Retrospective, Multicenter, Observational Study to Evaluate Overall Survival in Japanese Patients With HR+/HER2- Advanced Breast Cancer Treated With Palbociclib Plus Letrozole
Conditions: Breast Cancer
Sponsor: Pfizer

Palbociclib
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Retrospective, Multicenter, Observational 
Study to Evaluate Overall Survival in 
Japanese Patients With HR+/HER2-
Advanced Breast Cancer Treated with 
Palbociclib Plus Letrozole
Protocol number
A5481154
Protocol version identifier
Amendment 1
Date
07 April 2022
Active substance
Palbociclib (L01XE33)
Medicinal product
Palbociclib (IBRANCE)
Research question and objectives
To evaluate overall survival in Japanese 
patients with HR+/HER2- advanced breast 
cancer who have been treated with 
palbociclib plus letrozole in first-line setting 
Author
(NI study lead)
, Pfizer 
Oncology Japan
 
 Pfizer Oncology Japan
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
PPD
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS.......................... ERROR! BOOKMARK NOT DEFINED.
3. RESPONSIBLE PARTIES....................................................................................................5
4. ABSTRACT...........................................................................................................................5
5. AMENDMENTS AND UPDATES.......................................................................................5
6. MILESTONES.......................................................................................................................5
7. RATIONALE AND BACKGROUND..................................................................................6
8. RESEARCH QUESTION AND OBJECTIVES ...................................................................7
9. RESEARCH METHODS ......................................................................................................7
9.1. Study design ..............................................................................................................7
9.2. Setting........................................................................................................................8
9.2.1. Inclusion criteria ...........................................................................................8
9.2.2. Exclusion criteria..........................................................................................8
9.3. Variables....................................................................................................................8
9.4. Data sources ..............................................................................................................9
9.4.1. Data to be collected in this study..................................................................9
9.4.1.1. Assessment................................................................................10
9.4.2. Data collection time point and Data collection period ...............................11
9.4.3. Data collection method...............................................................................11
9.5. Study size ................................................................................................................13
9.6. Data management....................................................................................................13
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record........................................................................................................13
9.6.2. Record retention..........................................................................................13
9.7. Data analysis ...........................................................................................................14
9.7.1. Definition of analysis set ............................................................................14
9.7.2. Primary endpoint analysis (Overall survival).............................................14
9.7.3. Secondary endpoint analysis (type and duration of subsequent 
therapy) ............................................................................................................15
9.7.4. Other analysis .............................................................................................15

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9.8. Quality control.........................................................................................................15
9.9. Limitations of the research methods .......................................................................16
9.10. Other aspects .........................................................................................................16
10. PROTECTION OF HUMAN SUBJECTS ........................................................................16
10.1. Patient information................................................................................................16
10.2. Patient consent.......................................................................................................17
10.3. Patient withdrawal.................................................................................................17
10.4. Institutional review board (IRB)/Independent ethics committee (IEC)................18
10.5. Ethical conduct of the study..................................................................................18
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................18
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........20
13. REFERENCES ..................................................................................................................20
14. LIST OF TABLES.............................................................................................................21
15. LIST OF FIGURES ...........................................................................................................21
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................21
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................21
ANNEX 3. ADDITIONAL INFORMATION.........................................................................21
Exclusion criteria............................................................................................................23

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2. LIST OF ABBREVIATIONS
Abbreviation
Term
ABC
advanced breast cancer
AE
adverse event
AEM
adverse event monitoring
CDK
cyclin-dependent kinase
CI
confidence interval
CRF
case report form
CSA
clinical study agreement
DCF
data clarification form
DCT
data collection tool
ET
endocrine therapy
HER2-
human epidermal growth factor receptor 2-negative
HR+
hormone receptor‒positive
IEC
independent ethics committee
IRB
institutional review board
LET
letrozole
LSLV
last subject last visit
MHLW
Minister of Health, Labour and Welfare
NI
non-interventional
NIS
non-interventional study
OS
overall survival
PAL
Palbociclib
PFS
progression-free survival
SAP
statistical analysis plan

