A Real World Retrospective Database Study of Patients Diagnosed With Metastatic and/or Advanced Renal Cell Carcinoma and Treated With Sunitinib and/or Axitinib in a Specialist United Kingdom Oncology Centre
Conditions: Carcinoma, Renal Cell
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
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Study Information
Title
A real world retrospective database study of patients 
diagnosed with metastatic and/or advanced renal cell 
carcinoma and treated with sunitinib and/or axitinib 
in a specialist United Kingdom oncology centre
Protocol number
X9001180 
Protocol version identifier
Version 1.2
Date of last version of protocol
22 November 2018 (Draft 1.0)
Active substance
Axitinib (Anatomical Therapeutic Chemical Code 
[ATC]: L01XE17)
Sunitinib (ATC: L01XE04)
Medicinal product
Axitinib (ATC: L01XE17)
Sunitinib (ATC: L01XE04)
Research question and objectives
Research Questions:
To understand the clinical outcomes of patients 
treated with sunitinib in first line and axitinib in 
second line in a real world setting as therapies for 
metastatic and/or advanced renal cell carcinoma 
(mRCC).
Primary Objective:
1.
What is the progression free survival (PFS) of 
patients treated in first line with sunitinib, and 
stratified by Memorial Sloan-Kettering Cancer 
Center/International Metastatic Renal Cell 
Carcinoma Database Consortium 
(MSKCC/IMDC) risk category (favourable, 
intermediate, poor)? 
2.
What is the progression free survival (PFS) of 
patients treated in second line with axitinib, and 
stratified by MSKCC/IMDC risk category 
(favourable, intermediate, poor)? 
Secondary Objectives:
First Line:
1.
What is the overall survival (OS) of all patients 
in first line with sunitinib, and stratified by 
MSKCC risk (favourable, intermediate, poor)? 
2.
What is the duration of therapy with sunitinib in 
first line (using time to treatment discontinuation 
[TTD]) for all patients and stratified by MSKCC 

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risk (favourable, intermediate, poor).
3.
Objective response rate (ORR).
4.
Duration of objective response (complete 
response [CR] or partial response [PR]).
5.
Examine factors that predict TTD, eg, risk 
stratification, or individual/grouped parameters 
that comprise the prognostic classification 
systems.
a.
Less than one year from time of diagnosis.
b.
Karnovsky performance status less than 
80%.
c.
Haemoglobin less than the lower limit of 
normal (eg, less than 12 g/dl).
d.
Serum calcium greater than the upper limit 
of normal (eg, 10 mg/dl or: 2.5 mmol/l).
e.
Neutrophil greater than the upper limit of 
normal (eg, greater than 7.0 x109 dl).
f.
Platelets greater than the upper limit of 
normal (eg, greater than 400 000).
g.
Lactate dehydrogenase greater than 1.5 times 
the upper limit of normal.
h.
Fuhrmann grade of tumour.
i.
Tumour subtype eg, clear cell versus. 
non-clear cell.
6.
Safety and tolerability data reporting for first line 
sunitinib.
Second line:
1.
What is the OS of all patients in second line with 
axitinib, and stratified by MSKCC risk 
(favourable, intermediate, poor)? 
2.
What is the duration of therapy with axitinib in 
second line (using TTD) for all patients and 
stratified by MSKCC risk (favourable, 
intermediate, poor).
3.
ORR.
4.
Duration of objective response (CR or PR).

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5.
Examine factors that predict duration of TTD, 
eg, risk stratification, or individual/grouped 
parameters that comprise the prognostic 
classification systems.
a.
Less than one year from time of diagnosis.
b.
Karnovsky performance status less than 
80%.
c.
Haemoglobin less than the lower limit of 
normal (eg, less than 12 g/dl).
d.
Serum calcium greater than the upper limit 
of normal (eg, 10 mg/dl or: 2.5 mmol/l).
e.
Neutrophil greater than the upper limit of 
normal (eg, greater than 7.0 x109 dl).
f.
Platelets greater than the upper limit of 
normal (eg, greater than 400 000).
g.
Lactate dehydrogenase greater than 1.5 times 
the upper limit of normal.
h.
Fuhrmann grade of tumour.
i.
Tumour subtype eg, clear cell vs. non-clear 
cell.
6.
Safety and tolerability reporting for second line 
axitinib.
The objectives listed below will also be assessed as 
exploratory analyses for various patient subgroups of 
interest, and will be conducted if sufficient numbers 
of patients are available:
1.
Axitinib PFS and OS, as a second line therapy 
following sunitinib, pazopanib, or following 
other Tyrosine kinase inhibitors (eg, sorafenib).
2.
Axitinib PFS and OS as a third line therapy.
3.
Axitinib (and, if applicable, sunitinib) PFS and 
OS post-immunotherapy (IO), taking into 
consideration 2nd and 3rd therapy lines, following 
all IO therapy options, 
eg, atezolizumab/bevacizumab, 
nivolumab/ipilumimab, nivolumab, interleukin-2.
4.
For the post-sunitinib axitinib cohort: What was 
the duration of sunitinib therapy before patients 

