Clinical Outcomes and Therapy Management Among Patients With Advanced Renal Cell Carcinoma (aRCC) Receiving Systemic First-line (1L) Anti-cancer Treatment Under Daily Routine in Germany: Retrospective Chart Review (RENALISTIC Study)
Conditions: Carcinoma, Renal Cell
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Clinical outcomes and therapy management 
among patients with advanced Renal Cell 
Carcinoma (aRCC) receiving systemic first-
line (1L) anti-cancer treatment under daily 
routine in Germany: Retrospective Chart 
Review (RENALISTIC study).
Protocol number
A4061099
Protocol version identifier
1.0
Date
19-August-2022
Active substance

L01EX Other protein kinase inhibitors
o
L01EX01: sunitinib

L01EK Vascular endothelial growth factor 
receptor (VEGFR) tyrosine kinase 
inhibitors
o
L01EK01: axitinib

L01XC: Monoclonal antibodies
o
L01XC31: avelumab
Medicinal product

Sunitinib (Sutent®)

Axitinib (Inlyta®)

Avelumab (Bavencio®)
Research question and objectives
•
How is the 
effectiveness, defined 
as 
measurement of beneficial effects under “real 
world” clinical settings,  (e.g. progression-free 
survival, overall survival and best response) of 
Tyrosine Kinase Inhibitors (TKI) and/or 
Immune-Checkpoint-Inhibitors (ICI) as 1L in 
patients with aRCC? 

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•
How are patients with aRCC treated in 1L
under daily care conditions in Germany in 
general and
in
accordance
to medical
specialities (urology and medical oncology) 
and treatment settings (hospitals vs office-
based practices)?
•
Are all patients assigned to individual risk 
ratings under standard daily care conditions 
according to a scale developed by the 
International 
Metastatic 
RCC 
Database 
Consortium (IMDC) before start of a 1L?
•
How are patients treated in 1L in different risk 
rating groups and how is the adherence to 
national/international guidelines?
•
What kind of previous and subsequent 
therapies are administered before and after 
1L?
•
How often are evaluations for PD-L1 
expression performed before start of 1L and 
how many patients are positive (TPS 1%) or 
negative?
•
How long are patients treated with TKI + ICI 
and ICI + ICI in 1L in general and in relation 
to specific therapies like avelumab + axitinib?
•
How frequent are dose modifications and 
early discontinuations
and what are the 
reasons?
•
Are there differences in the handling of 
modifications among medical specialities?
To answer these questions the following 
objectives are derived:
Primary Objective(s):
•
Progression-free survival (PFS) for 1L
therapies, expressed as median and as rates at 

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timepoints of 6, 9, 12 and 18 months after start 
of 1L
Secondary Objectives:
•
Overall survival
(OS)
of 1L
therapies, 
expressed as median and rates at timepoints of 
12 and 18 months after start of 1L therapy
•
Best response in 1L overall and in dependence 
of administered drug regimen
•
Progression-free survival of 1L therapies in 
dependence of specific drug regimen
•
Pre-
and 
post-treatments
(i.e. 
surgery, 
radiotherapy, 
medicinal 
therapies) 
before/after TKI + ICI and ICI + ICI in 1L
•
Duration of response (DoR) in 1L overall and 
in dependence of administered drug regimen 
(TKI + ICI or ICI + ICI)
•
Frequency 
of
dose 
modifications
and 
temporary/permanent discontinuations of 1L 
therapies and their reasons
•
Proportions 
of 
modifications
by 
dose 
reduction compared to
skipping
single 
applications Effectiveness (PFS, OS and best 
response) of administered 1L therapies under 
real world conditions by medical speciality
(urology, medical oncology) and setting 
(practice, hospital)
Author
Pfizer Inc.
235E  42nd, New York, NY, 10017
Phone:
Email.
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.......................................................................................................4
2. LIST OF ABBREVIATIONS................................................................................................6
3. RESPONSIBLE PARTIES....................................................................................................9
4. ABSTRACT.........................................................................................................................11
5. AMENDMENTS AND UPDATES.....................................................................................20
6. MILESTONES.....................................................................................................................21
7. RATIONALE AND BACKGROUND................................................................................21
8. RESEARCH QUESTION AND OBJECTIVES .................................................................22
8.1. Primary Research Questions ...................................................................................24
8.2. Study Objectives .....................................................................................................25
9. RESEARCH METHODS ....................................................................................................25
9.1. Setting......................................................................................................................26
9.1.1. Inclusion criteria .........................................................................................26
9.1.2. Exclusion criteria........................................................................................27
9.2. Variables..................................................................................................................27
9.3. Data sources ............................................................................................................28
9.4. Study size ................................................................................................................29
9.5. Data management....................................................................................................30
9.5.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data 
record ...............................................................................................................30
9.5.2. Record retention..........................................................................................31
9.6. Data analysis ...........................................................................................................31
9.7. Quality control.........................................................................................................31
9.8. Limitations of the research methods .......................................................................32
9.9. Other aspects ...........................................................................................................32
10. PROTECTION OF HUMAN SUBJECTS ........................................................................32
10.1. Patient information................................................................................................32
10.2. Patient consent.......................................................................................................33
10.3. Institutional review board (IRB)/Independent ethics committee (IEC)................33
10.4. Ethical conduct of the study..................................................................................33
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................33

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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........35
13. REFERENCES ..................................................................................................................35
14. LIST OF TABLES.............................................................................................................36
15. LIST OF FIGURES ...........................................................................................................36
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................36
ANNEX 3. ADDITIONAL INFORMATION.........................................................................36

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
AEM
Adverse Event Management
AR
Adverse Reaction
aRCC
Advanced Renal Cell Carcinoma
AWMF
Arbeitsgemeinschaft der Wissenschaftlichen 
Medizinischen Fachgesellschaften = Working party of 
scientic medicial societies
CR
Complete response
CRF
Case Report Form
CRO
Contract Research Organization
CT
Computer tomography
DCF
Data clarification form
DGHO
Deutsche Gesellschaft fur Hämatologie und Onkologie = 
German Society for Hematology and Oncology
DoR
Duration of response
eCRF
Electronic Case Report Form
EU
European Union
FU
Follow-Up
GCP
Good Clinical Practice
GVP
Good Pharmacovigilance Practices 
ICD-10
International Classification of Disease 10.revision
ICI
Immune-Checkpoint-Inhibitors
IEC
Independent Ethics Committee

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ICMJE
International Committee of Medical Journal Editors 
IFN
Interferon
IMDC
International Metastatic Renal Cell Carcinoma Database 
Consortium
IRB
Institutional Review Board
IV
Intravenous
MRI
Magnetic resonance imaging
NA
Not applicable
ND
Not done
NIS
Non-Interventional Study
OP
Operation 
ORR
Objective response rate
OS
Overall survival
PASS
Post-authorization safety study
PD
Progressive disease
PD-L1
Programmed death ligand-1
PFS
Progression-free survival
PI
Product information
PI
Principle investigator
PR
Partial response
RCC
Renal Cell Carcinoma
RKI
Robert-Koch-Institute
RR
Response rate
SAE
Severe adverse event

