Clinical Effectiveness of Second-Line Sunitinib Following Immune-oncologic (IO) Therapy in Patients With Metastatic Renal Cell Carcinoma in the International Metastatic Renal Cell Carcinoma Database (IMDC)
Conditions: Metastatic Renal Cell Carcinoma (mRCC)
Sponsor: Pfizer

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Study information
Title
Clinical Effectiveness of Second-Line Sunitinib Following 
Immune-oncologic (IO) therapy in Patients with Metastatic 
Renal Cell Carcinoma in the International Metastatic Renal 
Cell Carcinoma Database (IMDC)
Protocol number
A6181233
Protocol version identifier
01
Date of last version of protocol
21 October 2019
Research question and objectives
The study aims to assess clinical outcomes in mRCC patients 
treated with sunitinib in second-line following 
immune-oncologic (IO) therapy in real world clinical 
practices.
Authors
, MD, MPH, FRCPC
University of Calgary
 
Email: 
 Duh, ScD, MPH
 
Email: 
, PharmD, MSc
, 
Email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................3
2. RESPONSIBLE PARTIES....................................................................................................4
3. AMENDMENTS AND UPDATES.......................................................................................5
4. MILESTONES.......................................................................................................................6
5. RATIONALE AND BACKGROUND..................................................................................6
6. RESEARCH QUESTION AND OBJECTIVES ...................................................................7
7. RESEARCH METHODS ......................................................................................................8
7.1. Study Design .............................................................................................................8
7.2. Setting........................................................................................................................9
7.2.1. Inclusion Criteria ..........................................................................................9
7.2.2. Exclusion Criteria.........................................................................................9
7.3. Variables....................................................................................................................9
7.4. Data Sources............................................................................................................11
7.5. Study Size................................................................................................................11
7.6. Data Management ...................................................................................................11
7.7. Data Analysis ..........................................................................................................11
7.8. Limitations of the Research Methods......................................................................12
7.9. Other Aspects ..........................................................................................................13
8. PROTECTION OF HUMAN SUBJECTS ..........................................................................13
8.1. Patient Information and Consent.............................................................................13
8.2. Patient Withdrawal..................................................................................................13
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............13
8.4. Ethical Conduct of the Study ..................................................................................13
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................14
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........14
11. REFERENCES ..................................................................................................................15
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................17
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................17
ANNEX 3. ADDITIONAL INFORMATION.........................................................................17

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
1L
First-line
2L
Second-line
AE
Adverse event
CIOMS
Council for International Organizations of Medical 
Sciences
EMA
European Medicines Agency
ENCePP
European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance
GEP
Good Epidemiological Practice
GPP
Guidelines for Good Pharmacoepidemiology Practices
Hb
Hemoglobin 
IEA
International Epidemiological Association
IEC
Independent Ethics Committee
IMDC
International Metastatic Renal Cell Carcinoma Database 
Consortium 
IO
Immuno-oncology 
IQR
Interquartile range
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and 
Outcomes Research
KPS
Karnofsky performance status 
LLN
Lower limit of normal
LSLV
Last subject last visit  
mRCC
Metastatic renal cell carcinoma
mTOR
Mammalian target of rapamycin
ORR
Objective response rate
OS
Overall survival 
PD-1
Programmed cell death protein 1 
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
RCC
Renal cell carcinoma
SD
Standard deviation
TKI
Tyrosine kinase inhibitors 
TTD
Time to treatment discontinuation
ULN
Upper limit of normal
US
United States
VEGFR
Vascular endothelial growth factor receptor 
CCI

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, 
degree(s)
Title
Affiliation
Address
, 
MD, MPH, 
FRCPC
Principal Investigator;
 
 MPH, 
ScD
Co-investigator;
 
 
PharmD, MSc
Co-investigator;
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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3. AMENDMENTS AND UPDATES
None.

