Real-World Treatment Patterns and Outcomes in Postmenopausal, Hormone-Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative, Metastatic Breast Cancer Patients Treated With Palbociclib Plus an Letrozole as Initial Endocrine Therapy at Community Oncology Practices in the U.S.
Conditions: Breast Cancer
Sponsor: Pfizer

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Study Information
Title
Real-World Treatment Patterns and Outcomes in 
Postmenopausal, Hormone-Receptor Positive, Human 
Epidermal Growth Factor Receptor 2 Negative,
Metastatic Breast Cancer Patients Treated with 
Palbociclib Plus an Letrozole as Initial Endocrine 
Therapy at Community Oncology Practices in the U.S.
Protocol number
A5481123
Protocol version identifier
1.0
Date 
20 November 2018
Active substance
Palbociclib/PD332,991
Medicinal product
Palbociclib
Research question and 
objectives
Objectives
Among postmenopausal women receiving palbociclib 
plus letrozole (palbociclib+LET) as initial endocrine 
therapy for hormone-receptor positive, human epidermal 
growth factor receptor 2 negative, advanced/metastatic 
breast cancer:
1. Describe the demographic and clinical 
characteristics of patients at the initiation of 
treatment.
2. Describe the frequency of laboratory monitoring 
for hematologic and cardiovascular toxicities 
during treatment.
3. Describe treatment patterns in terms of 
palbociclib+LET dosing, cycles received, and 
post-discontinuation treatment regimens.
4. Describe clinical outcomes in terms of objective 
disease response rates and progression-free 
survival during treatment.

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Author
 PhD, MPH
Cardinal Health
7000 Cardinal Place
Dublin, OH 43017
Email: 
 
Phone: 
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................5
2. RESPONSIBLE PARTIES....................................................................................................6
3. ABSTRACT...........................................................................................................................7
4. AMENDMENTS AND UPDATES.....................................................................................10
5. MILESTONES.....................................................................................................................11
6. RATIONALE AND BACKGROUND................................................................................12
7. RESEARCH QUESTION AND OBJECTIVES .................................................................13
7.1. Objectives................................................................................................................13
8. RESEARCH METHODS ....................................................................................................15
8.1. Study Design ...........................................................................................................15
8.2. Setting......................................................................................................................15
8.2.1. Inclusion Criteria ........................................................................................16
8.2.2. Exclusion Criteria.......................................................................................17
8.3. Variables..................................................................................................................17
8.4. Data Sources............................................................................................................19
8.5. Study Size................................................................................................................19
8.6. Data Management ...................................................................................................19
8.6.1. Case Report Forms (CRFs)/Electronic Data Record..................................20
8.6.2. Record Retention ........................................................................................20
8.7. Data Analysis ..........................................................................................................21
8.8. Quality Control........................................................................................................22
8.9. Limitations of the Research Methods......................................................................22
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................25
9.1. Patient Information..................................................................................................26
9.2. Patient Consent........................................................................................................26
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9.3. Patient Withdrawal..................................................................................................26
9.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............26
9.5. Ethical Conduct of the Study ..................................................................................27
10. MANAGEMENT AND REPORTING OF ADVANCE EVENTS/ADVANCE 
REACTIONS ......................................................................................................................27
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........28
12. REFERENCES ..................................................................................................................29
13. LIST OF TABLES.............................................................................................................31
14. LIST OF FIGURES ...........................................................................................................31
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS ...................................................31
16. ANNEX 2. ADDITIONAL INFORMATION...................................................................31

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
AEM
Adverse event monitoring
AI
Aromatase inhibitor
CBC
Complete blood count
CBR
Clinical benefit rate
CR
Complete response
CRF
Case report form
DOT
Duration of treatment
ECOG-PS
Eastern Cooperative Oncology Group performance status
eCRF
Electronic case report form
EMR
Electronic medical record
ER
Estrogen receptor
HER2
Human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HR
Hormone receptor
HR
Hazard ratio
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
LET
Letrozole
MBC
Metastatic breast cancer
NE
Not evaluated
NIS
Non-interventional study
OPEN
Oncology Provider Extended Network
ORR
Objective response rate
PD
Progressive disease
PFS
Progression-free survival
PHI
Protected health information
PR
Partial response
PR
Progesterone receptor
RCT
Randomized controlled trial
SAP
Statistical analysis plan
SD
Stable disease

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2. RESPONSIBLE PARTIES
Name, Degree(s)
Title
Affiliation
Address
, PhD, MPH
 
Cardinal 
Health
7000 Cardinal Place
Dublin, OH 43017
, DO
 
Cardinal 
Health
7000 Cardinal Place
Dublin, OH 43017
, MPH
Pfizer, Inc.
235 East 42nd Street
New York, NY, 10017
 MD, PhD
 
