Transcript Arimidex’ (anastrozole): The Ideal Profile for an

Ongoing
Clinical Research & Trials
Multidisciplinary Breast Centre
P. Neven
GYN ONCOL & MBC, UZ-KULeuven
May 2007
Ten most frequently occuring tumours in Flanders, 2000 - 2001
Source: Vlaams Kankerregistratienetwerk, VLK
Age-specific incidence of breast cancer in
women,
Flanders, 1997-2001
Source: Vlaams Kankerregistratienetwerk, VLK
SABCS 2006 2003: A decrease in breast cancer incidence
May be the incidence will come down?
I. Ongoing
Clinical Trials
II. Ongoing
MBC Research Projects
May 2007
I. Clinical Trials
Prevention, Adjuvant, Metastatic
Completed, Recruiting, Future Trials
Endocrine Therapy, Chemotherapy, Targeted Therapy
May 2007
Recently Closed
Clinical Trials
Adjuvant:
BIG-1-98, TEAM, (E-)ZOFAST
TACT, FEC-TXT (dd), Caelyx-Endoxan
HERA, AC-AT,
Metastatic:
Lapatinib trials, Tam + Iressa,
EFECT, Lapatinib + Zarnestra, …
Radiotherapy:
MSP-trial
May 2007
Recruiting Clinical Trials
Prevention:
IBIS-2 DCIS/High Risk
Neo- Adjuvant: Taxotere-Xeloda-Herceptin
Adjuvant:
SOFT, TEXT, TAGAS,
Pregnancy (pharmacokinetics & outcome)
Metastatic:
MoAb IGF-1R, FINDER-2,
Vinflunin, Oral Navelbine,
Xeloda +/- Sutent, BIBW, HKI
May 2007
Eye trial
(Maxidex vs Lacrystat Taxotere related dacrocystostenosis)
Future Clinical Trials
Neo- Adjuvant: Neo-Allto
Neoadjuvant Paclitaxel + Herceptin +/- Pertuzumab
Adjuvant:
Fertility trial, SOLE, ALTTO
MINDACT,
CASA
Metastatic:
Lapatanib +/- Pazopanib
May 2007
Recruiting Clinical Trials
IBIS-2
DCIS (tamoxifen standard)
High Risk (placebo standard)
Aromatase Inhibitors
versus Tamoxifen
Why IBIS-II?
Prevention
Incidence of Contralateral Breast Cancers
Number of
cases
ATAC
IES
MA17
BIG 1-98
50
40
30
48
20
10
16
14
12
28
26
26
21
0
A
T
E
T
L
T
L
T
(n=3125)
(n=3116)
(n=2352)
(n=2372)
(n=2582)
(n=2575)
(n=4003)
(n=4007)
Ongoing
Clinical Trials
Breast Cancer Prevention
Postmenopausal Women
IBIS-2: 20 countries recruiting
Prevention: Placebo vs Anastrozole 36/1516
ER+ DCIS: Tamoxifen vs Anastrozole 63/1014
Late
age 1st pregnancy, parity, age menopause, breast density, familial history, LCIS, ADH
Subprotocol: Bone, Lipid, Cognitive function
May 2007
IBIS-2
Recruiting Centres
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St.Luc Brussel
St.Pierre Brussel
VUB Brussel
Virga Jesse Hasselt
St.Elisabeth Namen
St.Augustinus Wilrijk
Erasmus Brussel
Bordet Brussel
Heilig Hart Leuven
OLVrouwZH Aalst
ZOL Genk
Clinique St.Pierre Ottignies
CHR Citadelle Luik
Brugmann Brussel
Centre Hospitalier de l’Ardenne
If you have small cell LCIS,
NSABP-P1 included 850 such patients
7-years of follow-up
Tamoxifen versus Placebo
Events13 (Tam) vs 38 (Placebo)
If placebo: incidence of event is 1-2%
Recruiting Clinical Trials
FINDER-II
2nd line Metastatic Endocrine
First Line: TTP Benefit of Fulvestrant over Tamoifen
in ER+ & PgR+ Patients*
Proportion 1.0
not
progressed
0.8
Median TTP:
Fulvestrant: 11.4 months
Tamoxifen: 8.5 months
Hazard ratio = 0.85 CI (0.63–1.15); p=0.31
Fulvestrant
Tamoxifen
0.6
0.4
0.2
0.0
0
100
ORR
F 44.3% vs T 29.8%; p=0.02
*Retrospective analysis
200
300
400
500
600
700
800
TTP (days)
Howell et al. JCO 2004; 22: 1605-13
Fulvestrant 250 mg/month Provides
Long-term Downregulation of ER Levels
p=0.001
Mean
ER
Hscore
30
0
25
0
20
0
15
0
10
0
50
0
p=0.01
Pretreatment
(n=29)
4-6
weeks
(n=26)
6
months
(n=20)
PD
(n=8)
Time on treatment
Gutteridge et al. SABCS 2004
Fulvestrant induces dose-related ER downregulation
(PgR and Ki67)*
Change
from
baseline
(%)
0
-10
-20
–13%
-30
-40
–39%
-50
–50%
-60
Pre-treatment
mean H-score
*Data not shown
Placebo
(n=29)
Fulvestrant
50 mg (n=31)
Fulvestrant
125 mg (n=32)
–59%
Fulvestrant
250 mg (n=32)
125
136
124
113
Robertson et al. Cancer Res 2001; 61: 6739–6746
