The Effect of Vascular Endothelial Growth Factor Receptor (VEGFR) Tyrosine Kinase Inhibitors (TKI) on Clinical Outcomes Among Patients With Metastatic Renal Cell Carcinoma (mRCC) Who Received First-Line Sunitinib in the International mRCC Database Consortium (IMDC) Based on Prognostic Risk Score
Conditions: Metastatic Renal Cell Carcinoma
Sponsor: Pfizer

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Study Information
Title
The Effect of Vascular Endothelial Growth Factor 
Receptor (VEGFR) Tyrosine Kinase Inhibitors (TKI) on 
Clinical Outcomes among Patients with Metastatic 
Renal Cell Carcinoma (mRCC) Who Received 
First-Line Sunitinib in the International mRCC Database 
Consortium (IMDC) based on Prognostic Risk Score
Protocol number
A6181229
Protocol version identifier
01
Date of last version of protocol
11 December 2018
Research question and 
objectives
The study aims to assess clinical outcomes in mRCC 
patients treated with sunitinib as first-line in real world 
clinical practices, stratified by International Metastatic 
Renal Cell Carcinoma Database Consortium (IMDC) 
prognostic risk groups.
Authors
, MD, MPH, FRCPC
Clinical Associate Professor
  
Email: 
, ScD, MPH
 
Analysis Group, Inc.
Boston, 
Email: 
, PharmD, MSc
 Global Health Economics & Outcomes 
Research, Pfizer Oncology
235 E 42nd Street
New York, NY 10017
Email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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, PhD
, 
Pfizer Oncology
235 E 42nd Street
New York, NY 10017
Email: 
, MD
 
Boston, 
Email:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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TABLE OF CONTENTS
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. LIST OF ABBREVIATIONS................................................................................................5
2. RESPONSIBLE PARTIES....................................................................................................6
4. MILESTONES.......................................................................................................................8
5. RATIONALE AND BACKGROUND..................................................................................8
6. RESEARCH QUESTION AND OBJECTIVES .................................................................10
7. RESEARCH METHODS ....................................................................................................10
7.1. Study Design ...........................................................................................................10
7.2. Setting......................................................................................................................11
7.2.1. Inclusion Criteria ........................................................................................11
7.2.2. Exclusion Criteria.......................................................................................11
7.3. Variables..................................................................................................................11
7.4. Data Sources............................................................................................................13
7.5. Study Size................................................................................................................13
7.6. Data Management ...................................................................................................13
7.7. Data Analysis ..........................................................................................................14
7.8. Limitations of the Research Methods......................................................................15
7.9. Other Aspects ..........................................................................................................15
8. PROTECTION OF HUMAN SUBJECTS ..........................................................................16
8.1. Patient Information and Consent.............................................................................16
8.2. Patient Withdrawal..................................................................................................16
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............16
8.4. Ethical Conduct of the Study ..................................................................................16
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................17
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........17
11. REFERENCES ..................................................................................................................18
12. ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................19
13. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ...................................19
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14. ANNEX 3. ADDITIONAL INFORMATION...................................................................19
LIST OF FIGURES
Figure 1.
Study Design Scheme...............................................................................11
APPENDICES
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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AGI
Analysis Group, Inc. 
CIOMS
Council for International Organizations of Medical Sciences
CI
confidence interval
EMA
European Medicines Agency
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
FDA
Food and Drug Administration 
GEP
Good Epidemiological Practice
GPP
Guidelines for Good Pharmacoepidemiology Practices
Hb
hemoglobin 
HR
hazard ratio
IRB
Institutional Review Board
IEA
International Epidemiological Association
IEC
Independent Ethics Committee
IMDC
International Metastatic Renal Cell Carcinoma Database Consortium 
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and Outcomes Research
KPS
Karnofsky Performance Status
LDH
lactate dehydrogenase 
LLN
Lower limit of normal 
LSLV
last subject last visit  
NCCN
National Comprehensive Cancer Network
OS
overall survival 
PFS
progression free survival 
RCC
Renal cell carcinoma 
SD
standard deviation
TTD
time to treatment discontinuation

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, 
degree(s)
Title
Affiliation
Address
, 
MD, MPH, 
FRCPC
Principal Investigator;
Clinical Associate Professor
 
 
 
, 
MD
Senior Investigator;
 
 
Associate Professor, 
 
 
 
.
 