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transitioned to axitinib? 
5.
For the post-pazopanib axitinib cohort: What was 
the duration of pazopanib therapy before patients 
transitioned to axitinib? 
6.
Is the duration of therapy on first line sunitinib 
and/or pazopanib related to duration of therapy 
for second line axitinib?
Author
Dr 
 UK 
 
 UK
PPD
PPD
PPD
PPD
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................6
2. LIST OF ABBREVIATIONS................................................................................................8
3. RESPONSIBLE PARTIES..................................................................................................11
4. ABSTRACT.........................................................................................................................11
5. AMENDMENTS AND UPDATES.....................................................................................12
6. MILESTONES.....................................................................................................................12
7. RATIONALE AND BACKGROUND................................................................................12
8. RESEARCH QUESTION AND OBJECTIVES .................................................................13
9. RESEARCH METHODS ....................................................................................................16
9.1. Study Design ...........................................................................................................16
9.2. Setting......................................................................................................................16
9.2.1. Inclusion Criteria ........................................................................................16
9.2.2. Exclusion Criteria.......................................................................................17
9.3. Variables..................................................................................................................17
9.4. Data Sources............................................................................................................18
9.5. Study Size................................................................................................................18
9.6. Data Management ...................................................................................................18
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic 
Data Record .....................................................................................................19
9.6.2. Record Retention ........................................................................................19
9.7. Data Analysis ..........................................................................................................20
9.8. Quality Control........................................................................................................24
9.9. Strengths and Limitations of the Research Methods...............................................24
9.10. Other Aspects ........................................................................................................25
10. PROTECTION OF HUMAN SUBJECTS ........................................................................25
10.1. Patient Information................................................................................................25
10.2. Patient Consent......................................................................................................26
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............26
10.4. Ethical Conduct of the Study ................................................................................26
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................26
11.1. Structured Data Analysis.......................................................................................26

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11.2. Human Review of Unstructured Data ...................................................................27
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........28
13. REFERENCES ..................................................................................................................29
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................31
ANNEX 2. ADDITIONAL INFORMATION.........................................................................34

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
AEM
Adverse Event Monitoring
aRCC
Advanced renal cell carcinoma
ATC
Anatomical Therapeutic Chemical
BOR
Best overall response
CIOMS
the Council for International Organizations of 
Medical Sciences
CIs
confidence intervals
CR
Complete response
CRF
Case Report Form
CSA
Clinical Study Agreement
DCT
Data Collection Tool
DOR
Duration of response
DRR
Durable Response Rate
ECOG
The Eastern Cooperative Oncology Group
EMA
European Medicines Agency
ENCePP
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance
FDA
Food and Drug Administration 
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practices
HR
Hazard Ratio
IEA
International Epidemiological Association

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Abbreviation
Definition
IEC
Independent Ethics Committee
IFN-α
Interferon-alpha
IL-2
Interleukin-2
IMDC
International Metastatic Renal Cell Carcinoma 
Database Consortium
IO
Immuno-oncology
IRAS
Integrated Research Application System
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
ISPOR
The International Society for Pharmacoeconomics 
and Outcomes Research
mRCC
Metastatic renal cell carcinoma
MSKCC
Memorial Sloan-Kettering Cancer Center
NE
Not evaluable
NHS 
National Health Service
NICE
National Institute for Health and Care Excellence
NIS
Non Interventional Study
ORR
Objective response rate
OS
Overall survival
PD
Progressive Disease
PDGF
platelet derived growth factor 
PFS
Progression free survival
PR
Partial response

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Abbreviation
Definition
RCC
Renal cell carcinoma
REC
Research Ethics Committee
RECIST
Response Evaluation Criteria in Solid Tumours
RWD
Real world data
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SD
Stable disease
TKI
Tyrosine kinase inhibitor
TNM
TNM Classification of Malignant Tumours
TTD
Time to treatment discontinuation
UK
United Kingdom
VEGF
Vascular endothelial growth factor
VHL
Von Hippel Lindau

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Title
Affiliation
Address
Dr 
PhD MMedSci 
MBBChBAO BSc
(Hons) MRCS 
DO-HNS
 
Pfizer GmbH
 
 
Germany
MSc, MBA
 
Pfizer Ltd
 
MSc
 
Pfizer Ltd
 
 
MPharm 
PGClinDip
 
Pfizer Ltd
 
 
Pfizer Ltd
 
Dr 
MBChB MCRP 
MD
 
 
 
 
, UK
Prof
 
MA MB BS PhD 
FRCP
 
 
 
 
 
, UK
Dr 
MBBChBAO 
MRCPI PhD
 
 
 
