visceral metastasis, and classified as 
"non-visceral" if it has only locally advanced / recurrent lesions and non-visceral lesions 
without visceral metastasis) 
16) Local recurrence (Yes/No), if yes, recurrence confirmed date 
17) Bajorin risk classification (0/1/2)  
<Bajorin risk classification 10> 
Risk factor 
Classification 
 Visceral metastases 
 Karnofsky performance status <80% 
No risk factor  
0 
One risk factor 
1 
Two risk factors 
2 
 
18) Concomitant drug  
 
* at the initiation of avelumab maintenance therapy (The latest data before the start of 
avelumab administration will be collected) 
 
9.2.2. Secondary endpoints 
Efficacy endpoint 
 
Time to treatment failure (TTF) of avelumab 
Definition of TTF is provided in 20. The following avelumab treatment data will be 
collected:  
1) Date of start and end of avelumab administration 
2) Dosage of avelumab 
3) Date of avelumab discontinuation and interruption 
4) Reason for avelumab discontinuation and interruption 
5) Date of of last survival confirmation 
 
 
Real-world progression-free survival (rwPFS) 
Definition of rwPFS is provided in 20. The following data will be collected:  
1) Date of start of avelumab treatment (administration) 
2) Date of first disease progression or death due to any cause, whichever came first 
3) Date of last survival confirmation  
 
 
Objective Response Rate (ORR) 
ORR is defined in 21. The following data will be collected:  
1) Tumor assessment (CR, PR, SD, PD) 
 
rwPFS from chemotherapy (rwPFS-c） 
Definition of rwPFS-c is provided in Section 9.2.3.4. The following data will be collected:  
1) Date of start of 1L Cht  (administration) 

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2) Date of first disease progression or death due to any cause during avelumab treatment, 
whichever came first 
3) Date of last survival confirmation  
 
Safety endpoints 
 
Corticosteroid therapy for immune-related adverse events (irAEs)  
The following data will be collected:  
1) Date of treatment 
2) Drug name of corticosteroid 
3) Starting dose of corticosteroid 
4) Duration of corticosteroid treatment 
 
Premedication for potential infusion-related reaction of avelumab 
The following data will be collected: 
1) Presence of premedication for infusion-related reaction of avelumab 
2) Drug name used for premedication for infusion-related reactions of avelumab 
 
Treatment for infusion-related reaction of avelumab 
The following data will be collected: 
1) Presence of treatment for infusion-related reaction of avelumab 
2) Drug name used for treatment for infusion-related reaction of avelumab 
 
Regimen after avelumab maintenance therapy 
The following data will be collected: 
1) Medication for UC after avelumab maintenance therapy (drug name, start date of 
treatment, end date of treatment) 
 
Hematological test (after the start of 1L Cht) 
The following data will be collected: 
1) Red blood cell count/ hemoglobin/ hematocrit/ white blood cell count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes)/ platelet count/ C-reactive protein 
(CRP)/ total protein/ albumin/ AST/ ALT/ LDH/ BUN/ creatinine/ Na/ K/ Cl 
Data collection scope: At the start of 1L cht / immediately before the first avelumab 
administration/ at the start of fourth cycle of avelumab treatment/ at the time of PD 
judgment (at the latest test during the observation period for those continuing 
avelumab treatment without disease progression) 
9.2.3. Definition of endpoints 
9.2.3.1. Time to treatment failure (TTF) 
TTF is defined as the following:  
TTF, defined as the time from start of avelumab maintenance therapy to the date of end of 
treatment due to any cause including death. If there is no record of the end of treatment, it be 
discontinued on the last observation date during the study period. 
9.2.3.2. rwPFS 
rwPFS is defined as the following:  
The time from start of avelumab maintenance therapy to date of first disease progression (as 