Finder-II
135 postmenopausal women with HR+ ABC
after failure on one prior endocrine therapy
Randomisation 1:1
Endpoints
 TTP (primary)
 ORR
 CB
 Safety
Fulvestrant HD
Fulvestrant AD
Fulvestrant LD
Progression
3-monthly
follow-up
HD, high-dose (500 mg IM on Day 0, 500 mg on Days 14 and 28 and 500 mg every 28 3 days thereafter)
LD, high-dose (500 mg IM on Day 0, 250 mg on Days 14 and 28 and every 28 3 days thereafter)
AD, approved dose (250 mg IM every 28 3 days)
Finder II Overview of Eligibility
(2nd line Breast Cancer Treatment)
Patients who previously received adjuvant treatment
Eligible?
ABC
EBC
R
12 Month
gap
KEY
Yes
Adjuvant Treatment
R
Yes
Eligible (randomised into
study)
R
No
Not Eligible
R
P
Yes
First Line Treatment
Patients who were diagnosed with Advanced Breast Cancer
R = Recurrence
P
Regulatory Definition of 2nd line Breast Cancer
P = Progression
Yes
Current & Future Clinical Trials
Targeted Therapies
ALTTO
Adjuvant
Two Targets, One Drug
Lapatinib Profile
Lapatinib is a novel oral dual-tyrosine
kinase inhibitor with specificity for
the ErbB-1 and
ErbB-2 receptors
 Belongs to the 4anilinoquinazoline class of
tyrosine kinase inhibitors
 Binds reversibly to the
cytoplasmic ATP-binding site of
the kinase, thereby preventing
receptor phosphorylation and
activation
Cl
O
HN
N
H
S O
O CH
3
O
N
N
2
H3C
GW572016
Lapatinib
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]4-quinazolinamine
F
O
S OH
O
ALTTO STUDY DESIGN
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Four-arm, randomised, open-label and multicentre study in women
with primary breast cancer that over expresses or amplifies HER2.
Sample Size 8000 patients
Primary Endpoint: DFS
Secondary Endpoints
 OS
 TTR (time to recurrence)
 TTDR (Time to distant recurrence)
 Safety and tolerability
Proposed start 2Q07
Study duration: 5 years (4 years for enrolment and 1 year as followup)
 2 Interim analyses (at 600 and 1000 DFS events, approximately)
ALTTO STUDY DESIGN
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4 Arms:
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Trastuzumab for 52 wks
Lapatinib for 52 wks
Trastuzumab + Lapatinib for 52 wks
Trastuzumab for 12 wks, 6 wk washout, Lapatinib for
34 wks
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Treatment Schema 1 - all (neo-)adjuvant chemotherapy completed
prior to administering targeted therapy
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Treatment Schema 2 - targeted therapy is initiated after
(neo)adjuvant anthracycline-based chemotherapy and given
concurrently with weekly paclitaxel
52 Weeks
Local
Determined
HER 2
positive
B
A
S
E
LI
N
E
Central
Determined
HER 2
positive
Surgery,
complete
Neo-adjuvant
Chemotherapy
LVEF  50%
R
A
N
D
O
M
IS
A
TI
O
N
Trastuzumab 3- weekly
8mg/kg then 6mg/kg
(+ radiotherapy when indicated)
Lapatinib 1500 mg/day
(+ radiotherapy when indicated)
Trastuzumab 4mg/kg
then 2mg/kg weekly for
12 wks
6 weeks
Washout
Lapatinib 1500
mg/day for 34 wks
(+ radiotherapy when indicated)
Lapatinib 1000
mg/day + Trastuzumab
3- weekly
8mg/kg then 6mg/kg
(+ radiotherapy when indicated)
Patients with ER or PgR-positive tumours receive endocrine therapy selected according to menopausal status:
endocrine therapy will be started after the end of the chemotherapy, will be administered concurrently with targeted
therapies and will be planned for at least 5 years
NEO - ALTTO STUDY DESIGN
(T>2 cm, Nx, M0, FISH +, IHC 3+)
Lapatinib (L)
1500 mg/day
L 1500 mg/day
+
paclitaxel 80 mg/m2 weekly
L 1000 mg/day
+
T 4 mg/kg,
then 2 mg/
kg weekly
L 1000 mg/day
+
T 2 mg/kg weekly
+
paclitaxel 80 mg/m2 weekly
6 weeks
12 weeks
T 6 mg/kg at 3 week intervals
L 1000 mg/day
+
T 6 mg/kg at 3 week intervals
