A Multicenter, NI, Retrospective, Observational Study Evaluating Real-World Treatment Outcomes in Japanese Patients With Metastatic Renal Cell Carcinoma (mRCC) Treated With Avelumab Plus Axitinib as First-line Therapy: J-DART2
Conditions: Renal Cell Carcinoma
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Avelumab (BAVENCIO®)
B9991052 NON-INTERVENTIONAL STUDY PROTOCOL
Protocol Version 1.2, 31 October 2022
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
A Multicenter, NI, Retrospective, Observational 
Study Evaluating Real-World Treatment 
Outcomes in Japanese Patients with Metastatic 
Renal Cell Carcinoma (mRCC) Treated with 
Avelumab plus Axitinib as First-line Therapy: J-
DART2
Protocol number
B9991052
Protocol version identifier
Version 1.2
Date
31 October 2022
Active substance
Avelumab
Medicinal product
Avelumab (BAVENCIO®)
Research question and objectives
To describe the demographic and clinical 
characteristics and treatment outcomes of 
Japanese patients with mRCC who were treated 
with avelumab plus axitinib as first-line therapy 
in a real-world setting. 
Author
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD

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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS .......................................................................................................2 
2. LIST OF ABBREVIATIONS ................................................................................................4 
3. RESPONSIBLE PARTIES ....................................................................................................6 
4. ABSTRACT ...........................................................................................................................6 
5. AMENDMENTS AND UPDATES .......................................................................................6 
6. MILESTONES .......................................................................................................................7 
7. RATIONALE AND BACKGROUND ..................................................................................7 
8. RESEARCH QUESTION AND OBJECTIVES ...................................................................8 
8.1. Primary objective ......................................................................................................8 
8.2. Secondary objectives .................................................................................................8 
..8 
9. RESEARCH METHODS ......................................................................................................8 
9.1. Study design ..............................................................................................................8 
9.2. Setting ........................................................................................................................8 
9.2.1. Inclusion criteria ...........................................................................................9 
9.2.2. Exclusion criteria ..........................................................................................9 
9.3. Variables ....................................................................................................................9 
9.3.1. Definition of clinical outcome measures ....................................................10 
9.4. Data sources ............................................................................................................11 
9.5. Study size ................................................................................................................11 
9.6. Data management ....................................................................................................11 
9.6.1. Case report forms (CRFs) /Data collection tools (DCTs)/ Electronic data 
record ...............................................................................................................11 
9.6.2. Record retention ..........................................................................................12 
9.7. Data analysis ...........................................................................................................12 
9.7.1. Analysis Population ....................................................................................12 
9.7.2. Analysis Methods .......................................................................................13 
9.8. Quality control .........................................................................................................13 
9.9. Limitations of the research methods .......................................................................13 
9.10. Other aspects .........................................................................................................13 
9.10.1. Reporting to the chief executive of the study site .....................................13 
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10. PROTECTION OF HUMAN SUBJECTS ........................................................................14 
10.1. Patient information ................................................................................................14 
10.2. Patient consent .......................................................................................................14 
10.2.1. For patients who are alive and continue to visit the study site .................14 
10.2.2. Patients who are alive and were transferred to another medical facility ..15 
10.2.3. Patients who are deceased ........................................................................15 
10.2.4. Disclosing study findings to patients ........................................................15 
10.3. Patient withdrawal .................................................................................................15 
10.3.1. Patients who are alive and continue to visit the study site, or were 
transferred to another medical facility .............................................................15 
10.3.2. Patients who are deceased ........................................................................15 
10.4. Institutional review board (IRB)/Independent ethics committee (IEC) ................16 
10.5. Ethical conduct of the study ..................................................................................16 
10.6. Predictable risks and benefits ................................................................................16 
10.7. Conflicts of interest ...............................................................................................16 
10.8. Registration and publication of study ....................................................................16 
10.9. Secondary use of  information obtained from subjects .........................................16 
10.10. Responding to consultations from patients and other related parties ..................17 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................17 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........18 
13. REFERENCES ..................................................................................................................18 
14. LIST OF TABLES .............................................................................................................19 
15. LIST OF FIGURES ...........................................................................................................19 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS  ........................................................19 
ANNEX 2. ADDITIONAL INFORMATION .........................................................................19 
  
