Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Ibrance® or Palbociclib
PROTOCOL NO.: A5481023

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PROTOCOL TITLE: Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase
3 Trial Of Fulvestrant (Faslodex®) With Or Without PD-0332991 (Palbociclib) ± Goserelinin Women with Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer
Whose Disease Progressed After Prior Endocrine Therapy.
Study Center(s): As of the data cutoff date (05 Dec 2014), the study was conducted at 144
sites in 17 countries, that randomized subjects in Australia (11 sites), Belgium (11 sites),
Canada (11 sites), Germany (2 sites), Ireland (1 site), Italy (9 sites), Japan (8 sites),
Netherlands (6 sites), Portugal (2 sites), Romania (4 sites), Russian Federation (5 sites),
Republic of South Korea (5 sites), Taiwan (2 sites), Turkey (1 site), Ukraine (6 sites), theUnited Kingdom (4 sites), and the United States (56 sites).
Study Initiation Date and Final Completion Dates
Study Initiation Date = 26 September 2013;
Date of cutoff = 05 December 2014.
Phase of Development: Phase 3
Study Objective(s):Primary Objective:

To demonstrate the superiority of palbociclib in combination with fulvestrant (with orwithout goserelin) over fulvestrant (with or without goserelin) alone in prolonging
investigator-assessed PFS in women with HR+/HER2- metastatic breast cancer
whose disease has progressed on prior endocrine therapy.

Secondary Objectives:

To compare measures of tumor control (including PFS, DR, CBR) between thetreatment arms.



To compare safety and tolerability between the treatment arms.

To evaluate trough concentrations of palbociclib when given in combination withfulvestrant or fulvestrant plus goserelin compared to historical palbociclib data.

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Protocol A5481023 - Final - 26 October 2015

To compare fulvestrant and goserelin trough concentrations when given in
combination with palbociclib to those when given without palbociclib.

To explore correlations between palbociclib exposures and efficacy/safety findings inthis subject population.



To compare Patient Reported Outcomes measures between treatment arms.

To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle,
drug targets, tumor sensitivity and/or resistance.



To conduct subgroup analysis for primary and secondary endpoints in stratified
groups.

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METHODS
Study Design: This study was an international, multicenter, 2:1 randomized, double-blind,placebo-controlled, parallel-group, Phase 3 clinical study with the primary objective of
demonstrating the superiority in prolonging PFS of palbociclib in combination withfulvestrant (Faslodex®) over fulvestrant plus placebo in women with Hormone Receptor(HR)-positive, Human Epidermal Growth Factor Receptor (HER2)-negative metastatic breast
cancer, regardless of their menopausal status, whose disease had progressed after priorendocrine therapy. Secondary endpoints [(progression free survival (PFS), overall response(OR), duration of response (DR), clinical benefit response (CBR), and overall survival (OS)],pharmacokinetic (PK), Patient-Reported Outcome (PRO) and safety of the 2 treatment arms
were also compared. Pre- and perimenopausal women were to receive therapy with theluteinizing hormone-releasing hormone (LHRH) agonist goserelin (Zoladex® or generic).
Approximately 417 eligible women were planned to be randomized on a 2:1 basis to receive
either palbociclib plus fulvestrant (approximately 278 women; investigational arm), or
placebo plus fulvestrant (approximately 139 women; comparator arm).
The study consisted of a screening visit within 28 days prior to randomization, an active
treatment phase, divided in cycles of 28 days each, an end-of-treatment visit, and a follow-up
period during which survival and new anti-cancer therapy information was collected every 3months for the first 9 months after the last dose of the investigational product, then every 6months thereafter.
Palbociclib/placebo was to be administered orally once a day for 21 days followed by 7 days
off treatment of every 28-day cycle. In Cycle 1, fulvestrant was administered intramuscularly(IM) on Day 1 and Day 15, every 28 ±7 days thereafter starting on Cycle 1 Day 1. Pre- andperimenopausal women continued receiving concurrent ovarian function suppression withgoserelin administered subcutaneously every 28 days during active treatment phase. Thesepre- or perimenopausal women should have started receiving goserelin or an alternative
LHRH agonist at least 4 weeks before the start of study treatment. For each subject, thetreatment phase lasted until study withdrawal criteria were met.
Subjects received their assigned study treatment until objective disease progression,
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whicheveroccurred first.

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Protocol A5481023 - Final - 26 October 2015

Schedule of Activities provides an overview of the protocol visits and procedures (Table 1).
Table 1:

Schedule of Activities

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Protocol Activity

Study Day
Visit Window

Active Treatment Phase a - One Cycle = 28
days
Cycles 1 and 2
Cycles 3
b
Day
15
Day 1
Day
1
Within 28 days prior
2 days7 days a
to randomization -2 days
unless specified

Screening

Informed Consent e
Medical/Oncological History f
Baseline Signs/Symptoms g
Physical Examination/Vital Signs hOphthalmic Examinationi
ECOG Performance Status
Laboratory Studies
Hematology j
Blood Chemistry j
Pregnancy test, serum estradiol andFSH (if applicable) j
12-Lead ECG (in triplicate)
Disease Assessment
CT/MRI Scans of Chest, Abdomen,
Pelvis, any clinically indicated sites of
disease, and of bone lesions; Clinicalevaluation of superficial disease k

X
XRadionuclide Bone Scan, Whole Body l

X

Other Clinical Assessments
Adverse Event Reporting m
Concomitant Medications/Treatments

X
X
X
X
X
X

Xg
Xb

X

X
X b
X b

X
X

7 days

Xi
X

X
X
X

X
X

X
X

X
X

End ofPost-Treatment
Treatment/Withdrawal Follow-Up dcX◄--► kPerformed every 8 weeks (7 days) for the firstyear, and then every 12 weeks (7 days) from thedate of randomization (See tumor assessment
requirements flowchart)

X

X
As clinically indicated or to confirm complete
response. (See tumor assessment requirements
l
X
X
X
X
X
◄--►
Recorded from 28 days prior to the start of study treatment up to 28 days after the last dose of study
treatment

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X

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Protocol A5481023 - Final - 26 October 2015

Active Treatment Phase a - One Cycle = 28
End ofPost-Treatment
days
Treatment/Withdrawal Follow-Up dcCycles 1 and 2
Cycles 3bStudy DayDay 15
Day 1
Within 28 days prior Day 1aVisit Window
-2
days
2
days
7
days
7 days
to randomization
unless specified
Pharmacokinetics (PK) nFirst 40 subjects: Sampling at pre-dose on Day 1
and Day 15 of Cycles 1 and 2, and Day 1 of Cycle
3; all other subjects: Pre-dose sampling on Day 15of Cycles 1 and 2
Banked Blood Biospecimens (Prep D1)
XoPlasma banking (Prep B1) p
X
X
X
Tumor Tissue for Biomarker Analysis q
X
X
EuroQol-5D (EQ-5D) r
X
Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and Day
X
European Organization for
1 of every other cycle thereafter starting with
Research and Treatment of Cancer
Cycle 6 (ie, Cycle 6,8, 10, etc)
Quality of Life Questionnaire
X
European Organisation for Research
and Treatment of Cancer Breast
Cancer Module (EORTC-QLQ-BR23)
Survival Follow-up s
XStudy Treatment
Randomization
X
Fulvestrant (both treatment arms) t◄--►t
IM administration on Days 1 and 15 of Cycle 1,
every 28 days (7 days) thereafter starting from
Palbociclib or placebo (Arm A only) u◄--►uOrally once daily on Days 1 to 21of each Cycle
followed by 7 days off treatment◄--►v
For pre-/peri-menopausal subjects only: SC administration atSCadministration
every 28 days
least 4 weeks before
Goserelin (both treatment arms, ifv
applicable)
study treatment startv

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Protocol Activitya.

Screening

Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated. Acceptable time windows for performing each
assessment are described in the column headers. One cycle consists of 28 days. A cycle could be longer than 28 days if ersistent toxicity delays initiation of thesubsequent cycle. Day 1 of any cycle visit should coincide with the day the palbociclib/placebo treatment begins. If there are delays due to toxicity, then the startof the next cycle visit will be delayed until the subject has recovered and can begin study treatment again. Fulvestrant injection will be given every 28 days (+/- 7 days)
with the exception of Cycle 1 during which it will be administered on Days 1 and 15 (2 days allowed according to the protocol visit time windows). Goserelin will beadministered every 28 days (+/- number of days allowed according to the protocol visit time windows). The active treatment phase is ongoing as long as the subject isreceiving both study drugs (ie, palbociclib/placebo and fulvestrant) or fulvestrant alone.

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Protocol A5481023 - Final - 26 October 2015b.
c.

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d.

e.
f.
g.
h.