Pfizer, Inc.
235 East 42nd Street
New York, NY, 10017
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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3. ABSTRACT
Title: Real-World Treatment Patterns and Outcomes Postmenopausal, Hormone-Receptor 
Positive (HR-positive), Human Epidermal Growth Factor Receptor 2 Negative 
(HER2-Negative), Metastatic Breast Cancer (MBC) Patients Treated with Palbociclib Plus 
Letrozole (Palbociclib+LET) as Initial Endocrine Therapy at Community Oncology Practices 
in the U.S.
Rationale and Background: Real-world research describing the demographic and clinical 
profile of patients, treatment patterns, and clinical benefit of palbociclib+LET as initial 
endocrine therapy for postmenopausal, HR-positive, HER2-negative MBC has been limited 
by small patient cohorts and short durations of follow-up. Similarly little is known regarding 
the profile of patients being prescribed newer agents such as ribociclib or what drives the
continued use of aromatase inhibitor (AI) monotherapy as initial endocrine therapy for MBC
with the availability of the cyclin-dependent kinase (CDK) 4/6 agents.
Research Question and Objectives: This study aims to describe demographics, clinical 
characteristics, toxicity monitoring, treatment patterns and clinical outcomes across a 
geographically diverse, representative cohort of MBC patients receiving palbociclib+LET
according to its labeled indication at U.S. community oncology practices.
Objectives
Among postmenopausal women receiving palbociclib+LET as initial endocrine therapy for 
HR-positive, HER2-negative, MBC:
1. Describe demographic and clinical characteristics of patients at the initiation of 
treatment.
2. Describe the frequency of laboratory monitoring for hematologic and cardiovascular 
toxicities during treatment.
3. Describe treatment patterns in terms of palbociclib+LET dosing, cycles received, and 
post-discontinuation treatment regimens.
4. Describe clinical outcomes in terms of objective response rates (ORR),
progression-free survival (PFS) during treatment and survival.
 
 
 
 
 
 
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Study Design: This will be a retrospective, observational study with all data used having 
been collected as a routine part of clinical care.  Providers will identify patients meeting the 
study selection criteria.  Providers will be recruited to participate from the Cardinal Health 
Oncology Provider Extended Network, a community of over 7,000 clinical personnel treating 
cancer patients in the U.S.  Providers who indicated treating patients of interest during a prior 
feasibility assessment will be asked to participate in the research.  Providers will abstract data 
from his/her patients’ medical records into an electronic case report form.  Cardinal Health 
will conduct data verification via telephone and electronic follow-up with providers.
Population: The study will include adult female patients with HR-positive/HER2-negative
MBC who were treated with palbociclib+LET as initial endocrine therapy on or after 
03 February 2015.  Providers will randomly select cases beginning with the earliest 
palbociclib+LET treated patient at least 3 months following the providers’ first use of 
palbociclib.
 
 
 
Variables: Patient demographics, clinical characteristics, treatments, complete blood count 
(CBC)/cardiac toxicity monitoring patterns, and clinical outcomes will be collected and 
analyzed.
Data Source: All data will be collected by the patients’ treating physician and entered into 
the eCRF.
Study Size: This is a descriptive study and sample size calculation is not applicable.  The 
target sample size of female, adult, HR-positive, HER2-negative MBC patients receiving 
initial endocrine therapy with palbociclib+LET is 200. 
 
Data Analysis: Descriptive analysis will be conducted to describe patient demographics, 
clinical characteristics, treatment and monitoring patterns, and clinical outcomes.  For PFS 
and other time to event analyses, Kaplan-Meier methods will be used estimate the time to 
event accounting for right-censoring. 
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Milestones:

Start of data collection: Q1 2019.

Final study report: Q2 2019.

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4. AMENDMENTS AND UPDATES
Amendment 
number
Date
Substantial or 
administrative 
amendment
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Reason

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5. MILESTONES
Milestone
Planned date
Project kickoff
30 May 2018
Study protocol development
Q3-Q4 2018
Study protocol finalization/approval
Q4 2018
Statistical analysis plan (SAP) & table shells
Q3-Q4 2018
SAP & table shells finalization/approval
Q4 2018
Case report form (CRF) development
Q4 2018
CRF finalization/approval
Q4 2018
Institutional review board 
preparation/submission/approval 
Q4 2018
Electronic CRF (eCRF) programming & testing
Q4 2018
eCRF pre-test (n=4)
Q4 2018
Recruitment & data collection – Phase 1
Q1 2019
Interim report 
Q1 2019
Recruitment & data collection – Phase 2
Q2 2019
Final results
Q2 2019
Final study report
Q2 2019

