NON-INTERVENTIONAL, NATIONAL STUDY OF REAL-WORLD EVIDENCE

IN ESTROGEN RECEPTOR POSITIVE, HER2 NEGATIVE METASTATIC

BREAST CANCER PATIENTS TREATED WITH PALBOCICLIB DURING A
2.5 YEARS FOLLOW-UP PERIOD

PALBO01/2021
CONTENTS

1. METASTATIC BREAST
CANCER
2. STUDY IDENTIFICATION
3. STUDY DRUG
4. STUDY OBJECTIVES
5. STUDY POPULATION
6. STUDY EXTENSION
7. CASE REPORT FORMS
8. STUDY STATISTICS
 METASTATIC BREAST CANCER

ESMO, ACOG and other leading

health and medical organizations At European level, MBC
recommend regular screening occurs in up to 20-30 percent
mammography to reduce breast of women diagnosed with
breast cancer.
cancer mortality.

Metastatic breast cancer (MBC) is the most advanced stage

of breast cancer, where the disease has spread to distant
sites beyond the axillary lymph nodes.

Currently, the median overall survival for patients with MBC is

approximately 5 to 6 years in developed countries, but lower
in developing countries.

In Romania, 8900 new cases of BC are diagnosed every year, with

80% being diagnosed in an advance stage of the disease (II, III, IV).
Furthermore, after initial BC treatment, approximately 50% will develop MBC.

Cardoso F, Spence D, Mertz S, Corneliussen-James D, Sabelko K, Gralow J, et al. Global analysis of advanced/metastatic breast cancer: Decade report (2005-2015). Breast
Edinb Scotl. 2018 Jun;39:131–8.
Oprean CM, Negru SM, Popovici DI, Saftescu S, Han R-A, Dragomir G-M, et al. Postmenopausal Breast Cancer in Women, Clinical and Epidemiological Factors Related to the
Molecular Subtype: A Retrospective Cohort Study in a Single Institution for 13 Years. Follow-Up Data. Int J Environ Res Public Health. 2020 Jan;17(23):8722.
 METASTATIC BREAST CANCER
Benefit of screening: Breast cancer mortality (Barbeau et al, 2017)
Age Relative Absolute Number needed GRADE Rating of
Risk** effect/ 1,000 to screen (95% Certainty of
screened CI) Evidence
(95% CI) median 7
yrs (95% CI)
40-49 0.85 0.58 fewer 1,724 ⨁⨁◯◯
(1,176 to 3,704) LOW
(0.78 to 0.93) (0.27 to 0.85
fewer)
50-59 0.85 0.75 fewer 1,333 ⨁◯◯◯
VERY LOW
(0.78 to 0.93) (0.35 to 1.10 (909 to 2,857)
fewer)
60-69 0.85 0.92 fewer 1,087 ⨁⨁◯◯
LOW
(0.78 to 0.93) (0.43 to 1.35 (741 to 2,326)
fewer)
70-74 0.85 1.55 fewer 645 ⨁◯◯◯
VERY LOW
(0.78 to 0.93) (0.72 to 2.27 (441 to 1,389)
fewer)
 STUDY IDENTIFICATION
Status Study Title Conditions Interventions Locations
Recruiting Non-Interventional, National Study Of  Metastatic  Drug:  Asociatia Oncohelp - Centrul
Real-World Evidence In Estrogen Breast Palbociclib de Oncologie Oncohelp,
Receptor Positive, Her2 Negative Cancer Timisoara, Timiș, Romania
Metastatic Breast Cancer Patients  Spitalul Clinic de Obstetrică
Treated With Palbociclib During a 2.5 și Ginecologie Filantropia,
Years Follow-Up Period Bucuresti, Romania
 Institutul Oncologic "Prof. Dr
I. Chiricuta", Cluj-Napoca,
Romania
 Centrul de Oncologie "Sf.
Sponsor: Dr. Cristina Oprean, ASOCIATIA ONCOHELP Nectarie", Craiova, Romania
Timisoara  Institutul Regional de
Oncologie, Iaşi, Romania
 Spitalul Clinic Județean de
Main objective: to investigate the safety and efficacy profile of Urgență Oradea ,
IBRANCE® in the real-world setting of clinical practice Oradea, Romania

No. of sites: 6 investigational sites located in Timisoara,

Bucharest, Cluj-Napoca, Iasi, Craiova, Oradea

The study was approved by the National Bioethics

Committee of Medicines and Medical Devices www.clinicaltrials.gov
Approval no 28SNI from 27.10.2022
ID NCT05135104
Protocol development and versioning
Protocol V1.0 dated 04 Oct 2021 - outdated
Protocol V2.0 dated 07 Mar 2022 - currently in use
 STUDY DRUG

Palbociclib, an orally active pyridopyrimidine,

is a potent and highly selective reversible  Palbociclib inhibits CDK4/6-catalyzed
inhibitor of CDK 4 and CDK6. phosphorylation of the retinoblastoma
protein (Rb), which is required for cell
division.