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SAP
Statistical Analysis Plan
SAR
Severe adverse reaction
SD
Stable disease
TKI
Tyrosine Kinase Inhibitor
TPS
Tumor Propotion Score
TTNT
Time-to-next-therapy
TTP
Time-to-progression
YRR
Your Reporting Responsibility
1L
First-line therapy
2L
Second-line therapy

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3. RESPONSIBLE PARTIES
Responsible Parties
Contact details
Principle Investigator
Medical and Protocol Lead
Prof. Dr. med. Christian Doehn, MD
Urologikum Luebeck
Am Kaufhof 2 
D - 23566 Luebeck
Email:
Phone:
Fax:
Dr. med.
 MD
GermanOncology GmbH
Überseeallee 1
D - 20457 Hamburg
Email:
Phone
Data Management
GermanOncology GmbH
Überseeallee 1
D - 20457 Hamburg
Email:
Phone:
Administration and Technical 
hotline
GermanOncology GmbH
Überseeallee 1
D - 20457 Hamburg
Email:
Phone:
Statistics and Analytics
GermanOncology GmbH
Überseeallee 1
D - 20457 Hamburg
Email:
Phone:
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Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
Melissa Kirker
Global Value 
and Evidence, 
Oncology
Pfizer Inc.
235E  42nd, New 
York, NY, 10017
Prof. Dr. Christian Doehn
Principle 
Investigator
Urologikum 
Luebeck
Am Kaufhof 2, 
D - 23566 Luebeck
Dr. Rainer Lipp
Project 
Management
GermanOncology 
Überseeallee 1, 
D-20457 Hamburg
Country Coordinating Investigators
Not applicable.

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4. ABSTRACT
Title
Clinical outcomes and therapy management among patients with 
advanced Renal Cell Carcinoma (aRCC) receiving systemic first-
line (1L) anti-cancer treatment under daily routine in Germany: 
Retrospective Chart Review (RENALISTIC study).
Rationale and 
background
In Germany RCC is a rare cancer type with around 15.000 new 
diagnoses per year and an incidence of 15.7 per 100.000 for men and 7.5 
per 100.000 for women (Robert Koch Institute, 2020). Regarding new 
incidences per year RCC is the 10th most common cancer type in women 
and 9th most common type in men, whereas the rate of mortality per year 
due to RCC was lower, 13th position in women with 1,8% and 13th
position in men with 2,5% of all cancer-associated deaths (Robert Koch 
Institute, 2020). Most of the newly diagnosed patients were amendable 
for radical surgery, but 4.000 – 5.000 patients per year will start a new 
systemic therapy due to their advanced or metastatic disease. Around 
70-80% of the new RCC are diagnosed at an early stage and could be 
treated by partial or radical surgical resections in a curative intention. At 
present no neoadjuvant or adjuvant setting is established, but new data 
with TKIs and/or ICIs could be expected in the next few years. A part of 
patients with locally aRCC are not suitable for curative treatment by 
surgery. These patients would be treated like patients with metastatic 
diseases with systemic therapies under palliative intention. Guidelines 
of the German Cancer Society (S3-Leitlinie Nierenkarzinom, 
Arbeitsgemeinschaft 
der 
Wissenschaftlichen 
Medizinischen 
Fachgesellschaften (AWMF), Nov 2021) and of the German Society for 
Hematology and Oncology (DGHO 2022) recommend for these patients 
combinations of ICI + TKI as the preferred 1L therapies for all risk 
groups.  For patients with intermediate and poor risk, a combination of 
nivolumab plus ipilimumab could be considered as an alternative 
treatment approach. In patients ineligible for ICI and a low risk rating 
bevacizumab + INF, pazopanib, sunitinib or tivozanib, with an 
intermediate risk rating cabozantinib, pazopanib, sunitinib or tivozanib
and with a high risk rating cabozantinib or sunitinib are recommended. 
During the treatment with combinations ICI (pembrolizumab or 
avelumab) + TKI higher rates of modifications and discontinuations of 
one or both drugs were seen in the pivotal studies. During the therapy 
with pembrolizumab + axitinib adverse events (AEs) of any cause led to 
permanent discontinuation of either drug in 30.5%, discontinuation of 

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both drugs in 10.7%, interruption of either drug in 69.9%, and dose 
reduction of axitinib in 20.3% of the patients in 1st line RCC of any risk 
(Rini TI et al, 2019). During the treatment with avelumab + axitinib 42% 
of the patients had at least one reduction in the dose of axitinib due to 
AEs and in 8% of the patients AEs led to a discontinuation of both 
avelumab and axitinib (Motzer R et al, 2019). Based on this, an 
important objective of this study is to gain more insights  how 
widespread the existing national guidelines are followed for the  1L 
treatments in this patient population. Additional objectives are to 
describe 
the 
frequencies 
of 
dose 
modifications 
and  
temporary/permanent discontinuations as well as the proportions of 
modifications by dose reductions in connection with drug combination 
of ICI + TKI and ICI + ICI in the standard care setting of urologists and 
hematologists in practices and hospitals in Germany.
Research questions
and objectives
•
How is the effectiveness, defined as measurement of beneficial 
effects under “real world” clinical settings,  (e.g. progression-free 
survival, overall survival and best response) of TKI and/or ICI as 
1L in patients with aRCC? 
•
How are patients with aRCC treated in 1L under daily care 
conditions in Germany in general and in accordance to medical 
specialities (urology and medical oncology) and treatment settings 
(hospitals vs office-based practices)?
•
Are all patients assigned to individual risk ratings under standard 
daily care conditions according to a scale developed by the IMDC 
before start of a 1L?
•
How are patients treated in 1L in different risk rating groups and how 
is the adherence to national/international guidelines?
•
What kind of previous and subsequent therapies are administered 
before and after 1L?
•
How often are evaluations for PD-L1 expression performed before 
start of 1L and how many patients are positive (TPS 1%) or 
negative?
•
How long are patients treated with TKI + ICI and ICI + ICI in 1L in 
general and in relation to specific therapies like avelumab + axitinib?
•
How frequent are dose modifications and early discontinuations and 
what are the reasons?

