these slides are intended to educate the scientific and medical community and keep them fully...
TRANSCRIPT
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These slides are intended to educate the scientific and medical community and keep them fully informed about continuing progress, as is their right, stipulated by the IFPMA code. However, in some cases, the data may refer to medicines and/or indications which are not
currently approved in your country. Under no circumstances should this information be taken as a recommendation for use of the medicine/indication.
Always consult relevant local prescribing before use.
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Fulvestrant (FASLODEX®): an emerging story providing an increasing role
William GradisharRobert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA
Breast Cancer Treatment Strategies:Clinical Decisions and Positive Conversations
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E
T
ER
FULLY ACTIVATED TRANSCRIPTION
(increased tumour progression)
dimerisationE E AF1 + AF2
active
Oestradiol
ER
PARTIALLY INACTIVATED
TRANSCRIPTION(reduced rate of
tumour cell division)
dimerisation AF1 activeAF2 inactive
Tamoxifen
T T
ERAF1 +AF2
inactive
FFulvestrant
F F
ACCELERATED RECEPTOR DEGRADATION
attenuated
dimerisation
NO TRANSCRIPTION
(no tumour cell division)
Fulvestrant has a different mode of action
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Tamoxifen: post-treatment
Fulvestrant: pre-treatment
Robertson et al. Cancer Res 2001; 61: 6739–6746
Tamoxifen: pre-treatment
Fulvestrant reduces cellular ER levels…
Fulvestrant: post-treatment
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250
300
150
200
50
100
0Pre-treatment
(n=29)4–6 weeks
(n=26)6 months
(n=20)PD
(n=8)
Time on treatment
Mean ERH-score
p=0.01
p=0.001
Gutteridge et al. Breast Cancer Res Treat 2004; 86, abs 4086
...and this effect is maintained over time
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Could long-term ER downregulation be beneficial to patients?
Breast Cancer Treatment Strategies:Clinical Decisions and Positive Conversations
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CoactivatorAF1 AF1
Accelerated tumour growth
HER2EGFR TGF
K K
ER
AKTMAPK
AF2
E EAF2
Phosphorylation
RNAPOL II
Cross-talk between GFR and ER is involved in the development of endocrine resistance
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CoactivatorAF1 AF1
Accelerated tumour growth
HER2EGFR TGF
K K
ER
AKTMAPK
AF2
E EAF2
Phosphorylation XFulvestrant
X RNAPOL II
Fulvestrant may delay the onset of resistance resulting in a sustained duration of response
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Median follow-up 22.1 months
Proportionof patientsresponding
1.0
0.8
0.6
0.4
0.2
0.00
Time (months)6 12 18 24 30 4236
Fulvestrant 250 mgAnastrozole 1 mg
Robertson et al. Cancer 2003; 98: 229–238
Fulvestrant
16.7
Anastrozole
13.7Median (months)
Trials 0020 / 0021: prospective combined analysis – duration of response
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Time (months)At risk:FulvestrantExemestane
Proportion of patients responding
Fulvestrant
Exemestane
0 3 6 9 12 15 18 21 24 27
0.0
0.2
0.4
0.6
0.8
1.0
20 20 16 11 8 3 0 018 18 15 10 5 4 3 3
0 03 3
Fulvestrant
13.5
Exemestane
9.8Median (months)
EFECT (post-AI): duration of response
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Predicting which patients may do best on fulvestrant
Breast Cancer Treatment Strategies:Clinical Decisions and Positive Conversations
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A new hypothesis (from 1989!)