Cycle 1/Day 1: Blood chemistry, hematology, and physical examination not required if acceptable screening assessment is performed within 7 days prior to
randomization.
End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and prior toinitiation of any new anticancer therapy. Obtain assessments if not completed during the previous 4 weeks on study (or within the previous
8 weeks or 12 weeks [as applicable] for disease assessments).
Post Treatment Follow-up: Subjects who discontinue study treatment should be contacted 28 calendar days (7 days) after discontinuation of study treatment(palbociclib/placebo or fulvestrant) to assess if there have been any new adverse events and/or any change to any previously reported adverse events. Telephone
contact is acceptable. Subjects who discontinue active study treatment for any reason other than objective disease progression or death will continue to have tumor
assessments performed every 8 weeks (7 days) for the first year, and then after 1 year every 12 weeks (7 days) (calculated from the date of randomization) until
documented progression or onset of new anticancer therapy. For subjects who discontinue study treatment due to objective disease progression, see table footnote s(Survival Follow-up) below.
Informed Consent: Informed consent must be obtained prior to any protocol required assessments being performed (with the exception of certain imaging
assessments if meeting the criteria).
Medical/Oncological History: To include information on prior anticancer treatments.
Baseline Signs/Symptoms: Baseline tumor related signs and symptoms will be recorded at the Cycle 1 Day 1 visit prior to initiating treatment and then reported asadverse events during the trial if they worsen in severity or increase in frequency.
Physical Examination/Vital signs: A full physical examination including an examination of all major body systems and breasts, height (at screening only), weight,
blood pressure and pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider. Physical examinations will be carriedout at Screening, Day 1 of every cycle and the End of Treatment/Withdrawal visit.

i.

Ophthalmology Examinations: Upon approval of Amendment 1, newly enrolled lens grading evaluable subjects will undergo an ophthalmic examination by anophthalmologist at screening, during study treatment on Cycle 4 Day 1, on Cycle 7 Day 1, on Cycle 13 Day 1 (ie, after 3, 6 and 12 months), every 12 months
thereafter (ie, Days 1 of Cycles 25, 37, etc.) and at the End of Treatment/Withdrawal visit. Additional ophthalmic examinations may be performed as clinicallyindicated. It is expected that a minimum of 100 evaluable subjects will participate in these examinations. Sites will be informed once these examinations are no longer
required for subjects newly enrolled in this study.
j. Laboratory tests: Hematology includes hemoglobin, WBC, absolute neutrophil count, platelet count. Blood chemistry includes AST/ALT, alkaline phosphatase,sodium, potassium, magnesium, total calcium, total bilirubin, blood urea nitrogen (BUN) (or urea), serum creatinine, and albumin. Additional hematology/chemistries
panels may be performed as clinically indicated. Upon approval of Amendment 2, hemoglobin A1c will be measured in all subjects every 3 months from the date of
randomization (ie, C4D1, C7D1, C10D1, etc), and at the End of Treatment/Withdrawal visit. Pregnancy test (serum) at screening only for women of childbearing
potential. Test may be repeated as per request of IRB/IECs or if required by local regulations. Serum estradiol and Follicle stimulating hormone (FSH) levels areanalysed at screening to confirm postmenopausal status of women <60 years old and who have been amenorrheic for at least 12 consecutive months.
k. CT/MRI Scans of Chest, Abdomen, Pelvis: Refer to the tumor assessment requirement flowchart for details and timing of procedures.
l. Radionuclide Bone Scan, Whole Body: Refer to the tumor assessment requirement flowchart for all details and timing of procedures.
m. Adverse Events (AEs): Serious Adverse events (SAEs) must be reported from the time the subject provides informed consent through and including 28 calendar days
after the last administration of the study drug. SAEs occurring after the active reporting period has ended should be reported if the investigator becomes aware ofthem; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor. All
AEs (serious and non serious) should be recorded on the CRF from the first dose of study treatment through last subject visit. It is expected that telephone contact withthe subject will be made in order to assess SAEs and AEs 28 calendar days (+/- 7 days) after the last administration of the study drug.
n. Pharmacokinetics (PK): In approximately the first 40 subjects randomized in the study, plasma PK samples will be drawn pre-dose on Day 1 and Day 15 of Cycles
1 and 2, and Day 1 of Cycle 3 for DDI assessment for palbociclib and fulvestrant (and goserelin if applicable). In all other subjects, plasma concentrations will bedrawn on Day 15 of Cycle 1 and Cycle 2 for palbociclib only. Additional PK blood samples may be collected from subjects experiencing unexpected or serious
adverse events, or adverse events that lead to discontinuation.

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Protocol A5481023 - Final - 26 October 2015o.
p.

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q.

r.
s.
t.
u.
v.

Banked Blood Biospecimens (Prep D1): A single 4 mL blood sample will be collected pre-dose at the Cycle 1 Day 1 to be retained for potential
pharmacogenomic/biomarker analyses related to drug response or adverse drug reactions. Samples will be collected from all subjects, unless prohibited by local
regulations. .
Plasma Banking (Prep B1): Blood samples for plasma collection (2x 10 mL each) will be drawn for exploratory analyses from all subjects pre-dose on Cycle 1 Days 1
and 15 and at End of Treatment/Withdrawal, unless prohibited by local regulations.
Tumor Tissue for Biomarker Assessments: Tumor tissue is required for subject participation, and subjects must agree to provide tissue from the metastatic orrecurrent site at the time of study entry. For the purpose of eligibility, documentation of ER-positive and/or PR-positive tumor and HER2-negative tumor will bebased on local results utilizing an assay consistent with local standards. Archived formalin-fixed paraffin embedded (FFPE) specimen will be collected. If archived
metastatic or recurrent tumor FFPE specimen is not available, a de novo biopsy will be required for subject participation, except for those with bone disease only who
will need to provide the original diagnostic FFPE tumor specimen. Subjects who relapsed while receiving adjuvant therapy and had surgery within the last 3 years,
may provide a tumor specimen from that surgery. Provision of new metastatic tissue from these subjects is strongly encouraged but not mandated. An optional denovo tumor biopsy will be collected from the site of progression at the End of Treatment visit. Details on sample preparation, processing, storage, and shipment will
be provided in the Study Manual.
Patient Reported Outcomes Assessments: All self-assessment questionnaires must be completed by the subjects while in the clinic and cannot be taken home. Interviewer
administration in clinic may be used under special circumstances.
Survival Follow-Up: For subjects who discontinue study treatment due to objective disease progression, survival data (ie, subject status along with start, stop and type of
new anticancer therapy) will be collected every 3 months for the first 9 months (Month 3, 6, and 9, 14 days), then every 6 months starting at Month 15 (14 days),
calculated from the last dose of study treatment. Telephone contact is acceptable.

Fulvestrant: To be administered on-site according to the local Summary of Product Characteristics for fulvestrant (Faslodex ). Fulvestrant injection will be given
every 28 days (+/- 7 days) with the exception of Cycle 1 during which it will be administered on Days 1 and 15 (2 days allowed according to the protocol visit time
windows).
Palbociclib or Placebo: Subjects will be required to return all bottles of palbociclib/placebo as well as the completed subject diary on Day 1 of each cycle for drug
accountability.
Goserelin (if applicable): Goserelin will be administered every 28 days (+/- number of days allowed according to the protocol visit time windows). Treatment with
goserelin (Zoladex or generic) as per local practice for all women who are pre- or peri-menopausal at study entry. Subjects must have commenced treatment withgoserelin or an alternative luteinizing hormone-releasing hormone (LHRH) agonist at least 4 weeks prior to randomization. If subjects have not received goserelin as their
LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial. It is recommended to administer goserelin (given every 28 days) on-sitewhen monthly fulvestrant is given. If goserelin is administered at home by the subject, a subject diary will be implemented.

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Protocol A5481023 - Final - 26 October 2015

Number of Subjects (Planned and Analyzed)
Approximately 417 subjects were planned to be randomized, 521 subjects (Intent-to-Treat[ITT] population) were randomized and analyzed for efficacy, and 517 subjects (As-Treated[AT] population) were treated.

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Diagnosis and Main Criteria for Inclusion

Women 18 years or older with metastatic or locally advanced disease, not amenable
to curative therapy

Confirmed diagnosis of HR+/HER2- breast cancer

Any menopausal status



Progressed on or within 12 months from prior endocrine adjuvant therapy or
progressed on or within 1 month from prior advanced/metastatic endocrine breast
cancer therapy

On an LHRH agonist for at least 28 days, if pre/perimenopausal, and willing to switch
to goserelin (Zoladex ®) at time of randomization

Measurable disease defined by response evaluation criteria in solid tumors (RECIST)
version 1.1, or bone-only diseaseEastern Cooperative Oncology Group (ECOG) performance status 0-1Adequate organ and marrow function, resolution of all toxic effects of prior therapy
or surgical procedures.



Subject must agree to provide tumor tissue from metastatic tissue at baseline.

Study Treatment
Subjects were randomized to either palbociclib/fulvestrant or placebo/fulvestrant arms.
Palbociclib/Fulvestrant: Subjects were administered an initial dose of 125 mg per day orally
continuously for 3 weeks followed by 1 week off that can be reduced to either 100 mg or 75
mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg
intramuscularly on days 1 and 15 of cycle 1 and then every 28 days starting from day 1 ofcycle 1. Pre- and perimenopausal women received goserelin at least 4 weeks before study
treatment start and continued receiving concurrent ovarian function suppression withgoserelin administered subcutaneously every 28 days during the active treatment phase.
Placebo/Fulvestrant: Subjects were administered placebo orally continuously dosed for 3
weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg
intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days starting from day 1 ofcycle 1. Pre- and perimenopausal women received goserelin for at least 4 weeks before study
treatment start and continued receiving concurrent ovarian function suppression withgoserelin administered subcutaneously every 28 days during the active treatment phase.

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Protocol A5481023 - Final - 26 October 2015

Efficacy, Pharmacokinetic, or Outcomes Research Endpoints
Primary Endpoint:Progression-Free Survival (PFS) as assessed by the Investigator.

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Secondary Endpoints:Overall Survival (OS).



1-year, 2-year, and 3-year survival probabilities.



Objective Response (OR): Complete Response (CR) or Partial Response (PR).