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•
Are there differences in the handling of modifications among
medical disciplines?
To answer these questions the following objectives are derived:
Primary Objective(s):
•
Progression-free survival (PFS) for 1L therapies, expressed as
median and as rates at timepoints of 6, 9, 12 and 18 months after start 
of 1L
Secondary Objectives:
•
Overall survival (OS) of 1L therapies, expressed as median and rates
at timepoints of 12 and 18 months after start of 1L therapy
•
Best response in 1L overall and in dependence of administered drug 
regimen
•
Progression-free survival of 1L therapies in dependence of specific 
drug regimen
•
Pre- and post-treatments (i.e. surgery, radiotherapy, medicinal 
therapies) before/after TKI + ICI and ICI + ICI in 1L
•
Duration of response (DoR) in 1L overall and in dependence of 
administered drug regimen (TKI + ICI or ICI + ICI)
•
Frequency of
dose modifications
and temporary/permanent 
discontinuations of 1L therapies and their reasons
•
Proportions of modifications by dose reduction compared to
cancelling single applications 
•
Effectiveness (PFS, OS and best response) of administered 1L 
therapies under real world conditions by medical specialty (urology, 
medical oncology) and setting (practice, hospital)
Study Design
This is a retrospective, non-interventional, observational, multicenter,
Medical Chart Review project in patients with aRCC, who received a 
systemic 1L therapy between 01 January 2020 – 31 December 2021 
under daily routine conditions in hospitals or practices in Germany. At 
timepoint of enrollment of patients, all decisions for specific treatment 
regimen or investigations were already made under discretion of the 
physicians and in accordance to the routine clinical practice. The study 
should describe and analyze in part 1 and part 2 for the the treatment 
situation from adult patients with aRCC in 1L as well as the clinical 

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outcomes and handling of intolerabilities from combination therapies in 
1L under daily routine in general and in relation to specific therapies. 
Only data from medical records for running therapies between 01
January 2020 - 31 December 2021 will be captured under conditions of 
full anonymization. Based on the full anonymization a written informed 
consent by the patients or an advice by participating doctors an 
Independent Ethical Committee (IEC) regarding accordance with 
professional law should not be necessary.
Population
Inclusion criteria for part 1 and 2:
•
Patients aged 18 years old
•
Patients with histologically/cytologically confirmed renal cell 
carcinoma (International Classification of Disease 10.revision
(ICD)-10 C64)
•
Full medical information regarding all treatments before, during and 
after 1L should be available.
Specific inclusion criteria only for Part 1:
•
Patients with locally advanced or metastatic disease and a start of 
any systemic 1L therapy against RCC between 01 January 2020 and 
31 December 2021 
Specific inclusion criteria only for Part 2:
•
Patients with locally advanced or metastatic disease, who were 
treated with a combination of ICI + TKI or ICI + ICI as 1st line
therapy against RCC and who had a completion of this therapy 
between 01 January 2020 - 31 December 2021 with a follow-up 
period of at least 3 months after completion of the 1L.
Exclusion criteria for part 1 and 2:
•
Patients participating in an interventional clinical study within 30 
days before start of 1L.
Outcomes
The following clinical outcomes are of relevance in the study and should 
be answered regarding the research questions:
Primary Outcome
o
Progression-free survival in 1L in median and at defined timepoints 
after start
Secondary outcomes

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o
Overall survival rates from start of 1L therapy, expressed as median 
and at pre-defined timepoints
o
Proportions of different therapy protocols used in 1L
o
Best responses to 1L therapies
o
Duration of response to 1L therapies
o
Time-to-progression to 1L therapies
o
Time-to-next-therapy to 1L therapies
o
Frequency of modifications and discontinuations in 1L
o
Reasons for modifications and discontinuations in 1L
o
Treatment continuation after modifications and discontinuations in 
1L (for all therapies and in relation to specific protocols like axitinib 
+ avelumab or nivolumab + ipilimumab)
Other Outcomes
o
Distribution of 1L therapy by age, gender and risk rating
o
Distribution
of
1L
therapy 
and 
frequency 
of 
modifications/discontinuations by medical speciality and institution
Variables
For the evaluations of the mentioned clinical outcomes the following 
parameters will be captured:
Part 1:
o
Demographic data (age, gender, weight, body surface)
o
Date of first diagnosis
o
Stage and risk rating (IMDC) at first diagnosis and at start of 1L
o
Assessments and results of PD-L1 expression
o
Non-medicinal 
pre-treatments 
(primary 
operation 
(OP), 
cytoreductive nephrectomy, radiotherapy)
o
Medicinal pre-treatments (adjuvant, neoadjuvant)
o
Location of administration and performing medical discipline
o
Administered drugs / protocols in 1L
o
If applicable: Reason for ineligibility of ICI
o
Dates of administrations for i.v. drugs in 1L
o
Duration of 1L treatment 
o
Dosages per administration
o
Dose modifications or drug administration cancelling or interim /
permanent discontinuations of single drugs / complete therapy in 1L
o
Reasons for modfications, cancelling of single administrations and  
discontinuations in 1L
o
Supportive drugs prescribed during 1L
o
Date of first response and best response to 1L incl. date and mode of 
assessment

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o
Assessment of first and best response in 1L 
o
Date of tumor progression
o
Reasons for end of 1L
o
Subsequent therapies (2L and higher) with drugs/protocol and dates 
for start / end
o
Concomitant diseases and therapeutic medications
Part 2:
If patients will qualify for part 1 and part 2 (completion of 1L and 
follow-up of at least 3 months after completion), the documented data 
from part 1 will be transferred to part 2 automatically, so that only 
additional parameters must be filled in. If patients are newly documented 
in part 2, all of the parameters have to be documented. 
o
Demographic data (age, gender, weight, body surface)
o
Date of first diagnosis
o
Stage and risk rating (IMDC) at first diagnosis and at start of 1L
o
Assessments and results of PD-L1 expression as TPS
o
Non-medicinal 
pre-treatments 
(primary 
OP, 
cytoreductive 
nephrectomy, radiotherapy)
o
Medicinal pre-treatments (adjuvant, neoadjuvant)
o
Location of administration and performing medical discipline
o
Administered drugs / protocols in 1L
o
If applicable: Reason for ineligibility of ICI
o
Dates of administrations for i.v. drugs in 1L
o
Dosages per administration
o
Dose modifications or drug administration cancelling or interim 
/permanent discontinuations of single drugs / complete therapy in 1L
o
Reasons for modfications, cancelling of single administrations and  
discontinuations in 1L
o
Supportive drugs prescribed during 1L
o
Date of first response and best response in 1L incl. mode of 
assessment
o
Assessment of first and best response in 1L
o
Date of tumor progression
o
Reasons for end of 1L
o
Subsequent therapies (2L and higher) with drugs/protocol and dates 
for start / end
o
Concomitant diseases and therapeutic medications