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4. MILESTONES
Milestone
Planned date
Start of data collection
October 2019
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).
November 2019
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 2020
5. RATIONALE AND BACKGROUND
An estimated 400,000 new cases of kidney cancer, of which renal cell carcinoma (RCC) 
accounts for approximately 90%, are diagnosed worldwide every year.1  RCC comprises 
2-3% of all adult malignancies, with approximately 63,000 incident cases and 14,000 deaths 
from RCC each year in the United States (US).2 Due to the lack of early symptoms and
clinical indications of disease, around 20% of patients present with the most advanced stage 
of the cancer, metastatic RCC (mRCC), at time of diagnosis.3,4  Prognosis is poor among 
mRCC patients, with 5-year survival rates of 5-10%.5  The burden of mRCC is projected to 
grow with the aging population and increasing prevalence of risk factors for RCC, such as 
obesity and hypertension.6-8
During the last decade, targeted therapies, which are agents that target the vascular 
endothelial growth factor (VEGF), VEGF receptor (VEGFR), or the mammalian target of 
rapamycin (mTOR), became standard of care for patients with mRCC.9  Since 2005, several
targeted therapies have been approved for the treatment of mRCC in the US, including 
bevacizumab (Avastin®), sunitinib (Sutent®), sorafenib (Nexavar®), pazopanib (Votrient®), 
axitinib (Inlyta®), cabozantinib (Cabometyx®, Cometriq®), everolimus (Afinitor®), and 
temsirolimus (Torisel®).9,10  Targeted therapies have been associated with improved 
progression-free survival (PFS) and overall survival (OS), favorable side effect profiles, and 
improved health-related quality of life.11-17

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Yet, recent advancements in immuno-oncology (IO) therapeutic agents have changed the 
treatment paradigm for mRCC. IO therapies work by blocking immune checkpoints 
(eg, programmed death-1 [PD-1]/PD-ligand 1 [PD-L1]) and restoring tumor-specific 
T-cell-mediated immune responses,18,19 and have demonstrated antitumor activity and 
durable responses in both pre-treated and treatment naïve mRCC.20,21 Specifically, among 
mRCC patients with intermediate or poor prognostic risk, the IO combination therapy of
nivolumab (Opdivo®) plus ipilimumab (Yervoy®) showed higher OS and objective response 
rate than sunitinib.21 Two recent phase 3 trials reported that patients treated with 1L IO 
therapies in combination with VEGFR-tyrosine kinase inhibitors (TKI) also had improved 
PFS and/or OS outcomes compared to patients treated with 1L sunitinib.22,23  However, 
despite promising early results of 1L IO therapy, some patients develop progressive disease 
requiring subsequent systemic therapy.19
Clinical decisions on optimal treatment sequences for patients with mRCC who discontinue 
IO therapy have been challenging for practitioners, since treatment guidelines and regulatory 
policies are not yet available. Further, real-world evidence on the effectiveness of treatment 
sequences for patients with mRCC who discontinue IO therapy is limited. Several studies 
have suggested antitumor activity of targeted therapy after PD-1/PD-L1 inhibition.24-28 One 
retrospective study examined targeted therapies following IO therapy and found that both 
VEGFR-TKI and mTOR inhibitor demonstrated antitumor activity following PD-1/PD-L1 
blockade.24 A recent retrospective study showed that among clear cell mRCC patients 
treated with second-line (2L) VEGFR-TKI after 1L IO therapy, 2L antitumor activity and 
tolerance was comparable to that in 1L TKI based on historical data.28 Another retrospective 
analysis found that clinical activity of subsequent VEGFR-TKI therapy after IO therapy was 
affected by the 1L combination therapy.26 That is, among mRCC patients treated with 2L
VEGFR-TKI, patients treated with IO only in 1L showed numerically higher ORR compared 
to patients treated with IO in combination with anti-VEGFR. However, these studies have 
only included mRCC patients enrolled in clinical trials, and thus lack generalizability to real-
world clinical settings. 
Given this gap in the literature, we will use real-world clinical data from the International 
Metastatic RCC Database Consortium (IMDC) database to evaluate clinical outcomes among 
patients with mRCC treated with IO therapies in 1L followed by sunitinib in 2L. 
6. RESEARCH QUESTION AND OBJECTIVES
The study aims to assess the clinical effectiveness of 2L sunitinib following IO therapy in 1L
(ie, IO monotherapy, IO + VEGFR, or nivolumab + ipilimumab), among patients with 
mRCC. The specific objectives are as follows:

To describe patient demographic and clinical characteristics among patients with
mRCC treated with IO in 1L followed by sunitinib in 2L.