Duration of Response (DR).

Clinical Benefit Response (CBR): CR or PR or Stable Disease (SD) ≥24 weeks.

Type, incidence, severity (as graded by the National Cancer Institute Common
Terminology Criteria for Adverse Events [NCI CTCAE] v4.0), seriousness andrelationship to study medications of Adverse Events (AEs) and any laboratory
abnormalities.



Trough plasma concentration of palbociclib, fulvestrant and goserelin (if applicable)in the subgroup of approximately 40 subjects included in the initial safety review.

PRO endpoints such as health related quality of life scores [EuroQol (EQ-5D) Score;
European Organization for Research and Treatment of Cancer Quality of Life
Instrument (EORTC QLQ-C30); European Organization for Research and Treatmentof Cancer Breast Cancer Module (EORTC QLQ-BR23); minimally importantdifference (MID) cut-off, and time to deterioration (TTD) composite endpoint.

Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1 and
CDKN2A, PIK3CA mutations), proteins (eg, Ki67, pRb, CCNE1), and RNA
expression (eg, cdk4, cdk6).

Safety Evaluations
Safety assessment consisted of monitoring of all AEs, including SAEs, regular monitoring ofhematology, serum chemistry, and routine monitoring of electrocardiograms (ECGs),
physical examinations, vital signs, Eastern Cooperative Oncology Group (ECOG)
performance status, pregnancy tests and chest computed tomography (CT).
Statistical Methods
The following analysis population sets were used:
Intent-to-Treat Population (Full Analysis Set):
The intent-to-treat (ITT) population or full analysis set included all subjects who wererandomized, with study drug assignment designated according to initial randomization,
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Protocol A5481023 - Final - 26 October 2015

which they were randomized. The ITT population was the primary population for evaluating
all efficacy endpoints and subject characteristics.
As-Treated (AT) Population (Safety Analysis Set):
The as-treated population or safety analysis set included subjects who received at least 1 doseof study medication, with treatment assignments designated according to actual study
treatment received. The AT population was the primary population for evaluating treatment
administration/compliance and safety. Efficacy and clinical benefits endpoints may beassessed in this population as well.
Other Analysis Sets:
Pharmacokinetic (PK) Analysis Sets: There were at least two PK analysis sets:

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1. Early Safety Review Set: The 40 subjects participating in the early safety review, who
are treated with palbociclib + fulvestrant ± goserelin or placebo + fulvestrant ±goserelin and have at least one measured plasma drug concentration.
2. Palbociclib PK Analysis Set: All subjects (including those in the Early Safety Review
Set) who have PK blood samples collected for palbociclib and have at least one
measured plasma drug concentration.
PK/Adverse Event Analysis Set (if applicable): subjects experiencing unexpected or serious
adverse events, or adverse events that lead to discontinuation who have PK blood samples
collected for palbociclib or fulvestrant (or goserelin if applicable) and have at least one
measured plasma drug concentration.
Patient Reported Outcome (PRO) Evaluable Population (PRO Analysis Set):
The PRO –evaluable population is defined as a subset of ITT subjects, who have completed abaseline and at least one post –baseline PRO assessment prior to end of study treatment.
Analysis of Primary Endpoint:
The primary endpoint was investigator-assessed PFS which was defined as the time from thedate of randomization to the date of the first documentation of objective progression of
disease (PD) or death due to any cause in the absence of documented PD, whicheveroccurred first. PFS data were censored on the date of the last tumor assessment on study for
subjects who did not have objective tumor progression and who did not die while on study.
Subjects lacking an evaluation of tumor response after randomization had their PFS time
censored on the date of randomization with the duration of one day. Additionally, subjects
who started a new anticancer therapy prior to documented PD were censored at the date of
the last tumor assessment prior to the start of the new therapy. Subjects with documentationof PD or death after an unacceptably long interval (ie, 2 or more incomplete or non-evaluableassessments) since the last tumor assessment were censored at the time of last objective
assessment that did not show PD. The primary analyses of PFS were performed in the ITT
population. A log-rank test (1-sided) stratified by the presence of visceral metastases andPage 9Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

sensitivity to prior hormonal therapy was used to compare PFS time between the 2 treatment
arms at the interim and/or final analyses with the overall significance level preserved at 0.025(1 sided). PFS for the two treatment arms was assessed using Kaplan-Meier methods anddisplayed graphically. The median event times and 95% CIs were estimated. Cox regression
models were used to estimate the HR and its 95% CI.
Sensitivity Analyses for the Primary Progression-Free Survival Endpoint:
The primary efficacy analysis on the primary PFS endpoint was based on well-documented
and verifiable progression events and deaths due to any cause. Other data were censored at
the time of the last tumor assessment documenting absence of PD and death. In addition, thesensitivity analyses (SA) on the primary PFS endpoint were performed in determining
whether the results of the primary PFS analysis were robust.

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Supportive Analyses for PFS
A sample-based blinded independent central review (BICR) approach was implemented as anauditing tool for PFS. A third-party core imaging laboratory performed BICR for a randomly
selected subgroup of subjects independent of investigator assessment or investigator assessed
determination of progression. The objective of this approach was to corroborate the analysis
results of the primary endpoint (i.e., investigator-assessed PFS) and to assist in the evaluationof potential investigator bias. The BICR audit approach was not intended to provide analternative means of definitive analysis.
Analysis of Secondary Endpoints:
Overall Survival (OS): OS was defined as the time from date of randomization to date ofdeath due to any cause. In the absence of confirmation of death, survival time was censoredto last date the subject was known to be alive. All subjects randomized were consideredevaluable for OS. OS was hierarchically tested for significance at the time of PFS analysis,
provided the primary PFS endpoint was statistically significant at the interim and/or final
analyses. A stratified log-rank test (using the same stratification factors as for the PFS
analysis) was used to compare OS between the treatment arms. OS for the two treatment
arms was assessed using Kaplan-Meier methods and displayed graphically whereappropriate. The median event times and 95% CIs were estimated. Cox regression models
were used to estimate the HR and its 95% CI. The 1-year survival probability was estimatedusing the Kaplan-Meier method and a two sided 95% CI for the log [-log(1-year survival
probability)] was calculated using a normal approximation using the Greenwood’s formula,and then back-transformed to give a CI for the 1-year survival probability itself. The 2-yearand 3-year survival probabilities were estimated similarly.
Objective Response (OR): OR was defined as a CR or PR according to RECIST v.1.1
recorded from randomization until disease progression or death due to any cause. A subject
was considered to have achieved an OR if the subject had a sustained CR or PR according to
RECIST v.1.1 definitions. Otherwise, the subject was considered as non-responders in the
OR rate analysis. Additionally, subjects with inadequate data for tumor assessment (eg, nobaseline assessment or no follow-up assessments) were considered as non-responders in the

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OR rate analysis. The OR rate in each randomized treatment arm was estimated by dividing
the number of subjects with OR (CR or PR) by the number of subjects randomized to therespective treatment arm (“response rate”). A 95% CI for the response rates was provided.
Response rate comparisons between the 2 treatment arms as randomized were assessed using
the Cochran–Mantel–Haenszel (CMH) test with the same stratification factors as for the PFS
analysis.

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Analyses of OR rate were performed on the ITT population based on the investigator’s
assessment, on the investigator-assessed ITT population with measurable disease at baseline
as well as on a randomly sampled audit subset of the ITT population based on the review ofthe blinded independent third-party core imaging laboratory.
Clinical Benefit Response (CBR): CBR was defined as CR or PR or SD ≥24 weeks
according to the RECIST version 1.1 recorded in the time period between randomization anddisease progression or death of any cause. The CBR rate in each randomized treatment arm
was estimated by dividing the number of subjects with CR, PR, or SD ≥24 weeks by the
number of subjects randomized to the treatment arm. A 95% CI for the CBR rate wasprovided. CBR rate comparison between the two treatment arms as randomized was assessedusing the CMH test with the same stratification factors as for the PFS analysis. Analyses for
CBR were performed on the ITT population based on the investigator’s assessment and on arandomly sampled audit subset of the ITT population based on the review of the blinded
independent third-party core imaging laboratory.
Duration of Response (DR): DR was defined as the time from the first documentation of
objective tumor response (CR or PR) to the first documentation of objective tumor
progression or to death due to any cause, whichever occurred first. DR data were censored on
the date of the last tumor assessment on study for subjects who did not have objective tumor
progression and who did not die due to any cause while on study. DR was only calculated forthe subgroup of subjects with an OR. DR for the two treatment arms was summarized using
Kaplan-Meier methods and displayed graphically, where appropriate. The median event timeand 95% CI for the median were provided for each endpoint.
Patient-Reported Outcomes (PRO): Completion rates were summarized by cycle. Patientreported global QOL, functioning and symptom scores assessed using the EORTC QLQ-C30
and BR-23 and change from baseline scores were compared between the treatment arms
using a longitudinal repeated measures mixed model approach adjusting for specified
covariates. Statistical significance of within treatment arm change from baseline wasinterpreted using the 95% CIs of the average change from baseline score. In addition to theabove analyses, the time to deterioration (TTD) in pain was carried out using survival
analysis methods. Deterioration was defined as an increase in score of 10 points or greaterfrom baseline. A log-rank test (1-sided) was used to compare time to deterioration between
the 2 treatment arms. TTD associated with each treatment arm was summarized using the
Kaplan-Meier method and displayed graphically. The Cox Proportional hazards model wasused to compute the treatment HR and the corresponding 95% CI. EQ-5D general healthstatus and EQ-5D Index scores between treatment arms were compared using longitudinal
repeated measures models. No adjustments were made for multiple comparisons.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

RESULTS
Subject Disposition
Between 26 Sep 2013 (first subject first visit [FSFV]) and 26 Aug 2014, a total of 521
subjects were randomized (Table 2) and reasons for discontinuation reported (Table 3).
Table 2:

Subject Disposition

Number (%) of Subjects

Palbociclib plus
Fulvestrant347
2 (0.6)345 (99.4)
0107 (30.8)
238 (68.6)

Randomized to study treatment
Randomized and not treatedRandomized and treatedCompleted 1
Discontinued 2
Ongoing at data cutoff date
1090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

2

Placebo plus
Fulvestrant
174
2 (1.1)172 (98.9)
0
97 (55.7)
75 (43.1)

Total
521
4 (0.8)517 (99.2)
0204 (39.2)
313 (60.1)

Completion is from the Subject Summary End of Study (EOS) page.
Includes subjects who discontinued palbociclib/placebo treatment for progression or any other reason.