 
 MPH, 
ScD
Co-investigator;
Chief Epidemiologist
Analysis 
Group, Inc.
 
 
, MSc, 
PharmD
Co-investigator;
 Global Health 
Economics & Outcomes 
Research, Oncology
Pfizer 
Oncology
235 E 42nd Street, 
New York, NY 
10017
, 
PhD
Co-investigator;
,
 
 
Oncology
Pfizer 
Oncology
235 E 42nd Street
New York, NY 
10017
PPD
PPD
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PPD
PPD
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PPD
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4. MILESTONES
5. RATIONALE AND BACKGROUND
Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for about 90% of 
all kidney cancers.1-3 It accounts for 2-3% of all adult malignancies with an estimated 
63,000 incident cases and 14,000 deaths per annum in the United States.4 Approximately 
25-30% of patients with RCC are diagnosed with metastatic disease due to the lack of early 
symptoms and clinical indications of disease.5 Prognosis is poor among metastatic renal cell 
carcinoma (mRCC) patients, with 5-year survival rates of 5-10%.6 As the population ages 
and risk factors for RCC become more prevalent, the burden of mRCC is expected to 
grow.1-3
Among patients with relapse or stage IV and surgically unresectable RCC, the National 
Comprehensive Cancer Network (NCCN) recommends sunitinib and pazopanib as category 
1, preferred first-line targeted therapy treatments.7 More recently, NCCN expanded its 
first-line RCC treatment recommendations to include cabozantinib after the Food and Drug 
Administration (FDA) approved cabozantinib for first-line treatment of mRCC in December 
2017 based on the CABOSUN (NCT01835158) trial results. The CABOSUN trial was a 
randomized, open-label phase II multicenter study in 157 patients with intermediate and 
poor-risk previously untreated clear cell mRCC.8 Intermediate and poor risk were classified 
based on IMDC prognostic risk groups (favorable, intermediate and poor). Patients received 
cabozantanib (n=79) 60 mg orally daily or sunitinib (n=78) 50 mg orally daily (4 weeks on 
treatment followed by 2 weeks off) until disease progression or unacceptable toxicity.8
Estimated median progression-free survival (PFS) for patients taking cabozantanib was 
8.2 months (95% confidence interval [CI]: 6.2, 8.8) compared with 5.6 months 
(95% CI: 3.4, 8.1) for patients taking sunitinib (hazard ratio for progression or death 
= 0.66; 95% CI: 0.46, 0.95; p=0.012).8 Based on these results, the NCCN guidelines 
recommended cabozantinib for first-line RCC treatment in poor- and intermediate-risk 
groups.
Milestone
Planned date
Start of data collection 
July 2018
End of data collection
For studies with primary data collection, enter the planned 
date for last subject last visit (LSLV).  For studies with 
secondary data collection, enter the planned date on which 
the analytical dataset will be first completely available; the 
analytic dataset is the minimum set of data required to 
perform the statistical analysis for the primary objective(s).
September 2018
Final study report
Enter the planned date for approval of final study report. 
For NI PASS protocols, the final study report must be 
submitted within 12 months of the end of data collection.
January 2019