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Data Sources
Source documents (paper or electronic medical charts) are those, in 
which patient data of daily care are recorded and documented in 
individual patient files. The data to be collected in the study will be 
obtained via a specific programmed eCRF. The data in the eCRF should 
be consistent with the relevant source documents. Medical records 
should contain demographic data, medical data, treatments and 
diagnostic documentations
according to common practice. The 
documentation will be performed under full anonymization, so that a re-
identification of single patients will not be possible. Based on this 
anonymization, queries for explanations or changes of data could not be 
submitted by the data management. All documented variables will be 
checked by data manager and/or medical lead of GermanOncology in 
relation to implausibility, inaccuracies or missing data. If implausibility 
or inaccuracies or missing data of single patients will be of great 
relevance for analyses, the data management and/or medical lead have 
the right to reject patients. For such rejected patients no payment will be 
triggered.
Study Size
Based on public data the population of patients with aRCC and an 
indication for a 1L therapy is around n = 4.500 - 5.000 patients per year 
(Robert Koch Institute 2020). In the period of 01 January 2020 – 31
December 2021, which is the main period of interest in the study for 
completing or starting 1L therapies, the total population of patients with 
aRCC would be around n = 9.000 - 10.000 patients. To estimate the 
needed number of patients in the study to reach adequate representation 
across Germany, the following common formula is used
N = population of patients with aRCC and indication for 1L = 10.000 patients in 24 months
= 0,5 (consensus, if attribute is unknown before study)
E = margin of error = 5% = 0,05
Z = 1,96 (for confidence interval of 95%)
Based on these assumptions (PFS of 1L therapies included in guidelines 
was 8.4 – 15.1 months in clinical studies) the number of patients needed 
for representative statement regarding the primary objective (= PFS rates 
at defined time points under real world conditions) is at least n = 370. 
With a buffer of around 10% the sample size in the study should be n = 
400 patients with aRCC and 1L therapies in the period from 01 January 
2020 – 31 December 2021. Based on published data for PFS it could be 

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assumed for part 2, that also the number of patients with combination 
therapies in part 2 (n = 300) will grant a representative statement to all 
research questions. Based on information of urological and oncological 
experts as well as own data of the GermanOncology *1 network (see 
below), the following assumptions could be set:

Number of patients with new 1L in urological practices (per 
practice 1- 3 urologists) = 4 - 6 per year
o
Number of patients with new 1L in period of 24 months 
= 8 - 12

Number of patients with new 1L in oncological practices (per 
practice 2- 4 oncologists) = 4 - 6 per year
o
Number of patients with new 1L in period of 24 months 
= 8 – 12

Number of patients with new 1L in hospitals with urological 
focus = 8 - 12 per year
o
Number of patients with new 1L in period of 24 months 
= 16 – 24

Proportion of 1L therapies in urological and oncological 
practices: 50% : 50%

Proportion of patients treated with 1L in practices and hospitals
(as most of therapies are oral therapies): 65% : 35%
Based on the assumptions the needed number of sites are at least:

Number of urological practices: 15

Number of oncological practices: 15

Number of hospitals with urological focus: 10

Total number of sites across Germany: 40
*1 GermanOncology operates a permanent network of 25 oncological practices across 
Germany, is collecting longitudinal RWE data about several tumor entities since 2012 and is 
able to analyze data from more than 25.000 patients with around 25 different tumor entities
Data Analysis
The following clinical outcomes will be measured:
Primary outcome:
o
PFS in 1L: 

described as median and rates of patients without disease 
progression or death for any cause at defined timepoints (6, 
9, 12 and 18 months) after start of 1L therapy.
Secondary outcomes:
o
OS in 1L

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
Defined as median and rates of patients alive at pre-defined 
timepoints (12 and 18 months) after start of 1L therapy.
o
Proportion of different drug regimen in 1L

Defined as percentages of therapy protocols used as 1L
therapy.
o
Best response rate (RR) in 1L

Defined as best response (complete response (CR) / partial 
response (PR) / stable disease (SD) / progressive disease 
(PD) / not done (ND)) recorded from the start of the therapy 
until disease progression/recurrence based on investigator´s 
assessment. A confirmation of response is not required.
o
Duration of Response (DoR) in 1L

Defined as time from documentation of first disease response 
to disease progression.
o
Time to progression (TTP) in 1L

Defined as time from start of therapy until objective disease 
progression without including deaths.
o
Time to next treatment (TTNT) in 1L

Defined as time from last drug administered to initiation  of 
next therapy.
o
Dose modifications and discontinuations in 1L

Defined of number of patients with at least 1 dose 
modification 
(reduction 
of 
dose 
or 
cancelling 
of 
administration) or with an interim/permanent discontinuation 
of one or all drugs of a therapy.
o
Handling after dose modification or discontinuations in 1L

Defined as continuation of therapies after dose modifications 
or temporary/permanent discontinuation of single drugs.
The clinical outcomes will be analyzed for the total group of all patients 
and for following subgroups:
o
Age: < 70 years vs. 70 years
o
Gender: male vs. female
o
Risk rating: favorable (low) vs. intermediate vs poor (high) risk
o
Medical disciplines: urology vs. medical oncology
o
Institutions: practices vs. hospitals
Milestones
Planned milestones:

Start of data collection: 1 October  2022

Interim analysis (expected): 31 October 2022

End of data collection: 30 January 2023

Final study report: 15 April 2023

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5. AMENDMENTS AND UPDATES
None.

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6. MILESTONES
Tab.1: Milestones of the study
Milestone
Planned date
Completion of feasibility assessment
31 January 2022
Start of data collection
1 October 2022
End of data collection
30 January 2023
Interim report 1 (after enrollment of 10% in Part 1 and 2)
31 October 2022
Final study report
15 April 2023
7. RATIONALE AND BACKGROUND
In clinical trials, patients are treated strictly according to a study protocol and show sometimes 
different risk factors, fewer comorbidities or a lower age than patients under standard care conditions. 
However, there is limited larger data collections on current therapy behavior in the 1L of patients with 
RCC, who are treated under standard care conditions in Germany.
The special interest of this retrospective Medical Chart Review project is to obtain in a Part 1 more 
precise data for the distribution of different 1L therapies of patients with aRCC, which have started 
within 01 January 2020 – 31 December 2021 and are representative for Germany. In Part 2 the 
effectiveness, sequences as well as the frequencies and handling of intolerabilities of combination 
therapies (ICI + TKI or ICI + ICI) in 1L aRCC will be analyzed by capturing data of patients, who 
completed a 1L in 01 January 2020 – 31 December 2021 with a follow up period of at least 3 months 
after completion. All data describe also the current therapy behavior and the resulting clinical 
effectiveness of the individual therapy protocols used in the 1L. These data allow the transferability 
of the results from clinical studies to standard care as well as the specific handling of intolerabilities. 
Particular emphasis is placed on analyses of this handling of intolerabilities during combination 
therapies with ICI + TKI or ICI + ICI. Information about current processes in decision findings 
regarding dose modifications or interruptions or interim / permanent discontinuations of one or both 
drugs can help to unify processes and to develop standard recommendations for daily care situations. 
Another point of the data analysis lies in the area of the medical disciplines and institutions that initiate 
and carry out 1L therapies for aRCC under standard care conditions. Questions about the different 
therapeutic behavior between urologists and medical oncologists, between practices and hospitals and 
between different regions in Germany are of particular relevance.
In conclusion, the rationale of this study is more clarity in the effectiveness of different 1L therapies, 
more clarity in the accordance of 1L therapies to national guidelines and more clarity in the handling 
of intolerabilities or other situations where dose modifications or discontinuation of treatment occurs 