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6. RATIONALE AND BACKGROUND
Palbociclib is approved for the treatment of HR-positive, HER2-negative MBC in 
combination with an AI as initial endocrine based therapy in postmenopausal women or in 
combination with fulvestrant in women with disease progression following endocrine 
therapy.1 Approval was based on the randomized phase II PALOMA-1 trial, which 
demonstrated that the addition of palbociclib to letrozole significantly improved PFS in 
patients with advanced estrogen receptor positive (ER-positive)/HER2-negaive MBC 
(median PFS, 20.2 months vs. 10.2 months; hazard ratio [HR]=0.448; P=0.0004).2
Palbociclib in combination with fulvestrant was approved one year later (February 2016) in 
pre- or postmenopausal women with disease progression following endocrine therapy based 
on results from the PALOMA-3 randomized controlled trial (RCT).3 In the phase III RCT, 
PALOMA-2, the findings of PALOMA-1 were confirmed.  The median PFS estimate in the 
palbociclib+LET arm was 24.8 months compared to 14.5 months in the placebo plus 
letrozole arm (HR=0.58; P<0.001).4
Since the initial approval of palbociclib in February 2015, real-world observational studies 
have described treatment patterns, dose modifications, and tolerability using multiple distinct 
retrospective databases.5-8 Estimates of the clinical benefit (partial response or better as 
reported by the treating provider) of palbociclib+LET presented in early 2018 were markedly 
similar ranging from 79.5% to 83.5%.6,8 Landmark PFS analysis varied between the two 
studies ranging from 80.0% to 96.7% at 6 months, 67.1% to 84.1% at 12 months, and 
54.7% to 69.3% at 18 months.6,8 A 24-month estimate was available from one study 
(reported the higher estimates at each of the 6-, 12-, and 18-month interval previously 
referenced), which found 64.3% of patients were progression-free at 24 months.  With an 
additional year of real-world experience accrued since the time of data collection for these 
studies, more precise estimates of disease response and PFS are available. 
The prior research was not statistically powered to compare outcomes between 
palbociclib-treated patients to those who received LET monotherapy.  A large proportion of 
female HR-positive/HER2-negative MBC continue to be prescribed AI monotherapy in lieu 
of the results of the PALOMA trials.9 Moreover, recently published research indicates a 
higher rate of discontinuation (45.8% vs. 34.5%) for women prescribed AI-monotherapy.9
The differences in the demographic and clinical disease characteristics of women receiving 
first-line treatment with LET versus those prescribed palbociclib+LET have not been 
explored nor have clinical outcomes between them been compared.  Additionally, since the 
completion of the previously described real-world research ribociclib was approved in same 
indication as palbociclib in March of 2017 (in combination with an AI as initial 
endocrine-based therapy for the treatment of postmenopausal women with 
HR-positive/HER2-negative MBC).10 No real-world data on clinical characteristics, 
treatment patterns (including dose reductions and rates of discontinuation), or early estimates 
of rates of progression have been explored in a real-world cohort of ribociclib+AI treated 
patients.  Further exploration of treatment patterns and clinical outcomes in terms of rates of 
progression, which patients receive LET or ribociclib+AI, and the outcomes of this treatment
is needed to understand the types of patients most likely to benefit from palbociclib+LET in 
the indicated population.

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7. RESEARCH QUESTION AND OBJECTIVES
The main objective of this study is to describe patient demographics, clinical characteristics, 
toxicity monitoring, treatment patterns and clinical outcomes among postmenopausal, 
female, HR-positive, HER2-negative, MBC patients receiving palbociclib+LET as initial 
endocrine therapy.  Demographic and clinical characteristics and outcomes will be presented 
overall, and among groups for the following three planned primary grouping variables:
1. Visceral vs. non-visceral at the initiation of initial endocrine therapy for MBC.
2. Received prior neo/adjuvant endocrine therapy versus no prior neo/adjuvant therapy.
3. De novo metastatic disease versus ≤12 months disease free interval since prior 
neo/adjuvant treatment versus >12 months disease free interval since prior 
neo/adjuvant treatment.
7.1. Objectives
Among MBC patients receiving palbociclib+LET according to its labeled indication as initial 
endocrine therapy for MBC the research objectives are to:
1. Describe the demographic and clinical characteristics of patients at the initiation of 
treatment:
a.
Demographic characteristics will include age, race/ethnicity, body mass index, 
insurance status, state of residence at the date of MBC diagnosis and palbociclib 
initiation.  Employment status will be assessed to the extent documented in the 
record.  Overall duration of follow-up (months) from the initiation of 
palbociclib+LET will be presented.
b. Clinical characteristics will include year of breast cancer and MBC diagnosis, 
stage of initial diagnosis, menopausal status, number and sites of distant 
metastasis at MBC diagnosis and palbociclib initiation, verification of HER2 and 
ER/progesterone receptor (PR) status, histology, menopausal status at
palbociclib+LET initiation, performance status and comorbid disease burden, 
including cardiovascular-related comorbidities (at MBC diagnosis and at 
palbociclib initiation), and modalities of treatment received in the neoadjuvant or 
adjuvant setting (chemotherapy, hormone therapy, surgery, radiation therapy).
2. Describe the frequency of laboratory monitoring for hematologic and cardiovascular 
toxicities during treatment:
a.
Note that CBC monitoring and cardiac function monitoring will be assessed, but 
lab results/values will not be assessed under this objective.