Table 3:
Subject Disposition at End of Treatment – Palbociclib plus Fulvestrant orPlacebo and Fulvestrant – Intent-to-Treat Population
Number(%) of Subjects

Reason for discontinuation 1
AE (reason for palbociclib/placebo discontinuation) 2
AE (reason for fulvestrant discontinuation)
Global deterioration of health status
Lost to Follow-Up
Medication error without associated AE
Objective progression or relapse plus progressive
diseaseProtocol violation
Study terminated by the sponsor
Subject died
Subject refused to continue treatment for reason otherthan AE
Subject started new treatment for disease under study
Withdrew consent
Other

Palbociclib
plus
Fulvestrant
N=347
n (%)

Placebo plus
Fulvestrant

Total

N=174
n (%)

N=521
n (%)

9 (2.6)7 (2.0)8 (2.3)0085 (24.5)

3 (1.7)3 (1.7)3 (1.7)0087 (50.0)

12 (2.3)
10 (1.9)
11 (2.1)00172 (33.0)000
1 (0.3)00
1 (0.6)
1 (0.6)00
1 (0.2)2 (0.4)0
4 (1.2)00
2 (1.1)00
6 (1.2)0Abbreviation: AE: adverse event, CRF: Case Report Form, N: number of subjects, n: number of subjects affected
1
Includes subjects who discontinued treatment for progression or any other reason. Discontinued is as per the Conclusionof Treatment page of the CRF.
2
The subjects A and B completed the End of Treatment CRF page for palbociclib/placebo only.
Percentages are calculated using N as a denominator.
0 mg doses have not been excluded from the algorithm determining subject status.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Demography
Table 4 presents demographic and other baseline characteristics.
Table 4:

Demographic Characteristics – Intent-to-Treat Population

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Number(%) of Subjects
Age (years) n (%)<65≥65
Mean (SD)Median (range)
Race n (%)
White
Black
Asian
Other
Unspecified
Ethnicity n (%)
Hispanic/Latino
Not Hispanic/Latino
Unspecified
Weight (kg)n (%)
Mean (SD)Median (range)
Height (cm)n (%)
Mean (SD)Median (range)

Palbociclib plus
Fulvestrant
N=347

Placebo plus
Fulvestrant
N=174

N=521

261 (75.2)
86 (24.8)
56.9 (11.7)
57.0 (30-88)

131 (75.3)
43 (24.7)
56.8 (10.4)
56.0 (29-80)

392 (75.2)
129 (24.8)
56.9 (11.3)
57.0 (29-88)

252 (72.6)
12 (3.5)
74 (21.3)
8 (2.3)1 (0.3)133 (76.4)
8 (4.6)31 (17.8)
1 (0.6)
1 (0.6)385 (73.9)
20 (3.8)105 (20.2)
9 (1.7)2 (0.4)17 (4.9)329 (94.8)
1 (0.3)

11 (6.3)
161 (92.5)
2 (1.1)28 (5.4)
490 (94.0)
3 (0.6)347 (100)
70.4 (17.5)
67.2 (35.6-142.0)

171 (98.3)
72.0 (17.6)
69.8 (35.1-126.8)

518 (99.4)
70.9 (17.6)
68.5 (35.1-142.0)

347 (100)
161.1 (7.0)
161.5 (139.8-182.9)

174 (100)(161.3 (7.6)
162.0 (121.9-180.3)

521 (100)
161.2 (7.2)
162.0 (121.9-182.9)

Abbreviations: N: number of subjects, n: number of subjects affected, SD: standard deviation,

Page 13

Total

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Efficacy, Pharmacokinetic, or Outcomes Research Results
Primary Endpoint: Progression-Free Survival (PFS) as assessed by the investigator
At the data cutoff date, the most common type of PFS event was disease progression, for
100 (28.8%) subjects in the palbociclib plus fulvestrant arm and 91 (52.3%) subjects in theplacebo plus fulvestrant arm. Two deaths were reported in each treatment arm. (Table 5)090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Table 5:
Summary of Progression-Free Overall Survival by Treatment,
Investigator Assessment – Intent-to-Treat Population

Number with event
Type of event
Objective progression
Death without objective progression
Number censoredReason for censorship
No adequate baseline assessments
No on-study disease assessments
Given new anti-cancer treatment prior to disease progression
and after last dose of study treatment
Discontinued study without disease progression or death
Withdrew consent for follow-up
Lost to follow-up
Other
Unacceptable gap (>20 weeks) between PD or death to themost recent prior adequate assessment
In follow-up for progression
Probability of being event free at Month 12 1 (95% CI 2)
Kaplan-Meier estimates of time to event (month)
Quartiles (95% CI) 3
25%
50%
75%
Stratified analysis
Hazard ratio 4
95% Hazard ratio
p-value 5
Unstratified analysis 6
Hazard ratio 4
95% Hazard ratio
p-value 5

Palbociclib plus
Fulvestrant
N=347
n (%)
102 (29.4)

Placebo plus
Fulvestrant
N=174
n (%)
93 (53.4)

100 (28.8)
2 (<1.0)245 (70.6)

91 (52.3)
2 (1.1)81 (46.6)

1 (<1.0)
7 ( 2.0)
8 ( 2.3)07 (4.0)4 ( 2.3)

2 (<1.0)
1 (<1.0)0
1 (<1.0)
0

0
0
0
0
0

227 (65.4)-

70 (40.2)-

3.9 [3.6, 5.5]
9.2 [7.5, NE]
NE [11.0, NE]

1.9 [1.8, 1.9]
3.8 [3.5, 5.5]
NE [5.7, NE]

0.422
0.318-0.560<0.000001
0.417
0.314-0.553<0.000001

Abbreviations: CI: confidence interval, N: number of subjects, n: number of subjects affected, NE: not estimable; PD:
progressive disease
1. Estimated from the Kaplan-Meier curve.
2. Calculated with the product-limit method.
3. Based on the Brookmeyer and Crowley method.
4. Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of the palbociclib
plus fulvestrant arm.
5. 1-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior hormonal
therapy per randomization.
6. Sensitivity analysis 2: used a 1-sided unstratified log-rank test and an unstratified Cox proportional hazards model.
7. Anti-cancer treatment included surgery containing a lesion removal or subsequent anti-cancer systemic therapies.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Secondary Endpoints:
Overall Survival (OS) and Survival Probabilities at Months 12, 24, and 36
The interim analysis of OS yielded inconclusive results due to immature OS data with asmall number of deaths observed at the time of the PFS analysis; 19 (5.5%) subjects had diedin the palbociclib plus fulvestrant arm and 9 (5.2%) subjects had died in the placebo plus
fulvestrant arm (Table 6). The estimated survival probabilities at Month 12 were 89.3% forboth treatment arms. The estimated survival probabilities at Month 24 and Month 36 could
not be calculated. (Table 6)
Table 6:

Summary of Overall Survival by Treatment – Intent-to-Treat Population
Palbociclib plus
Fulvestrant
N=347
n (%)
19 (5.5)

Placebo plus
Fulvestrant
N=174
n (%)
9 (5.2)18 (5.2)
0
1 (<1.0)08 (4.6)0
0
1 (<1.0)

Number censoredReason for censorship
Subject Remains In Follow-up
Subject No Longer Being Followed For Survival

328 (94.5)

165 (94.8)

324 (93.4)
4 (1.2)157 (90.2)
8 (4.6)

Survival Probability at Month 6 [1] (95% CI [2])Survival Probability at Month 12 [1] (95% CI [2])Survival Probability at Month 24 [1] (95% CI [2])Survival Probability at Month 36 [1] (95% CI [2])94.2 (90.7, 96.4)
89.3 (78.1, 95.0)-

95.9 (90.9, 98.2)
89.3 (77.8, 95.0)-

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Number of deaths
Cause of death
Disease Under Study
Study Treatment Toxicity
Unknown
Other[1] Estimated from the Kaplan-Meier curve[2] Calculated from the product-limit method.