, UK
4. ABSTRACT
Not applicable.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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5. AMENDMENTS AND UPDATES
None.
6. MILESTONES
Milestone
Planned date
Start of data collection 
01 August 2019
End of data collection
15 August 2019
Final study report
31 October 2019
7. RATIONALE AND BACKGROUND
Metastatic renal cell carcinoma (mRCC) is a global health problem, resulting in the deaths of 
more than 14,000 patients every year. Over the past 20 years, there has been a shift from 
cytokine based therapy towards agents targeting vascular endothelial growth factor (VEGF) 
receptors, due to the conference of longer progression free survival and overall survival rates 
with these agents.
Pfizer have two VEGF targeted medicines to treat mRCC: sunitinib and axitinib, and these 
are used in first and second line respectively. It is important that we have a clear 
understanding of the real world use and efficacy of our medicines. 
The Christie Hospital has been building a detailed database of information regarding patients 
with mRCC, and now has over 3000 patients’ details included. 
The information that has been collated includes: 
1. Memorial Sloan-Kettering Cancer Center (MSKCC) Criteria (see annex 3.1).1
2. Heng Criteria (see annex 3.2).2
3. The Eastern Cooperative Oncology Group (ECOG) performance status (see 
annex 3.3).3
4. PFS.
5. OS.
6. Lines of therapy.
7. Fuhrmann grade (see annex 3.4).4
8. TNM Classification of Malignant Tumours (TNM) stage (see annex 3.5).5

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9. Best response.
10. Stable disease vs partial response.
11. Metastasis diagnosis.
12. Histology.
13. Duration of therapy.
14. Therapy discontinuation due to toxicity/progression.
Although more than 4,000 patients die due to kidney cancer in the UK every year,6 in the 
past 20 years there has been considerable progress in survival outcomes achieved through the 
delivery of systemic therapy for metastatic and advanced renal cell carcinoma (mRCC and 
aRCC).7 For many years, cytokine therapies including, interferon alpha (IFN-α) and 
interleukin-2 (IL-2), were the preferred first-line treatments; however, they have been 
replaced by therapies with longer PFS and OS.8
Understanding the abnormal signal transduction pathways in mRCC has enabled the 
identification and development of molecular targets. For example, loss of the von Hippel 
Lindau (VHL) tumour suppressor gene leads to upregulated transcription of platelet derived 
growth factor (PDGF) and VEGF, both of which are major factors in mRCC tumorigenesis 
(Najjar and Rini, 2012).9 As a result of this, there has been a large shift from cytokine based 
therapy towards agents targeting VEGF pathways, and in particular tyrosine kinase inhibitors 
(TKIs). 
The Food and Drug Authorization (FDA), European Medicines Agency (EMA) and the 
National Institute for Health and Care Excellence (NICE) have approved several TKIs over 
the years, the first being sorafenib and sunitinib, and later pazopanib, axitinib, cabozantinib 
and lenvatinib.10 It is important that first-line therapies are strategically chosen to devoid the 
need for sequential therapy lines. In order for HCPs to select the optimal first-line TKI, 
head-to-head RCT comparison studies are undertaken.11
This study presents an opportunity to investigate TKI therapies used for the treatment of 
renal cell carcinoma, using a high quality real world evidence database, which was developed 
and has been maintained at the Christie Hospital, Manchester. 
8. RESEARCH QUESTION AND OBJECTIVES
Research Questions:
To understand the clinical outcomes of patients treated with sunitinib in first line and axitinib 
in second line in a real world setting as therapies for mRCC and/or aRCC.

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Primary Objective:
1. What is the PFS of patients treated in first line with sunitinib, and stratified by 
MSKCC/IMDC risk category (favourable, intermediate, poor)? 
2. What is the PFS of patients treated in second line with axitinib, and stratified by 
MSKCC/IMDC risk category (favourable, intermediate, poor)? 
Secondary Objectives:
First Line:
1. What is the OS of all patients in first line with sunitinib, and stratified by MSKCC 
risk (favourable, intermediate, poor)? 
2. What is the duration of therapy with sunitinib in first line (using time TTD) for all 
patients and  stratified by MSKCC risk (favourable, intermediate, poor).
3. ORR.
4. Duration of ORR (CR or PR).
5. Examine factors that predict duration of therapy on sunitinib (TTD), eg, risk 
stratification, or individual/grouped parameters that comprise the prognostic 
classification systems.
a.
Less than one year from time of diagnosis.
b. Karnovsky performance status less than 80%.
c.
Haemoglobin less than the lower limit of normal (eg, less than 12 g/dl).
d. Serum calcium great than the upper limit of normal (eg, 10 mg/dl or: 2.5 mmol/l).
e.
Neutrophil greater than the upper limit of normal (eg, greater than 7.0 x109 dl).
f.
Platelets greater than the upper limit of normal (eg, greater than 400 000).
g. Lactate dehydrogenase greater than 1.5 times the upper limit of normal.
h. Fuhrmann grade of tumour.
i.
Tumour subtype eg, clear cell vs. non-clear cell.
6. Safety and tolerability data reporting for first line sunitinib.