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
To characterize the following clinical outcomes in patients with mRCC treated with 
IO in 1L followed by sunitinib in 2L, overall and stratified by IMDC prognostic risk 
groups, pending on sample size:

OS;

Time to treatment discontinuation (TTD);

Reasons for treatment discontinuation;

Physician-assessed best response.

To describe treatment patterns among patients with mRCC treated with IO in 1L 
followed by sunitinib in 2L (eg, duration of IO therapy, duration of sunitinib therapy, 
time from IO therapy discontinuation to initiation of sunitinib therapy).
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 for selected academic clinical sites participating in 
this study (detail on clinical sites is provided in Section 7.4). A cohort of patients treated 
with sunitinib as the 2L therapy after treatment with IO agents as 1L therapy will be 
assessed. 
The index date will be defined as the date of initiation of 2L 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.
Figure 1.
Study Design Scheme
mRCC 
diagnosis
Death or end 
of data 
availability
Index date:
Initiation of 2L 
sunitinib 
therapy
Baseline period

Demographic characteristics

Clinical characteristics

IMDC prognostic risk factors
Follow-up period

Treatment discontinuation/reasons

Physician-assessed best response

Death
Initiation 
of 1L IO 
therapy

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7.2. Setting
7.2.1. Inclusion Criteria
Patients will be selected based on the eligibility criteria listed below. Participation in an
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;

Received IO therapy as 1L therapy;

Received sunitinib as 2L therapy;

Age 18 years or over at the time of mRCC diagnosis;

Actively treated at an IMDC clinical center (to avoid incomplete data).
7.2.2. Exclusion Criteria
There are no exclusion criteria for this study.
7.3. Variables
Primary exposure 

Sunitinib as 2L therapy following IO as 1L therapy.
Outcomes

OS, defined as the time between initiation of 2L sunitinib therapy and death.

TTD, defined as the time between initiation of 2L sunitinib therapy and 
discontinuation of therapy for any reason including progression, death, and toxicity.

TTD for 1L IO (ie, time between initiation of 1L IO and discontinuation of 
therapy for any reason).

Time to initiation of 2L sunitinib from discontinuation of 1L IO.

Reasons for treatment discontinuation in 1L IO and 2L due to:

Disease progression;

Toxicity;

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•
Death;
•
Other reasons.
•
Physician-assessed best response in 2L while being treated with sunitinib, defined as 
the objective response rate (ORR) (sum of partial response and complete response),
progressive disease, and stable disease.
Covariates (assessed during the baseline period or on index date)
•
Gender;
•
Age at time of 2L sunitinib initiation;
•
Race
;
•
Date of mRCC diagnosis;
•
Prior nephrectomy status;
•
.
•
Histology type:
•
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, bone metastasis).
•
IMDC prognostic risk factors:
•
Time from RCC diagnosis to systemic treatment initiation <1 year.
•
Karnofsky performance status (KPS) <80%.
•
Hemoglobin <lower limit of normal (LLN).
•
Serum corrected calcium >upper limit of normal (ULN).
•
Neutrophil count >ULN.
•
Platelet count >ULN.
CCI
CCI

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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 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. 
will collaborate with Dr. 
 from the University of Calgary 
 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, and data cleaning and consolidation of the data occur twice a year. 
For this proposed study, a "limited" dataset of patients treated with 1L IO therapy and 2L 
sunitinib therapy will be provided only. The "limited" dataset will be anonymized and will 
not contain any personal data. All 1L IO and 2L 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 73 patients who received 1L IO and 2L sunitinib. Power 
calculations were not performed as the objectives were descriptive.
7.6. Data Management 
 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 
 over a secured network to ensure that the latest available data are used in the analysis.  
Data provided to 
 will be anonymized and will not contain any personal data. After 
obtaining the data, 
 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.  
7.7. Data Analysis 
Identification of study cohort
The study population of interest in this study are patients with mRCC treated with 2L 
sunitinib therapy following 1L IO therapy whereby the earliest date of 2L sunitinib initiation 
was April 15, 2014. Each patient's eligibility for this study will be verified against the 
eligibility criteria.
PPD
PPD
PPD
CCI
CCI
CCI
CCI
CCI