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Findings from the CABOSUN trial showed that patients (IMDC intermediate and poor risk) 
taking sunitinib had a PFS of 5.6 months. This was lower than the results from a phase III 
trial that examined sunitinib versus interferon alfa in untreated clear cell mRCC patients 
where the PFS was 11.0 months in the sunitinib group vs. 5.0 months in the interferon alfa 
group.9 A recent retrospective analysis of the phase III trial demonstrated that, of the 
373 patients treated with sunitinib, there were 36% favorable, 55% intermediate, and 
9% poor based on the IMDC prognostic risk group. In addition, the median PFS for patients 
treated with sunitinib was 14.1 months (95% CI: 13.4, 17.1), 10.7 months 
(95% CI: 10.5, 12.5), and 2.4 months (95% CI: 1.1, 4.7) for favorable, intermediate, and poor 
risk groups, respectively. When intermediate and poor IMDC risk groups were combined, 
the median PFS was 10.6 months (95% CI: 8.1, 10.9).10 CheckMate 214 was another 
phase III trial that compared nivolumab plus ipilimumab (nivo+ipi) with sunitinib for 
previously untreated clear cell mRCC. The results from this trial showed that among patients 
in the intermediate and poor IMDC risk groups, the median PFS was 11.6 months 
(95% CI: 8.7, 15.5) in the nivo+ipi vs. 8.4 months (95% CI: 7.0, 10.8) in the sunitinib. Of 
the 426 patients in the intermediate and poor risk groups, 334 (79%) and 91 (21%) patients 
were identified as intermediate and poor risk, respectively.11 Based on the differences in 
PFS between these studies, patient IMDC prognostic risk group may play a role in the effect 
of first-line treatment on clinical outcomes. 
In addition to differences between IMDC prognostic risk groups, heterogeneity may exist 
within a risk group as well. Specifically, patients with IMDC intermediate risk group 
(defined as having 1 or 2 IMDC risk factors) may have different clinical outcomes depending 
on the number of risk factors. A retrospective analysis of six clinical trials examining 
sunitinib treatment for mRCC reported that among patients in the intermediate risk group,
time interval less than 1 year from RCC diagnosis to targeted therapy was the most common 
risk factor as observed in 36% of patients with 1 risk factor alone or in combination with low 
serum hemoglobin as observed in 25% of patients with 2 risk factors. The study also found 
that patients with 1 risk factor had longer OS (25.6 vs. 16.3 months) and PFS (9.8 vs. 
8.6 months), and greater ORR (39.5% vs. 31.8%) when compared to those with 2 risk 
factors.12 These results are comparable to those from the retrospective analysis of sunitinib 
vs. interferon alfa phase III trial, where the median OS in patients with 1 risk factor was 
28.2 months vs. 16.3 months in those with 2 risk factors. ORR was 33.3% 
(95% CI: 25.9, 41.5) in patients with 1 risk factor and 31.7% (95% CI: 20.3, 45.0) in those 
with 2 risk factors. Median PFS in intermediate risk group patients with 1 or 2 risk factors 
was 10.7 months.10
Given the high interest to examine the effect of lines of treatments on clinical outcomes by 
IMDC prognostic risk group, Analysis Group, Inc. (AGI) will conduct a study to further 
understand the clinical outcomes in mRCC patients treated with sunitinib as first-line 
stratified by IMDC prognostic risk groups in real-world clinical practices using the IMDC 
database. This will provide contemporary benchmarks for outcomes and survival among 
mRCC treated with first-line sunitinib in the real world. Additionally, the clinical 
heterogeneity within the IMDC intermediate risk group and impact of individual IMDC 
prognostic risk factors will be explored.  

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6. RESEARCH QUESTION AND OBJECTIVES
The study aims to address the following:
1. To describe patient demographic and clinical characteristics among all mRCC 
patients treated with sunitinib in first-line, stratified by IMDC prognostic risk score 
(ie, favorable, intermediate, and poor).
2. To characterize the following clinical outcomes in patients treated with sunitinib in 
first-line, stratified by IMDC prognostic risk groups and Karnofsky Performance
Status (KPS).

OS;

Time to treatment discontinuation (TTD);

Reasons for treatment discontinuation;

Physician-assessed best response (objective response rate [ORR], progressive 
disease, stable disease).
3. To conduct a subgroup analysis assessing demographic and clinical characteristics 
and the following clinical outcomes among mRCC patients in the intermediate IMDC 
prognostic risk group, stratified by patients having only 1 IMDC risk factor versus 
2 IMDC risk factors.