Palbociclib is indicated for the treatment of ER+/HER2- MBC:

• in combination with an aromatase inhibitor;
• in combination with fulvestrant in women who have
received prior endocrine therapy.

 Palbociclib has selectivity for CDK4/6, with little or no activity

In pre- or perimenopausal against a large panel of 274 other protein kinases including other
women, the endocrine CDKs and a wide variety of tyrosine and serine/threonine kinases.
therapy is combined with a
luteinizing hormone-releasing
hormone (LHRH) agonist.
 STUDY DRUG

 In Romania, initial marketing approval

was obtained in 11 November 2016
The list of the approved pharmaceutical dosage forms and Mas:
• IBRANCE 75 mg x 21 hard capsules, MA no. 1147/2016/01
• IBRANCE 75 mg x 21 tablets, MA no. 1147/2016/010
IBRANCE 100 mf cps x 21 hard capsules, MA no.
1147/2016/03
• IBRANCE 100 mg x 21 tablets, MA no. 1147/2016/012
• IBRANCE 125 mg x 21 hard capsules, MA no. 1147/2016/05
• IBRANCE 125 mg x 21 tablets, MA no. 1147/2016/014

TREATMENT DURATION
Recommended dose
One dose/day 125 mg
Complete
for 21 7 days off
cycle of 28
consecutive treatment
days
days

The treatment duration must be at least 3 months for eligible

patients.
 STUDY OBJECTIVES
Primary objective
To identify pathological and clinical
features of MBC that are associated
with Palbociclib’s best efficacy,
measured by Response Rate (Overall
Response Rate, Duration of Response
and Best Clinical Response),
Progression-Free Survival and Overall
Survival during a follow-up period of 2.5
years.
Primary endpoints
Disease Control Rate (DCR) in
participants included in the clinical
study;
Overall Survival (OS) in participants
included in the clinical study;
Duration of Response (DOR) in
participants included in the clinical
study.
 STUDY OBJECTIVES

Secondary objective Secondary endpoints

To identify the medium duration of the
The medium duration of the
treatment with Palbociclib in
treatment (T) with Palbociclib in
combination with aromatase inhibitors
combination with aromatase inhibitors
(AI) in first-line and with fulvestrant in
(AI) in first-line and with fulvestrant in
second-line.
second-line;
To identify type and number of the
The Clinical Benefit Rate (CBR),
subsequent lines of treatments after
defined as the proportion of patients
progression under Palbociclib and
with no disease progression after 6
hormonotherapy.
months of therapy.
 STUDY OBJECTIVES

Safety objective
Monitoring of grade 3 and 4 neutropenia
(absolute neutrophil count/L), grade 3 and 4
treatment-related thrombocytopenia,
grade 3 and 4 treatment-related anemia,
grade 3 and 4 treatment-related elevated
liver enzymes, grade 3 and 4 fatigue,
grade 3 and 4 upper respiratory
infections, grade 3 and 4 nausea and
grade 3 and 4 treatment-related toxicities
as defined in CTCAE v5.0.
 STUDY POPULATION

Participants Excluded
650
• Participants with advanced,
Participants symptomatic, visceral spread, such
as patients with massive
Patients will be identified by means uncontrolled effusions (pleural,
of data extracted from the centres. pericardial, peritoneal), pulmonary
lymphangitis, and over 50% liver
1. Documentation of histologically or cytologically confirmed diagnosis of breast cancer with IHC
of estrogen receptor (ER) expression > 1% and/or progesterone receptor (PR) expression >1 %
involvement).
breast cancer based on local laboratory results. • Palbociclib treatment as part of a
2. Scoring of 0 or 1+ for HER2 protein expression by a validated immunohistochemistry assay or clinical trial or prescription prior to
+1/+2 with negative HER2 amplification FISH/ISH ratio lower than 1.8 or HER2 gene copy less
than 4.0. market approval (Nov 2016).
3. Eligible participants must have undergone a treatment with Palbociclib for at least 3 months.
4. Evaluable disease as defined per modified Response Evaluation Criteria in Solid Tumours
(mRECIST) V1.1 criterion (at least 2 entries).
Treatment with Palbociclib
5. Premenopausal or postmenopausal status.
• First-line therapy (LOT1), if
• no prior systemic treatment for MBC or at least 1
a. Patients who are not postmenopausal must have undergone a treatment with LHRH year from the completion of adjuvant endocrine
agonist.
b. Postmenopausal status is defined as:
therapy.
o prior bilateral surgical oophorectomy, or
• Second-line therapy (LOT2), if
o spontaneous cessation of regular menses for at least 12 consecutive months • given post progression on a first-line treatment for
MBC or on relapse at or within 1 year from the end
in case of doubt serum estradiol <20 umol/l and follicle stimulating hormone (FSH) levels >15 IU/L.
of adjuvant hormone therapy.
 STUDY EXTENSION

