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These slides were released by the speaker for internal use by Novartis
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Extending adjuvant therapy beyond 5 years
William Gradishar (Feinberg School of Medicine, Northwestern University, Chicago, IL, USA)
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Thousands of patients currently completing tamoxifen therapy
• Most women on adjuvant endocrine therapy in the EU (> 450,000) are on tamoxifen (> 300,000)1
• Estimated 80,000–100,000 patients finish 5 years of tamoxifen each year in the EU1
• These women exposed to continuing risk of relapse
– Majority of breast cancer deaths and recurrences occur post-tamoxifen2
• Risk of late recurrence (> 5 years after diagnosis) particularly high in women with HR+ disease3
1Fletcher-Louis M, Ireland S. Onkos Study 48: Breast Cancer. Decision Resources Inc., Waltham, MA; 20002Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
3Saphner et al. J Clin Oncol 1996;14:2738–46
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Recurrences Breast cancer deaths
Most breast cancer recurrences and deaths occur post-tamoxifen
Adapted with permission. Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717
Years
85.2
73.7
0
20
40
60
80
100
0 5 10 15
TamoxifenControl
15% 17%
0
20
40
60
80
100
0 5 10 15
87.8
Years
TamoxifenControl
9% 18%
91.4
% o
f p
atie
nts
% o
f p
atie
nts
54.9
68.2 73.0
64.0
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Hortobagyi et al. Proc ASCO 2004;23:23s(abstract 585)
Years post-diagnosis
ER/PgR– (n = 430)
ER+ and/or PgR+ (n = 778)
p < 0.001Pro
po
rtio
n d
isea
se-f
ree
2015105
1.0
0.9
0.8
0.7
0.6
0.5
0.4
N+ and N– disease
RFS continues to decrease regardless of ER/PgR status
• Late recurrences (> 5 years) more frequent in ER+ and/or PgR+ tumors
RFS: relapse-free survival
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MA.17: trial design
• Eligibility criteria: postmenopausal, HR+/unknown, recurrence-free, completed 4.5–6 years’ tamoxifen, ECOG PS 0–2
• Primary endpoint: DFS (ipsilateral, chest wall, local, metastatic, contralateral new)
• Secondary endpoints: OS, rate of contralateral BC, safety, QoL
• Substudies:Substudies: BMD/bone markers, lipid profile
Goss et al. J Natl Cancer Inst 2005;97:1262–71Goss et al. N Engl J Med 2003;349:1793–802
Randomization(all patients disease-free)
Tamoxifen
Approx. 5 years adjuvant 5 years extended adjuvant
0–3months
Letrozole 2.5 mg qd (n = 2582)
Placebo qd † (n = 2586)
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March Aug
Toxicity Efficacy
2003
1998 2003 2004
Oct
MA.17: initial and final analyses
1Goss et al. N Engl J Med 2003;349:1793–802; 2Goss et al. J Natl Cancer Inst 2005;97:1262–71
Interim analysis1 Final analysis2
DFS events 207 247
Deaths 73 113
No. of patients at 40 months 384 1115
Median follow-up (months) 27.5 30
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DFS: letrozole significantly decreased risk of recurrence
p = 0.00004
Letrozole Placebo
0
20
40
60
80
100
Time from randomization (months)
No. at risk (letrozole)
No. at risk (placebo)
0
2583
2587
10
2497
2489
20
1905
1874
30
1110
1075
40
541
519
50
176
164
60
6
8
% o
f p
atie
nts
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentationGoss et al. J Natl Cancer Inst 2005;97:1262–71
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Distant DFS: letrozole reduced risk of distant metastases by 40%
All patients
No. at risk (placebo)
p = 0.002
0
20
40
60
80
100
Time from randomization (months) No. at risk (letrozole)
0
2583
2587
10
2497
2489
20
1905
1874
30
1110
1075
40
541
519
50
176
164
60
6
8
% o
f p
atie
nts
Letrozole Placebo
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentationGoss et al. J Natl Cancer Inst 2005;97:1262–71
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OS: letrozole reduced mortality by 39% in patients with N+ disease
Letrozole
Placebo