 

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2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AEM 
adverse event monitoring 
BOR 
best overall response 
CI 
confidence interval  
CR 
complete response 
CRFs 
Case report forms 
CSA 
clinical study agreement 
CRP 
C-reactive protein 
DCF 
data clarification form 
DCTs 
Data collection tools 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
FAS 
Full analysis set 
HR 
hazard ratio 
IMDC 
International Metastatic RCC Database Consortium 
IEC 
independent ethics committee 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
JUA 
Japanese Urological Association 
mRCC 
metastatic renal cell carcinoma 

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NIS 
non-interventional study 
NE 
not Evaluable 
NI 
non-interventional 
OS 
Overall survival 
ORR 
objective response rate 
PR 
partial response 
PD 
progressive disease 
PD-L1 
anti-programmed death ligand 1 
PFS 
progression-free survival 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
TNM 
tumor-node-metastasis 
TKI 
tyrosine kinase inhibitor 
TTD 
time to treatment discontinuation 
YRR 
your reporting responsibilities 
 
 
 

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3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
The implementation structure of this study will be prepared in Annex 1. 
4. ABSTRACT 
Not applicable 
5. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Protocol section(s) 
changed 
Summary of amendment(s) 
Reason 
1.1 
14 Oct 2022 
6. MILESTONES 
9.8. Quality control 
10.2.4. Disclosing study 
findings to patients 
ANNEX 1. LIST OF 
STAND ALONE 
DOCUMENTS 
6. added anticipated study start date 
9.8. added data monitoring 
procedure 
10.2.4. addded plans to 
communicate study results to 
participants 
ANNEX 1. changed the name of the 
site 
6. to clarify study period 
9.8. to clarify data 
monitoring procedure 
10.2.4.to clarify how to deal 
with study results including 
incidental or secondary 
findings 
ANNEX 1. to correct typos 
1.2 
31 Oct 2022 
9.8. Quality control 
9.8. added the affiliation of the data 
manager 
9.8. to clarify who is in 
charge of data monitoring 
 
 
 

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6. MILESTONES 
 
 
 
 
7. RATIONALE AND BACKGROUND 
In Japan, nearly 30,000 patients were diagnosed with renal cancer in 2018, and the number of patients 
has increased annually since the 1980s 1). The 5-year relative survival rate for renal/urinary tract  
cancer (excluding bladder cancer) was 68.6% between 2009 and 2011. In 2020, Nine Thousand Seven 
Hundred Twelve deaths occurred, with a mortality rate of 7.6 per 100,000 persons. Although the 
incidence of renal cell carcinoma (RCC) in Japan is lower than that in other modernized countries, it 
continues to increase 1,2). 
Recently, the immunotherapeutic approaches have demonstrated clinical efficacy in several types of 
cancer, and certain immune checkpoint inhibitors have been approved for the treatment of RCC. 3-7) 
One of these immune checkpoint inhibitors is avelumab, an anti-programmed death ligand 1 (PD-L1) 
antibody. In December 2019, avelumab plus axitinib combination therapy was approved in Japan as  
the first-line treatment for unresectable or mRCC. 4) This is the first therapy approved in Japan that 
has combined an immuno-oncology drug with a tyrosine kinase inhibitor (TKI) in order to treat 
patients with mRCC. The recent Japanese Urological Association (JUA) guidelines for renal cancer 
recommended the combination of avelumab and axitinib as first-line therapy for RCC [Grade B]. 8) 
The Phase 3 JAVELIN Renal 101 trial compared the combination of avelumab plus axitinib with 
sunitinib monotherapy in previously untreated patients with advanced RCC. 4)  The results showed a 
statistically significantly longer median progression-free survival (PFS) in those treated with the 
combination therapy (13.8 months; 95% confidence interval [CI]: 11.1–inestimable) as compared with 
sunitinib (7.2 months; 95% CI: 5.7–9.7) as well as a hazard ratio (HR) of 0.61 for disease progression 
or death (95% CI: 0.47–0.79; P <0.001). These findings were sustained even after a minimum follow-
up of 13 months (HR: 0.62; 95% CI: 0.49–0.78; one-sided P <0.0001), 9) and similar results were 
obtained in subgroup analyses within each age category (<65 years, 65-74 years, ≥75 years), including 
the population aged 75 years and over. 10) 
Although several clinical trials have focused on avelumab plus axitinib regimens in the treatment of 
mRCC, there is limited evidence in real-world settings in Japan. Moreover, because more than  1-year 
follow-up period is required to assess the real-world effectiveness of this combination therapy, such 
as in regard to PFS, we planned a series of 3 studies with different long-term follow-up periods. As 
the first of these studies, J-DART1-B9991043, was conducted to evaluate the treatment outcomes over 
the course of 1-year in Japanese patients with mRCC who were treated with avelumab plus axitinib as 
first-line therapy in a real-world clinical setting (NCT05012865). This second study, J-DART2-
B9991052, is being conducted in order to describe the demographic and characteristics of the patients 
as well as the treatment outcomes over the course of more than 2-years of follow-up in Japanese 
Milestone 
Planned date 
Study start date 
Date of approval at each site 
Start of data collection    
15 December 2022 
End of data collection  
30 April 2023 
Final study report 
30 November 2023 