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clinically assessed by local investigator based on radiology, laboratory evidence, pathology, or 
other assessments) or death due to any cause, whichever occurred first. If there were no clinical 
records of death or disease progression, they will be censored at the date of initiation of the 
next line of therapy for the patients undertaking 2 or more lines of therapy (subsequent therapy 
after avelumab maintenance therapy) based on the record, or at their last observation date 
during the study period for the patients undertaking only 1 line of therapy (only avelumab 
maintenance therapy) based on the record. 
9.2.3.3. Objective response rate (ORR) 
OR is defined as the following: 
Complete or partial response as the best adjudication result (CR > PR > SD > PD) in a method 
that complies with Response Evaluation Criteria in Solid Tumors (RECIST) version. 1.1 tumor 
assessment as closely as possible in clinical practice by investigator’s judgment. 
9.2.3.4. rwPFS-c 
rwPFS-c is defined as the following:  
The time from start of 1L Cht to date of first disease progression (as clinically assessed by 
local investigator based on radiology, laboratory evidence, pathology, or other assessments) or 
death due to any cause during avelumab treatment, whichever occurred first. If there were no 
clinical records of death or disease progression, they will be censored at the date of initiation 
of the next line of therapy for the patients undertaking 2 or more lines of therapy (subsequent 
therapy after avelumab maintenance therapy) based on the record, or at their last observation 
date during the study period for the patients undertaking only 1 line of therapy (only avelumab 
maintenance therapy) based on the record. 
 
9.3. Setting 
This study is a post-approval, company-sponsored, observational study in Japan. 
9.3.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1) Diagnosed with locally advanced or metastatic UC before receiving Avelumab 1L 
maintenance therapy 
2) Started 1L maintenance therapy with avelumab for locally advanced or metastatic UC 
from 24 Feb 2021 (launch date) to 30 Nov 2021 
3) Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects 
of the study 
(1) Written consent is not required for patients who were transferred to a hospital, and 
registration with verbal consent is acceptable 
(2) Opt-out enrollment is allowed for patients who have already died 
4) Deceased patients are also required to meet the inclusion criteria 1)-2) 

A v el u ma b 
B 9 9 9 1 0 4 8   N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L 
Pr ot oc ol versi o n 4. 1 , 2 9 J u n 2 0 2 2  
 