The clinical study has been conducted from

November 2021 to March 2022 in one
investigational centre located in Timisoara, From March 2022, the clinical study has been
Romania (Site 01): extended to national level to 6 investigational centres
ASOCIATIA ONCOHELP – CENTRUL DE located in Romania:
ONCOLOGIE ONCOHELP • ASOCIATIA ONCOHELP – CENTRUL DE
DEPARTMENT OF MEDICAL ONCOLOGY. ONCOLOGIE ONCOHELP, Timisoara;
• CENTRUL DE ONCOLOGIE "SF. NECTARIE“,
Craiova;
• INSTITUTUL ONCOLOGIC “PROF. DR. ION
Site 01
CHIRICUTA, Cluj-Napoca;
enrolled until now • SPITALUL CLINIC DE OBSTETRICA SI
90 patients out of GINECOLOGIE FILANTROPIA, Bucharest;
150 planned. • INSTITUTUL REGIONAL DE ONCOLOGIE, Iasi;
• SPITALUL CLINIC MUNICIPAL “DR. GAVRIL
CURTEANU”, Oradea.
As it is an Investigator - Initiated study,
Dr. Cristina Marinela Oprean
coordinates and leads the clinical
study.
 CASE REPORT FORMS

All data generated at site level is

captured electronically at the
study site using an electronic
CASE REPORT FORM
(OpenClinica)

OpenClinica complies with 21 CFR Part

11 and Good Clinical Practice.

Data entry statistics can be verified in real time.

Currently the enrollment rate achieved is 13.84%
from the total number of expected enrollment (N=650)
 STUDY STATISTICS - DESCRIPTIVE DATA
Data of the first 50 patients were analyzed. 25
Descriptive statistics were used to group
subjects by category (e.g.: age groups,
diagnostic history, family history, etc.).
20
No. of
Age at the patients Percent (%)
diagnosis 15
N = 50
29 – 40 years 5 10.00 % Column1

41 – 50 years 4 8.00 % 10
51 – 60 years 8 16.00 %
61 – 70 years 23 46.00 %
5
> 70 years 10 20.00 %
TOTAL 50 100.00 %
The average age at the time of diagnosis was 60.10 0
years, with an interval between 29 and 77 years. 29-40 years 41-50 years 51-60 years 61-70 years over 70 years

From the total of 50 patients studied, 68.00% come from the urban environment,
while 32.00% come from the rural environment.
Regarding the history of the disease, 58.00% of the patients have recurrent
cancer, 40.00% de novo, while for one patient (2.00%) the history is unknown.
 STUDY STATISTICS – HISTOLOGICAL & MOLECULAR SUBTYPE
26 out of 50 patients presented Luminal B molecular subtype,
From the analyzed data, 74% of the patients
whilst 22 presented Luminal A molecular subtype. One patient
presented ductal subtype as histological
presented Luminal HER+ molecular subtype and for one
subtype, 12% lobular and 14% other.
patient data was unknown.

No of No. of
Histological Molecular
patients Percent (%) patients Percent (%)
Subtype Subtype
N = 50 N = 50
Ductal 37 74.00% LUMINAL A 22 44.00 %
Lobular 6 12.00% LUMINAL B 26 52.00 %
NST 5 10.00 % LUMINAL HER+ 1 2.00 %
Unknown 2 4.00 % Unknown 1 2.00 %
TOTAL 50 100.00% TOTAL 50 100.00 %
40 30
35 25
30
20
25
20 15 Column1
Column1
15 10
10
5
5
0 0
Ductal Lobular NST Unknown Luminal A Luminal B HER+ Unknown
 STUDY STATISTICS – ESTROGEN RECEPTOR LEVEL

45

Estrogen receptor level was over 50% 40

in 82% of the patients analyzed. 35

30

25
Column1
Estrogen No. of 20

Receptor patients Percent (%) 15

Level N = 50 10

5
< 10 % 6 12.00 %
0
10 – 50 % 3 6.00 % < 10% 10-50% > 50%

> 50 % 41 82.00 %
TOTAL 50 100.00 %
 STUDY STATISTICS – PROGESTERONE RECEPTOR LEVEL

35

Progesterone receptor level was over 30

50% in 58% of the patients analyzed.
25

20
Column1
Progesterone No. of 15
Receptor patients Percent (%)
10
Level N = 50
5
< 10 % 5 10.00 %
0
10 – 50 % 0 0.00 % < 10% > 50% Unknown