9 weeks
Tumor biopsy
Tumor biopsy
PET
FEC x 3 courses
T 2 mg/kg weekly
+
paclitaxel 80 mg/m2 weekly
Surgery
Trastuzumab
(T)
4 mg/kg, then
2 mg/kg
weekly
L 1500 mg/day
34 weeks
New drugs for targetting HER-1 / HER-2 / …
Dual-Target HER-1 Drugs in the Pipeline
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Lapatinib
HKI-272
BIBW-2992
AEE788
BMS-599626
CI-1033
…
HER-1, HER-2
HER-1, HER-2
HER-1, HER-2
HER-1, HER-2, VEGF
HER-1, HER-2
HER-1, HER-2, HER-4
GSK
Phase III breast
WyethPhase II breast
Boehringer Phase II breast
Novartis
Solid tumours
BMS
Solid Tumours
Pfizer
Phase II breast
Metastatic
Recruiting Clinical Trials
Targetted Therapies
Exemestane +/-IGF-1R
1st Line Metastatic Endocrine
IGF and its receptor
Important mediators of cell growth
Combining Endocrine and Biological Agents in M+ Breast Cancer
Oestrogen Receptor- Mediated
Signalling Pathways in Breast Cancer
IGF
IGF regulates the malignant phenotype
IGF is a strong breast cancer mitogen
There is cross talk between ER and IGF signalling
Non-genomic or genomic ER
IGF is a regulator of estrogen-mediated growth
IGF induces proliferation of ER+ breast cancer cells
Upregulation in tamoxifen-resistant breast cancer cells
Oestrogen Receptor- Mediated
Signalling Pathways in Breast Cancer
IGF-1R
IGFR is Tyrosine Kinase type 1 receptor
Small molecules and MoAb
Monoclonal AB
Oestrogen Receptor- Mediated
Signalling Pathways in Breast Cancer
Exemestane + MoAb/IGF-1R vs Exemestane
ER+ First
Line Measurable Metastatic
Randomized (1:1) and Open Label
150 patients
PFS
CP 751,871 // 20mg/kg // q3w
Arm A Exemestane 2.5mg + CP
Arm B Exemestane 2.5mg
CB,
Safety,
PK parameters,
CTC markers for expression of IGF-1R,
HRQoL
Pfizer
 Fulvestrant + CP q4w
 CP
II. Own Clin. And Basic Research
Recently Published …(leaving out clin. trials)
Prophylactic mastectomy and subclinical breast pathologies
HER-2 expression by body weight
Arthralgia and AIs
The prognostic value of PR in breast cancer
LHRH-agonists to protect ovarian function in ER-pos BrCa
The continuous importance of tamoxifen as an adjuvant therapy
Endometrial thickness on AI-switch
MMP in breast cancer
Associations between ER/ PR/ HER2 expression in operable BrCa
May 2007
Ongoing
May 2007
Clinical & Basic Research
Early relapse by ER/ PR/ HER2 expression: “Improving NPI”
HER-1 / uPAR in triple negative and other breast cancers
PET-CT in staging large and locally advanced breast cancer
Correlations LN-status - ER/PR/HER-2, LN-status - age
Correlations Age - ER/PR/HER-2 expression
Retrospective and prospective registration study: Breast cancers & Mirena
Postmenopausal breast cancer characteristics by use of HRT
Paloprai, ER-PR+ breast cancers, Fulvestrant and uterine volume
Molecular genetic analysis as an addition to the morphologic classification of breast cancers
The clinical relevance of protease in breast cancer: matrix metalloproteinasen and cathepsines
Menopausal symptoms of breast cancer therapies
Proteonomics in breast cancer
Genetics in breast and ovarian cancer
PhD topics
Breast Cancer Prognosis
ER -
Global molecular genetic approach
ER +
?
basal-like
HER-2 +
luminal type (subtype A, B/C)
DFS in 1962 operable breast cancers
Subgroup Analysis by ER/PR/HER-2
subgroup
Mean NNN
NNP
PNN
PNP
PPN
PPP
173
91
191
31
1361
115
1962
55,65
56,37
60,53
58,68
57,72
51,70
57,41
4,95
5,04
4,33
4,61
4,11
4,98
4,30
84.40
75.81
89,49
80,42
93,76
81,47
90,16
Numbers
Age at diagnosis
NPI
DFS at 3.5 yrs of FU (%)
All
Thesis Lic Biomed. Sc. (S. Pintens) and Project Co-Assist. (O. Brouckaert)
Early breast cancer relapse
by ER/PR/HER-2 – n=1962
O Brouckaert & S Pintens DFS by ER/PR/HER-2
UZ Leuven 2000 - 2005
Annual incidence of relapse
NNN Early relapse
Can we improve NPI?