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patients with mRCC who were treated with avelumab plus axitinib as first-line therapy in a real-world 
clinical setting. 
 
8. RESEARCH QUESTION AND OBJECTIVES 
8.1. Primary objective 
x 
To describe the demographic and clinical characteristics of Japanese patients with mRCC 
treated with avelumab plus axitinib as first-line therapy in a real-world setting. 
8.2. Secondary objectives 
x 
To evaluate the treatment outcomes of avelumab plus axitinib as first-line therapy for patients  
with mRCC in a real-world setting, as determined by the following endpoints: 
̽ 
Real-world PFS. 
̽ 
Overall survival (OS) . 
̽ 
Objective response rate (ORR). 
̽ 
Best overall response (BOR) for primary lesions. 
̽ 
Time to treatment discontinuation (TTD) of avelumab plus axitinib as first-line therapy. 
x 
To describe the treatment patterns for avelumab plus axitinib as first-line therapy in a real-world 
setting. 
x 
To describe the clinical use of corticosteroids for immune-related adverse events (irAEs) 
occurring during  the course of administering avelumab plus axitinib combination therapy. 
x 
To describe the pre-treatment and treatment of infusion-related reactions caused by avelumab. 
x 
To describe the subsequent treatment of avelumab plus axitinib combination therapy. 
 
 
 
 
9. RESEARCH METHODS  
9.1. Study design  
This study is a multicenter, NI, retrospective, medical chart review of patients with mRCC who were 
treated with avelumab plus axitinib as first-line therapy in Japan between 20 December  2019 and 17 
October 2022. 
The source population comprises patients who initiated avelumab plus axitinib as first-line therapy 
between 20 December 2019 and 17 October 2022. 
9.2. Setting 
This retrospective chart review will evaluate patient data derived from patient’s existing medical 
records from the enrolled patients. All decisions regarding the clinical management and treatment of 
the patients are made by the investigator as part of standard care in a real-world setting and are not 
contingent upon the patient’s participation in the study. Data will be collected at each study site (if 
available). 
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The study period is from 20 December 2019 to 31 October 2022. Patients with index date between 
20 December 2019 and 17 October 2022 will be enrolled in this study. To ensure a 2 weeks follow 
up period, patients with an index date between 20 December 2019 and 17 October 2022 will be 
included in this study. The period of 2 weeks is determined based on the dosing interval for 
avelumab, in consideration of the fact that the start times of administration for avelumab and axitinib 
may differ. 
• 
Index date: The date of first prescription of avelumab plus axitinib combination therapy. 
• 
Observation period: Patients will be followed from the index date to 31 October 2022. 
9.2.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the study: 
1） Diagnoses of mRCC based on the General Rule for Clinical and Pathological Studies on 
RCC (Fifth Edition) before receiving avelumab plus axitinib as first-line therapy. Patients 
with mRCC who have unresectable disease, either unresectable locally advanced or 
metastatic disease. 
2） Age over 18 years at the time of the first administration of avelumab plus axitinib as first-
line therapy for mRCC (baseline).  
3） Index date from 20 December 2019 to 17 October 2022. 
9.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1） Patients participating in a prospective interventional clinical trial assessing an investigational 
product during the observation period. 
2） Patients (or a patient’s legally representative) refusing to provide patient data during the 
consent process.  
9.3. Variables 
Only data available from the treating physician’s routine clinical assessments as per local standard of 
care will be collected. Variables and data sources are described in Table 1. Detailed definitions will 
be included in the Statistical Analysis Plan (SAP). 
Table 1. Variables in this study 
Variable 
Role 
Data 
source(s) 
Operational definition 
Patient 
characteristics 
Baseline 
characteristics, sub-
group idntifiers 
Patient 
medical 
records 
Patient characteristics at baseline, including the most 
recent data prior to initial treatment with avelumab plus 
axitinib: age, sex, height, weight, body mass index, 
smoking history,  comorbidities, concomitant use of 
drugs, Eastern Cooperative Oncology Group (ECOG) 
performance status, pathological diagnosis (Fuhrman 
grade, TNM classification, histological type sarcomatoid 
compornent) ,  the number of metastatic organs and the 
site of metastasis, the presence or absence of 