> 50 % 29 58.00 %
Unknown 16 32.00 %
TOTAL 50 100.00 %
 STUDY STATISTICS – LOCATION OF METASTASES
Tissue Pulmonary
No. of Liver
Metastases No. of cases Metastases No. of cases
cases Metastases
Locations Locations
Bone lesions 5 Bilateral metastasis 2 Multiple lesions 2
Multiple
Bone metastases 11 Pulmonary lesions 4 4
metastases
Bone tissue 11 Pulmonary metastases 4 One lesion 1
Breast node 1 Pulmonary
1 4.5
Breast tumor 1 micronodules
Chest 1 Lymphatic 4
1 3.5
The most encountered tissue metastases carcinomatosis
were bone metastases and metastases Pleural effusion 3 3
located in bone tissue. 2.5
Subpleural nodules 1
12 2 Column1
4
10 1.5
3
8 1
2
6 0.5
4 1 0
Multiple Multiple One lesion
2 Column1 0 Column1 lesions metastases
is ns es s is n es
0 t as sio tas dule tos usio dul
as le tas no a ff o
s s e e or est et r y om a l e al n
i on ase ssu nod m e r o n
s t ti u Ch l m na m ic ci r r
le tas e st
stt e ra mo ary y m car le u leu
ne e n ea a t l
on na atic
r P bp
Bo e m Bo Br Bre Bi
la Pu
m o Su
n u l m p h
l
Bo P
Pu Lym
 STUDY STATISTICS – OTHER METASTASES
10
9
Other 10 types of metastases were declared by the study 8
7
patients and included in the analyzed data, as presented below:
6
5
Type of Metastasis No. of cases 4
3
AXILLARY 7 2
LYMPHADENOPATHY 1
HILAR 3 0
Y S E S Y N Y ES S S
LIMPHADENOPATHIES H IE D N H IA H S N SI
AT TH
O I O A T R A T
TA ES
IO A Column1
LYMPHNODE 9 O
P A H
N
ES O P VA O P S A ST
P P L O A L T
LYTIC BONE LESIONS 1 EN N O YM N E EN EN ET IC ME
D E L D D M N
A D BO H A A E LE NE
MEADIASTINAL 5 PH H A C P P H U P
M P TI YM M
IS
S S BO
LYMPHADENOPATHY LY LIM LY _L LY T A L
R
Y R 0b AL F T N
OVARIAN 2 A A 0 E R
ILL H
IL
_ x0 C
H SO TE
PARATRACHEAL 2 A S
AX AL T R
LYMPHADENOPATHY I N A
A ST A R
SOFT TISSUE 1 I P
A D
METASTASES E
M
SPLENIC LESIONS 1
STERNAL BONE 1
METASTASIS
 STUDY STATISTICS – CORELATIONS
35
The correlation between the age groups and the molecular subtype
showed an inversely proportional relationship between the two
variables but it was declared as statistically insignificant 30
(r = -0.280; p > 0.05).
25

Molecular Subtype
20
Age at Luminal
Luminal A Luminal B TOTAL
diagnosis HER+ 15

29 – 50 1 8 0 9
10
years 11.11 % 88.89 % 0.00 % 100.00 %

51 – 70 14 16 0 30 5

years 46.67 % 53.33 % 0.00 % 100.00 %

0
29 – 50 years 51 – 70 years over 70 years
over 70 7 2 1 10
Luminal A Luminal B Luminal HER+
years 70.00 % 20.00% 10.00% 100.00%
 STUDY STATISTICS – CORELATIONS

Tumoral 25
Age at diagnosis TOTAL
grade

  29 – 40 41 – 50 51 – 60 61 – 70 > 70  
20

1 0 0 3 2 6
G1
16.67 % 0.00 % 0.00 % 50.00 % 33.33 % 100.00 %
15

3 4 5 15 6 33
G2
9.09 % 12.12 % 15.15 % 45.45 % 18.18 % 100.00 %
10

1 0 0 1 2 4
G3
25.00 % 0.00 % 0.00 % 25.00 % 50.00 % 100.00 %
5

0 0 0 0 0 0
G4
0.00 % 0.00 % 0.00 % 0.00 % 0.00 % 0.00 %
0
29 – 40 years 41 – 50 years 51 – 60 years 61 – 70 years > 70 years
0 0 0 2 3 5
Gx G1 G2 G3 G4 Gx
0.00 % 0.00 % 0.00 % 40.00 % 60.00 % 100.00 %

Applying the Pearson correlation, it could not be demonstrated that there is

a correlation between age groups and tumor grade (r=-0.009; p > 0.05).
For more information on PALBO01/2021 study,
please contact:

Dr. Cristina Oprean, ASOCIATIA ONCOHELP

59 Ciprian Porumbescu Street, Timisoara

Pharm. Ramona Petrita

MDX RESEARCH (CRO)
1-3 Vasile Loichita Street, Timisoara