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b. Evaluate the extent of laboratory monitoring using CBC per cycle:
i.
The frequency of assessment of CBC with or without differential will be 
evaluated during the initial endocrine-based therapy for MBC.
c.
Assess the frequency of cardiac toxicity monitoring using electrocardiogram, liver 
function panels, and electrolytes:
i.
The frequency of assessment of cardiac monitoring by each method will be 
evaluated during the initial endocrine-based therapy for MBC.
3. Describe treatment patterns in terms of palbociclib+LET dosing, cycles received, and 
post-discontinuation treatment regimens:
a.
Palbociclib dosing will include description of the starting dose, dose adjustment, 
discontinuation, and time to dose adjustment for palbociclib.
b. Duration of palbociclib in terms of the number of cycles completed prior to the 
discontinuation of initial treatment for MBC.
c.
Treatment patterns includes the distribution of regimens administered, by line, 
from MBC diagnosis through the end of the medical record.
d. Treatment patterns also includes the sequence of treatments across lines, from 
MBC diagnosis through the end of the medical record.
4. Describe clinical outcomes in terms of objective disease response rates and 
progression-free survival during treatment:
a.
Describe the rate of objective disease response during initial endocrine-based 
therapy:
i.
Tumor response will be classified per provider report for each regimen 
received during MBC treatment.
ii. Tumor response will be classified under a primary response classification as 
complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD), and unknown/not evaluated (NE).
iii. Tumor response will be classified under a secondary response classification as 
matching the primary classification, but patients with NE responses 
classifiable as Other Favorable or Other Unfavorable so classified.
b. Describe progression-free survival and/or time to progression from the initiation 
of initial endocrine-based therapy:
i.
Landmark PFS and/or rate of progression at 3, 6, 12, 18, and 24 months.
ii. Proportion alive at 6, 12 and 24 months.

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8. RESEARCH METHODS 
8.1. Study Design
The current study will be conducted as a retrospective observational cohort study using a 
chart review methodology.  Providers in the Cardinal Health Oncology Provider Extended 
Network (OPEN) will be recruited to participate in the patient identification and data 
abstraction for this research study.  All study data are secondary data and will have been 
collected retrospectively from existing clinical data originally collected as part of routine 
care. 
Patient eligibility will be confirmed by the treating physician.  Providers will abstract the 
patient level data necessary to achieve the research objectives into an electronic case report 
form (eCRF).  Providers may complete a maximum of 20 eCRFs; verification of submitted 
data will be performed by Cardinal Health Clinical Research Operations via clinical data 
quality review of submitted eCRFs (further description of data verification processes are 
provided in Section 8.8).  In order to achieve the research objectives related to the estimation 
of a 24-month PFS, providers will be asked to select consecutive patients starting with the 
earliest patient treated with palbociclib+LET meeting all the study eligibility requirements 
(See Section 7.2).  In addition, providers will be asked to consider the “earliest” 
palbociclib+LET treated patient as the first patient treated 60 days after the first instance they 
prescribed palbociclib+LET in clinical practice outside of a clinical trial.  In total up to
200 patients treated with palbociclib+LET per labeled indication will be identified. 
8.2. Setting
Providers from OPEN will identify patients meeting the study selection criteria.  OPEN is a 
community of over 7,000 oncologists, hematologists and urologists providing care to cancer 
patients geographically distributed across the U.S. and practicing in both community and 
academic research settings.  OPEN community members include medical doctors, nurse 
practitioners, pharmacists and other individuals providing care to cancer patients.  
Community members are not limited to any specific group purchasing organization or any 
other membership requirements.  Community members are included in OPEN if they and 
their practice utilizes Cardinal Health’s proprietary Point-of-Care claims remittance software 
for practice management purposes or if they have participated in Cardinal Health sponsored 
research activities.  Providers within the OPEN database are evenly distributed between 
regions (Northeast, Midwest, South and West regions) across different size practices (small, 
medium or large practice) and years of experience in providing cancer care.
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To be eligible for participation in this research study, a physician must have treated or be 
treating two or more HR-positive/HER2-negatie MBC patients who meet the eligibility 
criteria for the study.  Providers who responded to the initial feasibility survey will be the 
first set of physicians asked to participate in the research.  Should further recruitment be 
required to achieve the desired sample size Cardinal Health will recruit from its entire 
database of providers.
Providers will be allowed to complete up to 20 eCRFs.  Providers will be asked to indicate 
the number of patients considered eligible for the research but for whom records were not 
entered.  No data for the patients not entered into the eCRF will be collected.  Providers must 
also be able to participate in the research monitored by a central Institutional Review Board 
(IRB).  No site specific IRB approval will be sought and providers requiring this approval 
will not be eligible. 
After IRB approval of the research protocol, the eCRF will be pre-tested with 4 providers;
data collected as part of the pre-test will not be used in the final analytical dataset.  After 
testing and revisions (if necessary), providers who completed a feasibility assessment for the 
research will be contacted and asked to participate in the research.  Data collection will be 
conducted over the course of 4-weeks.  Providers are compensated at fair market value for 
each completed and verified eCRF assuming a rate of payment based on one hour of data 
collection (see Section 8.6.1). 
8.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Diagnosed with locoregional recurrent or metastatic female breast cancer.
2. Pathologically confirmed HR-positive/HER2-negative diagnosis.
3. Received treatment with palbociclib in combination with letrozole as initial 
endocrine-based therapy for advanced/metastatic breast cancer:
a.
Initiated treatment with palbociclib at least 3 months following the provider’s first 
use of palbociclib following its FDA approval.
b. At least 1 month of follow-up (at least one visit with the provider) after initiation 
of palbociclib.
4. Postmenopausal (or receiving surgical or medical treatment to induce menopause) at 
the time of initiation of palbociclib.
5. ≥18 year old at initiation of palbociclib.