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Second line:
1. What is the OS of all patients in second line with axitinib, and stratified by MSKCC 
risk (favourable, intermediate, poor)? 
2. What is the duration of therapy with axitinib in second line (using TTD) for all 
patients and  stratified by MSKCC risk  (favourable, intermediate, poor).
3. ORR.
4. Duration of ORR (CR or PR).
5. Examine factors that predict duration of therapy on axitinib (TTD), eg, risk 
stratification, or individual/grouped parameters that comprise the prognostic 
classification systems.
a.
Less than one year from time of diagnosis.
b. Karnovsky performance status less than 80%.
c.
Haemoglobin less than the lower limit of normal (eg, less than 12 g/dl).
d. Serum calcium great than the upper limit of normal (eg, 10 mg/dl or: 2.5 mmol/l).
e.
Neutrophil greater than the upper limit of normal (eg, greater than 7.0 x109 dl).
f.
Platelets greater than the upper limit of normal (eg, greater than 400 000).
g. Lactate dehydrogenase greater than 1.5 times the upper limit of normal.
h. Fuhrmann grade of tumour.
i.
Tumour subtype eg, clear cell vs. non-clear cell.
6. Safety and tolerability reporting for second line axitinib.
The objectives listed below will also be assessed as exploratory analyses for various patient 
subgroups of interest, and will be conducted if sufficient numbers of patients are available:
1. Axitinib PFS and OS, as a second line therapy following sunitinib, pazopanib, or 
following other TKIs (eg, sorafenib).
2. Axitinib PFS and OS as a third line therapy.
3. Axitinib (and, if applicable, sunitinib) PFS and OS post-immunotherapy (IO), taking 
into consideration 2nd and 3rd therapy lines, following all IO therapy options, 
eg, atezolizumab/bevacizumab, nivolumab/ipilumimab, nivolumab, interleukin-2.

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4. For the post-sunitinib axitinib cohort: What was the duration of sunitinib therapy 
before patients transitioned to axitinib? 
5. For the post-pazopanib axitinib cohort: What was the duration of pazopanib therapy 
before patients transitioned to axitinib? 
6. Is the duration of therapy on first line sunitinib and/or pazopanib related to duration 
of therapy for second line axitinib?
9. RESEARCH METHODS 
This will be a retrospective real world data (RWD) non-interventional study examining
aspects of first and second line therapy for renal cell carcinoma. 
9.1. Study Design
A retrospective RWD non-interventional study examining aspects of first and second line 
therapy for renal cell carcinoma, using the Christie National Health Service (NHS) database, 
from its inception until the end of June 2017.
9.2. Setting
All data will be sourced retrospectively from participant medical records of care received at 
The Christie NHS Foundation Trust. 
NHS staff members with permitted access to medical records have searched the electronic 
medical record database and paper medical records to identify participants. This data 
collection was conducted independently of this study, at an earlier time point. This is a 
clinical database, used in the routine care of patients.
Patients with a diagnosis of renal cell carcinoma will be eligible for inclusion, and 
recruitment of patients to the wider data collection study at the NHS trust is/was by 
consecutive ongoing enrollment. This cohort is therefore felt to be representative of the 
patient population being studied. 
Patients were followed up until they withdrew consent, death occurred or the patient could no 
longer be contacted by the clinical team. Data collection for the wider study is ongoing. 
For this non-interventional study, patients who are have been treated with sunitinib and/or 
axitinib will be selected, as these are the medicines of interest to the Pfizer Oncology team. 
This is a secondary data collection study, as the clinical database already exists, and the 
clinical academic team who administrate the database have agreed to provide data to the 
Pfizer team for research purposes.
9.2.1. Inclusion Criteria
1. Over the age of 18 years.
2. Diagnosis of renal cell carcinoma.

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3. Treatment with sunitinib and/or axitinib.
4. Timeframe: from database inception date (2002) until the end of June 2017.
Research Ethics Committee (REC) approval has been sought in the UK. The Integrated 
Research Application System (IRAS) number for this study is: 266899 and the REC number 
is 19/LÖ/1041. No data will be transferred until this approval has been granted. 
9.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Under the age of 18 years.
2. Diagnosis other than renal cell carcinoma.
3. No treatment with sunitinib and/or axitinib.
9.3. Variables
Variable
Operational definition
Demographic details
Anonymised, linked details
Diagnosis Date
Date of diagnosis
Diagnosis
Renal cell carcinoma: clear cell, non-clear cell
Prior surgery eg, nephrectomy
Yes/No; add details as necessary
Line of therapy
1st line, 2nd line, 3rd line
Start date
Start date of therapy
Drug treatment
Drug name
MSKCC Risk Grade
Numeric value, subcategorise if possible: favourable/intermediate/poor 
risk. Include individual parameters that comprise this grading system 
where possible
IMDC/Heng Risk Grade
Numeric value, subcategorise if possible: favourable/intermediate/poor 
risk. Include individual parameters that comprise this grading system 
where possible
ECOG performance status at 
outset
Numeric value with related functional level attributed to this
TNM Stage
3 part cancer staging system; provide details where possible
Histology; Fuhrmann grade
Histopathological diagnosis and grading system
Metastasis diagnosis, if 
applicable
Site and extent of metastatic disease
Response to treatment
PFS, OS, TTD, Best overall response (BOR)
Date of discontinuation
Date of discontinuation of drug treatment
Therapy discontinuation
Reason for discontinuation