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Organization of study operationwill be prepared as Appendix 1.
4. ABSTRACT
Not applicable
5. AMENDMENTS AND UPDATES
Amendment 
number
Date
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Reason
Amendment 
1
07 April 
2022
Section 9.2.1
description revised
To clarify inclusion criteria
Amendment 
1
07 April 
2022
Sections 9.6.2, 
10.2, and 12
descriptions revised
Based on the findings of 
Institutional Review Board 
(IRB)/Independent Ethics 
Committee (IEC)
Amendment 
1
07 April 
2022
Sections 
9.10.1, 10.6, 
10.7, 10.8
Sections added
Based on the findings of 
IRB/IEC
Amendment 
1
07 April 
2022
Section 9.7.5
Section added
To conduct interim analysis 
based on the data at the 
second data collection
Amendment 
1
07 April 
2022
Section 6
description revised
To conduct interim analysis 
based on the data at the 
second data collection
Amendment 
1
07 April 
2022
Other minor edits were 
made
6. MILESTONES
Milestone
Planned date

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Start of data collection 
15 December 2020
Completion of interim analysis
15 December 2022
End of data collection
31 December 2024
Final study report
30 November 2025
7. RATIONALE AND BACKGROUND
Breast cancer is the most common cancer in women in Japan, with nearly 86,500 new cases 
diagnosed in 2018 and breast cancer is the fifth leading cause of cancer-related death in 
Japanese females [1]. Breast cancer prevalence rate of Japanese women by age group began 
to increase from the 30s, peaked in the latter half of the 40s, after that it remained almost 
constant, and gradually decreased from the late sixties[2]. Hormone receptor‒positive (HR+) 
breast cancer accounts for approximately 71% of new cases worldwide[3]. Endocrine therapy
has been a mainstay of HR+ breast cancer treatment and recommended by the Japanese 
Breast Cancer Society and international guidelines for initial treatment of HR+ disease[4, 5]. 
However, hormonal blockade alone provides only modest benefit in women with advanced 
breast cancer (ABC), with many patients having de novo or acquired resistance to endocrine 
therapy. 
Palbociclib is a selective, oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that 
prevents cell proliferation by blocking cell cycle progression from the G1 to the S phase. In 
Japan, palbociclib was approved in 2017 for the treatment of HR+/human epidermal growth 
factor receptor 2-negative (HER2-) inoperable or recurrent breast cancer. The safety and 
efficacy of palbociclib were investigated in 2 phase 3, randomized, double-blind, placebo-
controlled, multicenter trials (PALOMA-2, -3) and have shown significant activity in the 
first- or subsequent line treatment of HR+/HER2- ABC when combined with endocrine 
therapy (ET), demonstrated an approximate doubling of progression-free survival (PFS) 
when compared to ET alone[6, 7]. In Japanese patients with HR+/HER2− ABC, a phase 2, 
single-arm, open-label study of palbociclib in combination with letrozole as first-line 
treatment was conducted, and the combination treatment demonstrated effectively 75.0% 
(90% CI, 61.3%-84.4%) of investigator-assessed 1-year progression-free survival (PFS) 
probability, with a manageable safety profile[8].
There is limited data regarding the effectiveness of standard subsequent line therapies 
(chemotherapy, targeted agents or ET) after progression on CDK4/6 inhibitor-based 
regimens. Recent analyses in the overall population from PALOMA-2 and PALOMA-3 have 
shown that the type of subsequent therapy was similar between the palbociclib plus ET and 
placebo plus ET groups and that PFS improvement associated with palbociclib plus ET was 
retained in subsequent lines of therapy[9, 10]. While overall survival (OS) data are not yet 
available for Paloma-2, Paloma-3 has demonstrated that in patients sensitive to endocrine 
therapy, this combination therapy also brings about longer OS than fulvestrant monotherapy 