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nephrectomy,  laboratory data (C-reactive protein (CRP), 
estimated glomerular filtration rate (eGFR), proteinuria) , 
and 
International Metastatic RCC Database Consortium 
(IMDC) risk score   
-  <1 year from time of diagnosis to systemic therapy 
-  Karnofsky Performance Status <80% 
-  Hemoglobin < lower limit of normal 
-  Corrected calcium > upper limit of normal 
-  Neutrophils > upper limit of normal 
-  Platelets > upper limit of normal)   
Avelumab plus 
axitinib 
treatment 
patterns 
Exposure, outcome, 
sub-group idntifier 
Patient 
medical 
records 
Start and end date of avelumab plus axitinib as first-line 
therapy. 
Management of 
AE 
Exposure, outcome, 
sub-group idntifier 
Patient 
medical 
records 
Corticosteroid treatment for irAEs occurring during 
treatment with avelumab plus axitinib (drug, dose), the 
presence or absence of pre-medication and treatment for 
infusion-related reactions. 
Subsequent 
treatment 
patterns 
Exposure, outcome, 
sub-group idntifier 
Patient 
medical 
records 
Subsequent treatment (drug name and duration of use for 
second-line therapy). 
Clinical 
outcomes 
Outcome 
Patient 
medical 
records 
BOR, assessment of disease progression, real-world PFS, 
OS, ORR, TTD. 
For the patients not nephrectomized at baseline: BOR for 
the primary lesion, the date of nephrectomy after 
administration of avelumab plus axitinib. 
 
9.3.1. Definition of clinical outcome measures 
Real-world progression-free survival (PFS) 
Real-world PFS is defined as the time from the start of treatment with avelumab plus axitinib to the 
date of first disease progression (as clinically assessed by a local investigator based on a radiology 
assessment, laboratory evidence, pathological data, and/or other assessments) or death due to any 
cause, which ever came first. If there are no clinical records of death or disease progression, patients 
will be censored at the date of initiation of the next line of therapy for those undertaking 2 or more 
lines of therapy based on the details in their medical records or at their last visit date during the study 
period for those undergoing only first line of therapy. However, if the nephrectomy is performed 
earlier than the above date, the data is to be treated as censored at the date of nephrectomy. 
9.3.1.1. Overall Survival (OS) 
OS is defined as the time from the start of treatment with avelumab plus axitinib to the date of death 
due to any cause. If there are no clinical records of death, the date when the patient was last 
documented to be alive will be confirmed based on medical records. The data will be censored at the 
date of last contact. 