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Data cut offs
Overall survival, loss to follow-up, withdrawal from study
Data cut-off date for OS and PFS is June 2017
Adverse event reporting
It is expected that this data will have been reported through normal 
mechanisms, and will not have been recorded in the clinical database 
9.4. Data Sources
This study is a secondary data collection of information held on a clinical database within the 
Christie Hospital in Manchester, which is specific to renal cell carcinoma. This database was 
administered and managed by a nominated staff member during the period of interest (until 
June 2017). The internal source validity of this information will be performed by another 
team member at the Christie Hospital, who has expertise in medical oncology, but who has 
had no prior role related to data entry to this resource. A sample of the entries (10%) in the 
database will be checked prior to transfer to Pfizer Ltd.
9.5. Study Size
The clinical database, in its entirety, comprises approximately 3000 patients. The observed 
incidence of RCC in the UK is around 21 per 100,000, and this is expected to rise to 32 per 
100,000 by 2035.12 The rarity of the disease makes it challenging to locate cases. 
A specific power calculation was not performed, as this is a descriptive analysis. The 
expected number of patients eligible for this study is approximately 678 patients who 
received sunitinib, and 163 who received axitinib (based on information from the Christie 
NHS Foundation Trust).
9.6. Data Management 
Participants will be pseudo- anonymised by the assignment of a unique patient identification 
number to each record.
Data will be transferred using a secure data transfer to Pfizer, which satisfies the Pfizer 
secure data transfer requirements, and allows an audit trail.  There will be a data validation 
step to ensure all data have been transferred successfully.
Any missing or illegible data on any patient will result in Pfizer contacting the physician with 
the anonymized-linked identifier and submitting the form for validation of the missing data 
against the patient’s medical chart.  However, certain information may not be available in 
charts, in which case it will be described as unknown/ missing.
All work will be subject to quality control and documentation procedures to make certain the 
report is accurate and thorough, and the analyses can be reproduced.

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9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data Record
As used in this protocol, the term CRF/DCT should be understood to refer to either a paper 
form or an electronic data record or both, depending on the data collection method used in 
this study.
A CRF/DCT is required and has been completed for each included patient (current database).  
The completed original CRF/DCTs will become the 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 CRF/DCT are securely stored at the study site in encrypted electronic 
and/or paper form and will be password protected or secured in a locked room to prevent 
access by unauthorized third parties.
The investigator at the NHS institution has ultimate responsibility for the collection and 
reporting of all clinical, safety, and laboratory data entered on the CRF/DCTs and any other 
data collection forms (source documents) and for ensuring that they are accurate, 
authentic/original, attributable, complete, consistent, legible, timely (contemporaneous), 
enduring, and available when required.  The CRF/DCTs must be signed by the investigator or 
by an authorized staff member to attest that the data contained on the CRF/DCTs are true.  
Any corrections to entries made in the CRF/DCTs 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 this case, as an electronic 
health record.  In these cases, data collected on the CRF/DCTs must match this record. 
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, CRF/DCTs and hospital records), copies of all 
CRF/DCT 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 records must be retained for longer than 15 years if required by applicable 
local regulations. 

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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
9.7. Data Analysis 
The Statistical Analysis Plan (SAP) for this study will be outlined in this section, not in a 
separate document.  Consequently any major modifications to the analysis plan will be 
reflected in a NI protocol amendment. Statistical Analysis Software (SAS) (Version 9.1, 9.2, 
9.3 or 9.4) will be used for all analyses. 
Descriptive Analysis
Descriptive statistics will be reported for all variables of interest. Results will be reported in 
aggregate, and for the subgroups described below provided there are sufficient subjects in 
each subgroup to create a meaningful summary. The number and percent of patients along 
with descriptive statistics (mean, standard deviation, median, 25th and 75th percentiles, 
number of non-missing and number of missing values) will be reported for continuous data. 
Categorical variables (eg, age groups) – sometimes created from continuous variables – will 
have the number and percent of patients reported. In case of missing observations, the 
calculation of percentages will always include the missing category. Counts of missing 
observations will thus be included in the denominator and presented as a separate category. 
Patient demographics, selected clinical characteristics, and line of therapy treatment response 
will be summarised.
Baseline characteristics
All baseline characteristics will be summarised by the treatment groups listed below, where 
the data are available: 

Gender (male/female);

Race (Caucasian, Other);

Age;

Continuous variable;

Categorised: <65, 65-74, 75-84, and ≥85;

Weight (kg);

Height (m);

BMI (Weight[kg]/Height[m]2);

Co-morbidities;

Risk Stratification: IMDC (Heng) and/or MSKCC;

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
Date of metastatic and/or advanced RCC diagnosis (dd/mm/yyyy);

RCC diagnosis (advanced or metastatic);

Stage at diagnosis (eg, TNM).
Treatment groups
The proposed analyses will be presented for each of the following treatment groups:

Sunitinib as a first line therapy;

Axitinib as a second line therapy eg, post-sunitinib, post-pazopanib etc.
Descriptive analyses will be presented for each of the following treatment groups:

Axitinib as a third line therapy;

Axitinib (and, if applicable, sunitinib) post-immunotherapy (IO), taking into 
consideration 2nd and 3rd therapy lines, following all IO therapy options.