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(39.7 months vs 29.7 months; Hazard ratio, 0.92; 95% CI, 0.55–0.94) suggesting that 
progression on palbociclib has no significant effect on the therapeutic benefit derived from 
subsequent treatments received [10]. Although these findings in the overall population 
suggest that the treatment benefit of subsequent therapy was not compromised by 
palbociclib, in the postmenopausal woman with moderately pre-treated HR+/HER2- ABC, 
limited benefit from post palbociclib treatment are reported[11].
Real-world data in the United States demonstrated that palbociclib plus letrozole 
significantly prolonged progression-free survival by 45% versus letrozole alone (P < .0001) 
and significantly improved overall survival by 48% versus letrozole alone (P < .0001), 
according to a retrospective analysis of electronic health records[12].
The data on the effectiveness of palbociclib containing treatment sequence in Japanese 
patients are very limited. The health insurance system, available treatment option and 
healthcare outcomes are different in countries[13]. These differences may influence clinical 
outcomes of palbociclib in each country. To explore the effectiveness of palbociclib as first-
line treatment in Japan, this non-interventional study was planned to follow up the OS and 
also to investigate the type and duration of subsequent therapies after palbociclib treatment in 
the phase 2 study conducted in Japan.
8. RESEARCH QUESTION AND OBJECTIVES
Primary objective
To evaluate overall survival (OS) in Japanese patients with HR+/HER2- advanced breast 
cancer who have been treated with palbociclib plus letrozole in first-line setting
Secondary objective
To describe the type and duration of subsequent therapy after palbociclib plus letrozole 
treatment in Japanese patients with HR+/HER2- advanced breast cancer
9. RESEARCH METHODS 
9.1. Study design
This is a retrospective, multicenter, observational study in Japan. The primary objective is to 
evaluate OS in Japanese patients with HR+/HER2- advanced breast cancer who have been 
treated with palbociclib plus letrozole. This observational study was planned as follow-up 
study of Japanese phase 2 study of palbociclib (NCT01684215, phase 2 portion of A5481010 
study, hereafter described as J-Ph2).
In J-Ph2, 43 patients were enrolled, and 42 patients were treated with palbociclib plus 
letrozole. At the study completion of J-Ph2 [Last Subject Last Visit (LSLV): 25 October 
2018], 8 deaths were reported. Of the remaining 34 patients without death reported, 4 
patients refused further follow-up and 30 patients were under follow-up for survival.

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For the 30 patients under follow-up for survival in J-Ph2, OS and subsequent therapy data
will be retrospectively collected from individual patient medical records (See Section 9.3 and 
9.4 for detail). If the patient had been transferred to another hospital, the investigator will be 
asked to collect data as much as possible from the hospital. The investigator will complete 
paper-based case report forms (CRFs) at study initiation at each study site and at an annual 
reporting period set by the sponsor. Patient demographics and other relevant data collected in 
J-Ph2 will be used and matched with data collected in this study through patient IDs for 
analysis.
For 8 patients with OS events confirmed in J-Ph2 and 4 patients who refused further follow-
up in J-Ph2, data collected in J-Ph2 will be used for analysis.
9.2. Setting
Thirty patients who participated, treated with palbociclib plus letrozole, and under follow-up
for survival in J-Ph2 will be enrolled in this study for data collection. See Appendix 2 for 
inclusion and exclusion criteria in J-Ph2.
9.2.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Participated, treated with palbociclib plus letrozole in J-Ph2, and was under follow-up for 
survival at the study completion of J-Ph2.
2. For patients who are still alive and have routine visits to the study site, evidence of a 
personally signed and dated informed consent document indicating that the patient has 
been informed of all pertinent aspects of the study. For patients who are still alive and 
had been transferred to another hospital, evidence that the patient has been informed of 
all pertinent aspects of the study and oral or written informed consent is obtained. For 
patients who had already passed away, the conduct of this study will be disclosed, and the 
patients’ legally acceptable representatives will be guaranteed an opportunity to refuse 
data collection for the patients in accordance with the Ethical Guidelines for Medical and 
Health Research Involving Human Subjects.
9.2.2. Exclusion criteria
There are no exclusion criteria for this study.
9.3. Variables
The same patient IDs will be used for this study and J-Ph2. Data collected in this study will 
be combined and evaluated with J-Ph2 data, including patient demographics, study treatment, 
and baseline tumor assessment, through matching with patient IDs. Variables and data 
sources are described in Table 1. Detailed definitions will be included in the statistical 
analysis plan (SAP).

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Table 1. Variables in this study
Variable
Role
Data source(s)
Overall Survival
Outcome
J-Ph2 database
A5481154 database
Type of subsequent therapy
Outcome
J-Ph2 database
A5481154 database
Duration of subsequent therapy
Outcome
J-Ph2 database
A5481154 database
Clinical response of subsequent therapy
Outcome
A5481154 database
Palbociclib dose modification
Exposure, Outcome
J-Ph2 database
A5481154 database
Palbociclib treatment duration
Exposure, Outcome
J-Ph2 database
A5481154 database
Letrozole treatment duration
Exposure, Outcome
J-Ph2 database
A5481154 database
Demographic and baseline characteristics
Baseline characteristics
J-Ph2 database
9.4. Data sources
9.4.1. Data to be collected in this study
Data to be collected in this study is described in Table 2. See Section 9.4.2 and 9.4.3 for data 
collection time point and data collection methods. 