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with combinations with ICI + TKI or ICI + ICI in the standard care settings of urologists and 
hematologists in practices and hospitals in Germany.
8. RESEARCH QUESTION AND OBJECTIVES
In Germany RCC is a rare cancer type with around 15.000 new diagnoses per year and an incidence 
of 15,7 per 100.000 for men and 7,5 per 100.000 for women (Robert Koch Institute, 2020). Regarding 
new incidences per year RCC is the 10th most common cancer type in women and 9th most common 
type in men, whereas the rate of mortality per year due to RCC was lower, 13th position in women 
with 1,8% and 13th position in men with 2,5% of all cancer-associated deaths (Robert Koch Institute, 
2020). The mean age of onset in Germany is 72 years for women and 68 years for men. Risk factors 
for RCC are hereditary disease (ca. 5% of all cases with RCC) like von Hippel - Lindau – syndrome 
or Birt-Hogg-Dubé syndrome or acquired factors like obesity, chronic kidney failure, smoking or 
arterial hypertension, but also some professional exposition with halogenated hydrocarbons or long-
term x-ray exposure (DGHO May 2022). Around 70-80% of the new RCC are diagnosed at an early 
stage and could be treated by partial or radical surgical resections in a curative intention. Most of the 
newly diagnosed patients were amendable for radical surgery, but 4.000 – 5.000 patients per year will 
start a new systemic therapy due to their advanced or metastatic disease. At present no neoadjuvant or 
adjuvant setting is established, but new data with TKIs and/or ICIs could be expected in the next few 
years. In stage I-IV (without metastases) the standard therapies are partial or radical nephrectomy (fig. 
1).
Fig. 1: Guidelines for Renal Cell Carcinoma Stage I – IV (DGHO 2022 and German Cancer Society 2021)

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In Stage IV with few number of resectable metastases, the partial or radical nephrectomy should be 
supplemented by metastatectomy of all metastases. Patients in stage IV without option for full 
resection of all metastases, a systemic anticancer therapy is recommended (fig. 1). Additionally, in 
selected patients with stage IV, a cytoreductive/palliative nephrectomy should be considered.
A part of patients with locally aRCC are not suitable for curative treatment by surgery. These patients 
would be treated like patients with metastatic diseases with systemic therapies under palliative 
intention. 
In the guideline of the German Cancer Society (S3-Leitlinie Nierenkarzinom, AWMF, Nov 2021) and 
of the German Society for Hematology and Oncology (DGHO, May 2022) for these patients 
combinations of pembrolizumab or avelumab with axitinib or pembrolizumab + lenvatinib or 
nivolumab + cabozantinib are recommended as the preferred first-line therapy for all risk groups 
(fig.2). As an alternative for patients with intermediate and high risk, the combination of nivolumab 
plus ipilimumab could be used. In patients ineligible for ICI and a low risk rating bevacizumab + INF, 
pazopanib, sunitinib or tivozanib, with an intermediate and poor risk rating cabozantinib and  sunitinib 
are recommended.
Fig. 2: Guidelines for Treatment of Stage IV Renal Cell Carcinoma (DGHO May 2022 and German Cancer 
Society Nov 2021)
For subsequent therapies in case of progression, relapse, no response or intolerable toxicities the 
recommended first choices for 2L are nivolumab or cabozantinib or lenvatinib + everolimus. As 
alternatives or second choices, axitinib or sunitinib or everolimus or pazopanib or sorafenib are listed. 

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In the pivotal studies the effectiveness for the combinations of ICI + TKI wwa shown with PFS ranges 
of 15,1 – 23,9 months, with OS rates at 12 months of 89,9 – 91% and with objective response rate
(ORR) ranges of 51,4 – 71% (Bini TI et al, 2019; Motzer R et al, 2019, Motzer R et al, 2021).
In pivotal studies, a higher rate of modifications and discontinuations of one or both drugs were seen 
for combinations of ICI (pembrolizumab or avelumab) + axitinib. During the therapy with 
pembrolizumab + axitinib AEs of any cause led to discontinuation of either drug in 30.5%, 
discontinuation of both drugs in 10.7%, interruption of either drug in 69.9%, and dose reduction of 
axitinib in 20.3% of the patients in 1L line RCC of any risk (Bini TI et al, 2019). During the treatment 
with avelumab + axitinib 42% of the patients had at least one reduction in the dose of axitinib due to 
AEs and in 8% of the patients AEs led to a discontinuation of both avelumab and axitinib (Motzer R 
et al, 2019). In the pembrolizumab-plus-lenvatinib group, AEs of any grade led to discontinuation of 
lenvatinib, pembrolizumab, or both drugs in 37.2% of patients (lenvatinib, 25.6%; pembrolizumab, 
28.7%; both drugs, 13.4%), to dose reduction of lenvatinib in 68.8% of patients and to interruption of 
lenvatinib, pembrolizumab, or both drugs in 78.4% of patients (Motzer R et al, 2021). A comparable 
situation could be found for combination of Nivolumab + Ipilimumab as also for this combination 
dose delays were described in up to 58% and discontinuations in up to 22% (Motzer R et al, 2018).
But the present handling of severe AEs in the standard care setting of combinations ICI + TKI or ICI 
+ ICI in 1L RCC (e.g. dose reduction or interim discontinuation of axitinib or interim/permanent 
discontinuation of both drugs) seems to be unclear as no detailed data are available.
8.1. Primary Research Questions
Based on the above background, there are currently a number of unanswered questions for health 
services research:
•
How is the effectiveness, defined as measurement of beneficial effects under “real world” clinical 
settings,  (e.g. progression-free survival, overall survival and best response) of TKI and/or ICI as 
1L in patients with aRCC? 
•
How are patients with aRCC treated in 1L under daily care conditions in Germany in general and 
in accordance to medical specialities (urology and medical oncology) and treatment settings 
(hospitals vs office-based practices)?
•
Are all patients assigned to individual risk ratings under standard daily care conditions according 
to a scale developed by the IMDC before start of a 1L?
•
How are patients treated in 1L in different risk rating groups and how is the adherence to 
national/international guidelines?
•
What kind of previous and subsequent therapies are administered before and after 1L?
•
How often are evaluations for PD-L1 expression performed before start of 1L and how many 
patients are positive (TPS 1%) or negative?