eg, atezolizumab/bevacizumab, nivolumab/ipilumimab, nivolumab, interleukin-2.
Primary Endpoint
Progression free survival (PFS)
PFS will be measured from the index date of each treatment line to the date of progression, or 
date of death due to any cause, or date of initiation of new regimen. Patients who are still 
alive and have not progressed at the last office visit date without clinical or radiographic 
evidence of progression will be censored (final study cutoff will be June 2017). PFS will be 
estimated in months using the Kaplan-Meier method with 95% CIs, and summary tables of 
the number of events and censored patients at each month interval included. Kaplan-Meier 
plots for PFS will be presented for the overall population and stratified by MSKCC/IMDC 
risk category (favourable, intermediate, poor). A log rank test will be performed to compare 
the stratification groups.
Secondary Endpoints
All secondary endpoints will be analysed as follows:
Overall survival (OS)
OS will be defined as the time between the index date (dependent on treatment line) and the 
date of death from any cause. Patients who are still alive at the study end date or the last visit 
date available will be censored (using whichever occurred first). If a death date is known 
beyond the study end date, then the study end date (June 2017) will be used as the censoring 

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date. Median OS will be estimated in months using the Kaplan-Meier method with 
95% confidence intervals (CIs), and summary tables of the number of events and censored 
patients at each month interval included. Kaplan-Meier plots will be presented for Overall 
Survival for the overall population, and stratified by MSKCC/IMDC risk (favourable, 
intermediate, poor). A log rank test will be performed to compare the stratification groups.
Best overall response (BOR)
In prospective clinical trials, BOR is generally assessed according to the Response 
Evaluation Criteria In Solid Tumours (RECIST) 1.1.13 However, the parameters underlying 
these criteria are less reliably available in retrospective, observational studies. While an 
attempt will be made to mimic the RECIST guideline, it should be noted that assessments 
based on information garnered during routine clinical practice could be more subjective than 
assessments in a controlled clinical trial and decision making about continued therapy could 
include symptomatic criteria. Additionally, timing of repeat imaging may vary. All 
evaluation in this observational study will be as best determined by clinicians, either as noted 
in the patient chart by the radiologist-written scan report or the treating physician’s progress 
notes or as interpreted by the clinician reviewer. The BOR for a line of treatment is the best 
response across all timepoints during that line of therapy assessed using the following 
categories: Complete response (CR), Partial Response (PR), Stable Disease (SD), 
Progressive Disease (PD), Not Evaluable (NE).
Objective response rate (ORR)
BOR will be summarized as ORR, which is defined as the number of patients having reached 
a BOR of CR or PR divided by the number of patients (the primary analysis population), 
including the NE patients. 
ORR = Number of patients achieving a response (BOR = PR or CR)/Number of patients 
(BOR=CR+PR+SD+PD+NE).
Patients who do not have a BOR assessment for a particular line of therapy will be excluded 
from the summary for that line of therapy. The number of patients with a missing BOR 
assessment will be summarized.
Duration of response (DOR)
DOR will be calculated for each patient with a BOR of CR or PR as the duration of time 
from first documented CR/PR, to the earliest date of first progression or recurrent disease, or 
date of death, or date of initiation of new regimen. Patients who are still alive and did not 
progress will be censored at the last physician office visit date without clinical or 
radiographic evidence of progression. DOR will be estimated in months using Kaplan-Meier 
method with 95% CIs, and summary tables of the number of events and censored patients at 
each month interval included.

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Time to treatment discontinuation (TTD)
TTD will be calculated as the duration between the start of a treatment line to the end of the 
treatment line for patients with discontinuation of treatment for any reason, or censoring if a 
stop date is not documented (at end of study), if the patient dies, is lost-to follow up, or is still 
on-therapy. Patients without a discontinuation event will be censored on the study end date 
or at last office visit date without clinical or radiographic evidence of progression, whichever 
occurred first. Time to TTD will be analysed using the Kaplan-Meier method with 95% CIs, 
and summary tables of the number of events and censored patients at each month interval 
included.
Durable response rate (DRR)
DRR will be determined as the proportion of patients with objective response (CR or PR) 
with a duration of at least 6 months. Duration of response will be calculated as previously 
defined for DOR.
Time-to-Event Analysis
The Kaplan-Meier method will be used to estimate median OS, PFS and TTD. P values 
comparing survival curves by stratification groups, will be calculated using log-rank tests. 
Univariate and multivariable Cox proportional hazards regressions will be used to evaluate 
explanatory factors and to calculate hazard ratios (HRs) with two-sided 95% CIs for OS, PFS 
and TTD. Demographic and clinical factors will be included in multivariable Cox regression 
models based on their clinical relevance and/or the univariate significance level (assessed at 
the level of p<0.05).
In order to account for the impact of baseline patient and disease characteristics outlined in 
this protocol and the disease characteristics below, unadjusted Cox models and multivariable 
Cox models adjusting for selected patient demographics and clinical characteristics identified 
by Pfizer as clinically relevant will be included in the adjusted models. Time-to-event 
analyses will be assessed in the overall population and by stratifications of interest 
(MSKCC/IMDC category). The disease characteristics of interest are:
a.
Less than one year from time of diagnosis;
b. Karnovsky performance status less than 80%;
c.
Haemoglobin less than the lower limit of normal (eg, less than 12 g/dl);
d. Serum calcium greater than the upper limit of normal (eg, 10 mg/dl or: 2.5 mmol/l);
e.
Neutrophil greater than the upper limit of normal (eg, greater than 7.0 x109 dl);
f.
Platelets greater than the upper limit of normal (eg, greater than 400 000);
g. Lactate dehydrogenase greater than 1.5 times the upper limit of normal;