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Table 2. Data to be collected in this study
CRF
Variables
Informed consent
Patient status at study initiation4
Informed consent obtained
Date of informed consent
Survival status
Survival status
Date last known to be alive
Date of death
Cause of death
Subsequent therapy
Drug name of subsequent therapy
Start and Stop date of subsequent therapy
Clinical response of subsequent therapy1
PAL+LET exposure
Total daily dose2
Start and Stop date of each dose3
Reason for dose change2
PAL+LET discontinuation
Date of treatment discontinuation3
Reason for treatment discontinuation3
Disease site and tumor assessment at treatment discontinuation
Abbreviation; LET=letrozole, PAL=palbociclib
1.
Clinical response of subsequent therapy will be evaluated with Complete response, Partial response, Stable 
disease, Progression disease, and Unknown. See Section 9.4.1.1. for detail. 
2.
Palbociclib only
3.
Data will be collected for palbociclib and letrozole, respectively
4.
Patient status at study initiation will be collected as alive and has routine site visit, alive and had transferred to another 
hospital, dead
9.4.1.1. Assessment
Clinical response of subsequent therapy
Clinical response of subsequent therapy will be evaluated with Complete response, Partial 
response, Stable disease, Progression disease, and Unknown. These are not any protocol-
specified criteria and/or method for response evaluation, and this will be recorded based on 
investigator’s discretion (eg, radiology reports, patients’ medical chart). 

Complete response will be selected where “Complete response” has been recorded at any 
time on treatment. 

Partial response will be selected where “Partial response” has been recorded at any time 
on treatment without Complete response recorded. 

Stable disease will be selected (1) if the treatment continued for a minimum of 24 weeks 
or (2) if the treatment discontinued within 24 weeks but the initial response was not 
Progressive disease, without Complete or Partial response recorded at any time on 
treatment.

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
Progressive disease will be selected if the treatment discontinued within 24 weeks and 
the initial response was Progressive disease without subsequent Complete or Partial 
response recorded. 
9.4.2. Data collection time point and Data collection period
In this study, data will be collected with paper-based CRFs. The Investigator will complete 
CRFs for all the patients who remain in follow-up and submit them to the sponsor at the 
below time points;
1.
Study initiation at each study site
2.
Annual reporting period set by the sponsor (eg, every April)
For each patient, data collection will be continued until death unless patients withdraw 
consent or if the study gets sufficient OS events.
For the study, data collection will be continued until sufficient number of OS events are 
obtained to determine median OS.
9.4.3. Data collection method
Relevant CRFs will be completed according to the patient status at each data collection time 
point. 
At the study initiation at each study site
Investigators will complete the CRF for “Informed consent” and relevant CRFs according to 
patient status at last visit of J-Ph2 and current patient status (see Table 3 in detail). For 
example, if patient was receiving palbociclib plus letrozole treatment at last visit of J-Ph2 
and the patient still receives palbociclib plus letrozole, investigator will complete CRFs for 
“Informed consent”, “Survival status” and “PAL+LET exposure”. See Appendix 3 for each 
patient status at last visit of J-Ph2.

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Table 3. CRFs to be completed at study initiation at each study site
Patient status
CRF to be completed
Case
At last visit of J-Ph2
At study initiation at study site
1
PAL+LET treatment ongoing
PAL+LET treatment ongoing
- Informed consent
- Survival status
- PAL+LET exposure
2
PAL+LET treatment discontinued 
and OS follow-up
- Informed consent
- Survival status
- Subsequent therapy
- PAL+LET exposure
- PAL+LET discontinuation
3
Death
Same with Case 2
4
PAL+LET treatment discontinued 
and OS follow-up
OS follow-up
- Informed consent
- Survival status
- Subsequent therapy
5
Death
Same with Case 4
Abbreviation; LET=letrozole, OS=overall survival, PAL=palbociclib
At the annual reporting period
Investigators will complete the relevant CRF according to patient status at previous and 
current reporting period (see Table 4 in detail).  For example, if the patient status was 
“PAL+LET treatment discontinued and OS follow-up” at previous reporting period and 
current patient status is “Death”, investigator will complete CRFs for “Survival status” and 
“Subsequent therapy”).
Table 4. CRFs to be completed at annual reporting period
Patient status
CRF to be completed
Case
At previous reporting period
At current reporting period
1
PAL+LET treatment ongoing
PAL+LET treatment ongoing
- Survival status
- PAL+LET exposure
2
PAL+LET treatment 
discontinued and OS follow-up
- Survival status
- Subsequent therapy
- PAL+LET exposure
- PAL+LET discontinuation
3
Death
Same with Case 2
4
PAL+LET treatment 
discontinued and OS follow-up
OS follow-up
- Survival status
- Subsequent therapy
5
Death
Same with Case 4
Abbreviation; LET=letrozole, OS=overall survival, PAL=palbociclib