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8.2.2. Exclusion Criteria
No exclusion criteria will be imposed for the selection of patients.i
8.3. Variables
For purposes of this study, a regimen will be defined as one or more anti-cancer agents given 
in combination, over a period of time.  Providers will be informed as to the definition of a 
regimen but will make the determination themselves as to what constituted a line of therapy 
in the advanced/metastatic setting.  However, re-assignment of the lines of therapy in the
metastatic setting may occur during data analysis based on the dates regimens were initiated 
and discontinued and the rationale for that discontinuation.  For example a patient treated 
with palbociclib+LET who discontinued palbociclib but continued with LET may be 
indicated as a single line by the provider but the use of LET monotherapy may be recoded as 
a subsequent line of therapy during the analysis phase.  All dates of initiation and 
discontinuation of individual agents when received in combination will be abstracted by the 
patient’s treating physician.
Additionally, disease progression is taken to have occurred when a pathology report or 
radiological scan note indicates disease progression and/or there is a physician progress note 
consistent with that determination.  Providers will be informed of these criteria and indicate 
the date of disease progression as recorded in the patient charts during initial endocrine 
therapy for MBC following that guidance.
The table below describes data elements to be abstracted by the provider (“Abstracted Data 
Points”) and independent/exposure variables calculated from the abstracted data (“Calculated 
Variables”).
Variable
Operational definition
Patient 
demographics
Abstracted Data Points: Year of birth, payer, state of residence, 
ethnicity, weight, height, ER status, PR status, HER2 status, family 
history of breast cancer.
Calculated Variables: age at advanced/metastatic diagnosis, age at 
initiation of endocrine-based therapy, body mass index.
Clinical 
characteristics
Abstracted Data Elements: date of initial breast cancer diagnosis, 
date of diagnosis of advanced/metastatic disease, AJCC stage, node 
status, menopause status, ECOG-PS (@ treatment for 
advanced/metastatic disease), sites of metastatic disease (@ 
initiation of treatment for advanced/metastatic disease), 
comorbidities (@ initiation of treatment for advanced/metastatic 
disease.
Calculated Variables: time to advanced/metastatic disease, 
Charlson comorbidity index.
                                                
i Participation in any interventional clinical trials following the diagnosis of metastatic or locoregionally 
advanced breast cancer will be flagged for further evaluation.

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Variable
Operational definition
Neo/adjuvant 
treatment history
Abstracted Data Elements: chemotherapy/hormonal therapy
regimens received, date of discontinuation of adjuvant treatment, 
type of surgery, receipt of radiotherapy.
Calculated Variables: disease free interval (time from 
discontinuation of adjuvant therapy to diagnosis of 
advanced/metastatic disease).
Initial
endocrine-based 
therapy treatment 
characteristics
Abstracted Data Elements: Drug and/or combination endocrine 
partner, date of initiation, date of discontinuation, total number of 
cycles received, dose at initiation, dose reductions, dose increases, 
rationale for dose increase/decrease, treatment interruptions 
(eg, drug holiday), rationale for treatment discontinuation 
(eg, progression, toxicity, patient choice).
Calculated Variables: duration of treatment (DOT) with initial 
endocrine-based therapy.
Initial 
endocrine-based 
therapy laboratory 
monitoring
Abstracted Data Elements: Frequency of CBC monitoring, dates 
of CBC monitoring during first 6 cycles of therapy, dates of cardiac 
monitoring using electrolyte panel, liver function panel, 
electrocardiogram.
Calculated Variables: None.
Clinical outcomes 
during initial 
endocrine-based 
therapy
Abstracted Data Elements: provider assessed response to therapy 
(CR, PR, SD, PD), date of best initial response (CR, PR, SD), date 
of disease progression, stable disease lasting >24 weeks, 
favorable/unfavorable response (if stable), development of new 
measurable target lesions since initiation of endocrine-based 
therapy.
Calculated Variables: visceral disease at initiation of 
endocrine-based therapy, duration of stable disease, ORR
(CR+PR+SD lasting greater than 24 weeks).
Advanced/metastatic 
treatment patterns 
following 
discontinuation of 
initial 
endocrine-based 
therapy
Abstracted Data Elements: drug regimens received post 
discontinuation of initial endocrine-based therapy (chemotherapy, 
switch to alternative endocrine), date of initiation and 
discontinuation of treatment regimens received.
Calculated Variables: total lines of therapy received in the 
metastatic setting.
Status at last 
follow-up
Abstracted Data Elements: date of last follow-up, receipt of 
hospice care, receipt of palliative care, date of death (if deceased), 
cause of death.
Calculated Variables: None.