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9.3.1.2. Objective response rate (ORR) 
The ORR is defined as the proportion of patients with a documented BOR (complete response (CR) 
or partial response (PR)) by the invesetigator during treatment with avelumab plus axitinib as first-
line therapy. The BOR is defined as the best tumor response recorded during the observation period. 
The definitions of tumor responses are as follows: 
Complete or PR as the best adjudication result (CR > PR > stable disease [SD] > progressive disease 
[PD], not Evaluable[NE]) complies with the RECIST tumor assessment guidelines as closely as 
possible in clinical practice. 
9.3.1.3. Time to treatment discontinuation (TTD) 
TTD is defined as the time from the start of treatment with avelumab plus axitinib to the end of 
treatment due to any cause except the effectiveness of the treatment. 
9.4. Data sources  
As this is a retrospective study, all data are to be collected from the patient medical records at the 
participating study sites. 
9.5. Study size 
This descriptive study aims to describe the demographic and baseline characteristics for patients 
treated with avelumab plus axitinib as first-line therapy for mRCC, rather than testing any 
predefined hypothesis. Since all analyses are descriptive, sample size calculations are not applicable. 
The expected number of patients is approximately 150 patients in total. However, this number 
should be considered flexible. 
9.6. Data management  
Investigators will complete electronic case report forms (eCRFs) based on medical charts reviews 
using electronic data capture (EDC). After completion, the eCRFs are transferred to a single 
electronic database. Only the de-identified and anonymized data will be included in this database. 
When receiving a query from the sponsor regarding the completed eCRF (ie, a data clarification 
form [DCF]), investigators will reconfirm the information in the source documents, fill out the DCF 
as required, and submit the DCF. 
9.6.1. Case report forms (CRFs) /Data collection tools (DCTs)/ Electronic data record 
As used in this protocol, the term CRF should be understood to refer an electronic data record in this 
study. 
A CRF is required and should be completed for each included patient. The completed original CRFs 
are the sole property of Pfizer and should not be made available in any form to third parties, except 
for authorized representatives of Pfizer or appropriate regulatory authorities, without written 
permission from Pfizer. The investigator shall ensure that the CRFs are securely stored at the study 
site in encrypted electronic form and will be password protected to prevent access by unauthorized 
third parties. 

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The investigator has ultimate responsibility for the collection and reporting of all clinical, safety, and 
laboratory data entered on the CRFs and any other data collection forms (source documents) and 
ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring, and available when required. The CRFs must be signed by the 
investigator or by an authorized staff member to attest that the data contained on the CRFs are true.  
Any corrections to entries made in the CRFs or source documents must be dated, initialed, and 
explained (if necessary) and should not obscure the original entry. 
The source documents are the hospital or the physician's chart. In these cases, data collected on the 
CRFs must match those charts.  
9.6.2. 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, CRFs and hospital records), all original signed informed consent/assent documents, 
copies of all CRFs, 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 study site and Pfizer have expressly agreed to a different period of retention via a 
separate written agreemen or as 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. Data analysis  
Detailed methodology for summary and statistical analyses of data collected in this study will be 
documented in a 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 fixed prior to data 
lock. The analysis is to be performed after the data lock. 
9.7.1. Analysis Population 
Full analysis set (FAS): The FAS will consist of patients who meet the inclusion criteria and do not 
meet the exclusion criteria. 
Efficacy analysis set: The efficacy analysis set is a subset of the FAS that includes patients whose 
index date is prior to 30 April 2022 to ensure a 6-months follow-up period.  

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Subgroups: A subgroup analysis will be considered, including but not limited to subgroups 
categorized by IMDC risk group, age ( 75 years or  75 years), and the presence or absence of 
corticosteroid administrations for irAE in the medical record. 
9.7.2. Analysis Methods 
Continuous variables will be summarized using descriptive statistics (ie, the number of non-missing 
and missing values [ie, n (missing) ], the mean, median, standard deviation [SD],  minimum and 
maximum, and the first and third quartiles). 
Qualitative variables will be summarized using frequency count and percentages.  
For the time-to-event endpoints (for eg, OS, TTD and real-world PFS), Kaplan-Meier estimates will 
be presented together with a summary of the associated statistics including the median time with 2-
sided 95% CIs. In particular, the survival rate at several time points will be estimated along with the 
corresponding 2-sided 95% CIs. These endpoints will be displayed graphically. 
 