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9.5. Study size
The number of patients eligible for this study is 42 who participated and were treated with 
palbociclib plus letrozole in J-Ph2.
9.6. Data management 
Investigators will fill out relevant CRFs based on source documents (eg, patients’ medical 
chart) with a pen, ballpoint pen, etc. After the completion of CRFs, the investigator will 
promptly submit them to the sponsor by mail.
When receiving a query from the sponsor on the completed CRF (ie, Data Clarification Form 
[DCF]), investigators will reconfirm the information on source documents, fill out the DCF 
as required, and submit the DCF to the sponsor.
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.  The investigator shall ensure that the 
CRFs are securely stored at the study site in paper form and will be secured in a locked room 
to prevent access by unauthorized third parties.
The investigator 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, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, e.g., 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 (e.g., letters, meeting minutes, and telephone call reports).  The records 

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should be retained by the investigator according to local regulations or as specified in the 
clinical study agreement (CSA), whichever is longer.  The investigator must ensure that the 
records continue to be stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), 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. 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless 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. Study records will be disposed appropriately 
according to each site regulation.
9.7. Data analysis 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a statistical analysis plan (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.
For the purposes of this study, analyses will be descriptive in nature. All variables will be 
summarized descriptively through the tabular and graphical display of means, standard 
deviations, medians, ranges of continuous variables of interest, and proportions and 
frequency distributions for categorical variables. No formal hypothesis testing is planned.
Data collected in this study will be combined and evaluated with J-Ph2 data, including 
patient demographics, study treatment, and baseline tumor assessment, through matching 
with patient IDs.
9.7.1. Definition of analysis set
Analysis set is defined as all patients who enrolled and have been treated in the J-Ph2 study
excluding alive patients without written or oral informed consent obtained.
9.7.2. Primary endpoint analysis (Overall survival)
The primary endpoint is OS defined as the time from first dose of study treatment in J-Ph2 to 
date of death due to any cause.  In the absence of confirmation of death, survival time will be 
censored to last date the patient is known to be alive. 
OS will be summarized using Kaplan-Meier methods and displayed graphically where 
appropriate.  The median event time and 95% CI will be estimated. 

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9.7.3. Secondary endpoint analysis (type and duration of subsequent therapy)
Frequency of patients who received subsequent therapy will be summarized by type of 
therapy (eg, endocrine-based therapy, chemotherapy) and/or by line of therapy (eg, first 
subsequent therapy, second subsequent therapy). Median treatment durations of subsequent 
therapy by line of therapy will be estimated based on the Kaplan-Meier method, and duration 
of all subsequent therapy will be plotted by each patient.
9.7.4. Other analysis

Clinical response of subsequent therapy - The number and proportion of each response 
will be summarized by type of therapy (eg, endocrine-based therapy, chemotherapy) 
and/or by line of therapy (eg, first subsequent therapy, second subsequent therapy). 
Clinical response of all subsequent therapy will be plotted by each patient along with 
duration of subsequent therapy.

Time to chemotherapy - Defined as the time from first dose of study treatment in J-Ph2
to the start of first subsequent chemotherapy or death due to any cause, whichever comes 
first. Time to chemotherapy will be summarized using Kaplan-Meier methods and 
displayed graphically where appropriate. The median event time and 95% CI will be 
estimated.

Palbociclib dose modification - The number and proportion of patients with dose 
reduction (eg, 1 dose reduction to 100 mg, 2 dose reductions to 75 mg) and the reason 
for dose reduction will be summarized.

Palbociclib and letrozole treatment duration - Duration of palbociclib plus letrozole 
treatment will be plotted by each patient.  For palbociclib, duration of treatment may be 
plotted by dose of palbociclib (eg, 125 mg, 100 mg, and 75 mg).
9.7.5. Interim analysis
An interim analysis will be performed based on the data at the second data collection (i.e. 
based on the data collected at the first annual reporting period. 9.4.2). Detailed methodology 
will be documented in the SAP.
9.8. Quality control
The sponsor will train investigators and study site staff with an onsite training visit or web-
training on the protocol, CRFs, and any applicable study processes. Any new information 
relevant to the performance of this study will be forwarded to the investigator and study site 
staff during the study. Remote data monitoring will be conducted during the life of the study 
to ensure timely reporting of data, data integrity, and consistency. CRFs for all included 
patients will be made available to the remote data monitor for review. The study sites will be 
queried and managed to request resolution to any issues that may arise during the course of 
the study.