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8.4. Data Sources
Providers will complete data abstraction into the eCRF using all structured and unstructured 
data, including laboratory, pathology, and radiology files from the selected patients’ 
electronic health records. 
8.5. Study Size
To ensure sufficient patients treated with palbociclib+LET could be identified a feasibility 
assessment was conducted.  A random sample of providers in the OPEN database were 
queried in March 2018 to determine the number of potential patients’ eligible for the 
research.  Among the 51 physicians who responded, 44 (86%) reported treating a total of 
804 HR-positive/HER2-negative MBC patients with palbociclib+LET in the past year.  
Among those 804 patients treated with palbociclib combination therapy in the past year, 
126 achieved CR, 340 achieved PR, 232 achieved SD, 95 achieved PD, and 11 were missing 
response documentation.  Based on the results of this query, it is estimated that Cardinal 
Health through OPEN will be able to identify 200 patients treated with palbociclib+LET, 
 for the study cohort.
8.6. Data Management 
All study data will be entered into the eCRF.  The eCRF is designed to allow providers to 
efficiently move through the patient chart or electronic medical record (EMR) based on the 
journey of the patient through the course of their disease.  The eCRF conforms to the rules 
and regulations of the Health Insurance Portability and Accountability Act (HIPAA) of 
1996 governing the abstraction and storage of protected health information (PHI).  No
protected health information will be collected in the course of the chart review or stored in 
the eCRF.
Physicians will be compensated through an honoraria payment for each completed and 
validated eCRF.  The eCRF is anticipated to take up to 45 minutes per patient to complete,
and the rate of payment to providers for participation in this study is $300/completed and 
validated eCRF.  Participating physicians will be asked to complete the chart review 
individually, meaning that site research staff or supportive staff will not complete any data 
abstraction. 
Cardinal Health will be responsible for the programming, testing, and hosting of data from 
submitted eCRFs.  Providers will access the eCRF through a secure web-based portal, 
including during the field testing procedures, with all data stored on encrypted, password 
protected and HIPAA compliant servers housed within the Cardinal Health electronic data 
storage infrastructure.  Cardinal Health will perform extensive testing of the eCRF to ensure 
functionality across web-based user environments, looping logic to ensure proper alignment 
of data-related fields (required responses to certain fields prior to entering data into 
subsequent field), and other programmatic checks to ensure the reduction of the input of 
erroneous data (such as specifying maximums for year of birth or initiation of first-line 
treatment within the dates of the enrollment period).  In addition, the eCRF will be 
field-tested among 4 providers to ensure its functionality, the correct interpretation of the 
questions in relation to the data points of interest, and the length of time required for 
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completion for a single patient.  The pre-test results will be reviewed by Pfizer with Cardinal 
Health staff; however, Pfizer will not have access to the individual data collected.  Any 
changes made to the eCRF document as a result of the pre-test will require the resubmission 
of the eCRF and study protocol to the IRB. 
8.6.1. Case Report Forms (CRFs)/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.  Cardinal Health shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
Cardinal Health 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 an authorized staff member of Cardinal Health 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.
In most cases, the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at Cardinal Health and at Pfizer that clearly identifies those data that will 
be recorded on the CRF, and for which the CRF will stand as the source document. 
8.6.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, 
Cardinal Health agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, 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 Cardinal Heath according to local regulations or as specified in the vendor 
study contract whichever is longer.  The investigator must ensure that the records continue to 
be stored securely for so long as they are retained.
If Cardinal Health 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, such as another investigator, another 
institution, or to an independent third party arranged by Pfizer. 