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•
How long are patients treated with TKI + ICI and ICI + ICI in 1L in general and in relation to 
specific therapies like avelumab + axitinib?
•
How frequent are dose modifications and early discontinuations and what are the reasons?
•
Are there differences in the handling of modifications among medical disciplines?
8.2. Study Objectives 
To answer these questions the following objectives are derived:
Primary Objective(s):
•
Progression-free survival (PFS) for 1L therapies, expressed as median and as rates at 
timepoints of 6, 9, 12 and 18 months after start of 1L
Secondary Objectives:
•
Overall survival (OS) of 1L therapies, expressed as median and rates at timepoints of 12 and 
18 months after start of 1L therapy
•
Best response in 1L overall and in dependence of administered drug regimen
•
Progression-free survival of 1L therapies in dependence of specific drug regimen
•
Pre- and post-treatments (i.e. surgery, radiotherapy, medicinal therapies) before/after TKI +
ICI and ICI + ICI in 1L
•
Duration of response (DoR) in 1L overall and in dependence of administered drug regimen 
(TKI + ICI or ICI + ICI)
•
Frequency of dose modifications and temporary/permanent discontinuations of 1L therapies 
and their reasons
•
Proportions of modifications by dose reduction compared to cancelling single applications 
•
Effectiveness (PFS, OS and best response) of administered 1L therapies under real world 
conditions by medical specialty (urology, medical oncology) and setting (practice, hospital)
9. RESEARCH METHODS 
The present 1L treatment of patients with aRCC in Germany is wide-ranging with several options like 
combinations of ICI + TKI, ICI + ICI or monotherapies with TKI alone. Some of these therapies are 
only recommended in specific risk situations or in cases of ineligibilities for ICI, but at present there 
is only limited information available about decisions in 1L aRCC. Additionally, a higher proportion 
of patients with combined therapies of ICI + TKI or ICI + ICI show intolerabilities with the necessary 
for dose modifications or interim / permanent discontinuations of one or both drugs, but the processes 
of decision finding between dose modifications, interruptions and discontinuation are also unclear, 
although these processes would be very important for the outcomes of the therapy. In contrast to study 
protocols with clear specifications for handling AEs, in standard daily care the decision processes 
seem to be in the discretion of every oncologist. But at present, no detailed information about these 

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processes in standard daily care are available. Such information is also important as these therapies
could be administered under in- or out-patient´s settings and by urologists or medical oncologists. 
Study design
The general design of this data project is a sampling of data about patients with aRCC receiving a 1L 
therapy, with a start (part 1) or completion (part 2) in 01 January 2020 – 31 December 2021. Data will 
be documented retrospectively and under full anonymization by investigators or their designees in a 
specific eCRF. All analyses and reports will be performed under aggregation of data as secondary data 
reports. 
9.1. Setting
This Medical Chart Review project will take place in Germany and especially in oncological and 
urological practices as well as in hospitals with urological/oncological departments and a high focus 
on systemic treatment for RCC.   
It is planned to recruit up to n = 40 study sites with a distribution of 37.5% practices hematology-
oncology, 37,5% practices urology and 25% hospitals with urological cancer focus. The number of 
study sites may increase if it becomes apparent that the number of patients to be recruited per site is 
lower than expected. The sites are addressed through direct contact by the project management of 
GermanOncology. As part of a feasibility process the potential case numbers and availability of study 
nurses or other documentation staff are also queried. All sites have to sign a service contract before 
start of study, in which rights and obligations as well as documentation fees are clearly defined.
9.1.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the study:
Part 1 and 2:
•
Patients aged 18 years old
•
Patients with histologically/cytologically confirmed renal cell carcinoma (ICD-10 C64)
•
Full medical information regarding all treatments before, during and after 1L should be
available.
Specific inclusion criteria only for Part 1:
•
Patients with locally advanced or metastatic disease and a start of any systemic 1L therapy 
against RCC between 01 January 2020 and 31 December 2021 
Specific inclusion criteria only for Part 2:
•
Patients with locally advanced or metastatic disease, who were treated with a combination of 
ICI + TKI or ICI + ICI as 1L therapy against RCC and who had a completion of this therapy 
between 01 January 2020 - 31 December 2021 with a follow-up period of at least 3 months 
after completion of the 1L.

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9.1.2. Exclusion criteria
Exclusion criteria for part 1 and 2
Patients meeting the following criteria will not be included in the study:

Patients participating in an interventional clinical study within 30 days before start of 1L
All sites are asked to document all of their patients with the fulfilled inclusion and not fulfilled 
exclusion criteria, starting with the earliest start (in part 1) and the longest follow-up period (in part 
2), respectively. The patients should be treated with the systemic 1L therapy in the site and data should 
be available in the medical records of the sites. The enrollment will be competitively over all 
participating sites without a limitation for the single sites. In part 2 quotas for groups with ICI + TKI 
and ICI + ICI and with the specific therapy avelumab + axitinib or nivolumab + ipilimumab will be 
set up.
9.2. Variables
The following variables will be captured by a spefic eCRF and are needed for the analysis of all 
outcomes and for answering all research questions.
Tab. 2: List of all variables, role, data source and operational definitions
Variable
Role
Data source(s)
Operational definition
Age and gender
baseline characteristic
Medical Chart
Years; male/female
Weight and body surface
baseline characteristic
Medical Chart
kg, m2
Date of first diagnosis
baseline tumor 
characteristic
Medical Chart
dd/mm/yyyy
Stage and risk rating 
(IMDC) at first diagnosis
and at start of 1L
baseline tumor 
characteristic
Medical Chart
Favorable risk / 
intermediate risk / poor 
risk
Assessments and results of 
PD-L1 expression as TPS
baseline tumor 
characteristic
Medical Chart
y/n; 0-100%
Non-medicinal pre-
treatments (primary OP,
cytoreductive nephrectomy
radiotherapy)
baseline tumor 
characteristic
Medical Chart
y/n; dd/mm/yyyy of OP; 
mode of OP; intention of 
OP (curative/palliative); 
period and dose of 
radiotherapy 
Medicinal pre-treatments 
(adjuvant, neoadjuvant)
baseline tumor 
characteristic
Medical Chart
y/n; start/stop and used 
therapy protocol
Location of administration 
and performing medical 
discipline
Relevant for outcomes
Medical Chart
Urological practice; 
hematological practice; 
hospital with urological 
department; hospital 
with oncological 
department
Administered drugs / 
protocols in 1L
Relevant for outcomes
Medical Chart
administered therapy 
protocol
If applicable: Reason for 
ineligibility of ICI
Relevant for outcomes
Medical Chart
Concomitant disease; 
patient´s wish
Duration of 1L
Relevant for outcomes
Medical Chart
Start/stop of therapy or 
every cycle;