Objective Response (OR) – percentage of participants with confirmed objective tumor
response
The analysis of investigator-assessed OR demonstrated a numerically higher OR rate which
did not reach statistical significance for palbociclib plus fulvestrant vs placebo plus
fulvestrant (odds ratio of 1.725 [95% CI: 0.835, 3.896; stratified 1-sided p-value of 0.0791](Table 7).
Table 7:
Summary of Best Overall Tumor Response by Treatment, Investigator
Assessment – Intent-to-Treat Population
Palbociclib plus
Fulvestrant
N=347
n (%)
0

Complete response

Page 15

Placebo plus
Fulvestrant
N=174
n (%)
3 (1.7)

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Partial response
Stable/no response
Objective progression
Indeterminate
Objective response and rate(complete response and partial response)
95% exact CI for OR rate 1090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Stratified analysis
Odds ratio 2
95% exact CI
p-value 3
Unstratified analysis
Odds ratio 2
95% exact CI
p-value 4

Palbociclib plus
Fulvestrant
N=347
n (%)
36 (10.4)244 (70.3)
57 (16.4)
10 (2.9)

Placebo plus
Fulvestrant
N=174
n (%)
8 (4.6)
97 (55.7)
57 (32.8)
9 (5.2)36 (10.4)

11 (6.3)[7.4, 14.1][3.2, 11.0]

1.725[0.835, 3.896]
0.07911.715[0.826, 3.834]
0.0843Abbreviations: CI: confidence interval, N: number of subjects, n: number of subjects affected, OR: objective response
1. CI was calculated using the exact (Clopper-Pearson) method.
2. An Odds Ratio >1 means better response in favor of the palbociclib plus fulvestrant arm.
3. 1-sided exact test stratified by the presence of visceral metastases and sensitivity to prior hormonal therapy per
randomization.
4. 1-sided p-value is from exact test.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Duration of Response (DR)The investigator-assessed median DR was longer in the palbociclib plus fulvestrant arm(9.3 months [95% CI: 4.0, not estimable] than in the placebo plus fulvestrant arm(5.7 months [95% CI: 3.7, 5.7]) (Table 8).
Table 8:
Summary of Duration of Objective Response by Treatment, Investigator
Assessments – Intent-to-Treat Population

Investigator Assessment

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Subjects with a response (CR/PR)
Number (%) of subjects with events
Number (%) of subjects censored
Kaplan-Meier estimate of duration of response (CR or PR) inmonths:Quartile (95% CI) 1
25%
50%
75%

Palbociclib plus
Fulvestrant
N=347
n (%)
36 (10.4)
5 (13.9)
31 (86.1)

Placebo plus
Fulvestrant
N=174
n (%)
11 (6.3)
2 (18.2)
9 (81.8)

4.0 [3.4, NE]
9.3 [4.0, NE]
NE [9.3, NE]

5.7 [3.7, 5.7]
5.7 [3.7, 5.7]
5.7 [NE, NE]

Abbreviations: CI: confidence interval, CR: complete response, N: number of subjects, n: number of subjects affected, NE:
not estimable, PR: partial response
1) Based on the Brookmeyer Crowley method.
Transformation applied while calculating CI.
Percentages for subjects with a response were calculated in reference to N.
Percentages for subjects with events and subjects censored were calculated in reference to the number of subjects with a
response.

Clinical Benefit Response (CBR)
The analysis of investigator-assessed CBR (CR, PR and SD≥24 weeks) in the ITT population
demonstrated a statistically significant improvement in CBR for palbociclib plus fulvestrant
compared with placebo plus fulvestrant (odds ratio of 2.189 [95% CI: 1.391, 3.523; stratified
1-sided p-value of 0.0002]) (Table 9).
Table 9:
Summary of Clinical Benefit Response by Treatment, Investigator
Assessment – Intent-to-Treat Population

Complete response
Partial response
Stable disease ≥24 weeks
Stable disease <24 weeks
Objective progression
Indeterminate
Clinical benefit response and rate (CR + PR + SD ≥24 weeks)
95% exact CI for CBR rate 1
Stratified analysis

Page 17

Palbociclib plus
Fulvestrant
N=347
n (%)
0
36 (10.4)
82 (23.6)
162 (46.7)
57 (16.4)
10 (2.9)

Placebo plus
Fulvestrant
N=174
n (%)
3 (1.7)8 (4.6)22 (12.6)
75 (43.1)
57 (32.8)
9 (5.2)118 (34.0)
29.0, 39.3

33 (19.0)
13.4, 25.6

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015
Palbociclib plus
Fulvestrant
N=347
n (%)
2.189
1.391,3.523
0.0002

Odds ratio 2
95% exact CI
p-value 3
Unstratified analysis
Odds ratio 2
95% exact CI
p-value 4

Placebo plus
Fulvestrant
N=174
n (%)

2.202
1.396,3.530
0.0002Abbreviations: CBR: clinical benefit response, CI: confidence interval, CR: complete response, N: number of subjects, n:number of subjects affected, PR: partial response, SD: stable disease
1. CI was calculated using the exact (Clopper-Pearson) method.
2. An Odds Ratio > 1 means better response in favor of palbociclib plus fulvestrant arm.
3. 1-sided exact test stratified by the presence of visceral metastases and sensitivity to prior hormonal therapy per
randomization.
4. 1-sided p-value is from exact test.

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Minimum Observed Plasma Trough Concentration (Ctrough) for Palbociclib, Fulvestrant and
Goserelin
The presence or absence of goserelin did not have a meaningful effect of palbociclib PK.
Palbociclib geometric mean steady-state Ctrough in the presence of concurrent fulvestrant
administration (without regard for goserelin dosing) in Study 1023 was 76.62 ng/mL while
the reported value from pooled historical studies where fulvestrant was not present was
58.77 ng/mL (Table 10).
Table 10:
Summary of Plasma Palbociclib Steady-State Pharmacokinetic
Parameters Following Daily 125 mg Oral Doses of Palbociclib by Unique Drug
Combination
Unique Drug Combination
Palbociclib + Fulvestrant +Goserelin
Palbociclib + Fulvestrant Goserelin
Palbociclib + Fulvestrant Total
Palbociclib Historical Data3

Parameter Summary Statistics1 by Treatment

Parameter[Units]N
Ctrough [ng/mL]N
Ctrough [ng/mL]N
Ctrough [ng/mL]N
Ctrough [ng/mL]

Cycle 1/Day 15
3562.04 (51)130
73.23 (42)165
70.70 (44)---Cycle 2/Day 15
33
69.39 (50)12776.91 (42)160
75.29 (44)---

Combined2
4372.04 (48)175
77.79 (40)218
76.62 (41)98
58.77 (45)Abbreviation: CV: coefficient of variation, N: Number of subjects contributing to the geometric mean estimation
1. Geometric mean (% CV)
2. Within-subject mean of steady-state Ctroughs.
3. From Studies 1001, 1002, and 1003.

The presence or absence of goserelin did not have an impact on fulvestrant PK, the“palbociclib plus fulvestrant Total” drug combination was the most appropriate selection for
the test treatment group and the “placebo plus fulvestrant Total” drug combination was the

Page 18

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

most appropriate selection for the reference group to assess the potential for palbociclib tofulvestrant plasma PK. (Table 11). Fulvestrant steady-state exposures, as measured by thegeometric mean of the within-subject mean steady-state Ctrough from Day 1 of Cycles 2 and 3,
were 10.80 ng/mL and 8.85 ng/mL in the presence and absence of concurrent palbociclib
administration respectively (Table 11).
Table 11:
Summary of Plasma Fulvestrant Steady-State Pharmacokinetic
Parameters by Unique Drug Combination
Unique Drug Combination
Palbociclib + Fulvestrant +Goserelin
Palbociclib + Fulvestrant Goserelin
Palbociclib + Fulvestrant Total
Placebo + Fulvestrant +Goserelin
Placebo + Fulvestrant - Goserelin

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Placebo + Fulvestrant Total

Parameter Summary Statistics1 by Treatment

Parameter[Units]N
Ctrough [ng/mL]N
Ctrough [ng/mL]N
Ctrough [ng/mL]N
Ctrough [ng/mL]N
Ctrough [ng/mL]N
Ctrough [ng/mL]

Cycle 2/Day 1
8
12.59 (42)27
11.51 (41)35
11.75 (41)510.79 (36)14
8.83 (59)19
9.31 (52)Cycle 3/Day 1
7
10.62 (57)22
9.68 (35)29
9.90 (42)37.85 (21)11
7.54 (79)14
7.60 (72)

Combined2
911.05 (49)28
10.72 (36)37
10.80 (39)5
10.36 (40)14
8.36 (64)198.85 (57)

Abbreviation: CV: coefficient of variation, N: number of subjects contributing to the geometric mean estimation
1. Geometric mean (% CV)
2. Within-subject mean of steady-state CtroughGoserelin steady-state exposures, as measured by the geometric mean of the within-subject
mean steady-state Ctrough from Day 1 of Cycles 2 and 3, were 302.9 pg/mL and 274.4 pg/mL
in the presence and absence of concurrent palbociclib administration, respectively (Table 12).
Table 12:
Summary of Plasma Goserelin Steady-State Pharmacokinetic Parameters
by Unique Drug Combination
Unique Drug Combination
Palbociclib + Fulvestrant +Goserelin
Placebo + Fulvestrant +Goserelin

Parameter Summary Statistics1 by Treatment

Parameter[Units]N
Ctrough [pg/mL]N
Ctrough [pg/mL]

Cycle 2/Day 1
9295.1 (153)5
302.5 (74)

Cycle 3/Day 17
344.8 (64)3288.5 (40)Abbreviation: CV: coefficient of variation, N=Number of subjects contributing to the geometric mean estimation, NC=not
calculated
1. Geometric mean (% CV)
2. Within-subject mean of steady-state Ctroughs

Page 192

Combined9
302.9 (115)5
274.4 (49)Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Change from Baseline in European Organization for Research and Treatment of Cancer
Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores
Descriptive statistics for change from baseline EORTC QLQ-C30 scores are presented inTable 13.