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Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
8.7. Data Analysis 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a SAP, which will be dated, filed and maintained by the sponsor.  The SAP 
may modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment.
Beyond the variables described in Section 8.3, non time-to-event clinical outcomes of interest 
include the ORR and clinical benefit rate (CBR) (CR+PR+SD lasting >24 weeks).  The ORR
and CBR will be evaluated according the provider assessed response to therapy.  
Additionally, providers will also enter the data of disease progression into the eCRF 
(or discontinuation due to toxicity or other rationale) as reported in the patient charts.  PFS
and/or time to progression will be assessed at 6-, 12-, 18-, and 24-month following the 
initiation of therapy (survival rates will also be reported separately).
All categorical or numeric non time-to-event variables collected from the chart data 
abstraction or calculated from said data will analyzed using descriptive statistical techniques.  
For numeric variables, the mean, standard deviation, median, and minimum/maximum will 
be calculated as appropriate.  For categorical variables, frequencies and percentages will be 
provided.  The number of missing or unknown observations will be described for both 
categorical and numeric variables.  The 95% confidence internals will be provided as a 
measure of estimated precision when appropriate.  Comparisons of categorical variable will 
be made using Chi-square tests (or Fisher exact test) while the student’s T-test (or Wilcoxon 
rank-sum test), F-test or other non-parametric equivalent test will be used to compare values 
for numeric variables.  Statistical significance will be determined using a two-sided =0.05.  
For univariate comparisons of proportions, any analysis resulting in less than 5 individuals in 
any cell will not be performed.  Similarly, the minimum number of patients to conduct an
analysis comparing means of some continuous variable is 30 patients.
Survival analysis, also called time to event analysis, will be used in the current research to 
describe duration of stable disease, time to disease progression, and PFS.  This method of 
analysis is employed when non-informative right-censoring of observed time-to-event 
occurs, as is the case for this study since not all patients will have progressed by the end of 
the study period, the Kaplan-Meier method (product limit estimator) will be used to generate 
median estimates of time to events if median time is reached within the population and 
survival curves will also be generated.  In addition to calculating the median survival 
estimate, the life-table method will be used to estimate progression free rates and PFS at 
6-, 12-, 18-, and 24-month following initiation of endocrine-based therapy in the metastatic 
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8.8. Quality Control
During data collection, Cardinal Health’s clinical research staff will review all submitted 
eCRFs for quality control.  Cardinal Health’s clinical research team will inspect each 
submitted eCRF for implausible dates (ie, date of death prior to last date of treatment), 
non-standard treatments, lab and radiology results which are inconsistent with known clinical 
parameters, or other clinical data which is inconsistent with known standards and outcomes.  
Should these items be discovered, Cardinal Health’s clinical research team will contact the 
provider submitting the eCRF for data verification.  All providers are informed in their 
contractual agreement that follow-up with clinical staff at Cardinal Health may be required.  
Participating providers are asked to create a 4-digit unique identifier code per patient which 
is provided to Cardinal Health through the eCRF and used for identifying the patient record 
for verification between Cardinal Health and the provider.
In addition to review of the submitted data by the clinical research team, the study statistician 
will conduct an analysis of submitted data to identify any data points which are inconsistent 
(outliers) with the study population average.  This analysis will include a descriptive analysis 
of the provider characteristics, demographics, baseline clinical and disease characteristics, 
and characteristics of treatment patterns (eg, DOT).  Data points flagged as outliers will be 
delivered to the clinical research team who will contact providers to validate data as 
previously described.
8.9. Limitations of the Research Methods
The key limitation of this research and research of this nature involving retrospective medical 
chart review abstraction by a patient’s treating providers is the reliance on the provider to 
accurately complete the eCRF.  In order to ensure clarity and consistency in reporting, the 
eCRF will be internally and externally pre-tested.  In addition, clinical data quality review 
will be conducted for each eCRF and invalid or outlier data will be flagged for further review 
with the treating clinician by Cardinal Health clinical research staff. 
Several other limitations impact the external generalizability the results of this retrospective 
cohort study.  Given that providers abstract data on selected patients there is an opportunity 
for the following to occur: (1) provider selection bias; (2) patient selection bias; (3) and 
information bias, related to the availability and quality of data contained within the patient 
charts.
In terms of the representativeness of the provider cohort by imposing a maximum number of 
eCRFs which can be completed this bias is reduced.  With a maximum of 20 eCRFs, the 
minimum number of providers participating is 30.  While the number of providers to be 
recruited is not specified, not all providers will submit the maximum number of patients.  In 
past research of this nature, the median number of eCRFs submitted per provider is 10.  
Based on this assessment, the expected number of providers participating is 60.  Providers 
invited to participate but not participating in the research will not be described.

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In this study, the magnitude of a patient selection bias will be assessed by quantifying the 
number of potentially eligible patients and the number of patients submitted for inclusion by 
the provider.  To address this potential bias, providers may only contribute a maximum of 
20 patient eCRFs, of which, no more than 10 eCRFs may be submitted for any single 
treatment group.  Differences between providers submitting fewer than 5 versus more than 
5 eCRFs may be explored to assess systematic differences and address the potential selection 
bias. 
In regard to information bias, while providers are asked to consult all available patient 
records certain elements such as the pharmacy dispensing record, data may not be available 
directly making it possible that items such as dates of initiation and discontinuation of 
treatment would be less accurate compared to data obtained from an administrative claims 
database.  Similarly, data points such as date of death will be determined based on patient 
records; providers are not asked to verify date of death based on the Social Security 
Administration or commercial entities which collect detailed death data.  In all these 
examples, the data are assumed to be missing at random and inspection of data elements will 
be used to confirm this hypothesis. 
There is also a risk of incomplete data as a result of variable patient follow-up with a single 
provider.  Patients may have initiated care at another provider and transitioned to the 
provider or practice completing the data abstraction.  Patients may also have received care 
from another provider within the practice at multiple points during the course of their disease 
management and treatment.  Thus, data elements from the prior period may not be captured 
in the participating physician’s EMR or clinical notes and providers abstracting the data may 
misinterpret the intent of the treating provider’s notes.  In this study, it is required that the 
patient submitted for study inclusion has been managed and or seen by the provider 
submitting the data or at the providers practice in order to minimize these potential biases.
 