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Dates of administrations 
for i.v. drugs in 1L
Relevant for outcomes
Medical Chart
Dates of every 
administration
Dosages per administration
Relevant for outcomes
Medical Chart
Dose of administered 
drugs per administration
Dose modifications or 
drug administration 
cancelling or 
interim/permanent 
discontinuations of single 
drugs / complete therapy in 
1L
Relevant for outcomes
Medical Chart
Each for single/all drugs: 
Dose modification; 
cancelling single 
administration; 
temporare 
discontinuation; 
permanent 
discontinuation 
Reasons for modifications, 
cancelling of single 
administrations and 
discontinuations in 1L
Relevant for outcomes
Medical Chart
Each for single/all drugs:
intolerability; age; 
performance status; 
patient´s decision; other
Supportive drugs 
prescribed during 1L
Relevant for outcomes
Medical Chart
Administered supportive 
drugs in connection with 
cancer therapy
Date of first response and 
best response in 1L incl. 
date and mode of 
assessment
Relevant for outcomes
Medical Chart
dd/mm/yyy; 
CT/MRI/ultrasound/x-
ray; clinical assessment; 
laboratory
Assessment of first and 
best response in 1L 
Relevant for outcomes
Medical Chart
CR/PR/SD/PD/ND
Date of tumor progression
Relevant for outcomes
Medical Chart
dd/mm/yyyy
Reasons for end of 1L
Relevant for outcomes
Medical Chart
Progression; 
intolerability; decision 
oncologist; patient´s 
wish; death; 
deterioration 
performance
Subsequent therapies 
(Second-line therapy (2L)
and higher) with 
drugs/protocol and dates 
for start / end
Relevant for outcomes
Medical Chart
y/n; used drugs/regime; 
start/stop
Concomitant diseases and 
therapeutic measures
Relevant for outcomes
Medical Chart
Detailed diagnosis; 
therapeutic measures 
OP/medicinal/none/other
9.3. Data sources
Source documents (paper or electronic medical charts) are those, in which patient data of daily care 
are recorded and documented in individual patient files. The data to be collected in the study will be 
obtained via a specific programmed eCRF. The data in the eCRF should be consistent with the relevant 
source documents. Medical records should contain demographic data, medical data, treatments and 
diagnostic documentations according to common practice. The documentation will be performed 
under full anonymization, so that a re-identification of single patients will not be possible. Based on 
this anonymization, queries for explanations or changes of data could not be submitted by the data 

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management. All documented variables will be checked by data manager and/or medical lead of 
GermanOncology in relation to implausibility, inaccuracies or missing data. If implausibility or 
inaccuracies or missing data of single patients will be of great relevance for analyses, the data 
management and/or medical lead have the right to reject patients. For such rejected patients no 
payment will be triggered. 
9.4. Study size
Based on public data the population of patients with aRCC and an indication for a 1L therapy is around 
n = 4.500 - 5.000 patients per year (Robert Koch Institute 2020). In the period of 01 January 2020 –
31 December 2021, which is the main period of interest in the study for completing or starting 1L 
therapies, the total population of patients with aRCC would be around n = 9.000 - 10.000 patients. To 
estimate the needed number of patients in the study to reach adequate representation across Germany, 
the following common formula is used
N = population of patients with aRCC and indication for 1L = 10.000 patients in 24 months
= 0,5 (consensus, if attribute is unknown before study)
E = margin of error = 5% = 0,05
Z = 1,96 (for confidence interval of 95%)
Based on these assumptions (PFS of 1L therapies included in guidelines was 8.4 – 151 months in 
clinical studies) the number of patients needed for representative statement regarding the primary 
objective (= PFS rates at defined time points under real world conditions) is at least n = 370. With a 
buffer of around 10% the sample size in the study should be n = 400 patients with aRCC and 1L 
therapies in the period from 01 January 2020 – 31 December 2021. Based on published data for PFS 
it could be assumed for part 2, that also the number of patients with combination therapies in part 2 (n 
= 300) will grant a representative statement to all research questions. Based on information of 
urological and oncological experts as well as own data of the GermanOncology *1 network (see 
below), the following assumptions could be set:

Number of patients with new 1L in urological practices (per practice 1- 3 urologists) = 4 - 6
per year
o
Number of patients with new 1L in period of 24 months = 8 - 12

Number of patients with new 1L in oncological practices (per practice 2- 4 oncologists) = 4 -
6 per year
o
Number of patients with new 1L in period of 24 months = 8 – 12

Number of patients with new 1L in hospitals with urological focus = 8 - 12 per year
o
Number of patients with new 1L in period of 24 months = 16 – 24

Proportion of 1L therapies in urological and oncological practices: 50% : 50%

Proportion of patients treated with 1L in practices and hospitals (as most of therapies are oral 
therapies): 65% : 35%
Based on the assumptions the needed number of sites are at least:

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
Number of urological practices: 15

Number of oncological practices: 15

Number of hospitals with urological focus: 10

Total number of sites across Germany: 40
9.5. Data management 
The main purpose of the specific eCRF is to obtain data required by the study protocol in a complete, 
accurate, legible and timely manner. The data in the eCRF should be consistent with the relevant 
source documents in the practices and hospitals. The investigator or his/her designee is responsible for 
ensuring that the data collected in the course of this study are accurate and documented appropriately 
and completely in all applicable forms. Data will be documented, processed, evaluated, and stored in 
fully anonymous form in accordance with applicable data protection regulations. The investigator must 
ensure that the eCRFs and any other associated documents forwarded to the project management 
contain no mention of any subject names or other personalized information. The data will be entered 
by the eCRF into a validated database. The project management will be responsible for data 
processing, in accordance with the Sponsor’s data management procedures. The sponsor will receive 
only full anonymized data or aggregated reports, without any options for re-identification of patients 
and/or sites. Database lock will occur once quality control and quality assurance procedures and 
second, that activities of documentation and coding have been completed. The eCRF has a modular 
structure with separation of contents to build up all sequences and information of treatments from date 
of first diagnosis up to the present date or death or lost-of-follow-up. Data must be filled in completely 
and legibly by choosing parameters out of a pre-defined              drop-down-list, or in a few cases by 
writing free text. All corrections will be listed in a history trail with name of corrector and date of 
correction. Relevant fields are declared as mandatory und must be fulfilled definitively before 
triggering any payment. As part of the data quality process, all entries in the eCRF will be checked by 
data manager. In cases of implausibility or incorrectness or inaccuracy or relevant missing data, the 
data manager together with the medical lead of GermanOncology are allowed to reject patients with a 
statement of an appropriate reason. Every patient´s documentation file is given a randomized code of 
numbers and letters, automatically generated by an encryption algorithm. As only anonymized data 
will be sampled, this data handling and storage can be described as “full anonymized” in accordance 
to the recital 25 of the German and EU General data protection regulation.
9.5.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record
As used in this protocol, the term CRF should be understood to refer to electronic data record.
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 CRFsare 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. 
9.5.2. Record retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, copies of all CRFs, safety reporting forms, and adequate documentation of 
relevant correspondence (e.g., 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 (e.g., 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 GermanOncology 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.
9.6. Data analysis 
The data analysis are carried out for all evaluable patients for whom the inclusion criteria are met, 
first-line therapy with at least 1 application has been documented and no exclusion criteria exist.  
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.
9.7. Quality control
The most relevant step in quality control and quality assurance will be an avoidance of inaccuracies 
or mismatches in terminology by data entries in data fields over a selection of parameters or 
descriptions out of pre-defined drop-down-lists. Free text is only intended for descriptions after 
selection of “other”, which will be possible in some data fields, where a pre-definition cannot be 