9.8. Quality control 
The sponsor will train the investigators and study site staff in regard to the protocol, eCRFs, and any 
applicable study processes via an on-site training visit or web training. Any new information 
relevant to the performance of this study will be forwarded to the investigators and the study site 
staff during the course of the study. Remote data monitoring will be conducted during the study 
period to ensure the timely reporting of data, data integrity, and consistency. The eCRFs for all 
included patients will be made available to the remote data monitor for review. The study sites may 
be queried and should be capable of resolving any issues that may arise during the course of the 
study. On-site monitoring visits have not been planned for this study. The data manager from the 
contract research organization commissioned by the sponsor prepares and submits the data 
monitoring report to the sponsor before the database is locked.  The data monitoring report includes 
the number of cases, the completion of eCRF, queries, and the possible issue or protocol deviation. 
9.9. Limitations of the research methods 
• 
This study is retrospective in nature. Therefore, only existing data reported in patient records is 
available for the present research. Missing data may affect the estimation accuracy. 
• 
High-volume centers were preferentially selected for this study, potentially leading to site 
selection and outcome reporting biases. Therefore, the study results may not accurately reflect 
clinical outcomes for all Japanese centers.  
• 
The evaluation of disease response may differ at each site, and measurement errors may be 
included in the estimated values. 
9.10. Other aspects 
9.10.1. Reporting to the chief executive of the study site 
Each investigator will report the following information to the chief executive at the study site: 
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1） Measurements to be revised in the protocol; 
2） Progression of the study; 
3） Termination, discontinuation, and interruption of the study. 
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 CSA and applicable privacy laws. 
10.2. Patient consent 
The investigator must obtain informed consent from the patients regarding the use of their medical 
records for this study as well as data provision to a third party prior to collecting the data for this 
study. 
The informed consent form must comply with local regulatory 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 independent ethics committee (IEC) and by Pfizer.  
10.2.1. For patients who are alive and continue to visit the study site 
The investigator must obtain written informed consent from each patient before data collection. 
After obtaining written informed consent, the investigators must retain the original signed consent 
form for each patient. When obtaining the oral informed consent in consideration of the patient’s 
condition or situation, the investigator will document the method and content of the explanation as 
well as the details of the obtained consent. 

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10.2.2. Patients who are alive and were transferred to another medical facility 
Investigators must obtain oral informed consent for data collection from each patient who was 
transferred to another hospital before data collection. When obtaining oral informed consent, the 
investigator will document the method and content of the explanation as well as the details of the 
obtained consent. 
 
When it is difficult to obtain oral informed consent for the following reasons, consent will not be 
required based on the Act on the Protection of Personal Information Article 27 (1) - (iii) and the 
Frequently Asked Questions related to the article: 
 
The study site does not obtain valid patient contact information.  
 
When considering the time available and research costs incurred in obtaining oral informed 
consent at the study site, it is concluded that obtaining oral informed consent at the study site 
could significantly impact the conduct of the study. 
 
Even in these cases, the study information must be disclosed, and the patients’ legally acceptable 
representatives will be guaranteed an opportunity to refuse to provide patient data to the sponsor. 
10.2.3. Patients who are deceased 
In accordance with Chapter 4 (“Informed Consent”) of the “Ethical Guidelines for Life Science and 
Medical Research Involving Human Subjects,” the study information needs to be disclosed, and the 
patients’ legally acceptable representatives will be guaranteed an opportunity to refuse providing the 
patient’s data to the sponsor. 
10.2.4. Disclosing study findings to patients 
Human genome and gene information will not be collected in this study.  It is highly improbable that 
study results include incidental findings or secondary findings, and the disclosure of the study results 
to patient individually is not planned for this reason. The study results will be published in the 
manner described in “10.8 Registration and publication of study”. 
10.3. Patient withdrawal 
10.3.1. Patients who are alive and continue to visit the study site, or were transferred to 
another medical facility 
During the course of this study, the patient can withdraw consent at any time. In any circumstance, 
every effort should be made to document patient outcomes, whenever possible. If the patient 
disagrees, the patient’s data will be removed from the study database. However, if published already, 
in such as within a congress presentation or in peer-reviewed manuscripts, the patient’s data will not 
be removed. 
10.3.2. Patients who are deceased 
When patients’ legally acceptable representatives refuse study participation on behalf of the 
deseased patient during the study period, all data must be removed from the dataset. If the results of 
this study had disclosed via publication or at a conference at the time of refusal, the patient’s data 
cannot be removed. 
 

