Study of Advanced Renal Cell Carcinoma Treatment Patterns and Unmet Needs Using Real World Claims and Electronic Medical Record Data.
Conditions: Renal Cell Carcinoma (RCC)
Sponsor: Pfizer

A6181232 Master Protocol to Study Treatment Patterns, Medication Adherence, Health and Economic 
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NON-INTERVENTIONAL STUDY OF ADVANCED RENAL CELL CARCINOMA 
TREATMENT PATTERNS AND UNMET NEEDS 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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Title
Study of advanced renal cell carcinoma treatment patterns and unmet 
needs using real world claims and electronic medical record data.  
Protocol number
A6181232
Protocol version 
identifier
01
Date of last version of 
protocol
4 October 2019
Research question 
and objectives
The study aims to assess treatment patterns and outcomes in advanced
RCC patients in real world clinical practices across various real world 
databases.  Four databases will be evaluated: IBM’s Truven MarketScan 
Commercial, Optum Clinformatics, the IMS PharMetrics claims 
databases and The PanTher (which has both Humedica EMR data 
including EMR notes linked to Optum claims).  
The primary study objectives include: 
1.
Treatment patterns: Characterize first-line and subsequents lines of 
therapy.  Treatment patterns will be summarized for the following 
therapy regimens: 

immuno-oncology (IO) monotherapy;

IO+IO combo-therapy;

IO+tyrosine kinase inhibitor (TKI) combo-therapy;

TKI monotherapy;

Other.
2.
Analyze Cohorts of Interest: To describe patient demographics and 
clinical characteristics, and select outcomes of interest among the 
following first-line advanced RCC cohorts of interest:

immuno-oncology (IO) monotherapy;

IO+IO combo-therapy;

IO+tyrosine kinase inhibitor (TKI) combo-therapy;

TKI monotherapy;

Other.
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3.
Analyze Select Outcomes of Interest:

Time to Treatment Failure (TTF) - the time from therapy start 
to treatment discontinuation or therapy change (next line of 
therapy – switch or augment), end of enrollment, or death;

Treatment Interruption – those with gaps in treatment greater 
than allowable gap but who restart the same medication with no 
indication of switching or augmentation;

Health Care Costs (inpatient, outpatient, pharmacy, other);

Health Care Utilization (inpatient hospitalizations, ER, 
outpatient visits);

Survival Time and Landmark Survival.  Mean/median 
survival time and % of population surviving 3, 6, and 12 months
will be explored, although regimens are too new for extensive 
follow-up time. (Note: survival analysis will only be available in 
the Optum Clinformatics Database).
, PharmD, MSc
Director, 
 
New York, NY 10017
Email: 
 
Sr. Director, 
Rockland, MA 02370
Email: 
, MD
Title
Address
Email: 
 
Executive Director, 
New York, NY 10017
Email: 
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, MPH
Director, 
New York, NY 10017
Email: 
, MPH
Manager,
New York, NY 10017
Email: 
Intern, 
New York, NY 10017
Email: 
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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................7
2. RESPONSIBLE PARTIES....................................................................................................9
3. AMENDMENTS AND UPDATES.....................................................................................10
4. RATIONALE AND BACKGROUND................................................................................10
5. RESEARCH QUESTION AND OBJECTIVES .................................................................11
6. RESEARCH METHODS ....................................................................................................12
6.1. Study Design ...........................................................................................................12
6.2. Setting......................................................................................................................17
6.2.1. Inclusion Criteria ........................................................................................17
6.2.2. Exclusion Criteria.......................................................................................18
6.3. Variables..................................................................................................................19
6.3.1. Treatment Pattern Variables .......................................................................19
6.3.2. Baseline Variables ......................................................................................21
6.3.3. Outcomes Variables....................................................................................26
6.3.4. Cost and Utilization Variables....................................................................27
6.4. Data Sources............................................................................................................30
6.5. Study Size................................................................................................................33
6.6. Data Management ...................................................................................................33
6.6.1. Record Retention ........................................................................................33
6.7. Data Analysis ..........................................................................................................34
6.8. Quality Control........................................................................................................35
6.9. Limitations of the Research Methods......................................................................35
6.10. Other Aspects ........................................................................................................35
7. PROTECTION OF HUMAN SUBJECTS ..........................................................................35
7.1. Patient Information..................................................................................................35
7.2. Patient Consent........................................................................................................35
7.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............35
7.4. Ethical Conduct of the Study ..................................................................................36
8. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................36
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9. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS..........36
10. REFERENCES ..................................................................................................................37
11. LIST OF TABLES.............................................................................................................39
12. LIST OF FIGURES ...........................................................................................................39
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................40
ANNEX 2. ADDITIONAL INFORMATION.........................................................................41
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1. LIST OF ABBREVIATIONS
Table 1.
Abbreviations
Abbreviation
Definition
AE
adverse event
AGI
Analysis Group, Inc. 
aRCC
Advanced Renal Cell Carcinoma
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 
IO
Immuno-oncology 
ISPE
International Society for Pharmacoepidemiology
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Abbreviation
Definition
ISPOR
International Society for Pharmacoeconomics and Outcomes 
Research
LDH
lactate dehydrogenase
LLN
Lower limit of normal 
LSLV
last subject last visit  
mRCC
Metastatic Renal Cell Carcinoma
NCCN
National Comprehensive Cancer Network
OS
overall survival 
PPPM
Per Patient Per Month
PFS
progression free survival 
RCC
Renal cell carcinoma 
SAP
Statistical Analysis Plan
SD
standard deviation
TKI
Tyrosine kinase inhibitor
TTD
time to treatment discontinuation
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2. RESPONSIBLE PARTIES
Table 2.
Principal Investigator(s) of the Protocol
Name, 
degree(s)
Title
Affiliation
Address
Sr Director, 
 
 
EMD Serono, 
 
 
MA, 02370 
 
PharmD
Co-investigator;
Director,
 
Pfizer 
Oncology
 
 NY 
10017
 
, MD
University of 
IA
 
 IA
Director
 
EMD Serono
 
 
MA, 02370
 
, 
PhD 
Executive Director,
 
Pfizer Global 
Product 
Development
, NY 
10017
 
, MPH
Co-investigator;
Director,
 
Pfizer Real 
World 
Analytics
, NY 
10017
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3. AMENDMENTS AND UPDATES
Table 3.
Amendments and Updates
Amendment 
number
Date
Protocol 
section(s) 
changed
Summary of amendment(s)
Reason
4. RATIONALE AND BACKGROUND
Approximately 2% of all incident malignant tumors worldwide are caused by renal cancers.1
In 2019, The American Cancer Society for Kidney Cancer in the United States estimates that 
there will be about 73,820 cases of kidney cancer. It also estimates that about 14,770 people 
will die from this disease.2 RCC often gets diagnosed in advanced stages: ~25-30% of the 
patients are diagnosed at the metastatic disease stage.3  Hence, patients with advanced 
disease often have high rates of morbidity and mortality.4  Until 2005, cytokine therapy was 
the only approved post-surgical treatment of advanced RCC. These therapies were highly 
toxic and offered limited long-term clinical benefit in a majority of patients. This was 
followed by targeted therapies for treatment of mRCC with sorafenib in December 2005 and 
sunitinib in January 2006.5  The US Food and Drug Administration (FDA)-approved tyrosine 
kinase inhibitors (TKIs) have expanded to included axitinib (January 2012) and pazopanib 
(October 2009).6 The 5-year relative survival rates for these therapies have ranged from 
10.4% for patients with later-stage disease involving distant metastases to 90.4% for early-
stage localized disease.7  
Treatment guidelines are determined by prognostic risk group using the International 
Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Criteria8 or Memorial Sloan 
Kettering Cancer Center Prognostic Model (MSKCC).9 According to 2019 NCCN 
guidelines, targeted therapy utilizing tyrosine kinase inhibitors, TKIs and/or VEGF 
antibodies (including pazopanib, sunitinib, bevacizumab, , axitinib, and cabozantinib) are 
recommended as first-and second-line treatments. Mammalian target of rapamycin (mTOR) 
(temsirolimus and everolimus) are also used in this setting.  Immune checkpoint inhibitors, 
which alter the interaction between immune cells and antigen-presenting cells, are the new 
revolution in treatment options.10  
In April 2018, the FDA approved the combination of the immuno-oncology (IO) checkpoint 
inhibitors ipilimumab and nivolumab for advanced RCC.11 This combination is currently 
recommended as the new standard of care for first-line for treatment of metastatic RCC 
(mRCC) patients with intermediate or poor prognosis.12
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This study will clarify current treatment patterns and unmet needs (eg, regimen adherence
and discontinuation patterns) among the various regimens used to treat mRCC.  This study 
characterize mRCC treated populations represented by the most prevalent treatment regimens 
and will quantify mRCC outcomes including treatment failure/duration of therapy, cost and 
utilization and survival in real world clinical practices toward demonstrating current unmet 
needs in mRCC.
5. RESEARCH QUESTION AND OBJECTIVES
The study aims to address the following key objectives among patient cohorts diagnosed with 
advanced/metastatic RCC:
Objective 1: Treatment patterns: Characterize first-line and subsequents lines of therapy.  
Treatment patterns will be summarized for the following therapy regimens: 

immuno-oncology (IO) monotherapy;

IO+IO combo-therapy;

IO+tyrosine kinase inhibitor (TKI) combo-therapy;

TKI monotherapy;

Other.
Objective 2: Analyze Cohorts of Interest: To describe patient demographics and clinical 
characteristics, and select outcomes of interest among the following first-line advanced RCC 
cohorts of interest:

immuno-oncology (IO) monotherapy;

IO+IO combo-therapy;

IO+tyrosine kinase inhibitor (TKI) combo-therapy;

TKI monotherapy;

Other.
Objective 3: Analyze Select Outcomes of Interest:

Time to Treatment Failure (TTF) - the time from therapy start to treatment 
discontinuation or therapy change (next line of therapy – switch or augment), end of 
enrollment, or death.
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
Treatment Interruption – those with gaps in treatment greater than allowable gap 
but who restart the same medication with no indication of switching or augmentation.

Health Care Costs (inpatient, outpatient, pharmacy, other).

Health Care Utilization (inpatient hospitalizations, ER, outpatient visits).

Survival Time and Landmark Survival.  Mean/median survival time and % of 
population surviving 3, 6, and 12 months will be explored, although regimens are too 
new for extensive follow-up time. (Note: survival analysis will only be available in 
the Optum Clinformatics Database).
6. RESEARCH METHODS 
This master protocol specifies more than one retrospective, longitudinal cohort studies that 
will be performed and replicated in various de-identified, real world administrative medical 
and pharmacy claims data and electronic medical records structured data.  Leveraging 
multiple databases will optimize the study sample size and provide more robust foundation to 
addressing the research questions.  The analyses will be performed using real world claims 
and EMR data, including Optum Clinformatics Claims, Truven Marketscan Commercial 
Claims, Pharmetrics Claims and the Optum PanTher containing the overlap of Optum claims 
and Humedica EMR structured data.  It should be noted that contractual obligations 
associated with these datasources require that they not be merged or combined.
6.1. Study Design
Patients receiving aRCC treatement (see Table 4), between April 2018 and the present, who 
have no prior aRCC treatment in their claims history will be identified for this study.  The 
index date for each analysis will be defined as the date of initiation of the aRCC treatment.  
Patients must have at least 2 RCC diagnoses at least 30 days apart to be included.  Patients 
must also have 2 secondary malignancy ICD9 or ICD10 codes (often used in claims data to 
suggest cancer metastases) at least 30 days apart in the 12 months pre and one month post 
index aRCC treatment.  
 
 Various algorithms and temporal 
relationships between the secondary malignancy codes, RCC diagnosis codes and other 
cancer codes were explored toward developing the criteria for metastatic advanced RCC for 
this study. 
Study will require a minimum of 12 months of enrollment prior to the index date.  Feasibility 
was assessed for various lengths of continuous enrollment criteria (3, 6 and 12 months post 
index date) toward understanding sample sizes available for analysis and follow-up periods.  
Study outcomes will be assessed for three patient cohorts (3, 6 and 12 month cohorts) 
according to their available months of continuous enrollment.  
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First line therapy cohorts will first be presented for all patients regardless of follow-up time 
available. Baseline characteristics, costs and utilization will be measured over the 6 months 
prior to the index date. Duration of therapy and utilization analysis will require at least 
6 months of post-index enrollment, with sub-analysis preformed on the cohorts with 
3-months and 12-months of post-index enrollment. Utilization and cost will be performed 
per-utilizer-per-month (PUPM), and then separately for each of the cohorts with 3-month, 
6-month and 12-months of post-index enrollment.  
The analysis will focus on, but is not limited to, the following regimens: 
a.
Combo IO: nivolumab combined with ipilimumab;
b. Monotherapy TKI: sunitinib, cabozantinib, and pazopanib;
c.
Combo TKI + IO: avelumab in combination with axitinib, pembrolizumab in 
combination with axitinib;
d. Other: all others regimens.
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Figure 1: Cohort Identification
Analysis 1.  Treatment Patterns and Duration
The purpose of this initial analysis is to characterize the treatment patterns and treatment 
duration of adult patients with advanced and metastatic RCC across various real world claims 
databases (Truven, Optum and Pharmetrics claims).  Treatment patterns for these various US 
population based claims dataset will be assessed for consistency and regimen-specific 
population differences, as well as assessing feasibility for sub-analyses.  
In order to isolate lines of therapy of interest, all medications used for advanced RCC must 
be considered.  Thus, lines of therapy will be performed considering the following RCC 
medications (see Table 4):
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Table 4.
Medications of Interest
First-line and subsequent lines (up to 3) of monotherapy and combo-therapy regimens for 
aRCC patients will be identified and the following metrics will be considered for first-line of 
therapy:

Time from first ever metastatic diagnosis to first line regimen;

Duration of first line therapy;

Patterns of switching, augmentation and discontinuation;

Treatment interruptions.
Treated Period Follow-Up. Patients will be followed over the period treated with advanced 
RCC therapy.  Time treated will be defined as the time from the index date to the date of the 
end of the last advanced metastatic RCC prescription (end of supply for orals/administration 
date plus 30 days for injectibles), end of enrollment, end of follow up, or death (see more 
specifics on oral versus injectable rules in 6.3.1 Variables section of this protocol). 
Analysis 2.  Describe various treated populations of interest by demographics, clinical 
characteristics, as well as cost and utilization 
Describe the demographics and other baseline characteristics of the first-line treated cohorts
of interest identified in the treatment patterns analysis (Analysis 1) for RCC patient as 
follows:  
Baseline Characteristics (see 6.3.2 Baseline Characteristics): 

Age at index;

Gender;

Race;

Region;
Drug Class
Ingredient
Brand Name
Dosage Form
Mechanism
TKI
Pazopanib
Votrient
Oral
Tyrosine Kinases Inhibitor
TKI
Sunitinib
Sutent
Oral
Multiple receptor tyrosine kinases (RTKs)
TKI
Axitinib
Inlyta
Oral
Kinase inhibitor
TKI
Caboznatinib
Cabometyx/Cometriq
Oral
New Novel TKI
TKI
Sorafenib
Nexavar
Oral
Multikinase inhibitor 
TKI
Levantinib
Lenvima
Oral
RTK inhibitor 
TKI
Erlotinib
Tarceva
Oral
Epidermal Growth Factor Receptor tyrosine kinase inhibitor 
mTOR
Temsirolimus
Torisel
Both oral and IV
Inhibitor of mammalian target of rapamycin
mTOR
Everolimus
Afinitor
Both oral and IV
Mammalian target if rapamycin inhibitor 
IO
Ipilimumab
Yervoy
Injection 
Human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody 
IO
Nivolumab
Opdivo
Injection 
Checkpoint monoclonal Antibody PD-1 Inhibitor
IO
Atezolizumab
Tecentriq
Injection 
Checkpoint monoclonal Antibody PD-L1 Inhibitor
IO
Durvalumab
Imfinzi
Injection 
Checkpoint monoclonal Antibody PD-L1 Inhibitor
IO
Pembrolizumab
Keytruda
Injection 
Checkpoint monoclonal Antibody PD-1 Inhibitor
IO
Avelumab
Bavencio 
Injection 
Checkpoint monoclonal Antibody PD-L1 Inhibitor
IO
Bevacizumab
Avastin
Injection 
Recombinant monoclonal antibody VEGF/VEGFR Inhibitor  
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
Payor;

Clinical characteristics: Quan-Charlson Comorbidity Index (CCI) scores and baseline 
comorbidities;

Prior treatment (6 months prior) - nephrectomy, radiation/ablation, interferon, 
high-dose interleukin-2, other anti-neoplastic medications;

Secondary malignancy locations (6 months prior);

Baseline costs of care (6 months prior);

Baseline health care resource utilization (6 months prior).
Analysis 3: Evaluate the key outcomes of interest for advanced RCC therapy regimens
toward demonstrating existing unmet needs in RCC given currently available therapies 
(eg, ipilimumab/nivolumab).
Treatment duration, discontinuation, interruption, switching and therapy augmentation will 
be presented, as will the burden of disease costs and health care utilization.  Survival will 
also be explored, although regimens are too new for extensive follow-up time.  
Overall Outcomes Study Period.  For the outcomes analysis, follow-up will be defined as 
the time from the index date to the end of specified follow up period of 6 months, end of 
enrollment, or death.  Follow-up may vary given sample sizes of study population, with by 
subanalysis using 1-year or 2-years of follow-up time from study index date for certain 
sub-populations. 
Outcomes include:

Time to Treatment Failure (TTF) – First line time to treatment failure (TTF) is 
defined as the time from first-line therapy start to treatment discontinuation for any 
reason, including switched, augmented therapy, end of enrollment, death.

% continuing – those with no gap in therapy greater than 30 days and who do not 
begin a new treatment during the study period.

% discontinuing – those with gap in therapy greater than 30 days and who do not 
begin a new treatment.

% with treatment interruption - those with gap in therapy greater than 30 days but 
who eventually continue the original treatment (have an additional administration or 
refill) and do not switch or augment therapy during the study period.

% switching – those with gap in therapy greater than 30 days and who begin a new 
treatment.

% augmenting – those who begin a new treatment but continue using the original 
treatment (have an additional administration or refill) and do not have a gap in 
therapy greater than 30 days of their original treatment.

Overall and aRCC Follow-Up Costs: Total and RCC-specific pharmacy, medical
costs from aRCC therapy index through follow-up period (costs summarized as: 
mean, median costs per patient and costs per patient per month).
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
Overall and aRCC Follow-Up Utilization: Total and RCC-specific inpatient, ER, 
outpatient visits from aRCC therapy index through follow-up period  (utilization will 
be summarized as: mean, median utilization per patient and utilization per patient per 
month).

Overall landmark survival: Using Optum claims and PanTher data, landmark 
survival will be described and compared over follow-up time periods (3, 6, 12 
months).

Mean/Median Survival: Using Optum claims and PanTher data median survival 
time will be described and compared over follow-up time periods determined after 
feasibilitied assessments of cohorts of interest.
6.2. Setting
Anonymized patient data available in US admistrative research database will be used for this 
study.  This study will utilize various databases including the Truven Marketscan 
Commercial, Optum Clinformatics DOD (includes death data from the Social Security Death 
Masterfile), and Pharmetrics Claims data all representing patients enrolled in US commercial 
health plans, Medicare or Medicaid.  Plan enrollment information is available with these 
data.  The Optum PanTher database will also be used as it represents patients with both 
Optum claims data and Humedica EMR data, which includes a large database of terms 
extracted from EMR notes fields.  Sub-analysis specified will use wider structured data 
elements, such as reasons for treatment failure, which may be extracted from the EMR notes 
fields.  
Inclusion and exclusion criteria are detailed below in Sections 6.2.1 and 6.2.2. All patients 
meeting eligibility requirements will be included in the analyses. The resulting population is 
expected to be representative of patients with the types of insurance coverage available in the 
source databases.  The databases listed in Section 6.4 will be evaluated.  This protocol may 
also be amended to include additional databases over time.  
6.2.1. Inclusion Criteria
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:

Index date: The first prescription or administration of one of the medications 
indicated for advanced RCC recorded in the database between April 2018-March 31, 
2019, among those with no aRCC treatment in their history.

Age 18 years or older in the year of the index first line therapy prescription.  

2 or more RCC diagnoses (ICD-9: 189.0; ICD-10: C64.1, C64.2, C64.9) at least 
30 days apart, in the 1 year prior to the index date until 30 days post index date. 
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
2 or more code for secondary malignancy codes indicating possible diagnoses for 
metastatic disease at least 30 days apart, in the 1 year prior to the index date until 
30 days post index date. (ICD-9: xx-199.xx; ICD-10: C77-C79, except ICD9: 198.0 
Secondary malignant neoplasm of the kidney and ICD10: C79.0 Secondary malignant 
neoplasm of the kidney and renal pelvis).  

 
 

Continuous enrollment from 12 months prior to the index date.  Patients will be 
required to have continuous enrollment from their index date until the end of the 
available data. This will allow for sub-analysis of cohorts with 3 months, 6 months
and 12 months of available data.
6.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study: 

Received advanced treatment prior to the study index date.

Prescription records with negative days of supply will be excluded from all the 
analyses except in cost variable calculation. The day of supply for claims with 
missing or 0 days will be imputed.

Only one RCC diagnosis in the 12 months prior or one mont post index date.

Patients with data for analysis (<3 months post index date).
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6.3. Variables
6.3.1. Treatment Pattern Variables
Table 5.
Treatment Pattern Variables
Variable
Operational definition
Initial (1L)Treatment Regimen
The first treatment regimen prescribed following a primary and secondary diagnosis of 
advanced/metastatic disease.
Monotherapy vs Combo therapy
Categorical: Yes/No Combo therapy is defined by a second medication filled on or within 30 days of the 
original medication and the originical medication is filled subsequently.  
 
Time to FL treatment received
Continuous: days
Length of time (days) from the first mRCC diagnosis (first ever secondary malignancy code associated 
with RCC) to first line therapy prescription.
Treatment discontinuation date (by LoT) – to 
be used for time to treatment failure (TTF) 
and time to next line of therapy
Date
Treatment discontinuation indicating the end of LOT will be identified as the earliest of:

For oral therapy: to the run-out date of the last prescription (ie, date of last prescription plus 
days supply) in the same treatment line.

For non-oral therapy: 30 days after the last observed prescription/administration prior to at least 
a 30 day gap in therapy of all agents included in the first line of therapy.

1 day before a new prescription/administration date, whichever occurred earlier. 

For multiple drug regimens: the above would be triggered by the last 
prescription/administration in the regimen. 

Death.

End of enrollment.
Days of continuous treatment (by LoT)
Continuous: days
The duration of each LOT will be measured from the first prescription or administration of line of 
therapy medication(s) to the end of the line of therapy, allowing for 30 day allowable gaps in therapy.
Treatment Continuation
Categorical (Y/N) 
There is no >30 day gap (ie, persistent treatment) for the index medication during follow-up period.
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Variable
Operational definition
Treatment Interruption
Categorical (Y/N) At least one instance of >30 day gap (ie, non-persistent treatment) for the index 
medication during follow-up period or LOT followed by resuming therapy (not mutually exclusive with 
switch, augment, discontinuation, but a sub-group within LOT).
Interrupted treatment duration
Continuous: days
Time from index medication to treatment discontinuation for those within treatment interruptions (>30 
day gaps).  Represents the time between index and end of last treatment, including any treatment gaps.
Regimen change (switching)
Categorical: Yes/No
At least one non-index advanced/metastatic RCC medication during or after the period of the last 
persistent index medication prescription’s days supply plus the 30 day gap (and before re-initiation of 
index medication or follow-up, if after).
Regimen change (augmentation)
Categorical: Yes/No
Addition of treatment to initial therapy prescribed, ie, initiation of a new therapy different from the 
initial therapy while continuation of the initial therapy.
Line of therapy definitions
Categorical: 1L vs. 2L vs. >=3L.
Treatment sequence
Categorical: Based on observed treatment sequences.
Treatment Sequence – Sequence of successive therapies for mRCC from 1L to 2L to 3L (stop after 3L).
Patient’s status at end of follow-up
Categorical: end of enrollment, end of data availability, death.
Patient is in one of the following mutually exclusive categories at the end of follow-up.
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6.3.2. Baseline Variables
Table 6.
Baseline Variables
Variable
Operational definition
Baseline demographics 
Index Date
Date of first RCC diagnosis on record 
Index Year
Index year for the patient 
Age
Continuous: Years
Patient age at index date
Sex
Categorical: Male or female 
Insurance Coverage
Categorical: Commercial, Medicare, or Medicaid
US Region
Categorical: Northeast, Midwest, South, West
Race
Categorical: based on each database
Clinical characteristics
Time to systemic therapy 
<1 year
From IMDC: <1 year from time of diagnosis to systemic therapy
NCI Charlson 
comorbidity index (DCI)
Categorical: 0, 1-2, 3+
History of smoking
Categorical: Yes/No
Prior history of smoking – record of smoking cessation medication or V code.
History of systemic 
therapy
Categorical: Yes/No
A record of being given certain systemic drugs (interferon, interleukin 2, gemcitabine and doxorubicin)
History of surgical 
resection
Categorical: Yes/No 
History of nephron sparing or radical nephrectomy.
ICD-10-CM Z90.5/ICD-9-CM V45.73 Acquired absence of kidney.
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Variable
Operational definition
History of radiation 
therapy
Categorical: Yes/No
ICD-10-CM Z51.0/ICD-9-CM V58.0 Encounter for radiotherapy.
ICD-10-PCS › D › Urinary System:

DT0 Beam Radiation;

DT1 Brachytherapy;

DT2 Stereotactic Radiosurgery;

DTY Other Radiation.
CPT Codes:
77401
Radiation treatment delivery, superficial and/or ortho voltage, per day;
77402
Radiation treatment delivery, >1MeV; simple;
77407
intermediate;
77412
complex.
New Codes
77085
Dual-energy x-ray absorptiometry (DXA), bone density study, 1 or more sites; axial skeleton (eg, hips, pelvis, spine), 
including vertebral fracture assessment.
77086
Vertebral fracture assessment via dual energy X-ray absorptiometry (DXA).
77306
Teletherapy isodose plan; simple (1 or 2 unmodified ports directed to a single area of interest), includes basic dosimetry 
calculation(s).
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Variable
Operational definition
77307
complex (multiple treatment areas, tangential ports, the use of wedges, blocking, rotational beam, or special beam 
considerations), includes basic dosimetry calculation(s).
77316
Brachytherapy isodose plan; simple (calculation[s] made from 1 to 4 sources, or remote afterloading brachytherapy, 
1 channel), includes basic dosimetry calculation(s).
77317
intermediate (calculation[s] made from 5 to 10 sources, or remote afterloading brachytherapy, 2-12 channels), includes basic 
dosimetry calculation(s).
77318
Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple.
77385
Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple.
77386
complex.
77387
Guidance for localization of target volume for delivery of radiation treatment delivery, includes intrafraction tracking, when 
performed.
Deleted Codes (may be in the historic data, though no longer in use)
72291
Radiological supervision and interpretation, percutaneous vertebroplasty, vertebral augmentation, or sacral augmentation 
(sacroplasty), including cavity creation, per vertebral body or sacrum; under fluoroscopic guidance.
72292
under CT guidance.
74291
Cholecystography, oral contrast; additional or repeat examination or multiple day examination.
76645
Ultrasound, breast(s) (unilateral or bilateral), real time with image documentation.
76950
Ultrasonic guidance for placement of radiation therapy fields.
77080
Dual-energy X-ray absorptiometry (DXA), bone density study, 1 or more sites; axial skeleton (eg, hips, pelvis, spine).
77305
Teletherapy, isodose plan (whether hand or computer calculated); simple (1 or 2 parallel opposed unmodified ports directed 
to a single area of interest).
77310
intermediate (3 or more treatment ports directed to a single area of interest).
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Variable
Operational definition
77315
complex (mantle or inverted Y, tangential ports, the use of wedges, compensators, complex blocking, rotational beam, or 
special beam considerations).
77326
Brachytherapy isodose plan; simple (calculation made from single plane, 1 to 4 sources/ribbon application, remote 
afterloading brachytherapy, 1 to 8 sources).
77327
intermediate (multiplane dosage calculations, application involving 5 to 10 sources/ribbons, remote afterloading 
brachytherapy, 9 to 12 sources).
77328
complex (multiplane isodose plan, volume implant calculations, over 10 sources/ribbons used, special spatial reconstruction, 
remote afterloading brachytherapy, over 12 sources).
77403
Radiation treatment delivery, single treatment area, single port or parallel opposed ports, simple blocks or no blocks; 6-10 
MeV.
77404
11-19 MeV.
77406
20 MeV or greater.
77408
Radiation treatment delivery, 2 separate treatment areas, 3 or more ports on a single treatment area, use of multiple blocks; 
6-10 MeV.
77409
11-19 MeV.
77411
20 MeV or greater.
77413
Radiation treatment delivery, 3 or more separate treatment areas, custom blocking, tangential ports, wedges, rotational 
beam, compensators, electron beam; 6-10 MeV.
77414
11-19 MeV.
77416
20 MeV or greater.
77418
Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, 
binary, dynamic MLC, per treatment session.
77421
Stereoscopic X-ray guidance for localization of target volume for the delivery of radiation therapy.
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Variable
Operational definition
Location of metastasis
Categorical: by location (% of patients for each): 
Lymph nodes (ICD9-196.xx, ICD10 – C77)
Lung (ICD9-197.0x, ICD10-C78.00)
Liver (ICD9-197.7x, ICD10-C78.7)
Brain (ICD9-198.3x, ICD10-C79.31)
Bones (ICD9-198.5x, ICD10-79.5x)
Adrenal gland (ICD9-198.7x, ICD10-79.7)
Other (ICD9 196.xx-199.xx and ICD10 C77-C80
exclusive of above categories)
Severe renal impairment
Categorical: Yes/No
ICD-9: 588.89, 588.9, 593.9, 274.02, 274.03
ICD-10: M10.3x, M1A.3x, N25.89, N25.9
Moderate-to-severe 
hepatic impairment
Categorical: Yes/No
ICD-9: 571, 572, 573
ICD-10: K70.4x, K71.0, K71.1X, K72, K73, K75, K76, K77
Constipation
Categorical: Yes/No

ICD9 code: 564.0x; ICD10 code: K59.0
Nausea
Categorical: Yes/No
ICD9 code: 787.01; ICD10 code: R11.0, R11.2
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6.3.3. Outcomes Variables
Table 7.
Outcomes Variables
Variable
Operational definition
Days to Treatment 
Failure (TTF) 
Time to treatment failure (TTF) is defined as the time from therapy start to treatment discontinuation for any reason, including 
switched, augmented therapy, end of enrollment, death. 
Discontinuation
% discontinuing – those with gap in therapy greater than 30 days and who do not begin a new treatment.
Switching
% switching  – those with gap in therapy greater than 30 days and who begin a new treatment.
Augmentation
% augmenting – those who begin a new treatment but continue using the original treatment (have an additional administration or 
refill) and do not have a gap in therapy greater than 30 days of their original treatment.
% Survived 3,6, 12 
months
Mean/Median Survival Time (Days): Survival time will be described over 3,6, 12 months given follow-up time available in the data.
Overall survival is defined as the length of time from index date of RCC diagnosis to patient death (or index date associated
with FL Tx?) or end of available data for with no death indication.
Overall landmark survival: described and compared over follow-up time periods (3,6, 12 months).
Percentage of patients alive at 3,6, 12 months.
Overall Survival Time
Continuous: days
Overall survival is defined as the length of time from index date of RCC diagnosis to patient death (or index date associated with FL 
Tx?)
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6.3.4. Cost and Utilization Variables
Table 8.
Cost and Utilization Variables
Variable
Operational definition
All-cause Health Resource Utilization:
Total inpatient, ER, outpatient visits from index aRC
period.
Any healthcare resource use per patient per month (PPPM) will be examined for each regimen-based cohort
under each LOT and will further be categorized as the following: 
Occurrence of (Categorical: Yes/No):

any inpatient stay;

any outpatient visit;

any ER visit.
Number of visits (Continuous):

inpatient stays;

outpatient visits;

ER visits.
Inpatient LOS (Continuous: days).
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Variable
Operational definition
aRCC HR Utilization:
RCC-specific inpatient, ER, outpatient visits 
from aRCC therapy index through follow-up 
period.
RCC-related healthcare resource use per patient per month (PPPM) will be examined for each regimen-based c
under each LOT. 
Medical claims will be considered RCC-related if they have an ICD-9/10-CM diagnosis code for RCC
in any position on the claim.
Occurrence of (Categorical: Yes/No):

any inpatient stay;

any outpatient visit;

any ER visit.
Number of visits (Continuous):

inpatient stays;

outpatient visits;

ER visits.
Inpatient LOS (Continuous: days).
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Variable
Operational definition
All-cause Healthcare Costs
Overall medical costs and pharmacy costs 
from aRCC therapy index through follow-up.
Continuous: dollars
All-cause healthcare costs will be examined for each for each regimen-based cohort under each LOT. Costs w
adjusted to 2019 US dollars (USD) using the medical care component of the Consumer Price Index (CPI). He
costs PPPM will be provided, and will be further categorized as: 

Inpatient stay costs;

Outpatient costs;

ER visit costs;

Pharmacy costs (medical);

Pharmacy costs (pharmacy);

Total costs.
mRCC-related Healthcare Costs
RCC-specific pharmacy, medical costs from aRCC
therapy index through follow-up period
Continuous: dollars
aRCC therapy Pharmacy claims for medication used to treat RCC will be included in the pharmacy costs using
pharmacy claim data.
RCC-related healthcare costs will be examined for each regimen-based cohort under each LOT. 
Costs will be adjusted to 2019 US dollars (USD) using the medical care component of the Consumer Price Ind
Health care costs PPPM will be provided, and will be further categorized as: 

Inpatient stay costs;

Outpatient costs;

ER visit costs;

Pharmacy costs (medical claims);

Pharmacy costs (pharmacy claims);

Total costs (total pharmacy + total medical.
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6.4. Data Sources
Results will be replicated to the extent possible across various real world databases in order 
to confirming and validate results across data sources.  At the start of the study, four 
databases will be evaluated.  IBM’s Truven MarketScan Commercial, Optum Clinformatics, 
the IMS PharMetrics claims databases and The PanTher (which has both Humedica EMR 
data including EMR notes linked to Optum claims). After population sizes are assessed in 
the various databases, sub-analysis for populations with adequate patient data will be 
clarified in an amendment to this protocol.  
Optum Clinformatics:
Optum Clinformatics has access to a proprietary research database containing claims and 
enrollment data dating back to 1993 with the opportunity to link patient and physician survey 
data to pharmacy and medical claims, medical record data, socioeconomic measures, and 
clinical laboratory results on over 123 million lives. Underlying information is 
geographically diverse across the United States, and is updated frequently. The research 
activities utilize de-identified data from the research database except in limited instances 
where applicable law allows the use of patient identifiable data.
Claims for pharmacy services are typically submitted electronically by the pharmacy at the 
time prescriptions are filled. The claims history is a profile of all outpatient prescription 
pharmacy services provided and covered by the health plan. Pharmacy claims data include 
drug name, dosage form, drug strength, fill date, days of supply, financial information, and 
de-identified patient and prescriber codes, allowing for longitudinal tracking of medication 
refill patterns and changes in medications. Pharmacy claims are typically added to the 
research database within 6 weeks of dispensing.
Medical claims or encounter data are collected from all available health care sites (inpatient 
hospital, outpatient hospital, emergency room, physician's office, surgery center, etc.) for 
virtually all types of provided services, including specialty, preventive and office-based 
treatments. Medical claims and coding conform to insurance industry standards. Claims for 
ambulatory services submitted by individual providers, eg, physicians, use the HCFA-1500 
format. Claims for facility services submitted by institutions, eg, hospitals, use the UB-82 or 
UB-92 format. Medical claims include: multiple diagnosis codes recorded with the 
ICD-9-CM diagnosis codes; procedures recorded with ICD-9-CM procedure codes, Current 
Procedural Terminology (CPT), or Health Care Financing Agency (HCFA) Common 
Procedure Coding System (HCPCS) codes; site of service codes; provider specialty codes; 
revenue codes (for facilities); paid amounts; and other information. Typically, facility claims 
do not include any drugs administered in hospital. Approximately 6-9 months following the 
delivery of services is required for complete medical data, therefore patients will be followed 
for this additional time period. In summary, the analysis window will include data from 
24 months pre index date, and 24 months post index date.
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Integrated Optum E.H.R and Claims (PanTher)
Integrated Optum E.H.R. (formerly Humedica) clinical data and Optum Clinformatics 
administrative claims data (United enrollees) are included in the Optum PanTher Database.
Estimated to be approximately 15% of the Optum Claims lives are represented in this 
database. This asset combines the clinical specificity of the Optum E.H.R. data with the 
administrative claims data which includes cost data, pharmacy fill data, and enrollment time 
periods among other things.
The Optum EHR database has broad geographic representation and includes patient 
demographic and clinical information, including diagnosis, medications, labs, procedures, 
microbiology and biomarkers.  Optum EHR also extracts data from physician notes using 
industry-leading Natural Language Processing (NLP).
The Optum EHR database includes patient records from multiple EMR systems which 
capture data from different sites of care and a full spectrum of inpatient and outpatient 
treatment (eg, both Written Prescription and Inpatient-Administered medications).  Records 
are completely de-identified and are fully compliant with the Health Insurance Portability 
and Accountability Act (HIPAA). Data is sourced from large Integrated Delivery Networks 
(IDN) with over 60% of patients having both outpatient and hospital information. The 
remainder of the patients are from large multi-specialty physician practices. 
Outpatient laboratory test results are available for subpopulations of the research database.
Standard Logical Observation Identifiers Names and Codes (LOINC) coding is used to 
define specific tests and results. Test results data can be linked to the other health care 
utilization and pharmacy claims data in the research database. Results included in the 
database are typically from blood-based tests (eg, low-density lipoprotein, glycated 
hemoglobin levels) that are sent for processing to two of the largest laboratory facilities in 
the country. Data are available for approximately 30-40% of members who were 
administered the test, depending on the test.
Truven Marketscan Commercial:
The MarketScan data warehouse is a family of databases from commercially insured lives. 
Pfizer licenses the following data sources: healthcare claims, hospital drug/discharge 
information with links to claims data and Medicare Supplemental files.  The Truven Health 
MarketScan Research Databases reflects the combined healthcare service use of individuals 
covered by Truven Health clients (including employers, health plans, and hospitals) 
nationwide. Truven Health builds databases comprise the healthcare experience of the 
clients’ covered populations, as well as information about the populations themselves and the 
providers that serve them. MarketScan Research Databases provide detailed cost, utilization, 
and outcomes data for healthcare services performed in both inpatient and outpatient settings. 
In the claims databases, the medical services are linked to outpatient prescription drug claims 
and person-level enrollment data using unique enrollee identifiers.
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The MarketScan Commercial Database contains the healthcare experience of privately 
insured individuals. Coverage is provided under a variety of fee-for-service, fully capitated, 
and partially capitated health plans, including preferred provider organizations, point of 
service plans, indemnity plans, and health maintenance organizations.
The Enrollment Detail Table provides a single record per month of enrollment for each 
enrollee, with detailed demographic information.
Claims are not included in the database until they have been adjudicated; there is a lag of 
approximately six months after the close of a calendar year or a quarter between services 
provided and their inclusion in the Research Databases. However, the Early View Database 
has a 90-day lag that includes paid amounts for 100 percent of prescription drugs, 
approximately 85 percent of physician office visits, and approximately 70 percent of hospital 
claims. The MarketScan Early View Database includes all of the components found in the 
standard MarketScan Commercial and Medicare Supplemental Databases. It includes 
standardized inpatient, outpatient, pharmaceutical, and health-plan enrollment data. The 
MarketScan Early View Database captures healthcare services incurred up to 90 days before 
data release and includes only adjudicated claims. However, the medical component of care 
for some patients will not be complete, since some claims (particularly inpatient claims) take 
longer to be adjudicated. Because this study is examining only comorbidities prior to and 
treatments during or prior to glasdegib initiation fully adjudicated claims are not required and 
all available data will be used including Commercial, Medicare Supplemental, and Early 
View Databases.
Pharmetrics Plus
The PharMetrics Plus database is comprised of fully adjudicated medical and pharmacy 
claims. Specifically, it contains a longitudinal view of inpatient and outpatient services, 
prescription and office/outpatient administered drugs, costs and enrollment information. 
With PharMetrics Plus, you can track an enrolled patient across all sites of care: hospital, 
specialist, emergency room, pharmacy, primary care, ambulatory, and more.
There are over 140 million unique enrollees with both medical and pharmacy benefits. The 
enrollee population in the PharMetrics Plus database is generally representative of the under 
65 commercially insured population in the US with respect to both age and gender. We have 
over 10 million enrollees who are over 65 years of age. Longitudinal enrollment range of 
individuals in the database on average is 36 months and more than 42 million patients have 
3 or more years of continuous enrollment.
The PharMetrics Plus database offers a diverse representation of payer types, provider 
specialties, geographic granularity and linking capabilities. Patient region and state are 
standard patient variables and zip3 is optional and available for a subset of patients. Provider 
identification is an optional variable and available for a subset of providers using the 
National Provider Identifier. Patient linking is achieved by leveraging IQVIA’s patented 
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technology for the subset of patients assigned a unique, encrypted patient key in multiple 
databases. Please note that there can be limits to the provisioning of the combination of 
some variables when linking is enabled.
Commercial insurance is the most frequent plan type captured for the enrollee population but 
other types are also found, including Commercial Medicare, Commercial Medicaid, 
Self-Insured, Indemnity and Others. In addition to standard fields such as inpatient and 
outpatient diagnoses and procedures, retail and mail order prescription records, PharMetrics 
Plus has detailed information on the pharmacy and medical benefit (copayment, deductible), 
the inpatient stay and provider details (provider specialty included in all extracts). Economic 
variables include the negotiated rate between the plan and providers (allowed) and the actual 
amount paid by health plans to the provider for all services rendered. Charge amount is also 
available for a subset of claims. Other data elements include dates of service, demographic 
variables (age, gender, and geographic region), product type (eg, HMO, PPO), payer type 
(eg, commercial), and start and stop dates of health plan enrollment. All data are HIPAA 
compliant to protect patient privacy.
While the most recent release of the PharMetrics Plus database is typically used to create all 
client deliverables, there may be a 4-6 month lag with newer claims largely owing to the 
typical processing time for claims adjudication mentioned above.
6.5. Study Size
The sample size for this study is fixed by the duration of the observation window. No formal 
sample size computation was performed as it is not applicable for this observational study. 
All patients who meet the entry criteria will be included in the analyses.
6.6. Data Management
All databases used in this study comply with both the spirit and the letter of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). These databases meet the 
criteria for a limited-use dataset and contain none of the data elements prohibited by HIPAA 
for limited-use datasets. Tables will be regenerated on a periodic basis based on scheduling 
of database updates and refreshes.  This study will use a combination of analytical tools, 
Boston Health Economic’s Instant Health Data (IHD) tool, with ad hoc programming 
performed using SAS software, version 9.4 (SAS Institute Inc, Cary, NC) or R software for 
statistical computing and graphics supported by the R Foundation for Statistical Computing.
6.6.1. Record Retention
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study. 
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6.7. Data Analysis 
The planned statistical methods to be used in this study are descriptive and are specified in 
this section.  No separate Statistical Analysis Plan is required.
Descriptive statistics will be used to report all study variables including demographic and 
clinical characteristics and treatment patterns.  Categorical variables will be summarized 
using frequency counts and percentages.  Continuous and cost variables will be summarized 
using means, medians, and standard deviations, minimum, maximum, 25th percentile, and 
75th percentiles for the 3 cohorts with corresponding 3, 6 and 12 month follow-up periods.  
Summary cost metrics will be calculated using the entire population as the denominator, 
including those not reporting costs as having 0 costs.  Standardized differences, defined as 
the absolute difference in sample means divided by an estimate of the pooled standard 
deviation of the variable, will be calculated for each variable. Additionally, costs and event 
rates per patient per month (PPPM) will be reported.  Kaplan-Meier curves will be generated 
to examine time-to-event variables (duration of therapy and survival).
Duration of therapy calculations, which hinge on how frequently each of the medications 
considered are administered for injectibles, and days of supply represented by a prescription 
for orals will necessitate imputation of days of supply for medications with days supply 
values which do not represent the number of expected days between administrations or 
refills.  The following imputations will be performed for the medications of interest to allow 
for treatment patterns and duration of therapy. 
Table 9.
Imputations of Days Supply
Ingredient
Route of Administration
Imputed 
Days 
Supply
Temsirolimus
Both oral and IV
7
Everolimus
Both oral and IV
28
Ipilimumab
Injection/Oral
21
Nivolumab
Injection/Oral
28
Atezolizumab
Injection 
21
Durvalumab
Injection 
28
Pembrolizumab
Injection 
21
Avelumab
Injection/Oral
14
Bevacizumab
Injection/Oral
14
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6.8. Quality Control
This is a retrospective study, so issues of quality control at study sites, eg, data queries, do 
not apply. Analyses are programmed according the specifications in the protocol, and if 
applicable, the statistical analysis plan and documented in a programming plan. Final 
deliverables are reviewed and verified by a second, independent data scientist using IHD.  
All quality checks will be documented.
6.9. Limitations of the Research Methods
When using claims and secondary databases as data sources for comparative analyses, 
several limitations may exist. Patients are not randomized to treatment, which may cause 
confounding. Multivariate analyses or matching techniques, such as propensity score 
matcing, can be used to address this confounding. It is difficult to assess disease severity, 
stage, and disease progression using claims data alone. As such, electronic medical records 
and specialty oncology data sources such as Concerto or Flatiron will be used when available 
to assess and supplement claims information on these factors. Additionally, claims may 
contain incomplete and inaccurate data on days supply and dosage of prescriptions, which 
may affect persistence and dosage change evaluations. Finally, there may be errors in claims 
coding, which may affect analyses and patient counts. No causal inference can be made in an 
observational study, and findings may not be generalizable to other populations. 
6.10. Other Aspects
Not applicable.
7. PROTECTION OF HUMAN SUBJECTS 
7.1. Patient Information 
This study involves data that exist in anonymized structured format and contain no patient 
personal information.  
7.2. Patient Consent
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required.
7.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
This study does not require IRB approval.
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7.4. 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 for 
retrospective observational studies, described in Guidelines for Good Pharmacoepidemiology 
Practices (GPP) issued by the International Society for Pharmacoepidemiology (ISPE), Good 
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR), and the GRACE (Good ReseArch for Comparative 
Effectiveness) Principles.
8. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves claims and EMR 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.
9. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
For all publications relating to the Study, Pfizer will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
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10. REFERENCES
1.
Hagiwara M, Borker R, Oster G. Economic burden of adverse events in patients with 
metastatic renal cell carcinoma. Clin Ther. 2013;35(12):1955-63.e2. 
2.
American Cancer Society: Cancer Facts and Figures 2019. Atlanta, GA: American 
Cancer Society; 2019. Available from: 
http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2012/index. 
Accessed July 11, 2019. 
3.
Borker R. Costs associated with adverse events in patients with metastatic renal cell 
carcinoma. J Med Econ. 2014;17(11):792-7. Drugs@FDA.
4.
Zarrabi K, Fang C, Wu S. New treatment options for metastatic renal cell carcinoma 
with prior anti-angiogenesis therapy. J Hematol Oncol. 2017;10(1):38.
5.
Tontonoz, M. (2015, October 1). In a First, FDA Approves Immunotherapy 
Combination for Advanced Melanoma. Retrieved July 12, 2019, from 
https://www.cancerresearch.org/blog/october-2015/fda-approves-immunotherapy-
combination-melanoma.
6.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed January 11, 2012. 
7.
Hess G, Borker R, Fonseca E. Treatment patterns: targeted therapies indicated for first-
line management of metastatic renal cell carcinoma in a real-world setting. Clin 
Genitour Cancer. 2013;11(2):161.
8.
Heng DY, Xie W, Regan MM, 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. J Clin Oncol 2009;27:5794-
5799.
9.
Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for 
clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncolb 
2002;20:289-296.
10.
NCCN (National Comprehensive Cancer Care Network). 2019 NCCN Guidelines for 
Kidney Cancer. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. 
Assessed on July 13, 2019.
11.
US Food and Drug Administration. (2018). FDA approves nivolumab plus ipilimumab 
combination for intermediate or poor-risk advanced renal cell carcinoma.
12.
Powles T, Albiges L, Staehler M, Bensalah K, Dabestani S, Giles RH, Hofmann F, Hora 
M, Kuczyk MA.
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13.
Lang K, Danchenko N, Gondek K, Schwartz B, Thompson D. The burden of illness 
associated with renal cell carcinoma in the united states. Urol Oncol. 
2007;25(5):368-375. doi: S1078-1439(07)00100-7 [pii]. 
14.
Pfizer Inc. Data on File.
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11. LIST OF TABLES 
Table 1.
Abbreviations..............................................................................................7
Table 2.
Principal Investigator(s) of the Protocol.....................................................9
Table 3.
Amendments and Updates........................................................................10
Table 4.
Medicaitons of Interest .............................................................................15
Table 5.
Treatment Pattern Variables .....................................................................19
Table 6.
Baseline Variables ....................................................................................21
Table 7.
Outcomes Variables..................................................................................26
Table 8.
Cost and Utilization Variables..................................................................27
Table 9.
Imputations of Days Supply .....................................................................34
12. LIST OF FIGURES
Figure 1: Cohort Identification ................................................................................................14
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ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
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ANNEX 2. ADDITIONAL INFORMATION
Comorbidities
ICD-9-CM Codes
ICD-10-CM Codes
Quan CCI comorbidities (Quan 2005)
AIDS
042.x–044.x
B20.x–B22.x, B24.x
Any malignancy
140.x–172.x, 174.x–195.8,
200.x–208.x, 238.6
C00.x–C26.x, C30.x–C34.x, C37.x–
C41.x, C43.x, C45.x–C58.x, C60.x–
C76.x, C81.x–C85.x, C88.x,
C90.x–C97.x
Cerebrovascular disease
362.34, 430.x–438.x
G45.x, G46.x, H34.0, I60.x–I69.x
Chronic pulmonary disease
416.8, 416.9, 490.x–505.x,
506.4, 508.1, 508.8
I27.8, I27.9, J40.x–J47.x, J60.x–J67.x,
J68.4, J70.1, J70.3
Congestive heart failure
398.91, 402.01, 402.11, 402.91,
404.01, 404.03, 404.11,
404.13, 404.91, 404.93,
425.4–425.9, 428.x
I09.9, I11.0, I13.0, I13.2, I25.5, I42.0,
I42.5–I42.9, I43.x, I50.x, P29.0
Dementia
290.x, 294.1, 331.2
F00.x–F03.x, F05.1, G30.x, G31.1
Diabetes with complications
250.4–250.7
E10.2–E10.5, E10.7, E11.2–E11.5,
E11.7, E12.2–E12.5, E12.7, E13.2–
E13.5, E13.7, E14.2–E14.5, E14.7
Diabetes without chronic complications
250.0–250.3, 250.8, 250.9
E10.0, E10.1, E10.6, E10.8, E10.9,
E11.0, E11.1, E11.6, E11.8, E11.9,
E12.0, E12.1, E12.6, E12.8, E12.9,
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