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h. Fuhrmann grade of tumour;
i.
Tumour subtype eg, clear cell vs. non-clear cell.
The SAP outlined in this section may be subject to modifications; any major modifications of 
primary endpoint definitions or their analyses would be reflected in a protocol amendment.
9.8. Quality Control
The data collection tool is an Microsoft Access database. The investigators have entered 
pseudo-anonymized data directly from patient charts/electronic records into the database, 
which will have a function to directly export the collected data into an Excel/CSV file. 
Therefore the data collection tool will also serve as a project database (once exported into 
Excel).
Review of the patient records was be conducted by a carefully selected team of physicians 
and/or their assigned staff trained on the study specific protocols and guidelines. Physicians 
and/or site staff will be instructed to assign a unique identifier for each patient enrolled in the 
study to facilitate follow-up on data queries and for data validation. 
The Data Collection Manager/Team Lead will review pilot data for accuracy and 
consistency. During full chart review, the Data Collection Manager/Team Lead will perform 
random checks. During both the pilot and full chart review, the study’s Principal Clinical 
Investigator addresses clinical questions posed by the chart review team. The Data 
Collection Manager will also initiate normalization of data, quality control all charts, and 
review of the final data set before submission to the sub-study team. 
Finally, the principal investigator and statistical lead will provide a final examination of the 
data before and during preparation of analyses. 
The principal investigator will create the CT24 Study Data Quality Control plan.
9.9. Strengths and Limitations of the Research Methods
This is a large scale retrospective non-interventional RWD study. The strengths of this 
methodology include:

A representative impression of the real world use and activity of medicines is 
obtained;

Patients who may not be eligible for randomized controlled trials can be included;

Retrospective nature mitigates bias in regard to treatment selection and outcome 
monitoring.

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Potential limitations of this study design are:

Compliance issues eg, missed doses, treatment breaks, schedule modifications may 
not be captured in detail;

The place of real world studies in the hierarchy of medical evidence levels is not fully 
understood;

Retrospective studies can detect associations, but not causality;

Data are collected on a voluntary basis (convenience sampling) without any 
requirement in terms of sample design and stratifications;

There could be errors in data entry that are unaccounted for, and which represent 
information bias. This cannot be controlled in the analysis.
In the analysis, all steps taken by the study team will be auditable. The protocol has been 
written very specifically, in order that the research objectives and methods are open and 
transparent. 
9.10. Other Aspects
Not applicable.
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 and/or paper form 
and will be password protected or secured in a locked room 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, 

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Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.2. Patient Consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required.  
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
Research Ethics Committee (REC) approval has been sought in the UK. The Integrated 
Research Application System (IRAS) number for this study is: 266899 and the REC number 
is 19/LÖ/1041. No data will be transferred until this approval has been granted.
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 Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice 
(GEP) guidelines issued by the International Epidemiological Association (IEA), Good 
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR), International Ethical Guidelines for Epidemiological 
Research issued by the Council for International Organizations of Medical Sciences 
(CIOMS), EMA European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Guide on Methodological Standards in 
Pharmacoepidemiology, and FDA Guidance for Industry: Good Pharmacovigilance and 
Pharmacoepidemiologic Assessment, FDA Guidance for Industry and FDA Staff: Best 
Practices for Conducting and Reporting of Pharmacoepidemiologic Safety Studies Using 
Electronic Healthcare Data Sets, Guidance for Industry: Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims and/or 
equivalent.
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
11.1. Structured Data Analysis
This study involves data that exist as structured data by the time of study start.
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (ie, identify a potential association between) a particular product and medical 
event for any individual.  Thus, the minimum criteria for reporting an adverse event (AE) 
(ie, identifiable patient, identifiable reporter, a suspect product, and event) cannot be met.

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11.2. Human Review of Unstructured Data
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 Non-interventional Study 
Adverse Event Report Form (see Annex 1) and reported, within 24 hours of 
awareness, to Pfizer Safety using the NIS AEM Report Form.

Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form.
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the data reviewed is captured in the Event Narrative 
section of the report form, and constitutes all clinical information known regarding these 
AEs.  No follow-up on related AEs will be conducted.
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources.  While not all demographic fields will be completed, at the 
very least, at least one patient identifier (eg, gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation.  All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...”  Other identifiers will have been removed.
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month/year of occurrence in the day/month/year 
(DD/MMM/YYYY) format.

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All research staff members must complete the following Pfizer training requirements:

“YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”. 
These trainings must be completed by research staff members prior to the start of data 
collection.  All trainings include a “Confirmation of Training Certificate” (for signature by 
the 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.
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
A final study report will be developed when data collection and analysis is complete.
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.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of.