P FI Z E R C O N FI D E N TI A L   
C T 2 4 -WI -G L 0 2 -R F 0 2  4. 0  N o n -I nterve nti o n al St u dy Pr ot oc ol Te m pl ate F or Sec o n d ary D at a C ollecti o n St u dy  
0 1 -J u n-2 0 2 2   
Pa ge 2 2  of 3 3  
9. 3. 2.  E xcl usi o n criteri a  
T here are n o e xcl usi o n criteria f or t his st u d y. 
9. 4.  V ari a bles  
C ollect t he i nf or mati o n s h o w n i n  Secti o ns  9. 2. 1  a n d 9. 2. 2  i n t his st u d y. H u ma n ge n o me a n d 
ge ne i nf or mati o n wil l n ot be c ollecte d. 
9. 5.  D at a s o urces   
As  t his  is  a  retr os pecti ve  st u d y,  all  data  will  be  c ollecte d  fr o m  me dical  rec or ds  at  t he  
partici pati n g st u d y site i n Ja pa n. 
9. 7.  D at a m a n a ge m e nt  
I n v esti gat ors will fill o ut electr o nic case re p ort f or ms (e C R Fs) base d o n t he me dical c harts b y 
electr o nic  data  ca pt ure  ( E D C).  After  t he  c o m pleti o n,  e C R Fs  are  tra nsferre d  t o  a  si n gle  
electr o nic  data b ase.  O nl y  t he  d e -i de ntifie d  a n d  pse u d o n y mize d  d ata  are  i ncl u de d.  W he n  
recei vi n g a q u er y fr o m t he data  ma na g er o n t he c o m plete d e C R F (ie, d at a clarificati o n for m 
[ D C F]), i n v esti gat ors will rec o nfir m t he i nf or mati o n o n s o urce d oc u m e nts, fill o ut t he D C F as 
re q uire d, a n d s u b mit t he D C F. 
9. 7. 1.  C ase re p ort f or ms ( eC R Fs)/ D at a c ollecti o n t o ols ( D C Ts)/ Electr o nic d at a rec o r d    
As use d i n t his pr ot oc ol, t he ter m C R F s h o ul d be u n derst o o d t o refer t o a n electr o ni c data 
rec or d or b ot h, de p e n di n g o n t he data c ollecti o n met h o d use d i n t his st u d y. A n e C R F is re q uire d 
a n d s h o ul d be c o m plete d f or eac h i n cl u de d patie nt. T he c o m plet e d ori gi nal e C R Fs are t he s ole 
pr o pert y of Pfizer a n d s h o ul d n ot be ma de a vaila ble i n a n y f or m t o t hir d parties, e xce pt f or 
a ut h orize d  re prese ntati ves  of  Pfizer  or  a p pr o priate  re g ulat or y  a ut h orities,  wit h o ut  writte n  
per missi o n fr o m Pfizer.  
T he i n vesti gat or s hall e ns ure t hat  t he e C R Fs are s ec urel y st ore d at t he st u d y site i n e ncr y pte d 
electr o nic f or m a n d will be pass w or d pr otect e d t o pre ve nt access b y u na ut h orize d t hir d parties. 
T he i n vesti gat or has ulti mate res p o nsi bilit y f or t he c ollecti o n a n d re p orti n g of all cli nical, 
safet y, a n d l a b orat or y d ata e nter e d o n t he e C R Fs a n d a n y ot her d ata c ollecti o n f or ms (s o urce 
d oc u me nts) a n d e ns uri n g t hat t he y are acc urate, a ut he ntic/ ori gi nal, attri b uta ble, c o m plete, 
c o nsiste nt, le gi ble, ti mel y (c o nte m p ora n e o us), e n d uri n g, a n d a vaila ble w h e n re q uire d.  
T he e C R Fs m ust be si g n e d b y t he i n vesti gat or or b y a n a ut h orize d staff me m ber t o attest t hat 
t he data c o ntai ne d o n t h e e C R Fs are tr ue. A n y c orrecti o ns t o e ntries ma d e i n t he e C R Fs or 
s o urce d oc u m e nts m ust be date d, i nitiale d, a n d e x plai ne d (if necessar y) a n d s h o ul d n ot o bsc ure 
t he ori gi nal e ntr y. T he s o urce d o c u me nts are t he h os pital or t he p h ysici a n's c hart. I n t hese cases, 
C CI

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data collected on the eCRFs must match those charts. 
9.7.2.Record retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, eCRFs and hospital records), all original signed  
informed consent documents, copies of all eCRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports). The records should  
be retained by the investigator according to local regulations or as specified in the clinical 
study agreement (CSA), whichever is longer. The investigator must ensure that the records 
continue to be stored securely for so long as they are retained. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The study 
records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or to an independent third party arranged by Pfizer.  
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless the retention period is specified in the contract between each research 
institution and Pfizer or required by the regulations of the implementing country. Record must 
be retained for longer than 15 years if required by applicable local regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, even 
if retention requirements have been met. 
9.7.3.Record disposal 
Study records must be disposed of appropriately according to each site regulation. 
9.8. Data analysis  
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated, filed, and maintained 
by the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a protocol 
amendment. The SAP must be finalized before data lock. The final analysis will be performed 
after data lock and may modify the plans outlined in the protocol. 
9.8.1. Analysis Population 
The analysis population is defined in the SAP.  
9.8.2. Analysis Methods 
Continuous variables will be summarized using descriptive statistics ie, number of nonmissing 
values and number of missing values [ie, n (missing)], mean, median, standard deviation (SD), 
minimum, maximum and first and third quartile. Qualitative variables will be summarized by 
frequency counts and percentages. These endpoints will also be displayed graphically, if 
necessary. 