OS;

TTD;

Physician-assessed best response (ORR, progressive disease, stable disease).
7. RESEARCH METHODS 
7.1. Study Design
This is a retrospective, longitudinal cohort study that involves the analysis of retrospective 
data collected through the IMDC database. A cohort of mRCC patients who initiated 
sunitinib as first-line therapy will be evaluated. 
The index date will be defined as the date of initiation of first-line sunitinib therapy. The 
baseline period will be defined as the time from mRCC diagnosis to the index date. The 
follow-up period will be defined as the time from the index date to the earliest of death or 
end of data availability. Figure 1 depicts the study design scheme.

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Figure 1.
Study Design Scheme
7.2. Setting
7.2.1. Inclusion Criteria
1. Patients will be selected based on the eligibility criteria listed below. Participation in 
interventional trial for mRCC disease is allowed. Subjects will be selected 
irrespective of their survival status.
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:

Diagnosed with mRCC;

Initiated treatment post mRCC diagnosis and received sunitinib as first-line therapy;

Age 18 years or over at the time of mRCC diagnosis;

Actively treated at an IMDC clinical center.
7.2.2. Exclusion Criteria

Initiated first-line sunitinib treatment before 2010;

Had non-clear cell mRCC.
7.3. Variables
Primary exposure 

Sunitinib as first-line therapy.
mRCC 
diagnosis
Death or 
end of data 
availability
Index date:
Initiation of sunitinib as first-line 
Baseline period

Demographic characteristics

Clinical characteristics

IMDC prognostic risk 
factors, including KPS
Follow-up period

Treatment discontinuation/reasons 

Physician-assessed best response

Death

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Outcomes

OS, defined as the time between index date and death.

TTD, defined as the time between index date and discontinuation of therapy due to
any reason including progression, death, or toxicity.

Reasons for treatment discontinuation, categorized as progression, death, toxicity, or 
other.

Physician-assessed best response, defined as ORR (sum of partial response and
complete response), progressive disease, and stable disease.
Covariates (assessed during the baseline period or at index date).

Gender.

Age at time of mRCC diagnosis.

Race.

Date of RCC diagnosis.

Date of mRCC diagnosis.

Prior nephrectomy.

Date of nephrectomy (if applicable).

Pathology.

Non clear cell RCC.

Clear cell RCC.

Number of metastatic sites (eg, 1 site or more than 1 site).

Site of metastases (eg, brain metastasis).

IMDC prognostic risk factors.

Time from diagnosis to treatment initiation.

Karnofsky performance status at index date.

Serum hemoglobin at index date.

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
Serum corrected calcium at index date.

Neutrophil count (absolute count) at index date.

Platelet count at index date.
7.4. Data Sources
Data will be obtained retrospectively from the IMDC clinical sites. 
The IMDC cohort is a multi-institutional cohort that collects data globally from 
35 international cancer centers in the United States, Canada, Denmark, Greece, South Korea, 
Australia, New Zealand, Japan, Singapore, Italy, and Belgium. Demographic, clinical, 
laboratory, and outcome data on patients with mRCC are collected retrospectively from 
medical charts using uniform database templates and standardized definitions to ensure data 
are collected consistently. Medical records include longitudinal information on patient 
demographic and disease characteristics, oncology-specific workups and evaluations, 
treatment types and duration, concurrent diagnoses as documented in physician notes, and 
treatment discontinuation/halt decisions. 
AGI will collaborate with Dr. 
 from the 
 
who will serve as the principal investigator for this study and who is also the Chair of the 
IMDC, to obtain data from clinical centers. The clinical centers send data to the IMDC 
database, which is updated frequently (ie, quarterly or continuously). Data cleaning and 
consolidation of the data occur twice a year. 
For this proposed study, a "limited" dataset of first-line sunitinib patients will be provided. 
The "limited" dataset will be anonymized and will not contain any personal data. All 
first-line sunitinib patients are included in the "limited" dataset, but only a select number of 
variables necessary to fulfill the study objectives will be included. 
 