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Table 13:
QLQ-C30 Scale Scores Between Treatment Comparison (Mixed Effects
Model) - PRO Analysis Set

Functional Scales

Palbociclib (PD0332991) +Fulvestrant (N=335)
Mean (95% CI)

Placebo +Fulvestrant(N= 166)
Mean (95% CI)

Palbociclib (PD-0332991) +Fulvestrant – Placebo +Fulvestrant
Mean
95% CI
P-value

Global health status /QoL-0.9 (-2.5 to 0.7)

-4.0 (-6.3 to -1.7)

3.1

0.3 , 6.0

0.0313

Physical functioning-0.7 (-2.1 to 0.7)

-1.7 (-3.7 to 0.2)

1.0

-1.4, 3.50.4000Role functioning-1.8 (-3.7 to 0.1)

-3.7 (-6.5 to -0.9)

1.9-1.5, 5.3

0.2615

Emotional
functioning

2.7 (1.1 to 4.3)

-1.9 (-4.2 to 0.5)

4.6

1.7, 7.4

0.0016

Cognitive functioning-1.7 (-3.1 to -0.2)-2.9 (-5.0 to -0.7)

1.2-1.4, 3.8

0.3650Social functioning-0.5 (-2.5 to 1.5)

-0.6 (-3.4 to 2.3)

0.1

-3.4, 3.5

0.9615

Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, andbaseline as covariate.
QLQ-C30 questionnaire employs 4-point scales with responses from ’not at all’ to ’very much’ on 28 items and a 7-point
scale with responses ’very poor’ to ’excellent’ on 2 items assessing global health and overall QOL. All scores are converted
to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning.
The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple
comparisons.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Change from Baseline in EORTC QLQ-C30 Symptom Scale Scores
Between-treatment comparisons of overall EORTC–QLQ-C30 scale scores from repeatedmeasures analyses are presented in Table 14.
Table 14:
QLQ-C30 Scale Scores Between Treatment Comparison (Mixed Effects
Model) - PRO Analysis Set
Palbociclib (PD0332991) +Fulvestrant (N=335)
Mean (95% CI)

Placebo +Fulvestrant(N= 166)
Mean (95% CI)

Palbociclib (PD-0332991) +Fulvestrant – Placebo +Fulvestrant
Mean
95% CI
P-value

Fatigue

1.8 (0.1 to 3.5)

3.3 (0.9 to 5.8)

-1.5

-4.5, 1.5

0.3200

Nausea and vomiting

1.7 (0.4 to 3.0)

4.2 (2.3 to 6.1)

-2.5

-4.8, -0.2

0.0369Pain-3.3 (-5.1 to -1.5)

2.0 (-0.6 to 4.6)

-5.3

-8.5, -2.1

0.0011

Dyspnoea

2.8 (1.0 to 4.7)

3.3 (0.6 to 6.0)

-0.5

-3.7, 2.8

0.7699Insomnia-2.4 (-4.4 to -0.4)-0.4 (-3.3 to 2.5)

-2.0

-5.5, 1.6

0.2721

Appetite loss

1.1 (-0.8 to 3.1)

1.7 (-1.1 to 4.6)

-0.6

-4.1, 2.9

0.7334

Constipation

3.5 (1.7 to 5.3)

2.8 (0.1 to 5.4)

0.7

-2.5, 3.9

0.6491

Diarrhoea

1.9 (0.6 to 3.1)

2.4 (0.5 to 4.3)

-0.6

-2.8, 1.7

0.6293Financial difficulties-3.7 (-5.6 to -1.9)-4.0 (-6.7 to -1.3)

0.3-3.1, 3.6

0.8812090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Functional Scales

Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, andbaseline as covariate.
QLQ-C30 questionnaire employs 4-point scales with responses from ’not at all’ to ’very much’ on 28 items and a 7-point
scale with responses ’very poor’ to ’excellent’ on 2 items assessing global health and overall QOL. All scores are converted
to a 0 to 100 scale. For symptom-oriented scales, a higher score represents more severe symptoms.
The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple
comparisons.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Change from Baseline in European Organization for Research and Treatment of Cancer
Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores
Between-treatment comparisons of overall EORTC -QLQ-BR23 functioning scale scoresfrom the repeated measures analyses are presented in Table 15.
Table 15:
QLQ-BR23 Scale Scores Between Treatment Comparison (Mixed Effects
Model) - PRO Analysis Set
Palbociclib (PD0332991) +Fulvestrant (N=335)
Mean (95% CI)

Placebo +Fulvestrant(N= 166)
Mean (95% CI)

Palbociclib (PD-0332991) +Fulvestrant – Placebo +Fulvestrant
Mean
95% CI
P-value

Body image

1.9 (0.2 to 3.6)

-0.3 (-2.8 to 2.1)

2.3

-0.7, 5.2

0.1386

Sexual functioning-1.1 (-2.5 to 0.2)

-0.4 (-2.3 to 1.5)

-0.8

-3.1, 1.6

0.5235

Sexual enjoyment-5.2 (-8.3 to -2.1)-6.6 (-11.6 to -1.7)

1.4-4.4, 7.3

0.6271

Future perspective

8.1 (5.8 to 10.4)

4.5 (1.2 to 7.9)

3.6

-0.5, 7.6

0.0845090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Functional Scales

Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, andbaseline as covariate.
QLQ-BR23 questionnaire employs 23 4 point scales with responses from ’not at all’ to ’very much’. All scores areconverted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning.
The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple
comparisons.

Page 22

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Change from Baseline in EORTC QLQ BR23 Symptom Scale Scores
Between-treatment comparisons of overall EORTC –QLQ-BR23 symptom scale scores fromthe repeated measures analyses are presented in Table 16.
Table 16:
QLQ-BR23 Scale Scores Between Treatment Comparison (Mixed Effects
Model) - PRO Analysis Set
Palbociclib (PD0332991) +Fulvestrant(N=335)
Mean (95% CI)

Placebo +Fulvestrant(N= 166)
Mean (95% CI)

Systemic therapy side
effects

3.8 (2.6 to 4.9)

Breast symptoms

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Functional Scales

Palbociclib (PD-0332991) +Fulvestrant – Placebo +Fulvestrant
Mean

95% CI

P-value

3.4 (1.8 to 5.0)

0.4

-1.6, 2.3

0.7273-2.2 (-3.2 to -1.3)-1.3 (-2.7 to 0.0)

-0.9

-2.6, 0.7

0.2671

Arm symptoms-2.2 (-3.6 to -0.9)-2.0 (-4.0 to -0.1)-0.2-2.6, 2.2

0.8750Upset by hair loss

2.9 (-1.7 to 7.4)

-6.0 (-12.3 to 0.3)

8.9

1.1, 16.6

0.0255

Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, andbaseline as covariate.
QLQ-BR23 questionnaire employs 23 4 point scales with responses from ’not at all’ to ’very much’. All scores areconverted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning.
The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple
comparisons.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Change from Baseline in EuroQoL 5D (EQ-5D)- Health Index scores
The between-treatment comparisons of EQ-5D Index scores and comparison for change frombaseline is presented in Table 17.
Table 17:
EQ-5D Index Between Treatment Comparison (Mixed Effects Model) PRO Analysis Set

EuroQoL 5D – HealthIndex Scores

Palbociclib (PD0332991) +Fulvestrant (N=335)
Mean (95% CI)

Placebo +Fulvestrant(N= 166)
Mean (95% CI)

0.006 (-0.01 to 0.03)-0.031 (-0.06 to 0.00)

Palbociclib (PD-0332991) +Fulvestrant – Placebo +Fulvestrant
Mean
95% CI
P-value
0.037

0.00, 0.07

0.0308Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, andbaseline as covariate.
Based on subjects who completed all 5 items needed to calculate the index-based summary score at the respective cycle.
Higher values indicate a better health state.
The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple
comparisons.

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Change from Baseline in EQ-5D Visual Analog Scale (VAS) scores scale
The visual analog scale within the EQ-5D assesses general health status; the change frombaseline scores is presented in Table 18.
Table 18:

EQ-VAS Scale Change from Baseline - PRO Analysis Set

EuroQoL 5D – HealthIndex Scores

Palbociclib (PD0332991) +Fulvestrant (N=335)
Mean (95% CI)

Placebo +Fulvestrant(N= 166)
Mean (95% CI)

Palbociclib (PD-0332991) +Fulvestrant – Placebo +Fulvestrant
Mean
95% CI
P-value-1.8 (-3.3 to -0.3)-2.6 (-4.8 to -0.4)

0.8-1.9, 3.5

0.5523

Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, andbaseline as covariate.
EQ-VAS ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from baseline = Cycle
X - Baseline. Negative changes from baseline indicate deterioration in health state.
The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple
comparisons.

Page 24

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Time to Deterioration (TTD)
An analysis of TTD in pain defined as time between baseline and first occurrence of increaseof ≥10 points in pain was carried out based on survival analysis methods using cox
proportional hazards model and log rank test. A summary of the TTD in pain is provided inTable 19.