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Onsite Monitoring visits are not planned in this study.
9.9. Limitations of the research methods
Limitations of the research method in this study include;
1.
Single-arm design. Since no control group is set in the study, there is a limitation on 
interpretation on results, especially time-to-event endpoints.
2.
Observational, retrospective design. Since this study collects data basically from medical 
charts of each patient, there is a potential for missing, inaccurate, or incomplete data. If 
the patients had been transferred to another hospital or had already passed away, data in 
these patients may not be fully collected or be missing information in this study. In 
addition, considering the observational nature, there is methodological challenges in 
attributing causality to outcomes.
3.
Small sample size. It may be difficult to draw definitive conclusion due to lack of power.
9.10. Other aspects
9.10.1. Secondary use of data
Data obtained in this study may be used for scientific research and to promote public health. 
Even in such case, the personal information of patients will be protected in accordance with 
the applicable personal information protection law so that study patients cannot be identified.
10. PROTECTION OF HUMAN SUBJECTS
10.1. 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 electronic and/or paper form 
and will be password protected or secured in a locked room 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.
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.  

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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.
10.2. Patient consent
For patients who are alive and still visit the study site
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. Also, the investigator 
should appropriately and promptly respond to consultations from each patient and persons 
concerned. The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient before any data is collected. The investigator will retain 
the original of each patient's signed consent form.
The informed consent form must be in compliance with local regulatory requirements and 
legal requirements. The informed consent form used in this study, and any changes made 
during the course of the study, must be prospectively approved by both the IRB/ IEC and 
Pfizer before use.
For patients who are alive and had been transferred to another hospital
In accordance with Chapter 5 “Informed Consent” of the Ethical Guidelines for Medical and 
Health Research Involving Human Subjects, it is not always necessary to obtain written 
informed consent from the patients who had been transferred to another hospital. However, 
the investigator, or a person designated by the investigator, will obtain at least oral informed 
consent from each patient before any data is collected, and document method and content of 
the explanation as well as details of consent obtained.
For patients who had already passed away
In accordance with Chapter 5 “Informed Consent” of the Ethical Guidelines for Medical and 
Health Research Involving Human Subjects, the conduct of this study will be disclosed, and 
the patients’ legally acceptable representatives will be guaranteed an opportunity to refuse 
data collection for the patients.
10.3. Patient withdrawal
Only for patients who are alive
Patients may withdraw from the study at any time at their own request. In any circumstance, 
every effort should be made to document patient outcome, if possible.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 

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collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
10.4. 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. 
10.5. 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 Ethical Guidelines for Medical and Health Research Involving Human Subjects 
issued by the Minister of Health, Labour and Welfare (MHLW).
10.6. Predictable risks and benefits for subjects
In this study, personal information will be handled in order to retrospectively collect 
necessary information from the medical records of individual patients. Handling of personal 
information complies with the ethical guidelines of the research and pays utmost attention, 
but there may be risk of the accidental disclosure of personal information.
This is a retrospective study, and participation in this study does not provide direct benefits. 
However, information obtained from participation in this research may help other patients in 
the future.
10.7. Report to the chief executive of the study site
Each study site’s investigator shall report following to the chief executive of the study site in 
writing:
1)
protocol and protocol amendments
2)
progression of the study
3)
discontinuation and interruption of the study.
10.8. Source of research funding and Conflict of interest
This study will be conducted with Pfizer funding. Any potential conflicts of interest in the 
planning, conduct, and publication of this study will be disclosed. Conflict of interest refers 
to an interest that may affect study results, including financial and personal relationships.
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 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 

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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 data collection tool (e.g., 
chart abstraction form) 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.      
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”. 

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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 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. 
The results of this study are not part of any regulatory submission. The results of this study 
will be submitted for abstracts and publications. The final output will be filed in Pfizer’s
Global Document Management System upon final study completion. This study will be 
registered in the ClinicalTrials.gov, etc. and the information will be disclosed.
13. REFERENCES
1.
Center for Cancer Control and Information Services, N.C.C. Projected Cancer 
Statistics, 2018. 2018/09/15 [cited 2020 2/14]; Available from: 
https://ganjoho.jp/en/public/statistics/short_pred.html.
2.
Foundation for Promotion of Cancer Research. Cancer Statistics in Japan -2018. 
Available from: 
https://ganjoho.jp/data/reg_stat/statistics/brochure/2018/cancer_statistics_2018_date_
J.pdf.
3.
American Cancer Society. Breast Cancer Facts & Figures 2017–2018.; Available 
from: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-
statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-
2018.pdf.
4.
Aihara, T., et al., The Japanese Breast Cancer Society Clinical Practice Guideline for 
systemic treatment of breast cancer, 2015 edition. Breast Cancer, 2016. 23(3): p. 329-
42.
5.
Cardoso, F., et al., ESO-ESMO 2nd international consensus guidelines for advanced 
breast cancer (ABC2). Breast, 2014. 23(5): p. 489-502.
6.
Rugo, H.S., et al., Impact of palbociclib plus letrozole on patient-reported health-
related quality of life: results from the PALOMA-2 trial. Ann Oncol, 2018. 29(4): p. 
888-894.
7.
Cristofanilli, M., 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(4): p. 425-439.