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9.8.3. Analysis of Primary Endpoints 
See 18. These endpoints will be descriptively summarized. These endpoints will also be 
displayed graphically, if necessary.  
9.8.4. Analysis of Secondary Endpoints 
Efficacy Endpoints  
See 19. For the time-to-event endpoints, eg, TTF and rwPFS, the Kaplan-Meier estimates 
(product-limit estimates) will be presented together with a summary of associated statistics 
including the median time with 2-sided 95% CIs. In particular, the survival rate at several 
timepoints will be estimated with corresponding 2-sided 95% CIs.  
Other Secondary Endpoints  
See 19. These endpoints will be descriptively summarized. These endpoints will also be 
displayed graphically, if necessary.  
9.9. Quality control 
The sponsor will train investigators and study site staff with an onsite training visit or web 
training on the protocol, eCRFs, and any applicable study processes. Any new information 
relevant to the performance of this study will be forwarded to the investigator and study site 
staff during the study. Remote data monitoring will be conducted during the life of the study 
to ensure timely reporting of data, data integrity, and consistency. eCRFs for all included 
patients will be made available to the remote data monitor for review. The study sites will be 
queried and managed to request resolution to any issues that may arise during the course of the 
study. 
9.10. Limitations of the research methods 
 
This study is retrospective in nature so only existing data reported in patient records will 
be available. Variables that are often missing may affect estimation accuracy.  
 
Center of excellence will be preferentially selected in this study, so site selection and 
outcome reporting bias may be included. For this reason, the study results may not reflect 
all Japanese clinical outcomes. 
 
Evaluation of disease response may differ at each site, and measurement errors may be 
included in the estimated value. 
9.11. Other aspects 
9.11.1. Report to the chief executive of the study site 
Each study site’s investigator shall report the following to the chief executive of the study site 
in writing: 
1) Measurements to be revised in the protocol; 
2) Progression of the study; 
3) Termination, discontinuation, and interruption of the study. 
 

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10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information  
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any reports, 
publications, or other disclosures, except where required by applicable laws.  
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access. The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster. In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of personal 
data, when study data are compiled for transfer to Pfizer and other authorized parties, patient 
names will be removed and will be replaced by a single, specific, numerical code, based on a 
numbering system defined by Pfizer.  All other identifiable data transferred to Pfizer or other 
authorized parties will be identified by this single, patient-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data, 
consistent with the clinical study agreement and applicable privacy laws. 
10.2. Patient consent 
10.2.1. For subjects who are alive and still visit the study site 
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. The investigator, or a 
person designated by the investigator, will obtain written informed consent from each subject 
before any data is collected. The investigator will retain the original of each subject's signed 
consent form.  
The informed consent form must be in compliance with local regulatory requirements and legal 
requirements. The informed consent form used in this study, and any changes made during the 
course of the study, must be prospectively approved by both the Institutional Review Board 
(IRB)/ independent ethics committee (IEC) and Pfizer before use. 
Information to be provided to subjects: 
1) Title of the study and the fact that approval of the chief executive of the study site has been 
given concerning its implementation.  
2) Names of the study site and the principal investigator [including names of the collaborative 
study site(s) and principal investigators of such collaborative study site(s), when the study 
is conducted collaboratively with other study site(s)]; 
3) Objectives and significance of the study; 
4) Method and time period of the study (including purpose of utilization of specimens or 
information acquired from the subject);  