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Table 19:
QLQ-C30 Time to Deterioration - Symptom Scale of Pain Increase of ≥10
Points - PRO Analysis Population

Subject had symptom scale of pain increase of ≥10 points while on
study [n (%)]
Subject did not have symptom scale of pain increase of ≥10 points
while on study [n (%)]
Kaplan-Meier estimates of time to event (month)
Quartiles (95% CI) 1
25%
50%
75%
Unstratified analysis 4
Hazard ratio 2
95% CI of Hazard ratio
p-value 3

Palbociclib plus
Fulvestrant
N=335
n (%)
131 (39.1)

Placebo plus
Fulvestrant
N=166
n (%)
83 (50.0)204 (60.9)

83 (50.0)

1.9 [1.2,2.2]
8.0 [5.6, NE]NE

1.0 [1.0,1.9]
2.8 [2.3,5.4]
NE

0.642
0.487-0.846<0.001Abbreviations: CI: confidence interval, EORTC-QLQ-C30: European Organization for Research and Treatment of Cancer
Quality of Life Questionnaire, N: number of subjects, n: number of subjects affected, NE: not estimable, PRO: subjectreported outcome
1
Based on the Brookmeyer and Crowley Method.
2
Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of the palbociclib
plus fulvestrant arm.
3
Used a 1-sided unstratified log-rank test and an unstratified Cox proportional hazards model.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Percentage of participants with Treatment-Emergent Adverse Events (TEAEs; All
Causalities)
Overall, 490 (94.8%) of all subjects (AT population) experienced a total of 4096 TEAEs;
337 (97.7%) subjects in the palbociclib plus fulvestrant arm experienced 3045 TEAEs, and153 (89.0%) subjects in the placebo plus fulvestrant arm experienced 1051 TEAEs(Table 20).
Table 20:
population

Treatment-Emergent Adverse Events All Causalities – As-treated090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Number of subjects

Number of subjects
Subjects evaluable for AEs
Number of AEs
Subjects with AEs
Subjects with SAEs
Subjects with Grade 3 or 4 AEs
Subjects with Grade 5 AEs 1
Subjects discontinued study due to AEs
Subject discontinued palbociclib/placebo due to AEs
Subjects discontinued fulvestrant due to AEs
Subjects temporarily discontinued palbociclib/placebo
due to AEs
Subjects temporarily discontinued fulvestrant due toAEs
Subjects with palbociclib/placebo dose reduction of
due to AEs
Subjects with dose interruptions of fulvestrant due to
AEs

Palbociclib
plus
Fulvestrantn (%)

Placebo plus
Fulvestrant
n (%)

n (%)

345
3045
337 (97.7)
33 (9.6)
242 (70.1)
3 (0.9)2 (0.6)
13 (3.8)
11 (3.2)
223 (64.6)

172
1051
153 (89.0)
24 (14.0)
31 (18.0)
2 (1.2)3 (1.7)7 (4.1)5 (2.9)14 (8.1)

517
4096
490 (94.8)
57 (11.0)273 (52.8)
5 (1.0)5 (1.0)20 (3.9)
16 (3.1)
237 (45.8)

83 (24.1)

6 (3.5)89 (17.2)

107 (31.0)

3 (1.7)110 (21.3)

3 (0.9)03 (0.6)Abbreviations: AE: adverse event, n: number of subjects affected, SAE: serious adverse event
Includes data up to 28 days after last dose of study drug.
Except for the Number of AEs subjects are counted only once per treatment in each row.
Percentages are calculated in the reference to number of subjects evaluable for AEs.
SAEs - according to the investigator’s assessment.
Severity counts are based on the maximum severity or grade of events.
1
Subject A died on study but no TEAE Grade 5 was recorded on CRF AE page.
MedDRA (v17.1) coding dictionary applied.

Page 26

Total

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Safety Results
AEs
All causality and treatment-related non-serious AEs are presented in Table 21. Overall, 333(96.5%) subjects in the Palbociclib + Fulvestrant arm and 147 (85.5%) subjects in thePlacebo + Fulvestrant arm experienced all causality treatment-emergent, non-serious AEs.
Overall, 311 (90.1%) subjects in the Palbociclib + Fulvestrant arm and 98 (57.0%) subjects
in the Placebo + Fulvestrant arm experienced treatment-related non-serious AEs.
SAEs

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

All causality and treatment-related SAEs are presented in Table 22. Overall, only
33 (9.6%) subjects in the Palbociclib + Fulvestrant arm and 24 (14.0%) subjects in thePlacebo + Fulvestrant arm experienced all causality treatment-emergent, SAEs. Overall, 12(3.5%) subjects in the Palbociclib + Fulvestrant arm and 3 (1.7%) subjects in the Placebo +Fulvestrant arm experienced treatment-related serious AEs.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

Table 21: Treatment-Emergent Non-Serious Adverse Events by System Organ Classand Preferred Term (All Causalities and Treatment-Related) – Safety Analysis Set.
System Organ Class

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Preferred Term

Number (%) of Subjects with Non-Serious
Adverse Events by System Organ Class
Blood and lymphatic system disorders
Anaemia
Leukopenia
Neutropenia
Thrombocytopenia
Gastrointestinal disorders
Abdominal pain
Abdominal pain upper
Constipation
Diarrhoea
Dry mouth
Dyspepsia
NauseaStomatitis
Vomiting
General disorders and administration site
conditions
Asthenia
Chest pain
Fatigue
Injection site pain
Oedema peripheral
Pain
Pyrexia
Infections and infestations
Nasopharyngitis
Upper respiratory tract infection
Investigations
Aspartate aminotransferase increased
Neutrophil count decreased
Platelet count decreased
White blood cell count decreased
Metabolism and Nutrition Disorders
Decreased appetite
Musculoskeletal and Connective Tissue Disorders
Arthralgia
Back pain
Muscle spasms
Musculoskeletal chest pain
Musculoskeletal pain
Myalgia
Pain in extremity
Nervous System Disorders
Dizziness

Palbociclib (PD0332991) + Fulvestrant(N=345)n (%)
All
Treatment
Causalities
related333 (96.5)
311 (90.1)

All
Causalities
147 (85.5)

Treatment
related98 (57.0)

247 (71.6)
88 (25.5)70 (20.3)
212 (61.4)
40 (11.6)
203 (58.8)
21 (6.1)
12 (3.5)
58 (16.8)
66 (19.1)
22 (6.4)
25 (7.2)
100 (29.0)
40 (11.6)
50 (14.5)181 (52.5)

242 (70.1)
80 (23.2)
70 (20.3)
209 (60.6)
39 (11.3)
139 (40.3)
28 (8.1)
37 (10.7)
18 (5.2)
77 (22.3)
37 (10.7)
27 (7.8)
109 (31.6)

18 (10.5)
17 (9.9)
2 (1.2)3 (1.7)0 (0.0)89 (51.7)
9 (5.2)11 (6.4)
24 (14.0)30 (17.4)
14 (8.1)
7 (4.1)44 (25.6)
4 (2.3)20 (11.6)
81 (47.1)

13 (7.6)
12 (7.0)
2 (1.2)2 (1.2)0 (0.0)59 (34.3)
13 (7.6)
20 (11.6)
10 (5.8)
34 (19.8)
2 (1.2)9 (5.2)43 (25.0)

23 (6.7)
6 (1.7)131 (38.0)
19 (5.5)
25 (7.2)
15 (4.3)
27 (7.8)42 (12.2)
25 (7.2)
20 (5.8)
128 (37.1)
19 (5.5)
73 (21.2)
27 (7.8)
92 (26.7)
44 (12.8)
44 (12.8)
123 (35.7)
45 (13.0)
38 (11.0)
21 (6.1)
9 (2.6)20 (5.8)
23 (6.7)
33 (9.6)
103 (29.9)
37 (10.7)

99 (28.7)
17 (4.9)
117 (33.9)
72 (20.9)
27 (7.8)
92 (26.7)
26 (7.5)
26 (7.5)
33 (9.6)
23 (6.7)
16 (4.6)
27 (7.8)-8 (4.7)9 (5.2)46 (26.7)
16 (9.3)
8 (4.7)
12 (7.0)
6 (3.5)16 (9.3)
9 (5.2)7 (4.1)
12 (7.0)
8 (4.7)3 (1.7)0 (0.0)5 (2.9)13 (7.6)
13 (7.6)
78 (45.3)
28 (16.3)
25 (14.5)
11 (6.4)
9 (5.2)11 (6.4)
12 (7.0)19 (11.0)
46 (26.7)
16 (9.3)

34 (19.8)
13 (7.6)5 (2.9)2 (1.2)0 (0.0)4 (2.3)10 (5.8)
10 (5.8)
21 (12.2)
13 (7.6)
9 (5.2)13 (7.6)-

Page 28

Placebo + Fulvestrant(N=172)n (%)

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015
Dysgeusia
Headache
Psychiatric Disorders
Anxiety
Depression
Insomnia
Respiratory, Thoracic and Mediastinal Disorders
Cough
Dyspnoea
Epistaxis
Oropharyngeal pain
Skin and Subcutaneous Tissue Disorders
Alopecia
Pruritus
Rash
Vascular Disorders
Hot flush

22 (6.4)
73 (21.2)
48 (13.9)
14 (4.1)
16 (4.6)
27 (7.8)
98 (28.4)
45 (13.0)
37 (10.7)
19 (5.5)
32 (9.3)
88 (25.5)
51 (14.8)
19 (5.5)
31 (9.0)51 (14.8)
51 (14.8)

27 (7.8)
65 (18.8)45 (13.0)
24 (7.0)39 (11.3)
39 (11.3)

3 (1.7)30 (17.4)
27 (15.7)
9 (5.2)10 (5.8)
12 (7.0)34 (19.8)
18 (10.5)
10 (5.8)
2 (1.2)9 (5.2)26 (15.1)
10 (5.8)
10 (5.8)
7 (4.1)28 (16.3)
28 (16.3)

13 (7.6)
13 (7.6)
9 (5.2)4 (2.3)21 (12.2)
21 (12.2)

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

The symbol “-”represents the event was not captured in the source table.
Subjects are only counted once per treatment for each row.
Includes data up to 28 days after last dose of study drug.
MedDRA (v17.1) coding dictionary applied.