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implemented for 100%. For all dates regarding parameters like first diagnosis, pre-treatments, therapy 
administrations automatic checks are implemented for data entries, so that the course of treatment will 
be shown correctly (e.g. adjuvant therapy after OP and before palliative therapy, end of 1L before start 
of 2L, end of therapy after last administration). In defined data fields new explanation fields will open 
up after selection of specific documentations (e.g. after selection of dose modification query for 
modified dose, after selection of end of therapy query for reason). In data fields with information like 
weight, height or age, automatic standard range checks, are implemented to avoid input errors. In 
addition to these automatic checks every data entry will also be checked by an experienced data 
manager and, if needed, by the medical lead. 
In case of relevant inaccuracy or implausibility, patient´s data files will be rejected before further 
analytical processes will start. After the decision for rejection of patients the investigator will be 
informed about the reason for rejection and all data will be deleted immediately.
9.8. Limitations of the research methods
For this data project only data out of the medical records of patients, who are treated under daily 
routine in oncological institutions like practices or hospitals will be used and these data of 
investigations or visits have to be generated under standard conditions. The documentation in the 
eCRF and so also the analyses are dependent on the availability of the data in the medical records. 
Such availability should be given for most of the mandatory data fields, as these will be standard facts 
during oncological treatments. If data are not available, this has to be documented explicitly. In case 
of a high amount of missing data, a patient can be rejected by the data manager or medical lead, as 
otherwise no representative analyses can be performed. 
9.9. Other aspects
Not applicable.
10. PROTECTION OF HUMAN SUBJECTS
As only fully anonymized data of patients will be used in the project, all requirements for data 
protection in accordance to the national and EU General Data Protection Regulations are fully 
preserved. The data will be captured retrospectively, so that all patients were already treated under 
standard daily conditions without any kind of additional investigations or other interventions.
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 documeted patient 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 documented patient 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 documented patient

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data can be recovered in the event of disaster.  In the event of a potential documented patient data 
breach, the study site shall be responsible for determining whether a documented patient 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 documented 
patient 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. In case of data transfer, Pfizer 
will maintain high standards of confidentiality and protection of patients’ documented data consistent 
with the clinical study agreement and applicable privacy laws.
10.2. Patient consent
As this study does not involve data subject to privacy laws according to applicable legal requirements, 
obtaining informed consent from patients by Pfizer should not be required.  
10.3. Institutional review board (IRB)/Independent ethics committee (IEC)
There must be prospective official statement or approval of the study protocol, protocol amendments, 
and other relevant documents (e.g., 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.
10.4. 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 
policies for Good Clinical Practice (GCP), Good Epidemiological Practice (GEP), Good 
Pharmacovigilance Practice (GVP) and the Declaration of Helsinki by the World Medical Association.
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:

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All serious and non-serious AEs with explicit attribution to any Pfizer drug that appear in the 
reviewed information must be recorded 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, 
axitinib, or sunitinib, during pregnancy, are not reportable unless associated with serious or non-
serious adverse events. 

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 (e.g., 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.”
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 Your Reporting 
Responsibilities training materials.

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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
In the event of any prohibition or restriction imposed (e.g., 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)
RKI Krebs in Deutschland 2017-2018, 13th edition, 2021.
(2)
S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Nierenzellkarzinoms, 
November 2021, Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche 
Krebshilfe, AWMF): Diagnostik, Therapie und Nachsorge des Nierenzellkarzinoms, 
Kurzversion 
3.0, 
2021, 
AWMF 
Registernummer: 
043/017OL, 
https://www.leitlinienprogramm-onkologie.de/leitlinien/nierenzellkarzinom/ Access on 30-
June-2022.
(3)
German Society of Hematology and Oncology, www.onkopedia.com; Guideline for Renal Cell 
Carcinoma, Mai 2020.
(4)
Rini BI et al: Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell 
Carcinoma. N Engl J Med 2019;380:1116-27
(5)
Motzer RJ et al: Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
N Engl J Med 2019;380:1103-15.
(6)
Motzer RJ et al: Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell 
Carcinoma. N Engl J Med 2021;384:1289-300.
(7)
Motzer RJ et al: Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell 
Carcinoma. N Engl. J Med 2018; 378(14):1277-1290
(8)
Chueiri TK et al: Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell 
Carcinoma. N Engl J Med 2021; 384(9):829-841
(9)
Chueiri TK et al: Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl 
J Med 2015; 373(19):1814-23.
(10)
Product information Pembrolizumab 2022
(11)
Product information Axitinib 2022
(12)
Product information Sunitinib 2022
(13)
Product information Lenvatinib 2022
(14)
von der Lippe P: Wie groß muss meine Stichprobe sein, damit sie reprä sentativ ist? Wie viele 
Einheiten mü ssen befragt werden? Was heißt "Reprä sentativitä t"?. Essay Februar 2011
(15)
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, November 2017, 
U.S. Department of Health and Human Services, www.ctep.cancer.gov.
(16)
Good Clinical Practice. 1 December 2016 EMA/CHMP/ICH/135/1995. Committee for Human 

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Medicinal Products. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-
r2-guideline-good-clinical-practice-step-5_en.pdf.
(17)
Guidelines and recommendations for ensuring Good Epidemiological Practice (GEP): a 
guideline developed by the German Society for Epidemiology. European Journal of 
Epidemiology (2019) 34:301–317
(18)
Good Pharmacovigilance Practice. 3 February 2021 EMA/54854/2021. 
https://www.ema.europa.eu/en/human-regulatory/postauthorisation/pharmacovigilance
/good-pharmacovigilance-practices.
(19)
WMA Declaration of Helsinki – Ethical principles for medical research involving human 
subjects. 64th version. https://www.wma.net/policies-post/wma-declaration-of-helsinki-
ethical-principles-for-medical-research-involving-human-subjects/
(20)
Heng DYC et al: External validation and comparison with other models of the International 
Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-
based study. Lancet Oncol. 2013; 14(2): 141–148.
14. LIST OF TABLES 
Tab.1: 
Milestones of the study
Tab.2: 
List of all variables, role, data source and operational definitions
15. LIST OF FIGURES
Fig. 1: Guidelines for Renal Cell Carcinoma Stage I – IV (DGHO 2022 and German Cancer 
Society 2021)
Fig. 2: Guidelines for Treatment of Stage IV Renal Cell Carcinoma (DGHO 2022 and 
German Cancer Society 2021)
Fig.3: Schedule for 2 parts of the project
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 3. ADDITIONAL INFORMATION
Not applicable.