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5) Reasons why asked to be enrolled in the study; 
6) Burdens to be caused on the subjects and predictable risks and benefits;  
7) The fact that subjects may withdraw their consent at any time even after they have given 
consent with regard to the study being commenced or continued (when it can be difficult 
to take measures that follow the withdrawal made by the study subject , a statement to that 
effect and the reason for the difficulty).  
8) The fact that the refusal or withdrawal of consent by a study subject with regard to the 
study is to be commenced or continued does not cause any disadvantage to such subject . 
9) Means to make information on the study public;  
10)  The fact that subjects can request and obtain or read the study protocol and documents 
concerning the method of the study, to the extent it does not interfere with the protection 
of personal information, of other subjects, or the originality of the study, as well as the 
procedure to obtain or read such protocols and documents;  
11) Handling of personal information (including process of pseudonymization, when 
pseudonymization is conducted); 
12) Means for storage and disposal of specimens and information;  
13) Status of study-related conflicts of interest of the study site, such as study fund resources 
as well as study-related conflicts of interest of each investigator, such as his/her individual 
income; 
14) Handling of results and other information obtained from the study; 
15) Response to consultation made by subjects, and other individuals concerned; 
16) With respect to specimens and information acquired from the subject, when any of those 
may be utilized or provided to other study site(s) for future study that is not identified at 
the time of obtaining consent from the study subject, a statement to that effect and the 
contents of utilization assumed at the time of obtaining consent;  
10.2.2. Subjects who are alive and had been transferred to another medical facility 
In accordance with Chapter 4 “Informed Consent” of the  “Ethical Guidelines for Life Science 
and Medical Research Involving Human Subjects”, it is not always necessary to obtain written 
informed consent when existing information isto be provided to another medical facility, but 
the individual providing existing information shall obtain oral informed consent. In this study, 
it is not required to obtain written informed consent from the subjects who had been transferred 
to another medical facility. In case the subject’s data will be collected from another medical 
facility for this study, investigator must ask primary doctor who currently cares for the patient 
at another hospital to obtain oral informed consent for the data collection. In addition, the 
conduct of this study will be disclosed, and the patients will be guaranteed an opportunity to 
refuse data collection. 
10.2.3. Subjects who are deceased 
In accordance with Chapter 4 “Informed Consent” of the “Ethical Guidelines for Life Science 
and Medical Research Involving Human Subjects”, the conduct of this study will be disclosed, 
and the subjects’ legally acceptable representatives will be guaranteed an opportunity to refuse 
data collection for the subjects. The following data must be made public:  
1）Purpose and method for which the data will be used;  

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2）Item of information to be used or provided;  
3）Name of the person responsible for data management;  
4）Range of users;  
5）At the request of the subjects’ legally acceptable representatives, the use of information 
that identifies the research subject or the provision to other research institutes will be 
suspended. And how to accept the request of the research subject's agent 
10.2.4. Response to important findings and other information concerning the health of  
subjects 
 With regard to the explanation of important findings and other information on the health of 
subjects obtained throughout this study, the principal investigator shall confirm at the time of 
obtaining consent whether disclosure is required in advance. If disclosure is required, an 
explanation shall be provided. In doing so, the following items shall be considered: 
1) Whether the results are sufficiently accurate and reliable as information to assess the health, 
etc., of subjects; 
2) Whether the results are important facts for the health, etc., of subjects; 
3) Whether the explanation of the results may significantly impede the proper conduct of the 
study. 
If the subject does not wish to receive an explanation of the results obtained from this study, 
his or her wishes will be respected. However, even if the subject does not wish to receive an 
explanation of the results obtained from the study, and if it is known that the results will have 
a serious impact on the life of the subject, blood relatives, etc., and if there is an effective way 
to deal with the situation, the principal investigator shall seek opinions from the IRB/IEC 
regarding whether to give an explanation, and the details and method of the explanation after 
considering the following: 
1) Effect on the lives of study subjects and their blood relatives, etc.;   
2) The availability of effective treatment and the health of study subjects; 
3) The possibility that blood relatives may be affected by the same disease; 
4) Description of the explanation of the results of the study at the time of informed consent 
Based on the opinions of the IRB or IEC, the principal investigator shall provide sufficient 
explanation to the subject, etc., and confirm the intention of the subject; if the subject still does 
not wish to receive the explanation, no explanation shall be provided. 
If the subject does not give consent, the principal investigator will not, in principle, explain the 
results obtained from the study pertaining to the subject to anyone other than the subject. 
However, if a legally acceptable representative, blood relative, etc., of the subject wishes to 
receive an explanation of the results obtained from the study, etc., the principal investigator 
shall provide such explanation as necessary, after obtaining the opinions of the IRB/IEC as to 
whether such explanation is permissible, based on the reason for the request and the necessity 
of the explanation. 
10.3. Patient withdrawal 
10.3.1. Subjects who are alive and still visit the study site, or subjects who are alive and 
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During the course of this study, the subject can withdraw his/her consent at any time. In any 
circumstance, every effort should be made to document patient outcomes, if possible. If the 
patient withdraws from the study and withdraws consent for disclosure of future information, 
no further evaluations should be performed and no additional data should be collected. The 
sponsor may retain and continue to use any data collected before withdrawal of consent. 
10.3.2. Subjects who are deceased 
When the subjects’ legally acceptable representatives refuse to participate in the study during 
the study period, all of their data must be excluded from the analysis dataset. If the results of 
this study are disclosed on paper or conference at the time of refusal, the subject’s data cannot 
be excluded. 
10.4. Institutional Review Board (IRB)/Independent ethics committee (IEC) 
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (eg, informed consent forms if applicable) from the relevant IRBs/IECs. 
The IRB/IEC to which the review is requested shall be selected in accordance with the policy 
established by each medical institution, and the details of the review requesters shall be 
described in Annex 1. All correspondence with the IRB/IEC must be retained. Copies of 
IRB/IEC approvals must be forwarded to Pfizer. Pfizer Inc. and the principal investigator will 
respond appropriately to the information on the status of the review. 
10.5. Ethical conduct of the study 
To ensure legal, regulatory and scientific purposes, values and rigor, This study will be 
conducted in accordance with the Helsinki Declaration of 1964 and later versions and “Ethical 
Guidelines for Life Science and Medical Research Involving Human Subjects”  issued by the 
Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, 
Labour and Welfare and the Ministry of Economy, Trade and Industry in Japan. 
10.6. Predictable risks and benefits 
10.6.1. Risk 
The subjects’ data will be collected retrospectively in this study, so there is no added risk to 
any individual subject. 
10.6.2. Benefits 
For individual subjects, there is no particular benefit because this study isa retrospective study 
design. 
10.7. Conflicts of interest 
This study will be sponsored by Pfizer Inc. The investigators will review any conflicts of 
interests that may affect the planning of this study or the interpretation of results by the 
IRB/IEC or the Conflicts of Interest Committee, according to the regulations of the study site. 
When the results of the study are published, accurate information will be disclosed by self-
reporting in compliance with the guidelines of the academic society or journal used for 