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8.
Masuda, N., et al., Palbociclib in combination with letrozole as first-line treatment 
for advanced breast cancer: A Japanese phase II study. Cancer Sci, 2018. 109(3): p. 
803-813.
9.
Rugo, H.S., et al., Palbociclib plus letrozole as first-line therapy in estrogen receptor-
positive/human epidermal growth factor receptor 2-negative advanced breast cancer 
with extended follow-up. Breast Cancer Res Treat, 2019. 174(3): p. 719-729.
10.
Turner, N.C., et al., Overall Survival with Palbociclib and Fulvestrant in Advanced 
Breast Cancer. N Engl J Med, 2018. 379(20): p. 1926-1936.
11.
Rossi, L., et al., Clinical outcomes after palbociclib with or without endocrine 
therapy in postmenopausal women with hormone receptor positive and HER2-
negative metastatic breast cancer enrolled in the TREnd trial. Breast Cancer Res, 
2019. 21(1): p. 71.
12.
DeMichele, A., et al., Abstract P1-19-02: Overall survival for first-line palbociclib 
plus letrozole vs letrozole alone for HR+/HER2- metastatic breast cancer patients in 
US real-world clinical practice. Cancer Research, 2020. 80(4 Supplement): p. P1-19-
02.
13.
Papanicolas, I., L.R. Woskie, and A.K. Jha, Health Care Spending in the United 
States and Other High-Income Countries. Jama, 2018. 319(10): p. 1024-1039.
14. LIST OF TABLES 
Table 1. Variables in this study
Table 2. Data to be collected in this study
Table 3. CRFs to be completed at study initiation at each study site
Table 4. CRFs to be completed at annual reporting period
15. LIST OF FIGURES
None
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
Appendix 1. Organization of study operation
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
ANNEX 3. ADDITIONAL INFORMATION
Appendix 2. Inclusion and Exclusion criteria in J-Ph2
Appendix 3. Each patient status at last visit of J-Ph2

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Appendix 2. Inclusion and Exclusion criteria in J-Ph2
Inclusion criteria
1. Adult women (≥ 20 years of age) with proven diagnosis of adenocarcinoma of the breast 
with evidence of locoregionally recurrent or metastatic disease not amenable to resection 
or radiation therapy with curative intent and for whom chemotherapy is not clinically 
indicated.
2. Documentation of histologically or cytologically confirmed diagnosis of ER(+) breast 
cancer based on local laboratory results. 
3. All patients must agree to provide tumor tissues for centralized retrospective 
confirmation of ER status and to evaluate correlation between genes, proteins, and RNAs 
relevant to the cell cycle pathways and sensitivity/resistance to the investigational agents.  
Freshly biopsied, recurrent/metastatic tumor samples must be provided whenever 
possible.  If such a biopsy is not feasible or cannot be safely performed, then an archived 
tumor sample may be accepted.  In either case a formalin fixed, paraffin embedded 
(FFPE) block or 12 unstained FFPE slides are required for patient participation.
4. Previously untreated with any systemic anti-cancer therapy for their locoregionally 
recurrent or metastatic ER(+) disease.
5. Postmenopausal women defined as women with: 

Prior bilateral surgical oophorectomy, or

Medically confirmed post-menopausal status defined as spontaneous cessation of 
regular menses for at least 12 consecutive months (and follicle-stimulating hormone 
[FSH] and estradiol blood levels in their respective postmenopausal ranges with no 
alternative pathological or physiological cause, if applicable).
6. Measurable disease as defined per RECIST v.1.1 or bone-only disease (with bone lesions 
confirmed by Computed Tomography [CT], Magnetic Resonance Imaging [MRI] or bone 
X-ray).  Tumor lesions previously irradiated or subjected to other locoregional therapy 
will only be deemed measurable if disease progression at the treated site after completion 
of therapy is clearly documented.
7. ECOG PS 0-2.
8. Adequate bone marrow and organ function defined as follows: 