“It would appear that when considering second-line hormonal therapy the previous effect of
first-line hormone therapy is a more direct and accurate means of identifying patients with hormone-
sensitive tumours than ER status”
Robertson et al. Eur J Cancer Clin Oncol 1989; 25: 469–75
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Proportion of patients progression-free
Time (months)At risk:FulvestrantExemestane
HR = 0.963, 95% CI (0.819, 1.133), p=0.6531
Cox analysis, p=0.7021
Fulvestrant
Exemestane
0 3 6 9 12 15 18 21 24 27
0.0
0.2
0.4
0.6
0.8
1.0
351 195 96 50 25 12 4 2342 190 98 41 21 12 8 6
01
00
Fulvestrant
3.7
Exemestane
3.7Median (months)
EFECT: TTP (overall population)
Chia et al. J Clin Oncol 2007; submitted
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Proportion of patients progression-free
0 3 6 9 12 15 18 21 24 27
0.0
0.2
0.4
0.6
0.8
1.0
93 54 31 12 7 4 3 1
97 51 23 7 2 0 0 0
Fulvestrant
3.8
Exemestane
3.7Median (months)
HR = 0.73, 99.8% CI *(0.45, 1.19)*CI adjusted for multiple subgroup comparisons
Chia and Gradishar. The Breast 2007; in preparation
EFECT: TTP (subset of 2nd-line and AI-sensitive patients)
At risk:FulvestrantExemestane
Fulvestrant
Exemestane
Time (months)
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Potential predictive factors
Prognostic factors from Trials 0020 / 0021
WHO PS <1 (p=0.0004)
Positive receptor status (p<0.0001)
Prior endocrine response (p=0.0272)
AstraZeneca, data on file
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Hormone responsive / resistant definition
Hormone responsive
– >2 years on adjuvant endocrine therapy
– CB (CR / PR / SD 24 weeks) on last endocrine treatment
Hormone resistant
– <2 years on adjuvant endocrine therapy
– PD in first-line setting
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Pro
po
rtio
n o
f p
atie
nts
pro
gre
ssio
n-f
ree
Responsive
Resistant
Trials 0020 / 0021:TTP responsive vs resistant
268 130 70 42 26 8
160 53 34 24 12 7
1
2
At risk:ResponsiveResistant
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
0 3 6 9 12 15 18 24 30 36332721
279 108 61 40 23 12 1
144 66 34 20 12 5 0
0.0
0.2
0.4
0.6
0.8
1.0
Time (months)
0 3 6 9 12 15 18 24 30 36332721
Responsive
Resistant
Fulvestrant Anastrozole
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Clinical trials in responsive patients
Study 004
19 confirmed hormone-responsive patients
– 69% of patients achieved CB
– versus ~40% of ER+ population in trials 20 / 21
Study 0-15-22
30 hormone-responsive Japanese patients
– 60% of patients achieved CB
Howell et al. Lancet 1995; 345: 29–30Watanabe et al. Anticancer Res 2004; 24: 1275–80
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…and from a clinical experience programme
No CB on last therapy (N=99)
CB on last therapy (N=293)
No CB on fulvestrant
70.7%
CB onfulvestrant
29.3%
No CB onfulvestrant
61.8%
CB onfulvestrant
38.2%
Med duration on fulvestrant= 4 months
Med duration on fulvestrant= 5 months
392 Belgian patients receiving fulvestrant
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Faslodex HD
720 postmenopausal women with HR+ advanced breast cancer after failure on one prior endocrine therapy
Progression Progression
3 monthly follow-up
Endpoints
TTP
ORR
CB
Safety
Faslodex AD
Randomisation 1:1
HD = fulvestrant 500 mg (IM) on Day 0, 500 mg (IM) on Day 14 and 28, and 500 mg/month (IM) thereafter
AD = fulvestrant 250 mg (IM) once-monthly
COmparisoN of Faslodex In Recurrent or Metastatic breast cancer
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Potential predictive factors for long-term disease control with fulvestrant
Prognostic factors from Trials 0020 / 0021
– WHO PS <1 (p=0.0004)
– positive receptor status (p<0.0001)
– prior endocrine response (p=0.0272)
Line of treatment
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Fulvestrant: the earlier the better
Fulvestrant as line of endocrine therapy in clinical trials
0251st-line ABC
0020/00212nd-line
186/428
170/313
CB rate (%)
0
80
70
60
50
40
30
20
10
EFECT3rd/2nd-line
87/270
0042nd-line
responsive
13/19
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Clinical experience data: CB by line of endocrine therapy for advanced breast cancer
Fulvestrant as line of endocrine therapy in clinical practice
1st (n=22)
2nd (n=125)
3rd
(n=105)4th
(n=58)5th
(n=22)6th
(n=5)
Steger et al. Can Treat Rev 2005; 31: S10–S16
0
10
20
30
40
50CB rate (%)
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Summary
Fulvestrant provides an effective and well-tolerated treatment option post-tamoxifen and post-AI for postmenopausal women with advanced breast cancer
Fulvestrant offers a durable response, explained in part by a different mode of action
Careful consideration of prognostic factors such as prior response, and use of fulvestrant earlier in the treatment sequence, may offer a better chance of achieving improved outcomes and lasting disease control