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publishing the results of the study. 
10.8. Registration and publication of study 
Prior to implementation of this study, summary of this study will beregistered in the public 
database of ClinicalTrials.gov. Registered content will be properly updated without delay. 
10.9. Secondary use of specimens and information obtained from subjects 
The data obtained from this study may be used in other studies with different purposes, such 
as another study linked to this study or an integrated analysis (meta-analysis, etc.) with other 
research data. Such use will only be possible if another protocol is developed and approved by 
the IRB/IEC, and in such a case, information on the newly specified purpose of use, etc., shall 
be notified or disclosed to the subjects and the opportunity for refusal from the subjects, etc., 
shall be guaranteed, in principle, regarding the implementation of another study. In addition, 
the provision of information collected in this study from organizations or individuals to outside 
of the responsible parties of this study shall be limited to cases in which Pfizer Inc. agrees. The 
ownership of rights, etc., arising from secondary use or provision to external parties shall be 
determined through consultation with Pfizer Inc. and the parties to which secondary use or 
provision is made. 
Furthermore, the possibility of future secondary use or external provision of the collected 
information will be explained to the subjects at the time of their participation in this study, and 
their informed consent will be obtained. 
10.10. Responding to consultations from subjects and other related parties 
The principal investigator will set up a helpline for handling consultations about this study 
from subjects and other related parties. Information about each site helpline is included in the 
informed consent form and document related to opt-out. 
 