ANC ≥1,500/mm3 (1.5 x 109 /L); 

Platelets ≥100,000/mm3 (100 x 109 /L); 

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
Hemoglobin ≥9 g/dL (90 g/L); 

Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as 
calculated using the method standard for the institution; 

Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease);

AST and/or ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present); 

Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present). 
9. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to 
NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a 
safety risk for the patient at investigator's discretion).
10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures.
11. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legal representative) has been informed of all pertinent aspects of the study 
before any study-specific activity is performed.
Exclusion criteria
1.
HER2-positive tumor as defined by documentation of erbB-2 gene amplification by 
FISH (as defined by a HER2/CEP17 ratio ≥2) or chromogenic in situ hybridization 
(CISH, as defined by the manufacturer’s kit instruction) or INFORM HER2 dual ISH (as 
defined by manufacturer’s kit instruction) or documentation of HER2-overexpression by 
IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local 
laboratory results utilizing one of the sponsor-approved assays.  If HER2 status is 
unavailable or was determined using a test other than a sponsor-approved assay, then 
testing must be performed/repeated using one of these assays prior to study registration. 
If tissue sample from both primary and recurrent/metastatic tumors are available, HER2 
assessment from the most recent sample (i.e., recurrent/metastatic sample) should be 
used to define eligibility whenever feasible.
2.
Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening 
complications in the short term (including patients with massive uncontrolled effusions 
[pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver 
involvement).
3.
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, 
or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or 
progressive growth.  Patients with a history of CNS metastases or cord compression are 
eligible if they have been definitively treated with local therapy (eg, radiotherapy, 

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stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 
4 weeks before study registration.
4.
Prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor 
(ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of 
completing treatment.
5.
Prior treatment with any CDK4/6 inhibitor.
6.
Patients treated within the last 7 days prior to study registration with:

Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, 
boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, 
fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, suboxone, 
telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit 
juice);

Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, 
nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and 
St. John’s wort). 

Drugs that are known to prolong the QT interval.
7.
Major surgery, chemotherapy, radiotherapy, any investigational agents, or other 
anti-cancer therapy within 2 weeks before study registration.  Patients who received prior 
radiotherapy to ≥25% of bone marrow are not eligible independent of when it was 
received.
8.
Diagnosis of any other malignancy within 3 years prior to study registration, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.
9.
QTc >480 msec (based on the mean value of the triplicate ECGs), family or personal 
history of long or short QT syndrome, Brugada syndrome or known history of QTc 
prolongation, or Torsade de Pointes (TdP).
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging 
drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
11. Any of the following within 6 months of study registration: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE 
version 4.0 Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure, cerebrovascular accident including transient 
ischemic attack, or symptomatic pulmonary embolism.

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12. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any 
upper gastrointestinal surgery including gastric resection.
13. Known hypersensitivity to letrozole, or any of its excipients, or to any PD-0332991 
excipients.
14. Known human immunodeficiency virus infection.
15. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
16. Patients who are investigational site staff members or relatives of those site staff 
members or patients who are Pfizer employees directly involved in the conduct of the 
trial.
17. Participation in other studies involving investigational drug (s) (Phases 1-4) within 2 
weeks before study registration and/or during participation in the active treatment phase 
of the trial.
18. Recent or active suicidal ideation or behavior.

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Appendix 3. Each patient status at last visit of J-Ph2
Site ID
Patient ID
Patient status
PAL+LET treatment ongoing
Patient refused further follow-up
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment ongoing
PAL+LET treatment ongoing
PAL+LET treatment discontinued and OS follow-up
Death
PAL+LET treatment discontinued and OS follow-up
Patient refused further follow-up
PAL+LET treatment ongoing
PAL+LET treatment discontinued and OS follow-up
Death
PAL+LET treatment discontinued and OS follow-up
Death
PAL+LET treatment discontinued and OS follow-up
Death
Patient refused further follow-up
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment discontinued and OS follow-up
Death
Death
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment ongoing
Patient refused further follow-up
PAL+LET treatment ongoing
PAL+LET treatment ongoing
PAL+LET treatment ongoing
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment ongoing
PAL+LET treatment ongoing
Death
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment discontinued and OS follow-up
Death
PAL+LET treatment ongoing
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment discontinued and OS follow-up
PAL+LET treatment ongoing
Abbreviation; LET=letrozole, OS=overall survival, PAL=palbociclib
PPD