Subgroup
DFS (%)
NPI <3,4
96,18
NPI 3,4-5,4
91,81
NPI > 5,4
80,69
NPI <3.4
HER-2-
96,45
NPI <3,4
HER-2+
90,62
NPI 3,4- 5,4
HER-2-
93,24
NPI 3.4- 5,4
HER-2+
82,84
NPI > 5,4
HER-2-
83,37
NPI > 5,4
HER-2+
68,08
The futureCyclin E as a prognostic factor
Stage I-II breast cancer: Total cyclin E predicts Survival
Interaction ER-status and age by HER-2 status
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
ER+ Probability
ER+ Probability
ER/PR and HER-2
0.6
0.5
0.4
0.3
0.6
0.5
0.3
0.2
0.1
0.1
0.0
20
30
40
50
60
70
Age (years)
HER-2 positive
0.4
0.2
N = 2227
HER-2 negative
HER-2 status
Negative (N = 1971)
Positive (N = 256)
0.0
80
90
100
20
30
40
50
60
70
80
Age (years)
The interaction between ER and age is HER-2 dependent
The negative association between ER and HER-2 is age dependent
90
100
Interaction PR-status and age by HER-2 status
ER/PR and HER-2
1.0
1.0
0.9
0.9
0.8
0.7
PR+ Probability
PR+ Probability
0.8
0.6
0.5
0.4
0.3
0.7
0.5
0.4
0.3
0.2
0.2
0.1
0.1
N = 2227
0.0
20
30
40
50
60
70
Age (years)
HER-2 negative
0.6
HER-2 positive
HER-2 status
Negative (N = 1971)
Positive (N = 256)
0.0
80
90
100
20
30
40
50
60
70
Age (years)
The interaction between PR and age is HER-2 dependent
The negative association between PR and HER-2 is age dependent
80
90
100
Interaction HER-status and age by ER/PR
ER/PR and HER-2
1.0
N = 2227
0.9
0.9
0.8
0.8
HER-2+ Probability
HER-2+ Probability
1.0
0.7
0.6
0.5
0.4
0.3
0.6
0.5
0.4
0.3
0.2
0.1
0.1
0.0
0.0
30
40
50
60
70
Age (years)
80
90
100
ER-/PR- (N = 281)
ER+/PR- (N = 230)
ER+/PR+ (N = 1716)
0.7
0.2
20
ER/PR status
20
30
40
50
60
70
80
Age (years)
The interaction between HER-2 and age is ER/PR dependent
The older one is the less likely HER-2 positive is only if the tumour is ER-positive
90
100
Adjuvant Therapy
Breast Cancer: Adjuvant Therapy
Treatment Side Effects
Lani Morales
Quality of Life
PROGRESS IN BREAST CANCER ADJUVANT THERAPY
Average treatment
effect
d)  20.000 $
c) 13.800 $
b)  7.400 $
a)  800 $
+++
++
+
±
L-PAM, MF
1970’s
CMF x 6
AC x 4
1980’s
Financial
toxicity
+ Herceptin: 40.000 euro
TAC x 6
FEC  docetaxel
+++
AC  paclitaxel dose-dense
FAC  FEC x 6
A(E)  CMF
AC x 4  Paclitaxel x 4
++
+
±
1990’s
2000’s
Successive generations of adjuvant CT regimens
++ ADJUVANT AIs ++
Adapted from G. Hortobagyi
Multidisciplinary Breast Centre- UZLeuven
May 2007
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Centrum Vergadering
Medical Director
Head of departments
Pathology
Radiology
Surgery
Med Oncol
Radiotherapy
Obstet & Gyn
Coordinator: MR Christiaens
Radiology: A Van Steen, C Van Ongeval
Pathology: M Drijkoningen
Surgery: MR Christiaens, A Smeets
Gynaecology: P Neven, K Leunen, F Amant, P Berteloot
Plastic Surgery: M Vandevoort, G Fabre
Med Oncology: R Paridaens, H Wildiers
Radiotherapy: W Van den Bogaert, E Van Limbergen, C Weltens
Human Genetics: E Legius
KanActief: L Serrien
Data Manager: W Hendrickx
Breast “nurses”, Physiotherapists, Trial “nurses”
PhD: I Van den Bempt, A Smeets, J De Cock
Assistents
I hope I gave you a touch of our
ongoing
Clinical Research & Trial Activities
Multidisciplinary Breast Centre