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Description of demographic and clinical characteristics among patients with mRCC
treated with 2L sunitinib therapy following 1L IO therapy
Baseline demographic and clinical characteristics prior to or on the index date will be 
described using the mean (standard deviation [SD]) and median (interquartile range [IQR]) 
values for continuous variables and frequency distributions for categorical variables. 
Characterization of clinical outcomes among patients with mRCC treated with 2L 
sunitinib therapy following 1L IO therapy
The clinical outcomes will be analyzed as follows:

OS and TTD will be analyzed using Kaplan-Meier estimator;

Reasons for 1L IO and 2L sunitinib therapy discontinuation will be described using 
relative frequencies;

Physician-assessed best tumor response (ie, ORR, stable disease, and progressive 
disease) to 2L sunitinib therapy will be described using relative frequencies.
Stratification by IMDC prognostic risk groups (ie, favorable, intermediate, and poor) may be 
performed pending on sample size. One interim analysis will be performed to examine 
sufficiency of sample size and duration of follow-up.
Description of real-world treatment patterns among patients with mRCC treated with 
2L sunitinib therapy following 1L IO therapy
The following treatment patterns will be described:

Median (IQR) and mean (SD) time from mRCC diagnosis to initiation of 1L IO 
therapy.

Median (IQR) and mean (SD) time from initiation of 1L IO therapy to 
discontinuation of IO therapy.

Median (IQR) and mean (SD) time from discontinuation of 1L IO therapy to 
initiation of 2L sunitinib therapy.

Median (IQR) and mean (SD) time from initiation of 2L sunitinib to discontinuation 
of sunitinib.
7.8. Limitations of the Research Methods
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.

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7.9. Other Aspects
Not Applicable.
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 line 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 for 
the IMDC database study.  All correspondence with the IRB/IEC should be retained in the 
Investigator File (ie, documentations of IRB approval) and will be provided as requested.  
8.4. Ethical Conduct of the Study
The study will be conducted in line 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

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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.
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
CT24-WI-GL02-RF02A Safety Reporting Language Secondary Data Collection Study 
Structured Data Analysis.
This study involves data that exist as structured data by the time of study start or a 
combination of existing structured data and unstructured data, which will be converted to 
structured form during the implementation of the protocol solely by a computer using 
automated/algorithmic methods, such as natural language processing.
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.
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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3.
Choueiri, T.K. and R.J. Motzer, Systemic Therapy for Metastatic Renal-Cell 
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Gupta, K., et al., Epidemiologic and socioeconomic burden of metastatic renal cell 
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Ljungberg, B., et al., The epidemiology of renal cell carcinoma. Eur Urol, 2011. 60(4): 
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8.
Protzel C, M.M., Hakenberg OW, Epidemiology, Aetiology, and Pathogenesis of Renal 
Cell Carcinoma. Eur. Urol. Suppl, 2012. 11: p. 52-59.
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Escudier, B., et al., Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J 
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Motzer, R.J., et al., Efficacy of everolimus in advanced renal cell carcinoma: a double-
blind, randomised, placebo-controlled phase III trial. Lancet, 2008. 372(9637): p. 449-
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Motzer, R.J., et al., Overall survival and updated results for sunitinib compared with 
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Motzer, R.J., et al., Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-
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Sunitinib 
NON-INTERVENTIONAL STUDY PROTOCOL: A6181233
Final 1, October 21, 2019 
Pfizer Confidential
Page 17 of 17
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
ANNEX 3. ADDITIONAL INFORMATION
Not applicable.