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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study protocol requires human review of patient-level unstructured data; unstructured data 
refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans 
(Magnetic resonance imaging, computed tomography, positron emission tomography, etc.), X-
rays, or narrative fields in a database. The reviewer is obligated to report adverse events (AEs) 
with explicit attribution to any Pfizer drug that appear in the reviewed information (defined 
per the patient population and study period specified in the protocol) to Pfizer. Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE. Pfizer will contact the manufacturer, Merck BioPharma, Inc. under 
the Safety Data Exchange Agreement if it obtains an AE that indicates a clear causal 
relationship with avelumab. The requirements for reporting safety events on the non-
interventional study (NIS) adverse event monitoring (AEM) Report Form to Pfizer Safety are 
as follows: 
 
All serious and non-serious AEs with explicit attribution to any Pfizer drug that appear 
in the reviewed information must be recorded on the EDC (cubeCDMS®) and reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
 
 Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy, 
and occupational exposure associated with the use of a Pfizer product must be reported, 
within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report Form.  
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted.  
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources. While not all demographic fields will be completed, at the 
very least, at least one patient identifier (eg, gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation. All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly male...” 
Other identifiers will have been removed. Additionally, the onset/start dates and stop dates for 
“Illness”, “Study Drug”, and “Drug Name” may be documented in month/year (mmm/yyyy) 
format rather than identifying the actual date of occurrence within the month /year of 
occurrence in the day/month/year (DD/MMM/YYYY ) format.  
All research staff members must complete the following Pfizer training requirements: 
“Your Reporting Responsibilities (YRR) Training for Vendors Working on Pfizer Studies 
(excluding interventional clinical studies and non-interventional primary data collection 
studies with sites/investigators)”.  
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by the 

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trainee) as a record of completion of the training, which must be kept in a retrievable format. 
Copies of all signed training certificates must be provided to Pfizer. Re-training must be 
completed on an annual basis using the most current Your Reporting Responsibilities training 
materials. 
 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The results of this study are not part of any regulatory submission. The results of this study 
will be submitted for abstracts and publications. The final output will be filed in Pfizer’s Global 
Document Management System upon final study completion.  
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately. 
 
 

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13. REFERENCES 
1. Bray F, Ferlay J, Soerjomataram I. et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A 
Cancer J for Clin, 2018; 68: 394-424. 
2. Malats N, Real FX. Epidemiology of bladder cancer. Hematol Oncol Clin North Am2015; 
29(2): 177-89. 
3. The cancer statistical forecast in 2021 conducted by the National Cancer Center  
Japan.https://ganjoho.jp/reg_stat/statistics/stat/short_pred.html 
4. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized 
trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus 
cisplatin in patients with bladder cancer. J Clin Oncol 2005;23(21):4602-8. 
5. Matsumoto H, Shiraishi K, Azuma H, Inoue K, Uemura H, Eto M, et al. Clinical Practice 
Guidelines for Bladder Cancer 2019 edition by the Japanese Urological Association: 
Revision working position paper. Int J Urol. 2020;27(5):362-8. 
6.  Flaig TW, Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK, et al. Bladder 
Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr 
Canc Netw. 2020;18(3):329-54. 
7. T Abe, K Minami, T Harabayashi, A Sazawa, H Chiba, H Kikuchi, H Miyata, R Matsumoto, 
T Osawa, S Maruyama, J Ishizaki, T Mochizuki, S Chiba, T Akino, M Murakumo, N 
Miyajima , K Tsuchiya, S Murai, N Shinohara. Outcome of maintenance systemic 
chemotherapy with drug-free interval for metastatic urothelial carcinoma. Jpn J Clin Oncol. 
2019;49(10):965-971. 
8. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab 
Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 
2020;383(13):1218-30. 
9. Tsuchiya, et al. ASCO GU Cancers Symposium 2021. Abstract No. 425 
10. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-
cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999 
Oct;17(10):3173-81. 
 
14. LIST OF TABLES  
None 
 
15. LIST OF FIGURES 
None 
 

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ANNEX 1. IMPLEMENTATION STRUCTURE AND LIST OF STUDY SITES AND 
PRINCIPAL INVESTIGATORS OF THE STUDY 
There are no plans to revise the protocol at this time, but when the protocol is to be revised in  
the future, these changes will be added to the protocol. Until then, please keep this document  
together with the protocol and treat it as part of the protocol. If necessary, please submit this  
document to the IRB/IEC. 
 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
None 
 
ANNEX 3. ADDITIONAL INFORMATION 
Not applicable