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13. REFERENCES
1.
Tsui, KE-Hung et al. Prognostic Indicators For Renal Cell Carcinoma: A Multivariate 
Analysis Of 643 Patients Using The Revised 1997 TNM Staging Criteria. The Journal 
of Urology 2000, 163 (4) , 1090-5.
2.
Daniel Y.C. Heng, Wanling Xie, et al. Prognostic Factors for Overall Survival in 
Patients With Metastatic Renal Cell Carcinoma Treated With Vascular Endothelial 
Growth Factor–Targeted Agents: Results From a Large, Multicenter Study. Journal of 
Clinical Oncology 2009 27:34, 5794-5799.
3.
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
4.
Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters 
in renal cell carcinoma. Am J Surg Pathol. 1982 Oct;6(7):655-63.
5.
L H Sobin (Editor) et al. TNM Classification of Malignant Tumours (7th Edition). 
Wiley-Blackwell, 2009.
6.
Cancer Research UK, accessed here: 
http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-canc
er-type/kidney-cancer.
7.
Khosravi-Shahi, P. 2017. Systemic Therapy for Metastatic Non-Clear Cell Renal 
Carcinoma. Cancer therapy & Oncology International Journal. 4(2).
8.
Takagi, T., Kondo, T., Kennoki, T., Iizuka, J., Kobayashi, H., Hashimoto, Y. and 
Tanabe, K. 2013. Comparison of Survival Rates in Patients with Metastatic Renal Cell 
Carcinoma According to Treatment Era Including Cytokine and Targeted Therapy. 
Japanese Journal of Clinical Oncology. 43(4),pp.439-443.
9.
Najjar, Y. and Rini, B. 2012. Novel agents in renal carcinoma: a reality check. 
Therapeutic Advances in Medical Oncology. 4(4),pp.183-194.
10.
Hutson, T. 2011. Targeted Therapies for the Treatment of Metastatic Renal Cell 
Carcinoma: Clinical Evidence. The Oncologist. 16(Supplement 2),pp.14-22.
11.
Zarrabi, K., Fang, C. and Wu, S. 2017. New treatment options for metastatic renal cell 
carcinoma with prior anti-angiogenesis therapy. Journal of Hematology & Oncology. 
10(1).
12.
Cancer Research UK, accessible at: 
http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-canc
er-type/kidney-cancer#heading-Zero.

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13.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). European Journal of Cancer, 2009; 45 (2):228-47.

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ANNEX 1. LIST OF STAND ALONE DOCUMENTS
Non-interventional Study Adverse Event Report Form 

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ANNEX 2. ADDITIONAL INFORMATION
1. MSKCC Criteria.1
Patients are stratified according to the presence of five risk factors:

KPS <80%;

Time from diagnosis to start of systemic therapy <12 months;

Haemoglobin < lower limit of laboratory’s reference range;

Lactate dehydrogenase 1.5 × the upper limit of laboratory’s reference range;

Corrected serum calcium >10.0 mg/dl (2.4 mmol/l).
The number of risk factors present is added up and the risk is stratified as follows:
Number of risk factors
Risk group
0
Favourable
1–2
Intermediate
3–5
Poor
2. IMDC (Heng) Criteria.2
Patients are stratified according to the presence of six risk factors:

Karnovsky performance status (PS) <80%;

Haemoglobin less than lower limit of normal;

Time from diagnosis to treatment <1 year;

Corrected calcium above the upper limit of normal;

Platelets greater than the upper limit of normal;

Neutrophils greater than the upper limit of normal.

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The number of risk factors present is added up and the risk is stratified as follows:
Number of risk factors
Risk group
0
Favourable
1–2
Intermediate
3–6
Poor
3. ECOG performance status.3
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities; 
up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5
Dead
4.
Fuhrmann grade.4
Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell 
type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing 
nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than 
each of the other parameters in predicting development of distant metastasis following 
nephrectomy.

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5. TNM stage.5
Staging of RCC (UICC TNM classification of malignant tumors, 7th edition, 2009).
T
Primary tumor
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor ≤7 cm in greatest dimension, limited to the kidney
T1a
Tumor ≤4.0 cm
T1b
Tumor >4.0 cm but ≤7.0 cm
T2
Tumor >7.0 cm in greatest dimension, limited to the kidney
T2a
Tumor >7 cm but ≤10 cm
T2b
Tumor >10 cm, limited to the kidney
T3
Tumor extends to major veins or peri-nephric tissues but not into the ipsi-lateral adrenal gland and 
not beyond Gerota fascia
T3a
Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or tumor 
invades peri-renal and/or renal sinus fat (peri-pelvic) but not beyond Gerota fascia
T3b
Tumor grossly extends into the vena cava below the diaphragm
T3c
Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava
T4
Tumor invades beyond Gerota fascia (including contiguous extension into the ipsi-lateral adrenal 
gland)
N
Regional lymph nodes

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NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in regional lymph node(s)
M
Distant metastases
cM0
Clinically no distant metastasis
cM1
Clinically distant metastasis
pM1
Pathologically proven distant metastasis, eg, needle biopsy
Stage grouping
Stage 
I
T1 N0 M0
Stage 
II
T2 N0 M0
Stage 
III
T3 N0 M0
T1-3 N1 M0
Stage 
IV
T4 Any M0
Any Any M1