7.5. Study Size
The IMDC database has approximately 7,000 mRCC patients who received sunitinib at any 
line of treatment. About 2,000-3,000 patients received first-line sunitinib. Power calculation
was not performed as the main objectives were descriptive.
7.6. Data Management 
AGI will work with the IMDC data manager and Dr. 
 to understand all available data 
elements from the IMDC database.  
Once study site contracts have been completed, the most recent data will be transferred to 
AGI over a secured network to ensure that the latest available data are used in the analysis.  
Data provided to AGI will be anonymized and will not contain any personal data. After 
obtaining the data, AGI will assess the quality of the data downloaded and work with data 
managers from each center to rectify any potential data entry errors and discrepancies.  
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7.7. Data Analysis 
Identification of the Study Cohort 
The study population of interest in the current study are patients treated with first-line 
sunitinib. Each patient's eligibility for study will be verified against the eligibility criteria. 
Description of patient demographic and clinical characteristics among patients in the 
study cohort, stratified by IMDC prognostic risk group
Baseline demographic and clinical characteristics prior to the index date will be described 
using the mean (standard deviation [SD]) and median values for continuous variables and 
frequency distributions for categorical variables. Demographic and clinical characteristics 
will also be summarized, stratified by IMDC prognostic risk groups (ie, favorable, 
intermediate, and poor). Comparisons will be performed using chi-square tests or Fisher's 
exact test, as appropriate, for categorical variables and Wilcoxon-Mann-Whitney 
non-parametric tests for continuous variables.
Characterization of clinical outcomes of mRCC patients treated with first-line sunitinib
The following clinical outcomes will be stratified by IMDC prognostic risk groups 
(ie, favorable, intermediate, and poor) and KPS (eg, 0-40%, 50-70%, and 80-100%).

OS and TTD will be analyzed using Kaplan-Meier estimator.

Reasons for first-line sunitinib therapy discontinuation will be described using 
relative frequencies. 

Physician-assessed best tumor response (ie, objective response rate, stable disease, 
and progressive disease) to first-line sunitinib will be described using relative 
frequencies. 
 
 
 
 
 
 
 
 
  
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Indirect qualitative evaluation of the real-world clinical outcomes of mRCC patients 
treated with first-line sunitinib with that of phase II and III clinical trials
An indirect qualitative, side-by-side evaluation of clinical outcomes will be conducted 
between the following groups:

Previously untreated sunitinib patients with intermediate or poor IMDC risk score 
from the real-world IMDC database vs previously untreated sunitinib patients with 
intermediate or poor IMDC risk score from the 1) CABOSUN trial, 2) CheckMate 
214, and 3) sunitinib vs. IFN-trial.
Subgroup analysis describing demographic and clinical characteristics and 
characterizing clinical outcomes among patients in the IMDC intermediate risk group, 
stratified by patients having only 1 vs 2 risk factors

Among patients identified as having intermediate IMDC risk score (defined as 
having 1 or 2 IMDC risk factors), a subgroup analysis will assess baseline 
demographic and clinical characteristics, distribution of individual IMDC risk factors,
and clinical outcomes (ie, OS, TTD, and ORR), stratified by patients having only 
1 risk factor vs. 2 risk factors. Demographic and clinical characteristics and clinical 
outcomes (ie, OS, TTD, and ORR) will be analyzed using the same methodology 
applied in the full study cohort. Absolute and relative frequency of each IMDC factor 
within the intermediate risk group will be reported.
7.8. Limitations of the Research Methods
With an analysis of non-randomized treatment groups, unmeasured confounders and 
reporting bias could account for any observed associations. In addition, there may be 
potential biases in the retrospective study design (eg, selection bias, recall bias, and non-
random missing data). 
In addition, assessments of disease progression and tumor response in real-world settings 
may be based on heterogeneous criteria and assessment schedules. In contrast to clinical 
trials with protocol-specified definitions of clinical events, assessments of progression and 
clinical response in retrospective studies of clinical practice may not be made consistently 
across subjects and across physician practices.
7.9. Other Aspects
Not Applicable.
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8. PROTECTION OF HUMAN SUBJECTS
This is a retrospective medical records review study where data collected will be strictly 
anonymous and will not be traceable back to individual subjects by the sponsor. No subject 
identifiers will be requested in this study to protect subject interests. Only anonymized 
aggregated data will be presented in the final study report
Compliance with Pfizer and regulatory standards provides assurance that the rights, safety, 
and well-being of subjects participating in non-interventional studies are protected 
(consistent with the principles that have their origin in the Declaration of Helsinki) and that 
the study data are credible and responsibly reported.
This study was designed and shall be implemented and reported in accordance with the 
Guidelines for Good Pharmacoepidemiology Practices (GPP) of the International Society for 
Pharmacoepidemiology (ISPE 2008), the STROBE (Strengthening the Reporting of 
Observational Studies in Epidemiology) guidelines (Vandenbroucke, et al 2008), and with 
the ethical principles laid down in the Declaration of Helsinki. 
8.1. Patient Information and Consent
The study will be conducted entirely using retrospective medical records and no subject 
identifiers will be requested in this study. Informed consent is not expected to be required in 
this study as the data collected does not contain personal identifiers. 
8.2. Patient Withdrawal
Not Applicable.
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval from the IRB/IEC.  All 
correspondence with the IRB/IEC should be retained in the Investigator File.  
8.4. 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), European Medicines Agency (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: 