Table 22: Treatment-Emergent Serious Adverse Events by System Organ Class andPreferred Term (All Causalities and Treatment-related) – Safety Analysis Set
System Organ Class
Preferred Term

Number (%) of Subjects with Serious Adverse
Events by System Organ Class
Blood and lymphatic system disorders
Disseminated intravascular coagulation
Febrile neutropenia
Neutropenia
Cardiac Disorders
Atrial fibrillation
Pericarditis
Endocrine Disorders
Hyperthyroidism
Gastrointestinal disorders
Abdominal pain
Ascites
Duodenogastric reflux
Intestinal obstruction
NauseaPancreatitis
Vomiting
General disorders and administration site
conditions
Chest pain
Device occlusion

Palbociclib (PD0332991) + Fulvestrant(N=345)n (%)
All
Treatment
Causalities
related33 (9.6)
12 (3.5)

Placebo + Fulvestrant(N=172)n (%)
All
Causalities
24 (14.0)

Treatment
related3 (1.7)3 (0.9)1 (0.3)1 (0.3)1 (0.3)2 (0.6)
1 (0.3)1 (0.3)1 (0.3)1 (0.3)4 (1.2)1 (0.3)0 (0.0)1 (0.3)1 (0.3)0 (0.0)0 (0.0)1 (0.3)8 (2.3)2 (0.6)
1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)0 (0.0)1 (0.6)0 (0.0)1 (0.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)2 (1.2)0 (0.0)2 (1.2)0 (0.0)0 (0.0)1 (0.6)
1 (0.6)
1 (0.6)4 (2.3)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)1 (0.6)0 (0.0)1 (0.3)-1 (0.6)0 (0.0)-Page 29090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015
Disease progression
General physical health deterioration
Non-cardiac chest pain
Oedema peripheral
Pain
Pyrexia
Hepatobiliary Disorders
Cholecystitis
Cholelithiasis
Hepatic failure
Infections and Infestations
Bacteraemia
Cellulitis
Erysipelas
Gastrointestinal infection
Otitis media acute
Pharyngitis
Pneumonia
Pyelonephritis
Upper respiratory tract infection
Urinary tract infection
Injury, Poisoning and Procedural Complications
Femur fracture
Fracture
Humerus fracture
Road traffic accident
Investigations
Alanine aminotransferase increased
Electrocardiogram QT prolonged
Neutrophil countTroponin increased
Metabolism and Nutrition Disorders
Dehydration
Musculoskeletal and Connective Tissue Disorders
Back pain
Osteonecrosis of jaw
Pain in extremity
Pathological fracture
Nervous System Disorders
Aphasia
Cerebral haemorrhage
Cerebrovascular accident
Dysarthria
Facial paresis
Migraine
Sedation
Somnolence
Psychiatric Disorders
Depression
Psychotic disorder
Respiratory, Thoracic and Mediastinal Disorders
Acute respiratory distress syndrome
Chronic obstructive pulmonary syndrome
Dyspnoea
Pleural effusion
Pulmonary embolism

2 (0.6)
1 (0.3)0 (0.0)1 (0.3)1 (0.3)3 (0.9)2 (0.6)0 (0.0)1 (0.3)1 (0.3)7 (2.0)1 (0.3)1 (0.3)1 (0.3)0 (0.0)1 (0.3)1 (0.3)1 (0.3)0 (0.0)1 (0.3)1 (0.3)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)4 (1.2)1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)2 (0.6)
1 (0.3)0 (0.0)1 (0.3)0 (0.0)3 (0.9)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)1 (0.3)1 (0.3)1 (0.3)2 (0.6)
1 (0.3)1 (0.3)6 (1.7)0 (0.0)1 (0.3)1 (0.3)1 (0.3)3 (0.9)Page 300 (0.0)1 (0.3)0 (0.0)1 (0.3)1 (0.3)3 (0.9)1 (0.3)1 (0.3)1 (0.3)1 (0.3)0 (0.0)3 (0.9)1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)-0 (0.0)0 (0.0)1 (0.6)
1 (0.6)0 (0.0)1 (0.6)
1 (0.6)
1 (0.6)0 (0.0)0 (0.0)4 (2.3)0 (0.0)0 (0.0)0 (0.0)1 (0.6)0 (0.0)0 (0.0)2 (1.2)1 (0.6)0 (0.0)0 (0.0)4 (2.3)1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)4 (2.3)2 (1.2)1 (0.6)0 (0.0)1 (0.6)3 (1.7)1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)7 (4.1)1 (0.6)
1 (0.6)
1 (0.6)3 (1.7)0 (0.0)1 (0.6)
1 (0.6)
1 (0.6)0 (0.0)0 (0.0)1 (0.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)1 (0.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)-Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015
Pulmonary hypertension
Skin and Subcutaneous Tissue Disorders
Rach maculo-papular
Vascular Disorders
Deep vein thrombosis

0 (0.0)1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)1 (0.3)-1 (0.6)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)-Palbociclib plus
Fulvestrant(N=345)n (%)

Placebo plus
Fulvestrant(N=172)
n (%)

Total
(N= 517)n (%)

4 (1.2)2 (1.2)6 (1.2)4 (1.2)000

1 (0.6)0
1 (0.6)0

5 (1.0)01 (0.2)0

15 (4.3)

7 (4.1)22 (4.3)

14 (4.1)00
1 (0.3)7 (4.1)00
0

21 (4.1)00
1 (0.2)The symbol “-”represents the event was not captured in the source table.
Subjects are only counted once per treatment for each row.
Includes data up to 28 days after last dose of study drug.
MedDRA (v17.1) coding dictionary applied.

DeathsTable 23 presents the summary of deaths in this study.
Table 23: Summary of Deaths – As Treated090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Number of deaths from start of treatment to last dose
including 28 days after last dose
Cause of Death
Disease under study
Study Treatment Toxicity
Other*
Unknown
Number of Deaths during Follow-Up period
Occuring after 28 Days after Last Dose
Cause of Death
Disease Under Study
Study Treatment Toxicity
Other
Unknown*Other category for a subject is specified as ’Intracerebral Haemorrhage, likely caused by arterio-venous malformation’.

Permanent Discontinuations due to AEs
Overall, a similar percentage of subjects in the palbociclib plus fulvestrant arm and in theplacebo plus fulvestrant arm experienced TEAEs associated with permanent discontinuation(3.8% vs 4.7%, respectively) of palbociclib/placebo or fulvestrant. In the palbociclib plus
fulvestrant arm, no TEAEs that were associated with permanent discontinuation werereported in more than 2 (0.6%) subjects; only anemia, neutropenia and thrombocytopenia
were reported in 2 subjects. All TEAEs associated with permanent discontinuation in theplacebo plus fulvestrant arm were reported in 1 (0.6%) subject each, except for ascites andpleural effusion, which were reported in 2 (1.2%) subjects.

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Public Disclosure Synopsis
Protocol A5481023 - Final - 26 October 2015

There were no notable differences between the treatment arms in the proportions of subjects
who experienced TEAEs associated with permanent discontinuation of palbociclib/placebo(3.8% vs 4.1%) or who experienced TEAEs associated with permanent discontinuation offulvestrant (3.2% vs 2.9%).

090177e18726f7a0\Approved\Approved On: 29-Oct-2015 16:43

Conclusions:

The addition of palbociclib to fulvestrant resulted in a statistically significant, andclinically meaningful improvement in PFS as compared with placebo plus fulvestrant
in the treatment of pre/peri- and postmenopausal women with HR-positive,
HER2-negative metastatic breast cancer whose disease had progressed after priorendocrine therapy (median PFS: 9.2 months vs 3.8 months; HR=0.422; 95% CI:
0.318 to 0.560, 1-sided p<0.000001).



The results across response-based analyses, including supportive PFS analyses, OR,DR, and CBR, are consistent and support the robustness of the primary PFS analysis
at the time of the data cutoff.

The combination of palbociclib plus fulvestrant was well tolerated and the majority of
TEAEs were non-serious and manageable, as evidenced by the low rates ofpermanent discontinuation due to treatment-related AEs. The majority of subjects
experienced TEAEs that were mild to moderate in severity with the exception of the
TEAEs under the system organ class (SOC) blood and lymphatic system disorders.



There was a lack of a clinically relevant drug-drug interaction (DDI) between
palbociclib and goserelin when the two drugs are coadministered.



There was a lack of a clinically relevant DDI between palbociclib and fulvestrant
when the two drugs are coadministered.



The subject-reported outcomes support the positive impact of palbociclib plus
fulvestrant, maintaining global QOL on treatment and resulting in a statisticallysignificantly higher on-treatment global QOL compared to placebo plus fulvestrant.
In addition, palbociclib plus fulvestrant had a statistically significantly greater
improvement from baseline in emotional functioning and pain. A significantly greater
delay in time to deterioration in pain was observed with palbociclib plus fulvestrant
than with placebo plus fulvestrant.

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