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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. All 
correspondence with the IRB/IEC must be retained.  Copies of IRB/IEC approvals must be 
forwarded to Pfizer. 
In addition, based on the Ethical Guidelines for Medical and Health Research Involving Human 
Subjects issued by the Ministry of Education, Culture, Sports, Science and Technology, the Minister 
of Health, Labour and Welfare, and Welfare and the Ministry of Economy, Trade and Industry, a 
multicenter study should be reviewed by the central IEC together. However, it is not prohibited for a 
review to be conducted by the individual IEC at each site. 
10.5. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as with 
scientific purpose, value and rigor and follow generally accepted research practices described in the 
“Ethical Guidelines for Life Science and Medical Research Involving Human Subjects” . 
10.6. Predictable risks and benefits 
This study is a retrospective chart review study. Therefore, participation in this study does not pose 
specific risks or benefits to individual patients.  
10.7. Conflicts of interest 
This study will be performed with funding from Pfizer Inc. The investigators will review any 
conflicts of interests that may affect the planning of this study or the interpretation of results through 
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 through self-
report, in compliance with the guidelines of the academic society or journal used for publishing the 
results of the study. 
10.8. Registration and publication of study 
Before implementation, this study will be registered at the ClinicalTrials.gov. The registered content 
will be properly updated without delay. 
10.9. Secondary use of  information obtained from subjects 
The data obtained from this study may be used within other studies for different purposes, such as 
within another study linked to this study or an integrated analysis (meta-analysis) using other 
research data. Such use will only be possible if another protocol is developed and approved by the 
IRB/IEC. In such a case, information on the newly specified purpose of use, among other considers, 
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 to organizations or individuals outside of the parties 
responsible for this study shall be limited to cases in which Pfizer Inc. agrees. The ownership of 
rights, arising from secondary use or provision to external parties shall be determined through 
consultation with Pfizer Inc. and the parties to which the secondary use or provision of study data is 
made. 

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Furthermore, the possibility of future secondary use or external provision of the collected 
information will be explained to the participants at the time of their enrollment in this study, and 
informed consent will be obtained. 
10.10. Responding to consultations from patients and other related parties 
The investigator will set up a helpline for consultations with the patients and other related parties in 
regard to this study. Information about each site’s helpline will be included in the informed consent 
form and in documents related to opt-outs. 
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, 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). 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. 
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 exposure during pregnancy in studies of pregnant women, data on the exposure to avelumab 
during pregnancy, are not reportable unless associated with serious or non-serious AEs. 
• 
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 

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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.” 
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 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 YRR 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 to conferences and/or peer-reviewed journals. 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.   
  
13. REFERENCES 
1. Cancer Information Service, National Cancer Center, Japan (National Cancer Registry, Ministry 
of Health, Labour and Welfare) . Cancer Statistics. [updated 2021 Jul 1; cited 2022 Jun 10]. 
Available from: https://ganjoho.jp/reg_stat/statistics/stat/cancer/22_renal.html. 
2. Washio M, Mori M, Mikami K, et al. Risk factors for renal cell carcinoma in a Japanese 
population. Asian Pac. J. Cancer Prev. 2014;15(21):9065-70. 
3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in 
advanced renal-cell carcinoma. N. Engl. J. Med. 2018;378(14):1277–90. 
4. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced 
Renal-Cell Carcinoma. N. Engl. J. Med. 2019;380(12):1103-15. 
5. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced 
renal-cell carcinoma. N. Engl. J. Med. 2019;380(12):1116-27. 

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6. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for 
advanced renal-cell carcinoma. N. Engl. J. Med. 2021;384(9):829-41. 
7. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for 
advanced renal cell carcinoma. N. Engl. J. Med. 2021;384(14):1289-300. 
8. The Japanese Urological Association (JUA) guideline for renal cancer , 
https://www.urol.or.jp/lib/files/other/guideline/33_renal_cancer_2017_rev2020_info.pdf 
9. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 
trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell 
carcinoma. Ann. Oncol. 2020;31(8):1030-9. 
10. Tomita Y, Motzer RJ, Choueiri TK, et al. Efficacy and safety of avelumab plus axitinib in 
elderly patients with advanced renal cell carcinoma: extended follow-up results from JAVELIN 
Renal 101. ESMO open. 2022;7(2):100450. 
14. LIST OF TABLES  
Table 1. Variables in this study 
15. LIST OF FIGURES 
None. 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS  
”Implementation Structure in This Study” will be prepared independently. 
Number 
Document reference 
number 
Date 
Title 
1 
ANNEX 1 
14 Oct 2022 
Implementation structure of this study 
 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable