REAL-WORLD TUMOR RESPONSE OF PALBOCICLIB IN COMBINATION WITH AN AROMATASE INHIBITOR AS FIRST-LINE THERAPY IN PRE/PERIMENOPAUSAL WOMEN WITH METASTATIC BREAST CANCER
Conditions: Metastatic Breast Cancer
Sponsor: Pfizer

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Study Information
Title
Real-World Tumor Response of Palbociclib in 
Combination With an Aromatase Inhibitor as 
First-Line Therapy in Pre/perimenopausal Women 
With Metastatic Breast Cancer 
Protocol number
A5481159
Protocol version identifier
FINAL Version 1.0
Date 
21 December 2020
Active substance
Palbociclib (IBRANCE®; PD-0332991)
Medicinal product
Palbociclib (IBRANCE®; PD-0332991)
Research question and objectives
Primary objective
•
To estimate real-world response rate (rwRR) for 
pre/perimenopausal patients treated with 
palbociclib + AI compared to AI alone as 
first-line therapy for HR+/HER2– MBC.
Author
, Pharm.D.,
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD
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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................4
3. RESPONSIBLE PARTIES....................................................................................................6
4. ABSTRACT...........................................................................................................................6
5. AMENDMENTS AND UPDATES.......................................................................................6
6. MILESTONES.......................................................................................................................6
7. RATIONALE AND BACKGROUND..................................................................................7
8. RESEARCH QUESTION AND OBJECTIVES .................................................................12
9. RESEARCH METHODS ....................................................................................................12
9.1. Study Design ...........................................................................................................12
9.2. Setting......................................................................................................................13
9.2.1. Inclusion Criteria ........................................................................................13
9.2.2. Exclusion Criteria.......................................................................................14
9.3. Variables..................................................................................................................15
9.4. Data Source .............................................................................................................26
9.4.1. Patient Selection .........................................................................................27
9.5. Study Size................................................................................................................28
9.6. Data Management ...................................................................................................28
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic 
Data Record .....................................................................................................30
9.6.2. Record Retention ........................................................................................30
9.7. Data Analysis ..........................................................................................................31
9.7.1. Statistical Hypotheses.................................................................................31
9.7.2. Sample Size Determination ........................................................................31
9.7.3. Cohort for Analysis.....................................................................................31
9.7.3.1. Propensity Score Matching (PSM)............................................31
9.7.3.2. Analyses of Primary Endpoint ..................................................32
9.7.3.3. Sensitivity Analyses ..................................................................33
9.7.3.4. Subgroup Analyses....................................................................34
9.7.3.5. Other Analyses ..........................................................................34
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9.7.3.6. Analyses of AEs of Special Interest..........................................34
9.8. Quality Control........................................................................................................34
9.9. Limitations of the Research Methods......................................................................38
9.9.1. Internal Validity of Study Design...............................................................38
9.9.2. External Validity of Study Design..............................................................39
9.9.3. Analysis Limitations...................................................................................39
9.9.4. Limitations Due to Missing Data and/or Incomplete Data.........................39
9.9.5. Real-World Tumor Response .....................................................................39
9.10. Other Aspects ........................................................................................................40
10. PROTECTION OF HUMAN SUBJECTS ........................................................................40
10.1. Patient Information................................................................................................40
10.2. Patient Consent......................................................................................................41
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............41
10.4. Ethical Conduct of the Study ................................................................................41
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS ......................................................................................42
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........43
13. REFERENCES ..................................................................................................................44
14. LIST OF TABLES.............................................................................................................48
15. LIST OF FIGURES ...........................................................................................................48
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.........................................................49
ANNEX 2. ADDITIONAL INFORMATION.........................................................................49
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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
1L
first line
ABC
advanced breast cancer
AE
adverse event
AEM
Adverse Event Monitoring
AI
aromatase inhibitor
AIDS
acquired immune deficiency syndrome
ASCO
American Society of Clinical Oncology
BC
breast cancer
BRCA
breast cancer susceptibility protein gene
CBR
clinical benefit rate
CCI
Charlson comorbidity index
CDK
cyclin-dependent kinase
CI
confidence interval
CR
complete response
CRF
case report form
DCT
data collection tool
DEI
Data, Evidence and Insight
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ER
estrogen receptor
ET
endocrine therapy
EHR
electronic health record
FDA
Food and Drug Administration
FISH
fluorescence in situ hybridization
FSH
follicle-stimulating hormone
FUL
fulvestrant
GOS
goserelin
GPP
Good Pharmacoepidemiology Practices
HER
human epidermal growth factor receptor
HIPPA
Health Insurance Portability and Accountability Act
HITECH
Health Information Technology for Economic and Clinical Health
HIV
human immunodeficiency virus
HR
hormone receptor or hazard ratio
ICD
International Classification of Diseases
IEC
Independent Ethics Committee
IHC
immunohistochemistry
iKM
iKnowMed
ILD
interstitial lung disease
IPTW
inverse probability treatment weighting 
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Abbreviation
Definition
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and Outcomes Research
ITT
intent-to-treat
IV
instrumental variable
LADMF
Limited Access Death Master File
LHRH
luteinizing hormone releasing hormone
LOT
line of therapy
MBC
metastatic breast cancer
NDI
National Death Index
NE
not evaluated; not estimable
NGS
next generation sequencing
NIS
non-interventional study
NOS
not otherwise specified
NSAI
non-steroidal aromatase inhibitor
OR
odds ratio; outcomes researcher
ORR
objective response rate
OS
overall survival
p
p-value
PALOMA
PALbociclib Ongoing Trials in the MAnagement of Breast Cancer
PASS
Post Authorization Safety Study
PBO
placebo
PD
progressive disease
PFS
progression-free survival
PR
progesterone receptor; partial response
PS
propensity score 
PSM 
propensity score matching
QC
quality control
RCT
randomized controlled trial
RECIST
Response Evaluation Criteria in Solid Tumours
rwPFS
real-world progression-free survival
rwRR
real-world response rate
rwTR
real-world tumor response
SAP 
Statistical Analysis Plan 
SD
standard deviation; stable disease
SSDI
Social Security Death Index
SSN
social security number
TMN
Tumor, Node, Metastasis
US
United States
USON
US Oncology Network
USPI
United States Package Insert
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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, Degree(s)
Job Title
Affiliation
Address
, MD
 
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
Clinician, 
Pfizer Global Product 
Development, Oncology
10555 Science Center Drive
San Diego, CA  92121
, MS
, 
Pfizer Global Product 
Development, Oncology
10555 Science Center Drive
San Diego, CA, 92121
, Pharm.D.
 
, 
 
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
, MBA, 
MA
 
 
Pfizer Oncology
235 E 42nd Street
New York, NY, 10017
, MPH
 
 
, 
MDCM
, 
 
 
4. ABSTRACT
Not applicable.
5. AMENDMENTS AND UPDATES
None.
6. MILESTONES
Milestone
Planned Date
Start of data collection (analyses for primary objectives)
1Q2021
Start of data collection (analyses for other objectives)
1Q2021
End of data collection
2Q2021
Final study report
4Q2021
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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PPD
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7. RATIONALE AND BACKGROUND
Breast cancer (BC) is the most common cancer in women and the second leading cause of
cancer deaths. Currently, the average risk of a woman in the United States (US) developing 
breast cancer sometime in her life is about 13% with 276,480 new cases of invasive BC and 
42,170 deaths from BC expected this year in the US. At this time there are more than
3.5 million women living with a history of BC in the US including women who are still being 
treated (Miller et al, 2016).21 In the US, women under the age of 50 years-old comprise 
20% of all BC diagnoses (Siegel et al, 2017; DeSantis et al, 2017)29,8 and young women with 
hormone receptor-positive (HR+) disease are seeing an annual increase of over 8% yearly 
from 1992-2009 (Shah et al, 2020).28 In 2017, it was estimated that 154,794 women in the 
US were living with metastatic BC (MBC); of these 3 out of 4 progressed from an early stage 
BC (Mariotto et al, 2017).19 MBC remains an incurable disease with 5-year survival rates of 
27% (American Cancer Society Facts and Figures, 2020)1 with young women presenting
with more aggressive disease than those who are postmenopausal (Shah et al, 2020).28
HR+ BC is the most commonly diagnosed subtype (approximately 70-80%) (Kumler et al, 
2016).16 The goal of treatment for MBC is to prolong the time to disease progression or 
extend life to the extent possible or improve/maintain quality of life of that survival (Tanguy 
et al, 2018).31
Palbociclib, an oral CDK4/6 inhibitor, is approved for HR+/HER2– advanced or MBC in 
combination with an aromatase inhibitor (AI) or fulvestrant. Palbociclib was approved in the 
US based on improved median progression-free survival (PFS) demonstrated in 3 pivotal 
clinical trials: PALOMA-1 and PALOMA-2 (initial endocrine-based therapy in combination 
with letrozole for advanced disease) and PALOMA-3 (in combination with fulvestrant after 
progression on or after prior endocrine therapy). An accelerated approval was first granted 
based on results from the Phase 2 PALOMA-1 trial (Finn et al, 2015)11 in February 2015.
The median PFS in the palbociclib and letrozole arm was 20.2 months versus 10.2 months in 
the letrozole only arm (hazard ratio [HR] = 0.488, 95% confidence interval [CI]: 0.319, 
0.748; 1-sided p=0.0004).
Palbociclib in combination with fulvestrant was approved 1 year later (February 2016) in pre 
or postmenopausal women with disease progression following endocrine therapy based on 
results from the PALOMA-3 trial (Turner et al, 2015; Cristofanilli et al, 2016)33,6 which 
showed a statistically significant improvement in the median PFS for the palbociclib 
+ fulvestrant arm compared with placebo + fulvestrant arm (11.2 versus 4.6 months,
respectively; HR = 0.50 [95% CI: 0.40, 0.62; p<0.001]). Final overall survival (OS) data 
from that study has been reported (Turner et al, 2018)34 demonstrating median OS of 
34.9 months versus 28 months in the palbociclib + fulvestrant arm versus the placebo 
+ fulvestrant arm (HR = 0.81; 95% CI; 0.64, 1.03; 1-sided p=0.0249), which was not 
statistically significant.
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The Phase 3 PALOMA-2 study confirmed the findings from the PALOMA-1 trial, 
demonstrating a median PFS in the palbociclib + letrozole arm of 24.8 months compared to 
14.5 months in the placebo + letrozole arm (HR = 0.58; 95% CI: 0.46, 0.72; 1-sided p<0.001) 
(Finn et al, 2016).12 Subgroup PFS analyses according to stratification factors and 
demographic characteristics or prognostic factors revealed consistent results in PALOMA-2 
(Finn et al, 2016)12 and PALOMA-3 trials (Turner et al, 2015; Cristofanilli et al, 2016)33,6 in 
all subgroups. The objective response rate (ORR) from PALOMA-2 was 42.1% (95% CI:
37.5, 46.9) in the palbociclib group versus 34.7% (95% CI: 28.4, 41.3) in the placebo group 
(odds ratio [OR]=1.40 [95% CI: 0.98, 2.01], p=0.06). Of note, pre/perimenopausal women 
were not included in the PALOMA-1 or -2 trials investigating palbociclib + letrozole as 
first-line treatment for women with ER+/HER2- advanced disease. The PALOMA-3 study 
investigating palbociclib + fulvestrant did include pre or perimenopausal women, and the 
study evaluated patients who were considered endocrine resistant. The subgroup of 108/521
(21%) pre or perimenopausal women randomized to palbociclib + fulvestrant + goserelin 
versus placebo + fulvestrant + goserelin showed a statistically longer median PFS of 
9.5 months versus 5.6 months, respectively (HR = 0.50; 95% CI: 0.29, 0.87) (Figure 1)
(Loibl et al, 2017).17 The ORR in this subgroup was 25% versus 11% (OR: 3.06; 95% CI: 
0.82, 13.38) and the clinical benefit rate (CBR) was 69.4% and 44.4% (OR: 2.89; 95% 
CI: 1.15, 7.34), respectively (Loibl et al, 2017).17 The safety profile from the PALOMA-2 
and -3 trials were consistent, with no new safety signals identified across the Phase 3 studies.
Long-term pooled safety analyses of the 3 randomized Phase 2 and 3 studies demonstrated no 
evidence of specific cumulative or delayed toxicities with palbociclib + endocrine therapy
(Dieras et al, 2018; Finn et al, 2019).9,13 The most frequently reported adverse event (AE) of 
palbociclib was neutropenia, which could be managed with dosing interruption and/or dose 
reduction. 
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Figure 1.
PALOMA-3 Subgroup Analysis by Menopausal Status 
Source: CSR A5481023.
*Data cutoff: 16 March 2015; overall ITT population.
FUL = fulvestrant; GOS = goserelin; ITT = intent-to-treat; NE = not estimable; PAL = palbociclib;
PBO = placebo; PFS = progression-free survival.
 
 
Furthermore, in the MONALEESA 7 randomized 
controlled trial (RCT), ribociclib, another approved CDK 4/6 inhibitor, in combination with a 
non-steroidal aromatase inhibitor (NSAI) demonstrated a significant median PFS benefit 
(23.8 versus 13.0 months; HR = 0.55; 95% CI: 0.44, 0.69; p<0.0001) in patients treated with 
ribociclib plus endocrine therapy (ET) versus ET alone (Tripathy et al, 2018).32 Similar 
results were demonstrated in the NSAI combination subgroup excluding tamoxifen patients 
(27.5 versus 13.8 months and HR = 0.57 [95% CI: 0.44, 0.74]; n = 495). OS benefit in the 
pre or perimenopausal patient population treated with ribociclib + NSAI was also statistically 
significant, with median OS of not estimable (NE) versus 42 months in the AI subgroup 
population (HR = 0.70; 95% CI: 0.50, 0.98) (Im et al, 2019).15 The recently published FDA
pooled analysis of CDK 4/6 inhibitor treatment for patients with HR+/HER2– advanced or 
MBC, reported for patients aged 40 years and under who were treated with a CDK 4/6 
inhibitor in combination with an AI in first-line, showed an HR = 0.50 (95% CI: 0.34, 0.74) 
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for PFS with a median of 19.8 versus 11.2 months, respectively (Figure 2) (Gao et al, 
2020).14 Lastly, results from the Phase 2 Young-PEARL study examined palbociclib and 
exemestane (and leuprolide) (n=92) versus capecitabine (n=86) in premenopausal women 
with advanced or metastatic HR+/HER2– BC with a primary endpoint of PFS. Median PFS 
in the palbociclib combination arm was 20.1 months versus 14.4 months in the capecitabine 
arm (95% CI: 14.2, 21.8) with HR = 0.659 (95% CI: 0.44, 0.10); 1-sided p=0.024. There was 
an ORR of 37% (34/92 patients) in the palbociclib group and 34% (29/86 patients) in the 
capecitabine group which achieved an objective response (p=0.781). The CBR differed 
between the groups, but the difference did not reach statistical significance (80.4% versus 
69.9%, p=0.105) (Park et al, 2019).22
Figure 2.
Progression-Free Survival for Patients ≤40 Years of Age in Pooled Studies of 
CDK 4/6 Inhibitors
Source: Gao et al, 2020.14
Understanding the effectiveness of new treatments in diverse clinical practice as a 
complement to RCT data is important as this provides evidence of the clinical benefit of 
these treatments in a more heterogeneous population with comorbid conditions and variations 
in care delivery seen in routine clinical practice. Since its approval in February 2015, 
palbociclib has rapidly become the standard of care in the treatment of HR+/HER2-
advanced breast cancer (ABC) and is globally available commercially. Palbociclib has been 
available for use in the US for over 5 years with over 315,000 patients treated worldwide and 
nearly 130,000 in the US as of June 2020 making it possible to study comparative 
effectiveness in a large and diverse US HR+/HER2– MBC population. 
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Real world (rw) assessment has also been shown to be feasible and meaningful. Analysis of 
data for patients with MBC has been conducted to show that clinically meaningful 
information can be derived from the assessment of real-world progression-free survival 
(rwPFS) and real-world tumor response (rwTR) based on electronic health record (EHR) data 
abstraction when proper quality controls and analytic methods are incorporated based on 
concordance shown between RCTs and rw data. Concordance of rwPFS and real world tumor 
response (rwTR) from the US EHR with RCT data in MBC was recently demonstrated in a 
retrospective analysis comparing the PALOMA-2 trial letrozole + placebo control arm 
population cohort with a corresponding real-world cohort of US MBC patients treated with 
letrozole alone indicating the potential for real-world data to provide clinically consistent 
outcomes information (Bartlett et al, 2020).3  
Real-world effectiveness for palbociclib combination therapy has been reported through 
retrospective analysis; however, follow-up has been limited. In a single-arm retrospective 
chart review, the palbociclib + AI treatment, landmark analyses showed that 84.1% of 
patients were progression-free and 95.1% were alive at 12 months with an ORR of 
79.5% (Taylor-Stokes et al, 201930 Real world effectiveness of palbociclib + letrozole versus 
letrozole alone on rwPFS and OS was evaluated as an exploratory objective in a HR+/HER2–
US MBC population (pre and postmenopausal patients) (DeMichele et al, 2019).7 This study 
analysis suggests an associated rwPFS and OS benefit for palbociclib in combination with 
letrozole versus letrozole alone in 772 patients and 658 patients, respectively (464 in each 
propensity score matched group). The HR for PFS was 0.54 (95% CI: 0.46, 0.65; p<0.0001)
and HR for OS was 0.58 (95% CI: 0.46, 0.73; p<0.0001) in the propensity score matched 
population. Tumor response was not reported in this analysis. In the subgroup of younger 
patients (patients aged 18-50 years), a benefit in OS was seen in patients treated with 
palbociclib + letrozole versus letrozole alone with a HR = 0.40 (95% CI: 0.13, 1.20);
however, the sample sizes, (n=37 and n= 31, respectively) were limited. Another analysis of
the EHR database assessed comparative real-world tumor response (rwTR) in a cohort of 
HR+/HER2– MBC patients receiving palbociclib + letrozole versus letrozole alone who had 
at least 1 tumor assessment postbaseline. rwTR was assessed using the treating physicians’ 
clinical assessment of changes in disease burden based on radiologic scans. In 430 propensity 
score matched patients (215 in each group), patients were more likely to respond to first-line 
palbociclib + letrozole than letrozole alone after propensity score matching (PSM) with a 
real-world best tumor response (defined as patients with a complete response or partial 
response) of 58.6% versus 39.1%, respectively; OR = 2.2 (95% CI: 1.5, 3.2), p<0.0001). In 
the same PSM-matched patients, a consistent benefit was demonstrated in additional 
effectiveness endpoints in the palbociclib combination arm with respect to PFS with a 
HR = 0.60 (95% CI: 0.46, 0.79), p=0.0002) and OS with a HR = 0.58 (95% CI: 0.39, 0.85;
p=0.0052) (Brusfky et al, 2020).4
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This would be consistent with current guidelines category 1 
recommendation for use of any CDK 4/6 inhibitor drug in this class (National 
Comprehensive Cancer Network, 2020).25
The study described in this protocol will evaluate data for all patients initiating palbociclib + 
AI or AI alone within the US Oncology Network (USON) who meet the entry criteria and 
initiated palbociclib combination therapy between 01 January 2010 and 30 June 2020. Data 
will be sourced from the USON’s iKM EHR.
The current protocol is not designed as a Post Authorization Safety Study (PASS) and the
study is not a commitment or requirement to any regulatory authority.
8. RESEARCH QUESTION AND OBJECTIVES
This study aims to assess real-world tumor response in pre/perimenopausal HR+/HER2–
MBC patients initiating palbociclib + AI or AI alone as first-line therapy during the period on 
or after 01 January 2010 to on or before 30 June 2020. Data will be obtained from structured 
data fields within the iKM EHR database and will be supplemented by additional 
unstructured data collected through a targeted chart review.
Primary Objective
•
To estimate the rwRR for pre/perimenopausal patients treated with palbociclib + AI 
compared to AI alone as first-line therapy for HR+/HER2– MBC.
9. RESEARCH METHODS 
9.1. Study Design
Protocol Component
Description
Eligibility criteria
All pre or perimenopausal patients with HR+/HER2– MBC 
who have not received prior systemic treatment for their 
MBC and initiating therapy during the period on or after 
01 January 2010 to on or before 30 June 2020 registered in 
the USON.
Treatment cohorts
Palbociclib + AI versus AI alone as the first-line MBC  
treatment.
Assignment procedures
Patients will be assigned to either cohort at baseline 
according to their observed first-line MBC treatment 
received.
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Protocol Component
Description
Follow-up period
Begins at their starting date of the first-line MBC treatment 
during the period of 01 January 2010 through 30 June 2020
to study end (data cutoff 31 December 2020).
Primary endpoint
rwRR defined as proportion of patients with real-world tumor 
response consisting of complete response (CR) or partial 
response (PR) based on all recorded response assessments 
during first-line therapy captured with chart review.
Analysis plan
The primary endpoint rwRR will be estimated. PSM
approach will be applied to adjust for potential imbalance in
baseline prognostic factors.
This is a retrospective observational cohort study utilizing data derived from the USON’s
iKM EHR database combined with chart review to estimate real world tumor response 
outcomes in pre or perimenopausal patients receiving palbociclib + AI or AI alone as 
first-line MBC treatment for HR+/HER2– MBC. All patients meeting the entry criteria with
HR+/HER2– MBC who have not received prior systemic treatment for their MBC during the 
period on or after 01 January 2010 to on or before 30 June 2020 will be included and 
analyses will be conducted utilizing secondary de-identified EHR data in the US. Structured 
data fields within the iKM EHR database will be supplemented by additional unstructured 
data collected through a targeted chart review.
9.2. Setting
This study uses secondary de-identified EHR data that involve patients who have been 
diagnosed with MBC and received treatment within the USON.
9.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for the study:
1. At least 18 years old at initial recorded MBC diagnosis.
2. Pre or perimenopausal at MBC diagnosis (Table 1 Key variables for definition).
3. Diagnosis of MBC at any point in patient history as recorded in the iKM database.
a.
Diagnosis of BC will be determined through a review of iKM’s discrete diagnosis 
and histology fields, which are populated during the routine course of care 
(specifically, the provider will select “breast cancer” from a list of diagnoses; 
International Classification of Diseases [ICD] codes will not be used). 
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b. Evidence of stage IV or recurrent MBC with a metastatic diagnosis date in the 
USON iKM EHR, as confirmed by unstructured clinical documents.
i. To identify patients with metastatic disease status, patients must have at least 
one of the following indicators: 1) receipt of a numbered line of therapy (LOT), 
2) Stage IV disease, 3) Tumor, Node, Metastasis (TNM) staging with M value 
of 1, 4) record of location of metastatic disease or 5) current or prior disease 
status containing reference to metastatic disease.
4. Confirmed HR+/HER2– status as defined as:
a.
HR+: ER+ or PR+ test;
b. HER2–: any HER2 negative test and the absence of a positive test (IHC positive 
3+, fluorescence in situ hybridization [FISH] positive/amplified, positive not 
otherwise specified [NOS]).
5. Received one of the following regimens as first-line treatment for MBC during the 
period from 01 January 2010 through index period 30 June 2020 until the data cutoff 
date of 31 December 2020.
•
Palbociclib + AI as first-line treatment for MBC.
or
•
Monotherapy AI as first-line treatment for MBC.
6. Received care at a USON site(s) utilizing the full EHR capacities of iKM at the time
of treatment.
7. EHR data available from the USON site(s) where the patient received treatment are 
accessible for research purposes.
9.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Evidence of prior treatment with CDK 4/6 inhibitors (palbociclib, ribociclib or 
abemaciclib) in the early BC or MBC setting.
2. First structured activity (clinical visit) greater than 120 days after MBC diagnostic 
date with chart review to confirm no initial MBC treatment outside USON.
3. Receipt of treatment indicated for another primary cancer during the study 
observation period (after initiation of Palbociclib + AI or AI monotherapy and before 
31 December 2020) or history of another primary cancer within USON.
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4. Enrolled in any interventional clinical trial after initiation of Palbociclib + AI or 
AI monotherapy AND before 31 December 2020.
9.3. Variables
All variables are assessed using the operational definitions shown in Table 1. Most data will 
originate from 1 of 2 sources: the iKM EHR database (structured data) or chart review 
(unstructured data), although some variables may be derived from these raw data sources 
(eg, age from date of birth). Derived and transformed data needed for the analysis are 
described and presented along with the operational definitions in Table 1. 
For variables that are listed as being sourced from both structured and unstructured fields, 
chart review is recommended and, in some cases, may be required. Specifically, many of
these are variables that are available in structured fields but have been found to be more 
reliably and comprehensively captured through chart review of unstructured fields. Other 
variables require information that can only be sourced through chart review (eg, response and 
progression). 
Variables described as being captured at “baseline” will be captured at the date closest to the 
index date initiation within 90 days prior. Variables described as being captured with “prior 
medical history” will be sourced from patients’ entire medical history within the USON prior 
to index treatment initiation. If multiple values are available during the time period of 
measurement, either baseline or prior medical history, the one closest (in absolute value) to 
treatment initiation will be used.
Some data elements will be captured from both iKM and chart review. Since the chart review 
data are expected to provide a richer source of information, if data are available from both 
sources for a single patient, then chart review data will supersede what is available in the 
structured iKM data for the final analysis.
As this study is expected to obtain an exception and waiver of informed consent from The 
US Oncology Institutional Review Board, a deidentified dataset will be used for analysis. To 
comply with applicable data regulations and to reduce the risk of patient reidentification, the 
deidentified dataset will be certified through an expert determination process before it is 
transferred to Pfizer. This expert determination will be performed by an experienced 
professional with appropriate statistical and scientific training. During the process, this 
individual will confirm which data elements can be transferred in the deidentified dataset. 
Some of the variables anticipated in the protocol may also need to be modified based on 
guidance received during expert determination, including the granularity of dates, race 
categories, and geographic location. 
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Table 1.
Key Variables
Variable
Source(s)
Period of 
measurement
Operational definition
Demographic and patient characteristics
Hormone receptor status
iKM structured 
data + chart 
review
Prior medical 
history
Patients who have a documented hormone receptor-
positive status, either estrogen and/or progesterone, 
will be included in the study.
Categories: 
ER positive only
PR positive only
ER and PR positive
Human epidermal 
growth factor receptor 
2-negative status
iKM structured 
data + chart 
review
Prior medical 
history
Patients who have a documented human epidermal 
growth factor receptor 2-negative status will be 
included in the study.
Documentation of human epidermal growth factor 
receptor 2 will be captured as recorded in the iKM 
EHR database.  
Sex
iKM structured 
data + chart 
review
Prior medical 
history
Patients will be categorized as:
Male
Female
No information 
For patients lacking a documented menopausal status, 
sex assigned at birth will be verified through chart
review. 
Age
iKM structured 
data (derived)
Baseline
Patient’s age (in years) at the date of diagnosis, which 
will be calculated as the integer of [(diagnosis date –
date of birth + 1) / 365.25]. 
Age groups
iKM structured 
data (derived)
Baseline
Multiple age categories will be created based on the 
continuous age data:
<30
≥30-45
≥45
No information
Race
iKM structured 
data
Prior medical 
history
Categorized as:
White/Caucasian
Black/African American
Other
No information
Height
iKM structured 
data
Baseline
Patient’s height in meters.
Weight
iKM structured 
data
Baseline
Patient’s weight in kilograms.
Body mass index (BMI) 
at index date
iKM structured 
data (derived)
Baseline
BMI value as calculated from height and weight values 
will be provided.
Smoking history
iKM structured 
data
Baseline
Categorized as:
Never smoked
Current smoker
Former smoker
No information
Family history of cancer
iKM structured 
data + chart 
review
Baseline
Categorized as:
Yes
No information
Menopausal status
iKM structured 
data + chart 
Baseline
Menopausal status will be first categorized as explicitly 
documented by physician as:
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Variable
Source(s)
Period of 
measurement
Operational definition
review
Pre-menopausal
Peri-menopausal
Among patients lacking a physician-documented 
menopausal status record, pre-menopausal status will 
be assigned to those whose sex assigned at birth is 
female, who are aged less than 60 years and meet 
either of the following criteria: 
–
No documented history of a prior bilateral 
oophorectomy and received an LHRH analog
AND/OR
–
Not amenorrhoeic
Healthcare setting and provider characteristics
Practice location
iKM structured 
data (derived)
Baseline
The US census region of the USON clinic where the 
patient received care at the index visit:
Midwest: Illinois, Indiana, Michigan, Ohio, 
Wisconsin, Iowa, Kansas, Minnesota, Missouri, 
Nebraska, North Dakota and South Dakota
Northeast: Connecticut, Maine, Massachusetts, 
New Hampshire, Rhode Island, Vermont, 
Pennsylvania, New Jersey and New York
South: Delaware, Florida, Georgia, Maryland, 
North Carolina, South Carolina, Virginia, 
Washington D.C., West Virginia, Alabama, 
Kentucky, Mississippi, Tennessee, Arkansas, 
Louisiana, Oklahoma and Texas
West: Arizona, Colorado, Idaho, Montana, Nevada, 
New Mexico, Utah, Wyoming, California, Oregon 
and Washington State
Missing clinic values will be captured in a “no 
information” category.
Some of the regions may need to be collapsed if there 
are small sample sizes (eg, South versus non-South). 
This determination will be confirmed after reviewing 
sample sizes and the added value to the study with 
McKesson’s Privacy and Compliance team.
 
 
 
 
 
 
 
Practice size
iKM structured 
data (derived)
1/1/2018 –
12/31/2018
The number of patients seen at the USON clinic where 
the patient receive care for his/her index visit in the 
year 2018:
<50 patients/year
50-99 patients/year
100-149 patients/year
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Variable
Source(s)
Period of 
measurement
Operational definition
≥150 patients/year
Physician BC patient 
volume
iKM structured 
data (derived)
1/1/2018 –
12/31/2018
The number of BC patients seen by the physician who 
provided care for the patient’s index visit in the year 
2018:
<10 patients/year
11-49 patients/year
>50 patients/year
Disease characteristics
Time since initial BC 
diagnosis
iKM structured 
data + chart 
review (derived)
Medical history 
prior to index
The duration of time, in weeks, between the date of BC 
diagnosis and presentation of metastatic disease. 
To assess BC diagnoses that occurred prior to index, 
patients’ available medical history in iKM will 
searched. The completeness of this history will vary 
based on the length of disease and the time within the 
USON. Records may also be incomplete for patients 
with an initial BC diagnosis that occurred outside of 
the USON.
Diagnosis of BC will be determined through a review 
of iKM’s discrete diagnosis and histology fields, which 
are populated during the routine course of care 
(International Classification of Diseases [ICD] codes 
will not be used).
If no initial diagnosis date is documented, the first 
recorded diagnosis date in iKM will be used. This date 
will be used in calculations, not reported separately.
Time since MBC 
diagnosis
iKM structured 
data + chart 
review (derived)
Medical history 
prior to index
The duration of time, in weeks, between the index date 
and presentation of metastatic disease.
Date of first recorded diagnosis of metastatic disease 
within the EHR. Patients will be qualified initially 
based on the date identified in the structured data; this 
will be confirmed during chart review among patients 
selected for chart review. Ultimately, the primary 
source will be the chart if available.
Patients without recorded evidence of metastatic 
disease will be excluded from the study.
Structured data will confirm the patient as metastatic 
and as available, indicate the earliest associated date 
of any of these criteria:
1.
Stage IV disease.
2.
Tumor, Node, Metastasis (TNM) stage with 
M value of 1.
3.
Record of location of metastatic disease.
4.
Current or prior disease status containing 
reference to metastatic disease.
Distant metastatic site(s)
iKM structured 
data + chart 
review
Baseline
Baseline metastatic location(s) will be captured as 
documented in patients’ charts.
Note, patients that lack documented metastatic sites 
can indicate that metastases were not documented in 
the chart, not necessarily that patients did not have 
metastases.
Visceral/non-visceral 
iKM structured 
Baseline
Categorized as outlined below (not mutually exclusive) 
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Variable
Source(s)
Period of 
measurement
Operational definition
status
Bone only
data + chart 
review (derived)
except for bone only, in which patients will have bone 
as their only metastatic site(s) identified:
Visceral: 
•
Liver
•
Lung
•
Pleura
Other (not exhaustive):
•
Adrenal gland
•
Ascites 
•
Axilla
•
Bilateral intraocular
•
Brain
•
Breast
•
Bronchus
•
Cervical nodes
•
Cervix
•
Chest wall
•
Duodenum, retroperitoneum & mesentery
•
Esophagus
•
Eye
•
Fallopian tube
•
Gallbladder
•
Gastrointestinal tract/stomach
•
Genital organ
•
Intestinal tract
•
Kidney
•
Large intestine
•
Leptomeningeal 
•
Leptomeninges
•
Lymph nodes – distant
•
Lymph nodes – NOS
•
Lymph nodes – regional 
•
Mediastinum
•
Muscle
•
Omentum
•
Other parts of nervous system
•
Other respiratory organ
•
Other urinary organ
•
Ovary
•
Pancreas
•
Pericardial effusion
•
Pericardium
•
Peritoneum
•
Pleural effusion
•
Rectum
•
Retroperitoneum
•
Skin
•
Small intestine
•
Soft tissue
•
Spinal cord
•
Spleen
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Variable
Source(s)
Period of 
measurement
Operational definition
Bone (not exhaustive):
•
Bone
•
Bone marrow
•
Pelvis
•
Ribs
•
Skull
•
Spine
Count of metastatic 
site(s)
iKM structured 
data + chart 
review (derived)
Baseline
The total count of metastatic site(s) at index:
No information
1
2
3
4+
Note, “no information” can indicate that metastases 
were not documented in the chart, not necessarily that 
patients did not have metastases.
Stage at diagnosis
iKM structured 
data
Medical history 
prior to index
Categorized as:
Stage 0
Stage IA
Stage IB
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IIIC
Stage IV
No information
Eastern Cooperative 
Oncology Group 
(ECOG) performance 
status
iKM structured 
data + chart 
review
Baseline
The ECOG performance status score is a rating of a 
patient’s disease status, daily living activities and 
quality of life, with low scores indicating greater 
functioning than high scores:
0
1
0/1
2
2+
3+
No information
Karnofsky performance status is a similar measure and 
will be converted to ECOG using the methodology 
outlined below. (Ma et al, 2010)18
Karnofsky 
Performance 
Status
ECOG 
Performance 
Status
ECOG 
Performance 
Status 
Description
100
0
Fully active
80, 90
1
Restricted in 
physically 
strenuous 
activity
60, 70
2
Ambulatory 
and capable of 
self-care but 
unable to work
40, 50
3
Capable only 
of limited self-
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Variable
Source(s)
Period of 
measurement
Operational definition
care
10, 20, 30
4
Completely 
disabled
0
5
Dead
CCI (Charlson 
Comorbidity Index) 
score
Chart review
Prior medical 
history
Calculated based on the presence of 17 Charlson
comorbidities at MBC diagnosis. 
Comorbidities and associated obfuscated dates 
documented prior to or on the index date will be 
captured and summarized as:
Myocardial infarction, congestive heart failure, 
peripheral vascular disease, cerebrovascular accident, 
hemiplegia, chronic obstructive pulmonary disease, 
ulcer disease, diabetes with chronic complications, 
diabetes without chronic complications, renal disease, 
connective tissue disease such as rheumatoid arthritis 
or lupus, Alzheimer’s or other dementia, cirrhosis or 
other serious liver disease, non-breast cancer 
malignancy (excluding sites of breast cancer metastasis 
and malignant neoplasm of skin), metastatic solid 
tumor (other than breast cancer), HIV/AIDS.
In addition, history of interstitial lung disease (ILD) 
and pneumonitis will be noted but not included in the 
CCI score.
Two approaches will be used to capture comorbidities 
documented in patients’ medical records. First, 
comorbidities explicitly documented by providers will 
be captured and reported. Separately, patients with 
suspected comorbidities based on receipt of 
medications associated with those conditions will be 
identified. 
To identify suspected comorbidities, an extract of all 
concomitant meds documented pre-index for the study 
population cohorts will be generated with patients’ 
entire treatment history documented in the structured 
data. The study team, including clinical experts and the 
Physician Investigator, will review the frequency 
distributions of the medications and map these to 
chronic conditions.  
For analysis purposes, comorbidities explicitly 
documented by providers versus those imputed by 
medication use will be differentiated.  
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Variable
Source(s)
Period of 
measurement
Operational definition
Disease histology
iKM structured 
data
Baseline
Categorized as:
Ductal
Lobular
Mixed
Metaplastic
Tubular
Mucinous
Other
No information
BRCA 1/2 status
iKM structured 
data + chart 
review
Baseline
Categorized as:
Positive
Negative
No information
ESR1 status
iKM structured 
data + chart 
review
Baseline
Categorized as:
Positive
Negative
No information
NGS status
iKM structured 
data + chart 
review
Baseline
Categorized as:
Positive
Negative
No information
Treatment characteristics
Pre-index treatment(s)
iKM structured 
data + chart 
review
Medical history 
prior to index
Patients’ treatments received prior to index, along with
obfuscated dates. This includes prior adjuvant 
hormonal treatment or prior neo-adjuvant/adjuvant 
chemotherapy.
Adjuvant treatment end 
dates
iKM structured 
data + chart 
review
Medical history 
prior to index
Obfuscated date of adjuvant treatment discontinuation.
Endocrine sensitivity
iKM structured 
data + chart 
review  
(derived)
Medical history 
prior to index
Relapse more than 12 months after completing 
adjuvant endocrine therapy.
Disease-free interval
iKM structured 
data + chart 
review (derived)
Medical history 
prior to index
Obfuscated dates between discontinuation of adjuvant 
therapy and the start of treatment for unresectable 
and/or metastatic disease. 
Radiotherapy
iKM structured 
data + chart 
review
Medical history 
prior to index 
and study 
observation 
period
All radiotherapy, along with obfuscated dates, received 
prior to or during the study observation period will be 
captured. During analysis, 2 variables will be 
constructed: 
“Concomitant radiotherapy” will be defined 
as radiotherapies given during 1L treatment
“Prior radiotherapy” will be defined as all 
radiotherapies prior to index date
Index treatment regimen
iKM structured 
data + chart 
review
Study 
observation 
period
Patients’ index treatment will be categorized based on 
the cohort descriptions in Section 9.1:
Palbociclib combination therapy with an AI 
(letrozole, exemestane or anastrozole) or 
AI monotherapy
LHRH treatment 
iKM structured 
data + chart 
review
Study 
observation 
period
LHRH treatment received during the study observation 
period will be captured.
Date of treatment 
initiation during the 
iKM structured 
data + chart 
Study 
observation 
The obfuscated date of initiation with a palbociclib-
based combination regimen or AI monotherapy 
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Variable
Source(s)
Period of 
measurement
Operational definition
patient identification 
period (ie, index date)
review
period
(letrozole, exemestane or anastrozole) during the study 
identification period. If a regimen consists of more than 
one drug with drugs given on different dates, the date 
of the first administration of any drug will be used.
Index treatment end 
date(s)
iKM structured 
data + chart 
review
Study 
observation 
period
Obfuscated date of final treatment for each drug or 
regimen. If a regimen consists of more than one drug 
with drugs ending on different dates, the date of the last 
administration of any drug will be used. It is possible 
that the patient’s treatment stop date is not documented 
if the patient dies, is lost-to follow-up or is still on-
therapy. The final treatment date, death date or end of 
study date will be used, whichever is earliest.  
Index line of therapy 
(LOT)
iKM structured 
data
Study 
observation 
period
LOT will be operationally defined as a course of care 
that continues until disease progression or 
unacceptable toxicity. As such, advancement in LOT 
will be assigned if there is documented or inferred 
progression or toxicity.
Switching between aromatase inhibitors (exemestane, 
letrozole, anastrozole) will not constitute a change in 
regimen, unless the next aromatase inhibitor is started 
due to provider-documented progression or toxicity. In 
contrast, switching between other classes of treatments 
(eg, CDK 4/6 inhibitors, chemotherapies), will 
constitute a change in regimen. 
Number of cycles (index 
treatment)
iKM structured 
data
Study 
observation 
period
The number of provider-documented therapy cycles 
received for the index treatment. 
Index treatment schedule 
(cycle length and 
frequency)
iKM structured 
data + chart 
review
Study 
observation 
period
The planned frequency and cycle length of the index 
treatment.
Index treatment schedule 
changes
iKM structured 
data + chart 
review
Study 
observation 
period
Each index treatment (either AI monotherapy or 
palbociclib combination therapy) schedule change will 
be captured and reported, along with the obfuscated 
date. 
Index palbociclib 
treatment starting dose
iKM structured 
data + chart 
review
Study 
observation 
period
The actual index treatment starting palbociclib dosage 
received. 
Categories to be presented: 
   75 mg
   100 mg
   125 mg
   Other
   No information
Palbociclib combination 
regimen
iKM structured 
data + chart 
review 
Study 
observation 
period
Classification of patients into the following treatment 
groups:
Palbociclib-letrozole
Palbociclib-anastrozole
Palbociclib-exemestane  
Reason for palbociclib 
dose changes
Chart review
Study 
observation 
period
Data for palbociclib dose change reason will 
exclusively come from chart review. Reviewers will be 
asked to select reason(s) as explicitly documented in 
patients’ charts.
If available, reason patients discontinued treatment 
will be abstracted:
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Variable
Source(s)
Period of 
measurement
Operational definition
Lack of response
Patient preference
Toxicity
Other
No information
Reviewers will specify other reasons; these will be 
reported if any represent >5% of patients.
Reason for treatment 
discontinuation (all 
treatment lines)
Chart review
Study 
observation 
period
Data for discontinuation reason will exclusively come 
from chart review. Reviewers will be asked to select 
reason(s) as explicitly documented in patients’ charts.
If available, reason patients discontinued treatment 
will be abstracted:
Provider-documented disease progression
Toxicity
Decline in performance status
Financial/insurance
Completed planned treatment
Death
Hospice
Patient preference
Physician preference
Other
No information
Reviewers will specify other reasons.
Reason for treatment 
initiation (all treatment 
lines)
Chart review
Study 
observation 
period
Data for treatment initiation reason will exclusively 
come from chart review. Reviewers will be asked to 
select reason(s) as explicitly documented in patients’ 
charts.
If available, reason for treatment initiation will be 
abstracted:
Initial diagnosis
Initial diagnosis with unresectable disease
Initial diagnosis with metastatic disease
Progressive disease
Other reasons; non-progression
Toxicity on prior therapy
Reason not specified 
Reviewers will specify other reasons.
Post-index treatment(s)
iKM structured 
data + chart 
review
Study 
observation 
period
Patients’ treatments received after index, along with 
obfuscated dates.  
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Variable
Source(s)
Period of 
measurement
Operational definition
Provider-documented tumor assessments
Provider-documented 
tumor assessment
Chart review
Study 
observation 
period
In prospective clinical trials, response is generally 
assessed according to Response Evaluation Criteria In 
Solid Tumors (RECIST) criteria. However, the 
parameters underlying these criteria are less reliably 
available in retrospective, observational studies. 
Instead, for this study, provider documented 
assessments of tumor response will be used. No 
attempts will be made to mimic the RECIST guidelines.
Response assessments documented for the index 
treatment (depending on cohort). It is possible that 
patients have multiple response assessments in their 
charts during this period. 
All documented responses to the index treatment (AI 
monotherapy or palbociclib combination therapy) 
described within progress notes (along with the 
associated, obfuscated progress note date) will be 
captured. For each tumor assessment, it will be 
documented if a scan report was documented as the 
basis of the assessment.
Tumor assessments will be classified as:
Complete response: Documented as “a complete 
response” to therapy; indication patient is in 
“remission”; “all lesions” have disappeared or 
“no evidence of disease”).
Partial response: Documented as partial reduction 
in size of visible disease in some or all areas 
without any areas of increase in visible disease 
(decrease in disease volume even though disease is 
still present).
Stable disease: Documented as disease is stable 
(not progressed or not improved; eg Stable 
appearance of lobe nodules and Mixed response: 
Combination of improved and worsened disease.
Progressive disease: Documented as disease has 
“progressed”; or worsening of disease.
Not evaluated: No documentation of status of 
disease.
Clinical outcomes
Last USON visit date
Chart review
Study 
observation 
period
Patients’ last visit date will be captured through chart 
review as a verified physical encounter with the 
practice as evidenced by treatment administration, 
measurement of vital signs, laboratory specimen 
collection or other office procedures. For patients with 
a death date, this last visit date should occur prior to 
the death date.
Death date
iKM structured 
data + 
LADMF/NDI + 
chart review
Study 
observation 
period
Obfuscated date of death will be captured from the 
LADMF, NDI as well as iKM. If dates conflict between 
the 3 sources, the NDI, followed by the LADMF date 
will be prioritized. If severe data discordance is 
observed (ie, death is reported to occur prior to the 
index date and/or there is a difference of more than 6 
months between them), then the iKM death date, as 
verified through chart review, will be used.
Pneumonitis and 
Chart review
Study 
Explicit attribution to treatment within chart will be 
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Variable
Source(s)
Period of 
measurement
Operational definition
interstitial lung disease
observations 
period
documented. Yes/No
9.4. Data Source
Table 1 represents the data elements that will be evaluated through this study and their 
associated source. Most study data will originate from the EHR system of the USON, iKM. 
The USON includes 1,200 affiliated physicians operating in over 470 sites of care in the US 
and treats approximately 1 million US cancer patients annually 
(https://www.usoncology.com/our-company). iKM captures outpatient practice encounter 
histories for patients under community-based care, including, but not limited to patient 
demographics such as age and gender; clinical information such as disease diagnosis, 
diagnosis stages, performance status information and laboratory testing results; and treatment 
information, such as dosages and treatment administration within the USON. 
Structured data fields within the iKM EHR database will provide information needed to 
address most research questions. These data will be supplemented by additional unstructured 
data collected through chart review (methodology described in Section 9.6). Electronic chart 
review data will be collected by means of a secure, web-based electronic case report form 
(eCRF) by healthcare professionals with oncology experience. 
The study will only use data from USON practices utilizing full EHR capacities of iKM. 
Data management and administrative processing is supported by McKesson’s quality 
assurance procedures. Additionally, iKM has previously been used to evaluate patient 
profiles, treatment patterns and outcomes among MBC patients and the results have been 
consistent with other published studies. (Patt et al, 2015, Patt et al, 2016, Robert et al,
2015).23,24,27
Real-world evidence sourced retrospectively from the EHR of the USON have previously 
been used to support FDA approval of a new drug application for Merkel cell carcinoma
(Cowey et al, 2017).5
The Limited Access Death Master File (LADMF) of the Social Security Death Index (SSDI) 
and the National Death Index (NDI) of the Centers for Disease Control will be additional 
sources of vital status (death), in addition to death dates recorded in the EHR. Common 
patient identifiers (patient identification, name, and birth date) will be used to link patients 
from the iKM data warehouse and iKM chart review. Patients’ names, dates of birth and 
social security numbers (SSN) will be used to link patients from iKM, LADMF and NDI data 
sources. All patients within iKM are assigned a unique patient identifier by iKM version 
(eg, some large practices have separate installations by location). When linking to the 
LADMF, patient SSN is used. Some practices do not collect SSN and some patients may not 
report it. 
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At the time structured EHR data are extracted for this project, an extract of the LADMF will 
also be requested from the Social Security Administration. Approximately 1 month prior to 
the deidentified data transfer to Pfizer, updated LADMF will be requested and updated death 
information from structured fields of the EHR will be extracted. 
Data from all sources and any derived variables will be merged into one master dataset for 
analysis. Data will be handled in compliance with the Health Insurance Portability and 
Accountability Act (HIPAA) and Health Information Technology for Economic and Clinical 
Health (HITECH).
Institutional Review Board approval of the study parent protocol will be obtained prior to 
study conduct and will include a waiver of informed consent. Data provided to third parties 
will be de-identified and provisions will be in place to prevent re-identification in order to 
protect patients’ confidentiality.
9.4.1. Patient Selection
Structured data will be used to screen patients who received treatment within the USON 
based on the eligibility criteria described in Table 2. The patient attrition will be based on 
this initial screening.
Study-eligible patients who received first-line AI monotherapy or palbociclib + AI 
combination therapy will be selected to undergo a targeted chart review. During the course of 
abstraction, patients’ eligibility for the study will be verified and some of these patients may 
be found to be ineligible. Reasons for disqualification will be captured and reported.
Table 2.
Patient Attrition (01 January 2010 - 30 June 2020)
Eligibility criteria 
Patient
count -
excluded
Patient
count -
remained
Documented diagnosis of hormone receptor-positive (estrogen receptor-
positive or progesterone receptor-positive), human epidermal growth 
factor receptor 2-negative metastatic breast cancer (MBC) who received 
a qualifying treatment (ie, palbociclib, letrozole, exemestane or 
anastrozole) within the USON during the study identification period.
-
27,835
Aged 18 years at initial recorded diagnosis of MBC
3
27,832
Exclusion of patients enrolled in an interventional clinical trial during 
the study observation period.
2,299
25,533
Did not receive a treatment indicated for another primary cancer during 
the study observation period.
2,548
22,985
Received care at a USON site(s) utilizing the full EHR capacities of iKM 
at the time of treatment.
0
22,985
Exclusion of patients with qualifying treatments (ie, palbociclib, 
letrozole, exemestane or anastrozole) received only prior to metastases 
date and not after advanced diagnosis.
1,143
21,842
Exclusion of patients with start of first regimen more than 120 days after 
metastases date.
2,345
19,497
Exclusion of patients from sites without USON data access agreement.
8,440
11,057
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Initial cohort counts (patients who initiated the cohort - specific regimen 
in an appropriate LOT)
Pb-AI: Palbociclib combination therapy with an aromatase inhibitor 
(letrozole, exemestane, or anastrozole) among patients as first-line
therapy in the advanced or metastatic setting. Patients with evidence of 
prior treatment with other CDK 4/6 inhibitors (ribociclib or 
abemaciclib), aromatase inhibitors (letrozole, exemestane, or 
anastrozole), tamoxifen, raloxifene, toremifene, or fulvestrant in the 
advanced or metastatic setting were excluded. 
-
1,524
AI mono: Aromatase inhibitor (letrozole, exemestane or anastrozole) 
monotherapy as first-line treatment in the advanced or metastatic setting. 
Patients with evidence of prior treatment with other CDK 4/6 inhibitors 
(ribociclib or abemaciclib), aromatase inhibitors (letrozole, exemestane, 
or anastrozole), tamoxifen, raloxifene, toremifene, or fulvestrant in the 
advanced or metastatic setting were excluded. 
-
4,395
Exclusion of patients who initiated qualifying regimens prior to the start of the study period (by cohort)
Pb-AI: aromatase inhibitor (letrozole, exemestane, or anastrozole) + 
palbociclib.
15
1,509
AI mono: aromatase inhibitor (letrozole, exemestane, or anastrozole) 
mono.
461
3,934
Table 3.
Menopausal Status by Cohort (Based on Structured Data Alone)*
Status
AI Mono (n=3,934)
PB-AI (n=1,509)
Perimenopausal 
50 (1.3%)
12 (0.8%)
Premenopausal 
185 (4.7%)
136 (9.0%)
Postmenopausal 
2,363 (60.1%)
1,082 (71.7%)
Not documented
1,336 (34.0%)
279 (18.5%)
* Based on initial feasibility estimate with menopausal status to be confirmed through chart review. Chart 
review will also examine those patients where menopausal status is “not documented” in the structured field.
9.5. Study Size
All eligible patients will be included for the primary analysis. Approximately 385 patients 
will be included with close to a 1:2 ratio between palbociclib + AI and AI alone cohorts 
based on examination of structured iKM data applying inclusion/exclusion criteria (Table 2
and Table 3) between 01 January 2010 and 30 June 2020 (see Section 9.7.2).
9.6. Data Management 
The McKesson study team will collaborate with McKesson’s Commercial Intelligence group 
to collect the structured iKM data that will be used for analysis. The Commercial Intelligence 
team will be provided with a Data Collections Variable List, which will detail the specific 
data elements that will need to be included in the study dataset. A Data Analyst will begin by 
generating high-level study sample counts that demonstrate attrition rates of the 
inclusion/exclusion criteria. 
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The study team will review the attrition count and the Data Analyst will proceed with 
collecting the remaining data elements on the Data Collections Variable List. The Data 
Analyst will perform an initial quality control check of the study dataset before providing the 
file to the study team’s Biostatistician on a secure server. Once received by the 
Biostatistician, data validation will continue and will consist of, but is not limited to, quality 
control checks for appropriate values, logical sequences and quantity of missing values. 
A list of patients eligible for chart review will be generated by the Data Analyst and the 
Biostatistician will apply the agreed upon sampling technique to identify the specific patients 
that will undergo chart review. This list of patients will then be securely transmitted to the 
Chart Review Team Manager. 
The McKesson study team will lead a training session with chart abstractors to discuss study 
specific considerations. Reference materials will also be provided to abstractors at this time. 
If chart abstractors have questions during the abstraction process, these will first be raised to 
the Chart Review Team Manager. If needed, questions can be escalated to the Outcomes 
Researcher and Principal Investigator. 
Chart review will be accomplished by use of a secure, web-based eCRF. The main purpose 
of the eCRF is to obtain data required by this non-interventional study protocol in a 
complete, accurate, legible and in a timely manner. 
Analyses will be conducted using statistical analysis software (SAS®; SAS Institute Inc., 
Cary, NC, US) and/or R: A Language and Environment for Statistical Computing 
(R Foundation for Statistical Computing, Vienna, Austria) as appropriate.
Once on Pfizer servers, Pfizer staff perform a semi-automated process for quality assurance 
on the data, checking that the metadata align with the data dictionary from USON dataset, the 
number of records equals that expected from the vendor, and that the data types and 
controlled vocabularies are correct. The data are then loaded into a secure Pfizer server. 
Pfizer servers are backed up nightly and have failover and off-site redundancy. Access to 
data is limited only to Pfizer colleagues and is monitored with all end user activity is logged. 
Pfizer maintains copies of all EHR or other real-world data in accordance with the FDA's 
July 2018 Industry Guidance on Use of Electronic Health Record Data in Clinical 
Investigations (FDA, 2018),10 though Pfizer maintains its data in excess of the guidance – for 
a minimum of 7 years.
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9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. McKesson shall ensure that the CRFs are 
securely stored at the study site in encrypted electronic and/or paper form and will be 
password protected or secured in a locked room to prevent access by unauthorized third 
parties.
McKesson has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
The source documents are the hospital or the physician's chart. In these cases, data collected 
on the CRFs must match those charts. 
9.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, 
McKesson agrees to keep all study-related records, including the identity of all participating 
patients (sufficient information to link records, eg, CRFs and hospital records), copies of all 
CRFs, safety reporting forms, source documents, detailed records of treatment disposition, 
and adequate documentation of relevant correspondence (eg, letters, meeting minutes, and 
telephone call reports). The records should be retained by McKesson according to local 
regulations or as specified in the research agreement, whichever is longer. McKesson must 
ensure that the records continue to be stored securely for so long as they are retained.
If McKesson becomes unable for any reason to continue to retain study records for the 
required period, Pfizer should be prospectively notified. The study records must be 
transferred to a designee acceptable to Pfizer.
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless McKesson and Pfizer have expressly agreed to a different period of 
retention via a separate written agreement. Record must be retained for longer than 15 years 
if required by applicable local regulations.
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McKesson must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met.
9.7. Data Analysis
Detailed methodology for summary and statistical analyses of the data collected in this study 
are outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor. The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.7.1. Statistical Hypotheses
The primary purpose of this study is to estimate real world tumor response for 
pre/peri-menopausal patients treated with palbociclib + AI or AI alone as first line treatment 
for HR+/HER2- MBC in the US clinical practice setting. No formal hypothesis testing will 
be performed.
9.7.2. Sample Size Determination
Approximately 385 patients will be included with close to a 1:2 ratio between palbociclib + 
AI and AI alone cohorts based on examination of structured iKM data applying 
inclusion/exclusion criteria (Table 2 and Table 3) between 01 January 2010 and 30 June 
2020. It is estimated that there will be approximately 135 patients in the palbociclib + AI arm
and 250 patients in the AI alone arm of which a subset will have documented post-baseline 
tumor assessment.  
9.7.3. Cohort for Analysis
All effectiveness analyses will be based on the pre/perimenopausal cohort. Eligible 
pre/perimenopausal patients with HR+/HER2- MBC will be included into the following 
cohorts:
Cohort to be analyzed for the primary objective:
a.
Pre/perimenopausal patients treated with palbociclib + an AI as the initial therapy for 
the treatment of MBC.
b. Pre/perimenopausal patients treated with an AI alone as the initial therapy for the 
treatment of MBC.
9.7.3.1. Propensity Score Matching (PSM) 
Propensity score matching (PSM) will be used to create matched sets of palbociclib treated 
and untreated patients who shared similar value of the propensity score. The propensity 
scores produce a set of matched pairs with similar distributions of the covariates but does not 
require close or exact matches for each individual matched pair of patients. Once the 
matched sample has been formed, the treatment effect can be estimated by directly 
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comparing outcomes between palbociclib treated and untreated patients in the matched 
sample. Variables to be used in the estimation of propensity scores (PS) may include key 
baseline demographics (ie, age, race) and clinical characteristics (Eastern Cooperative 
Oncology Group [ECOG] performance score, disease stage at initial diagnosis, visceral 
metastasis, Charlson Comorbidity Index, and number of disease sites). A final list will be 
specified in the SAP.
9.7.3.2. Analyses of Primary Endpoint
The primary endpoint is real-world response rate (rwRR) and the rwRR will be calculated as 
the proportion of patients with a real-world complete response (CR) or real-world partial 
response (PR) by treatment cohort. Patients with a best response of CR or PR are those 
patients with a CR or PR after 30 days of treatment initiation without a PD at any prior 
assessment.
Real-world tumor responses (rwTR) are assessed based on treating clinician’s assessment of 
radiological evidence for change in burden of disease over the course of treatment.
Assessments were not performed on a schedule and responses were not confirmed by 
subsequent assessment. Each assessment will be classified as follows:
•
Complete response (CR): Documented as “a complete response” to therapy; 
indication patient is in “remission”; “all lesions” have disappeared or “no evidence of 
disease”).
•
Partial response (PR): Documented as partial reduction in size of visible disease in 
some or all areas without any areas of increase in visible disease (decrease in disease 
volume even though disease is still present).
•
Stable disease (SD): Documented as disease is stable (not progressed or not 
improved; eg, stable appearance of lobe nodules) or Mixed response, which is a 
combination of improved and worsened disease.
•
Progressive disease (PD): Documented as disease has “progressed”; or worsening of 
disease.
•
Not evaluated (NE): No documentation of status of disease.
To overcome the potential imbalance of baseline characteristics between the 2 cohorts, the 
propensity score (PS) will be computed by a logistic regression model using baseline 
characteristics for each patient. The PSM technique will be used to control for potential
confounding factors when comparing the cohorts. Each patient in the palbociclib + AI cohort 
will be matched (1:1) to a patient in the AI alone cohort using a greedy matching algorithm, 
which sequentially without replacement selects the control patient whose propensity score is 
closest to that of the particular patient in the palbociclib + AI cohort. This matching process
will be performed independently and prior to the access of rwTR outcome data. 
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The analysis of the primary endpoint is to estimate the rwRR between the 2 cohorts 
(palbociclib + AI compared to AI alone) using PSM method to balance baseline demographic 
and clinical characteristics between the two real world treatment cohorts. 
The number and percentage of patients with a best overall response of CR, PR, SD, PD, and 
NE will be tabulated. The number and proportion of patients achieving rwTR (CR or PR) 
will be summarized along with the corresponding exact 2-sided 95% confidence interval 
calculated using a method based on Clopper-Pearson method. The odds ratio and the 
corresponding 2-sided 95% confidence interval will be calculated to contrast the treatment 
effectiveness on response rates. 
Two analyses of rwRR will be performed: 
1. rwRR among those patients who had at least one post-baseline tumor assessment 
documented in the database. 
2. rwRR among all eligible patients who met the inclusion and exclusion criteria as 
defined in study protocol. 
The rwRR rates will be estimated for each treatment cohort and compared by using PSM
methodology to control potential baseline confounding factors.
9.7.3.3. Sensitivity Analyses 
Sensitivity analysis will be performed to exam the robustness of the primary analysis.  
Sensitivity analysis 1: Inverse probability treatment weighting (IPTW)
Inverse probability treatment weighting will be used to balance baseline demographic and 
clinical characteristics between comparison cohorts in this analyses (Austin and Stuart, 
2015).2 In the event that IPTW method does not balance potential confounder variables, 
analysis by PS quintiles will be used.
Sensitivity analysis 2: Stratification by propensity score
This analysis will divide patients into 5 equal-sized groups using quintiles of the estimated 
propensity score. The treatment effect of rwRR can be estimated by comparing rwRR rates 
directly between patients in two cohorts within strata. The stratum-specific estimates of 
treatment effect can then be pooled across stratum to estimate an overall treatment effect.
Sensitivity analysis 3: Best tumor response imputation
For patients who did not have any post baseline tumor assessment information, their rwTR 
may be imputed using logistic regression predictive modelling to predict response for 
patients with similar baseline characteristics from known patients.
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9.7.3.4. Subgroup Analyses 
While inclusion of patients between 2010 and 2015, allows for patient to be included in the 
control arm prior to palbociclib being approved, which may help to reduce bias in physician 
choice of treatment and allow for more patients being matched, however, the varying time 
periods between cohorts may be a limitation.
A subgroup analyses will be performed including patients only after palbociclib approval in 
the US. Patients included in this analysis with be those who meet inclusion and exclusion 
criteria during an index period on and after 01 February 2015 until on or before 30 June 
2020.
Other subgroup analyses may be performed according to patient demographics and baseline 
characteristics as appropriate, based on availability of the data and sample sizes.
9.7.3.5. Other Analyses 
Descriptive analyses for patient baseline characteristics will be conducted.
9.7.3.6. Analyses of AEs of Special Interest
The number of cases of pneumonitis and interstitial lung disease (ILD) which are directly 
attributable to the treatment will be reported for each treatment cohort which occurred while 
on first line treatment plus 30 days. 
9.8. Quality Control
With the exception of supplementary vitality status and date of death, study data will 
originate in the EHR, then be extracted into a study dataset through a manual chart review 
process or programmatic queries. Following analytic file construction and deidentification 
process, the dataset will be securely transferred to Pfizer. Sites cannot enter data into the 
eCRF directly; to support consistency and accuracy of abstraction, dedicated abstractors from 
McKesson will have centralized access to the EHR from all practice sites, and enter 
retrospective data into the eCRF. 
This is a retrospective study, therefore issues of quality control at study sites, eg data 
clarification queries, do not apply. Analyses are programmed according the specifications in 
the protocol's SAP and all code and other technical artifacts are documented and stored 
following established programming practices on Pfizer servers and in Pfizer’s Global 
Document Management System. Quality control (QC) will follow the USON dataset’s 
standard procedure for quality control and assurance as described below.
For structured data, McKesson’s Data, Evidence and Insight (DEI) team conducts quality 
assurance checks on all analytics projects. The process includes both technical and clinical 
quality checks. Technical review of the dataset consists of identifying inappropriate values 
(eg, out of range, illogical), logical sequences and quantity of missing values. Illogical and 
missing data will be reported to the study team, which may opt to exclude or impute these 
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values. Clinical review of the data subsequently occurs to ensure aggregate data are aligned 
with expectations and prior publications. 
The quality assurance process includes the following areas:
•
Project scope and study rules;
•
Protocol/SAP development;
•
Data extraction and integrity;
•
Populated tables and Study Report development.
As results of quality assurance and quality control, McKesson confirms:
•
The source of the data and/or results will be documented, and that results/data will be 
verified against the source;
•
The internal consistency of the medical research data presented;
•
The conclusions are objective, balanced and consistent with the study results;
•
The format and content of the document are aligned with the agreed upon template 
and standards.
Quality control and validation of chart review (unstructured) data will occur in multiple 
phases. Chart review processes require that no interpretations be made during the data 
collection; instead, all data will be collected as documented by the physician in the chart. 
Prior to full chart review, a pilot will be conducted with at least 5% of the patient population, 
up to 25 patients. Charts will be reviewed by each reviewer on the team to ensure inter-rater 
reliability. Data Quality Specialists will review pilot data for accuracy and consistency, 
including implausible dates (ie, date of death prior to last date of treatment), non-standard 
treatments, results which are inconsistent with known clinical parameters or other clinical 
data which is inconsistent with known standards and outcomes. Chart review team will meet 
following pilot and before launch of full chart review to clarify ambiguous or conflicting data 
and address potential problems and questions. Pilot data will be presented to the research 
team for review and approval. If necessary, revisions to the tool and/or additional training 
will be implemented. 
Once the pilot chart review is complete, the remaining chart reviews will proceed. During 
this phase of chart review, Data Quality Specialists will perform random and detailed checks 
of the data by verifying original source data. The Data Quality Specialist will also initiate 
queries, quality control of randomly selected charts and review of final data set before 
submission to researcher. Finally, the researcher and study’s Biostatistician will provide a 
final examination of the final dataset by looking for missing or illogical data before preparing 
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it for analyses. This analysis will include a descriptive analysis of the provider 
characteristics, demographics, baseline clinical and disease characteristics, and 
characteristics of treatment patterns. Data points flagged as outliers will be reviewed by the 
Data Quality Specialist. 
Data queries are handled through multiple steps. Questions from the abstractors or first level 
monitors are submitted to the McKesson Data Quality Specialist via a question log. 
Questions are logged and answers documented in the log for reference throughout the study. 
The McKesson Data Quality Specialist will answer questions directly, or escalate to the lead 
McKesson Researcher or Physician Investigator as appropriate. Queries and flags generated 
directly by the Monitor/Data Quality Specialist are communicated and resolved through the 
electronic data capture system. A scheme of the adjudication process is presented in
Figure 3.
Figure 3.
Adjudication Process Scheme
The eCRF will be hosted by the OpenClinica electronic data capture system, which allows 
review/signature by investigator on all data entered into the eCRFs, to attest the data 
accuracy.
 
 
Based on extensive experience with chart abstraction of real-world oncology data, the 
McKesson Life Sciences team has created chart abstraction guidelines to reflect best 
practices in data collection across a number of disease areas. (Robert et al, 2019)26 The intent 
of this document is to ensure accurate, objective and consistent data capture. Algorithms used 
in data handling are validated through the QC and source data verification process. 
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Biostatisticians use SAS programs to QC data sets provided either by a structured database 
pull and from manual chart review. The team of biostatisticians and data analysts maintains a 
library of programming codes and algorithms that are used to analyze and classify any 
variables required for analyses. These codes are validated by the statistical analysis team. 
Any discrepancies are discussed and shared with the primary coder, data management, and 
biostatistician team.
For the primary endpoint, rwRR, chart abstraction will be undertaken to capture all tumor 
assessments associated with the index treatment (AI monotherapy or palbociclib + AI) 
documented in progress notes by treating physicians. Chart reviewers will classify these 
tumor assessments into the categories defined in Section 9.7.3.2, as well as capture the dates 
of assessment and whether they were based on radiologic imaging reports. As described 
above, McKesson Data Quality Specialists will perform random and detailed checks of the 
tumor assessment data by verifying original source data. If questions arise during capture of 
tumor assessments, these will be addressed with the adjudication process defined above. 
Risks involved in the handling of data and mitigation strategies are described below: 
•
Transferring from EHR to database. McKesson’s product management team 
manages the transfer of data entered into the EHR by practices into the centralized 
EHR database. Primary data management is handled by the DEI data management 
team. This is an automated process and does not require manual data entry. Prior to 
analysis the biostatistician will examine the data to ensure that all needed elements 
are within the datasets. During analysis, if the biostatistician discovers any data 
issues, this is first communicated to the project lead and/or research management for 
discussion. Data issues that require clinical judgement are examined and discussed 
with the physician investigator. Any systemic issues are then reported to the data 
management team. For instance, issues may be caused due to migration of data from
one server to another and the data management team must be notified of any 
abnormalities. Further, the data management team communicates with DEI leadership 
and biostatisticians regarding any upcoming changes in the data. 
•
Transferring from EHR database to eCRF. There is not direct transfer from the 
database to the eCRF. Data entered into the eCRF is manually performed via chart 
abstraction. Subsequently, data that is captured in the eCRF is automatically 
transferred to a dataset within the eCRF application. The dataset can be pulled from 
the application via automated process that is manually initiated. A multipronged 
approach is taken to reduce the potential of capturing incorrect information from the 
chart via manual abstraction. First, fields in the eCRF are built with logic checks 
ensure data entered fit the parameters of the field and the study. Second, quality 
monitors perform checks on data captured by verifying data entered to the chart. Last, 
McKesson Data Quality Specialists perform QC on the data set to determine the 
overall quality level meets McKesson standards/expectations.
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9.9. Limitations of the Research Methods
9.9.1. Internal Validity of Study Design 
Measurement Error(s)/Misclassification(s)
This observational and retrospective study uses iKM EHR data. The iKM database is not 
collected for research purposes but for clinical practice reasons. This may impede the 
standardization of the data collection methods and instruments and the reporting practices of 
the physician. As with all administrative databases, iKM data are subject to coding errors of 
omission and commission. Problems with inadequate or inaccurate codes in the databases 
may introduce some level of misclassification bias of certain diagnoses, events, or procedures 
of interest in the study. Likewise, some variables of interest may not be as complete across 
the entire population. The iKM EHR contains information on patients only when they are 
seen by USON physicians. Services and procedures provided outside of the USON are not 
captured by the database, as well as drugs received by patients from pharmacies not affiliated 
with USON practices. A patient’s treatment history prior to his/her first encounter at a USON 
practice may be only available in physician progress notes and is not well captured in the 
iKM EHR. We cannot rule out the possibility that some patients coded as receiving being 
treatment naïve for advanced disease in iKM EHR actually had previous chemotherapy for 
advanced disease in healthcare facilities outside the USON.
To minimize this risk, a targeted chart review is being performed to verify patients’ 
eligibility and data elements that may not be reliably captured in structured fields. With chart 
review, progress notes and additional free-text can be reviewed to provide much richer 
source of information. All patients in the study sample will be selected for this chart review. 
Information Bias
Due to the nature of the study design, there is potential for bias to be introduced into the 
calculations of clinical outcomes. Specifically, patients who initiated treatment during the 
patient identification period may be meaningfully different from other patients who initiated 
therapy prior or after the study identification period. To minimize this risk, the study 
observation period will begin on the date palbociclib was approved for the treatment of 
metastatic breast cancer so that the study cohorts will both represent the treatment landscape 
after this approval. 
Confounding
The iKM system is used for clinical practice reasons, not solely for research purposes. As 
such, associations but not causality can be detected, thus bias may be introduced by 
confounding factors. For example, data may be collected with an intent-to-treat (ITT)
approach, meaning based on when treatment is assigned rather than received. In particular, it 
will not be possible to determine if oral therapies were dispensed or taken. To reduce this 
potential for bias, an ITT approach will be used for analysis, with the assumption that all 
prescribed oral therapies were taken.
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Likewise, patients who do and do not receive the treatment at one point in time may be 
fundamentally different than those who received treatment during the observation period. 
These confounding factors are most likely to affect the outcomes being considered for this 
estimation study. Statistical methodology such as IPTW and PSM will be employed to try to 
mitigate these potential biases.
9.9.2. External Validity of Study Design
Not all community oncology practices are included in the USON, which utilizes the iKM 
EHR and decision-support technology. Therefore, the results of this study will be most 
generalizable to other community oncology practices that adhere to evidence-based treatment 
guidelines. 
9.9.3. Analysis Limitations
As a retrospective observational study, data entry errors at the point of care may occur and 
influence the results. To reduce this risk, a targeted chart review will be performed to capture
or verify data elements that may not be reliably sourced through structured data. 
Additionally, Section 9.8 describes the quality control process that will be taken to ensure 
data from the EHR are captured correctly, which includes additional verification of outlying 
and missing values. 
9.9.4. Limitations Due to Missing Data and/or Incomplete Data
Although data quality checks are conducted, it is possible that some variables of interest may 
not be as complete across the entire population. To reduce this risk, a targeted chart review 
will be performed to capture or verify data elements that may not be reliably sourced through 
structured data.
Prescriber bias is a component of real-world treatment patterns in the absence of 
randomization and with a change in standard of care and can be adjusted for when 
confounders are known with statistical approaches including propensity score matching and 
inverse probability of treatment weighting. Addressing unobserved variables presents greater 
challenges and requires the ability to discern their influence. The USON iKM EHR dataset 
represents information collected as part of routine clinical practice and thus has limitations 
typical of data collected for purposes other than research. 
9.9.5. Real-World Tumor Response
Given the retrospective nature of the study, some limitations are present including those 
typical of a data source where the primary purpose for collection was other than research. 
These include incomplete or missing data, potential for inaccurate data capture, lack of 
scheduled assessments and lack of standardized tumor assessments. In addition, response to 
treatment and disease progression were determined based on the individual treating 
physician’s clinical assessment or interpretation of radiographic scans or pathology results 
rather than a standard criterion such as RECIST.
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The USON has deployed the iKM EHR and decision-support technology to encourage the 
use of evidence-based treatment and complete documentation. Therefore, it is expected that 
high proportion of patients will have tumor assessments documented. As evidence of this, 
based on a preliminary feasibility assessment, it is estimated that over 80% of patients will 
have tumor assessments documented. 
9.10. Other Aspects
Not applicable.
10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient Information 
Structured Data Analysis
This study involves data that exist in anonymized structured format and contain no patient 
personal information.  
Human Review of Unstructured Data
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic form and will be
password protected to ensure that only authorized study staff have access. The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster. In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
Patient personal data will be stored with the USON’s iKM EHR database in encrypted 
electronic form and will be password protected to ensure that only authorized study staff 
have access. The McKesson study team will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, McKesson shall be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.
The investigator site will maintain a confidential list of patients who participated in the study, 
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linking each patient’s numerical code to his or her actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the research agreement and applicable privacy laws.
IRB approval will be received prior to any patient level data transfer that occurs between 
McKesson and Pfizer. All other data will be reported only in aggregate form and with 
attention to results that represent small counts of patients.
10.2. Patient Consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required. 
The McKesson study team will submit a request for exemption, waiver of informed consent 
and authorization to the IRB. This project involves the study of existing data and records; the 
McKesson team will prepare a de-identified dataset with study information. The Pfizer study 
team will not perform any analysis intended to re-identify research participants. Once 
exemption status and a waiver of informed consent are met, a waiver of authorization can be 
approved, allowing the retrospective study to occur.
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (eg, informed consent forms if applicable) from the relevant IRBs/IECs. 
All correspondence with the IRB/IEC must be retained. Copies of IRB/IEC approvals must 
be forwarded to Pfizer.
10.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE) research practices 
(https://www.pharmacoepi.org/resources/guidelines_08027.cfm), Good Practices for 
Outcomes Research issued by the International Society for Pharmacoeconomics and 
Outcomes Research (ISPOR) (http://www.ispor.org/workpaper/practices_index.asp) and
Good practices for real-world data studies of treatment and/or comparative effectiveness: 
Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in 
health care decision making (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639372/) and 
similar standards.
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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS
Structured Data Analysis
This study involves data that exists 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.
Human Review of Unstructured Data
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol). Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) Adverse 
Event Monitoring (AEM) Report Form to Pfizer Safety are as follows:
•
All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded and reported, within 24 hours of 
awareness, to Pfizer Safety using the NIS AEM Report Form.
•
Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form.
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted.
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All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources. While not all demographic fields will be completed, at the 
very least, at least one patient identifier (eg, gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation. All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...” Other identifiers will have been removed. 
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month /year of occurrence in the day/month/year 
(DD/MMM/YYYY) format.
All research staff members must complete the following Pfizer training requirements: 
•
“YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”. 
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format. Copies of all signed training certificates must be provided to Pfizer. 
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials. 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
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 McKesson 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. 
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13. REFERENCES
1.
American Cancer Society. Cancer Facts & Figures 2020. Atlanta: American Cancer 
Society; 2020.
2.
Austin PC, Stuart EA. Moving towards best practice when using inverse probability of 
treatment weighing (IPTW) using the propensity score to estimate causal treatment 
effects in observational studies. Stat Med 2015;34:3661-79.
3.
Bartlett CH, Mardekian J, Cotter MJ, et al. Concordance of real-world versus 
conventional progression-free survival from a phase 3 trial of endocrine therapy as first-
line treatment for metastatic breast cancer. PLoS One. 2020 Apr 21;15(4):e0227256.
4.
Brufsky A, et al. Real-World Tumor Response of Palbociclib Plus Letrozole vs 
Letrozole for Metastatic Breast Cancer in US Clinical Practice. Abstract 176P. ESMO 
BC 2020. 
5.
Cowey CJ, Mahnke L, Espirito J, et al. Real-world treatment outcomes in patients with 
metastatic Merkel cell carcinoma treated with chemotherapy in the USA. Future 
Oncology 2017;13(9):1699-1710.
6.
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus 
Fulvestrantplus placebo for treatment of hormone-receptor-positive, HER2-negative 
metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): 
final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. 
Lancet Oncol. 2016;17(4):425-439.
7.
DeMichele A, Cristofanilli M, Brufsky A, et al. Overall survival for first-line 
palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast 
cancer patients in US real-world clinical practice. Poster Presented at: 2019 San 
Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX.
8.
DeSantis CE, Ma J, Goding Sauer A, et al. Breast cancer statistics, 2017, racial disparity 
in mortality by state. CA Cancer J Clin 2017;67:439–48.
9.
Dieras V, Rugo HS, Schnell P, et al. Long-term pooled safety analysis of palbociclib in 
combination with endocrine therapy for HR+/HER2- advanced breast cancer. J Natl 
Cancer Inst. 2018;111(4):419-30.
10.
FDA's July 2018 Industry Guidance on Use of Electronic Health Record Data in 
Clinical Investigations
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/UCM501068.pdf.
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11.
Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib 
in combination with Letrozole versus Letrozole alone as first-line treatment of 
oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-
1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16(1):25-35.
12.
Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. 
N Engl J Med. 2016;375(20):1925-1936.
13.
Finn R, Rugo R, Karen G, et al. Long-Term Pooled Safety Analysis of Palbociclib in 
Combination With Endocrine Therapy for Hormone Receptor–Positive/Human 
Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Updated 
Analysis. Poster presented at: 2019 San Antonio Breast Cancer Symposium; December 
10-14; San Antonio, TX.
14.
Gao JJ, Cheng J, Bloomquist E, et al. CDK4/6 inhibitor treatment for patients with 
hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US 
Food and Drug Administration pooled analysis. Lancet Oncol 2020;21(2):250-60.
15.
Im SA, Lu YS, Bardia A. Overall survival with ribociclib plus endocrine therapy in 
breast cancer. N Engl J Med 2019;381:307-16.
16.
Kumler I, Knoop AS, Jessing CA, et al. Review of hormone-based treatments in 
postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors 
and Fulvestrant. ESMO Open. 2016;1(4):e000062.
17.
Loibl S, Turner NC, Ro J, et al. Palbociclib combined with fulvestrant in premenopausal 
women with advanced breast cancer and prior progression on endocrine therapy: 
PALOMA-3 Results. Oncologist 2017;22(9):1028-38.
18.
Ma X, Nussbaum NC, Magee K, el al. Comparison of real-world response rate (rwRR) 
to RECIST-based response rate in patients with advanced non-small cell lung cancer 
(aNSCLC). Poster presented at: 2019 Congress of the European Society for Medical 
Oncology (ESMO); September 2019; Barcelona, Spain. 
19.
Mariotto AB, Etzioni R, Hurlbert M. et al. Estimation of the number of women living 
with metastatic breast cancer in the United States. Cancer Epidemiol Biomarkers Prev. 
2017;26(6):809-815.
20.
Mehrotra DV, Liu F, Permutt T. Missing data in clinical trials: Control‐based mean 
imputation and sensitivity analysis. Pharm Stat 2017;16:378-92. 
DOI: 10.1002/pst.1817.
21.
Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. 
CA Cancer J Clin. 2016;66(4):271-289.
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22.
Park YH, Kim TY, Kim GM, et al. Palbociclib plus exemestane with gonadotropin-
releasing hormone agonist versus capecitabine in premenopausal women with hormone 
receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a 
multicentre, open-label, randomised, phase 2 trial. Lancet Onc; 2019 Dec;20(12):1750-
1759.
23.
Patt D, Rembert D, Corzo D: Treatment of metastatic breast cancer with -paclitaxel in 
the community practice setting: a US Oncology survey. J Community Support Oncol
13:173-80, 2015.
24.
Patt D, Jiao X, Fonseca E, Clark J, Fox P, Horblyuk R, Mcroy L, Mardekian J, 
Arondekar B: Real-world use of first-line chemotherapy in post-menopausal patients 
with HR-positive HER2-negative metastatic breast cancer (MBC) in a US community 
oncology network. Presented at the ASCO Annual Meeting, Chicago, IL, Jun 3-7, 2016.
25.
National Comprehensive Cancer Network. Breast cancer (Version 2.2020). Available 
from: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 
6 February 2020.
26.
Robert N, Espirito J, Haydon W, Jenson K, Montelongo N, Spark S: Development of 
Playbook for Chart Review in Real-World Data. Presented at the ISPOR, New Orleans, 
LA, May 21, 2019.
27.
Robert N, Goertz HP, Jiao X, Yoo B, Patt D, Antao V: Pertuzumab (P) use in first-line 
HER2-positive metastatic breast cancer (MBC) in US community oncology practices: 
Treatment patterns and outcomes. Presented at the San Antonio Breast Cancer 
Symposium, San Antonio, TX, Dec 8-12, 2015.
28.
Shah AN, Metzger O, Bartlett CB, et al.  Hormone Receptor–Positive/Human 
Epidermal Growth Receptor 2–Negative Metastatic Breast Cancer in Young Women:
Emerging Data in the Era of Molecularly Targeted Agents. The Oncologist 2020;25: 
e900-e908.
29.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;
67:7–30.
30.
Taylor-Stokes G, Mitra D, Waller J, et al. Treatment patterns and clinical outcomes 
among patients receiving palbociclib in combination with an aromatase inhibitor or 
fulvestrant for HRþ/HER2-negative advanced/metastatic breast cancer in real-world 
settings in the US: Results from the IRIS study. The Breast 2019;43:22-7.
31.
Tanguy M, Cabel L, Berger F, et al. Cdk4/6 inhibitors and overall survival: Power of 
first-line trials in metastatic breast cancer. NPJ Breast Cancer 2018;4:14. 
DOI: 10.1038/s41523-018-0068-4.
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32.
Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for 
premenopausal women with hormone-receptor-positive, advanced breast cancer 
(MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018;19(7):904-915. 
DOI: 10.1016/S1470-2045(18)30292-4.
33.
Turner NC, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor-Positive Advanced 
Breast Cancer. N Engl J Med. 2015;373(3):209-219.
34.
Turner NC, Slamon DJ, Ro J, et al. Overall Survival with Palbociclib and Fulvestrant in 
Advanced Breast Cancer. N Engl J Med 2018;379:1926-36.
35.
US Oncology website: www.usoncology.com/our-company.
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14. LIST OF TABLES
Table 1.
Key Variables ...........................................................................................16
Table 2.
Patient Attrition (01 January 2010- 30 June 2020)...................................27
Table 3.
Menopausal Status by Cohort (Based on Structured Data Alone)* .........28
15. LIST OF FIGURES
Figure 1.
PALOMA-3 Subgroup Analysis by Menopausal Status ............................9
Figure 2.
Progression-Free Survival for Patients ≤40 Years of Age in Pooled 
Studies of CDK 4/6 Inhibitors..................................................................10
Figure 3.
Adjudication Process Scheme...................................................................36
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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None.
ANNEX 2. ADDITIONAL INFORMATION
Not applicable.
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