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Patient-Reported Outcome Measures: Use in Medical Product Development to Support 
Labeling Claims and/or equivalent.
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
CT24-GSOP-RF06 Safety Reporting Language: Secondary Data Collection Study - Does Not 
Include Protocol-Required Human Review of Unstructured Data
 
 
 In these 
data sources, 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) are not available and AEs are not reportable as individual AE reports.
All research staff members will complete the Pfizer requirements regarding training on the 
following: “Your Reporting Responsibilities: Monitoring the Safety, Performance and 
Quality of Pfizer Products (Multiple Languages)” and any relevant Your Reporting 
Responsibilities supplemental training.  This training 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. 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
COMMUNICATION OF ISSUES
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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11. REFERENCES
1.
Gupta, K., et al., Epidemiologic and socioeconomic burden of metastatic renal cell 
carcinoma (mRCC): a literature review. Cancer Treat Rev, 2008. 34(3): p. 193-205.
2.
Ljungberg, B., et al., The epidemiology of renal cell carcinoma. Eur Urol, 2011. 60(4): 
p. 615-21.
3.
Protzel C, M.M., Hakenberg OW, Epidemiology, Aetiology, and Pathogenesis of Renal 
Cell Carcinoma. Eur. Urol. Suppl, 2012. 11: p. 52-59.
4.
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 
2015. 65(1): p. 5-29.
5.
Lam, J.S., et al., Novel approaches in the therapy of metastatic renal cell carcinoma. 
World J Urol, 2005. 23(3): p. 202-12.
6.
Haferkamp, A. and M. Hohenfellner, Medical treatment options in patients with 
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Network, N.C.C. NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer V 
2.2017. 2017; Available from: 
https://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf.
8.
Choueiri, T.K., et al., Cabozantinib Versus Sunitinib As Initial Targeted Therapy for 
Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The 
Alliance A031203 CABOSUN Trial. J Clin Oncol, 2017. 35(6): p. 591-597.
9.
Motzer, R.J., et al., Overall survival and updated results for sunitinib compared with 
interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol, 2009. 
27(22): p. 3584-90.
10.
Rini, B.I., et al., Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical 
Outcome According to International Metastatic Renal Cell Carcinoma Database 
Consortium Risk Group. Clin Genitourin Cancer, 2018.
11.
Motzer, R.J., et al., Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-
Cell Carcinoma. N Engl J Med, 2018. 378(14): p. 1277-1290.
12.
Sella, A., et al., Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal 
Cell Carcinoma Treated With Sunitinib. Clin Genitourin Cancer, 2017. 15(2): p. 291-
299.e1.

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NON-INTERVENTIONAL STUDY PROTOCOL: A6181229
Amendment 1, 11 December 2018
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12. ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
13. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
14. ANNEX 3. ADDITIONAL INFORMATION
Not applicable.

Sunitinib 
NON-INTERVENTIONAL STUDY PROTOCOL: A6181229
Amendment 1, 11 December 2018
Page 20
CCI

Sunitinib 
NON-INTERVENTIONAL STUDY PROTOCOL: A6181229
Amendment 1, 11 December 2018
Page 21
CCI