 
 
 
 
 
 
 
  
 
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9. PROTECTION OF HUMAN SUBJECTS
All study materials, including the research protocol and paper-version of the eCRF, will be 
reviewed by a central IRB prior to any data abstraction including field-testing of the eCRF.  
Providers are required to be able to participate in research monitored by a central IRB.  At all 
times, patients’ PHI will be kept confidential in accordance with HIPAA.  The eCRF will not 
capture any data related to the patients’ name, full date of birth, social security number, 
health insurance plan number, medical record number, or other such PHI although PHI 
related to dates of treatment or clinical events will be collected.  A waiver for obtaining 
informed consent from the provider or patient is sought for this research given the minimal 
risk imposed by the data elements to be collected. 
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This study was designed and shall be implemented and reported in accordance with the 
Guidelines for Good Pharmacoepidemiology Practices of the International Society for 
Pharmacoepidemiology (ISPE) 2008, the STROBE (Strengthening the Reporting of 
Observational Studies in Epidemiology) guidelines,12 and with the ethical principles laid 
down in the Declaration of Helsinki. 
9.1. Patient Information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted form and will be password 
protected to ensure that only authorized study staff have access.  Cardinal Health will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural, persons with regard to the processing of 
personal data when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single patient-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the Clinical Study Agreement and applicable privacy laws.
9.2. Patient Consent
As this study involves anonymized structured or unstructured data, which according to 
applicable legal requirements do not contain data subject to privacy laws, obtaining informed 
consent from patients by Pfizer is not required. 
9.3. Patient Withdrawal
Not applicable.
9.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
The study will be submitted to a centralized independent IRB in the U.S. for approval of the 
methodological approach and for obtaining a waiver of informed consent.  An exemption will 
be sought on the basis that the study will collect only secondary data, no PHI will be 
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9.5. 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 
ISPE, Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR), the STROBE (Strengthening the 
Reporting of Observational Studies in Epidemiology) guidelines, and with the ethical 
principles laid down in the Declaration of Helsinki.
10. MANAGEMENT AND REPORTING OF ADVANCE EVENTS/ADVANCE
REACTIONS
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database.  The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol).  Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the CRF 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.
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.

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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.
11. 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 the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.

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12. REFERENCES
1.
Xu H, Yu S, Liu Q, et al. Recent advances of highly selective CDK4/6 inhibitors in 
breast cancer. J Hematol Oncol 2017;10:97.
2.
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;16:25-35.
3.
Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus 
fulvestrant plus 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;17:425-39.
4.
Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast 
Cancer. N Engl J Med 2016;375:1925-36.
5.
Kish JK, Ward MA, Garofalo D, et al. Real-world evidence analysis of palbociclib 
prescribing patterns for patients with advanced/metastatic breast cancer treated in 
community oncology practice in the USA one year post approval. Breast Cancer Res 
2018;20:37.
6.
McRoy L MJ, Trocio J. Real-World Clinical Outcomes in Patients Treated with 
First-Line Palbociclib in Combination Endocrine Partner at 2 Years Postapproval. 35th
Annual Miami Beach Breast Cancer Conference, March 8-11, Miami Beach, FL, USA 
2018.
7.
Xu W MJ, McRoy L, Wang Y, Harnett J, Bell T. Population Characteristics and 
Utilization Patterns of Patients Treated with Palbociclib Over 2 Years of Postapproval. 
San Antonio Breast Cancer Symposium December 5-9, San Antonio, TX, USA 2017.
8.
Mitra D T-SG, Waller J, Gibson K, Milligan G, Iyer S. Real World Treatment Clinical 
Outcomes Assocaited with Palbociclib Combination Therapy in the United States: 
Results from the IRIS Study. 35th Annual Miami Beach Breast Cancer Conference, 
March 8-11, Miami Beach, FL, USA 201.
9.
Goldschmidt D, Dalal AA, Romdhani H, et al. Current Treatment Patterns Among 
Postmenopausal Women with HR+/HER2- Metastatic Breast Cancer in US Community 
Oncology Practices: An Observational Study. Adv Ther 2018;35:482-93.
10.
Blank CU, Larkin J, Arance AM, et al. Open-label, multicentre safety study of 
vemurafenib in 3219 patients with BRAF (V600) mutation-positive metastatic 
melanoma: 2-year follow-up data and long-term responders' analysis. Eur J Cancer 
2017;79:176-84.

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11.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
12.
Vandenbroucke, JP, Von Elm, E, Altman, DG, et al. Strengthening the Reporting of 
Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS 
Med 2008, 4:297.

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13. LIST OF TABLES 
None.
14. LIST OF FIGURES
None.
15. ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
16. ANNEX 2. ADDITIONAL INFORMATION
Not applicable.