Months from randomization 0 10 20 30 40 50 60
% S
urv
ivin
g
0
20
40
60
80
100
p = 0.04
• No significant increase in OS in total study population or N– disease
• Similar reduction in breast cancer events occurred in N– and N+ diseaseGoss et al. J Natl Cancer Inst 2005;97:1262–71
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N+disease
HR 0.61*(95% CI 0.45–0.84)
HR 0.53*(95% CI 0.36–0.78)
HR 0.61*(95% CI 0.38–0.98)
DFS*DistantDFS* OS
N– disease
HR 0.45*(95% CI 0.27–0.75)
HR 0.63(95% CI 0.31–1.27)
HR 1.52(95% CI 0.76–3.06)
MA.17: summary of key efficacy results
A similar reduction in local recurrences, new primaries, and distant recurrences occurred in patients with N+ and N– disease
*Statistically significant benefit of letrozole
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentationGoss et al. J Natl Cancer Inst 2005;97:1262–71
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MA.17 safety profileLetrozole is comparable to placebo
% of patients
Letrozole Placebo p value
Hot flashes 58 54 0.003
Arthritis/arthralgia 25 21 < 0.0001
Muscle pain 15 12 0.04
Vaginal bleeding 6 8 0.005
Hypercholesterolemia 16 16 0.79
Cardiovascular events 6 6 0.76
Osteoporosis 8 6 0.003
Discontinuations due to AEs 5 4 0.02
Discontinuations for other reasons 4 5 0.1
*90% of AEs grade 1or 2 Goss et al. J Natl Cancer Inst 2005;97:1262–71
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ABSCG-6a extended adjuvant trial
Jakesz et al. J Clin Oncol 2005;23:10S(abstract 527)
• Postmenopausal women completing 5 years’ tamoxifen (n = 450) or tamoxifen plus aminoglutethimide (n = 409)
• Re-randomized to anastrozole or no treatment for 3 years (no placebo control)
• Median follow-up 5 years• Anastrozole significantly reduced recurrence:
HR = 0.64, 95% CI 0.41–0.99, p = 0.047• No significant difference in OS• No safety data reported
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NCIC CTG MA.17 update
• Duration of therapy• Ingle et al. Breast Cancer Res Treat
March 2006 published online • Post-unblinding analysis
• Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
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Increasing benefit of letrozole with longer duration of treatment
• Purpose• To assess impact of duration of treatment on outcomes for
extended adjuvant letrozole vs placebo in MA.17 as measured by hazard ratios over 48 months
• End points: DFS (primary), distant DFS, OS• Cohorts evaluated
• All randomized patients (n = 5170)• N+ (n = 2360) • N– (n = 2568)
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
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Letrozole 2583 2531 2425 2060 1555 1110 768 464244
Placebo 2587 2528 2409 2020 1530 1075 723 436231
Hazard rates for DFS over 48 months(letrozole vs placebo)
Ha
zard
ra
te
Months after randomization
Letrozole
Placebo
0.0000
0.0005
0.0010
0.0015
0.0020
0.0025
0.0030
0.0035
0 6 12 18 24 30 36 42 48
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Hazardratio 0.52 0.35 0.45 0.19
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0.0
0.2
0.4
0.6
0.8
0 6 12 18 24 30 36 42 48
Haz
ard
rat
io
Months after randomization
Upper 95% confidence limit
Lower 95% confidence limit
Ratio estimate
p < 0.0001 for HR trends based on time-dependent Cox model
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Increasing benefit of letrozole with longer duration of treatment: DFS
0.52 I
0.19 I
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Increasing benefit of letrozole with longer duration of treatment: summary
• Significant improvements in HR between 12 and 48 months of letrozole vs placebo for DFS and distant DFS overall, for all three endpoints in N+ disease and for DFS in N– disease
Ingle et al. Breast Cancer Res Treat Mar 2006 published online
DFS Distant DFS OS HR 0.52–0.19 HR 0.43–0.21 HR 0.87–0.79 p < 0.0001 p = 0.0013 p = NS
HR ~0.6–~0.25 HR ~0.35–~0.25 HR ~0.55–~0.4 p = 0.0004 p = 0.0005 p = 0.038
HR ~0.7–~0.5 HR ~0.25–~0.2 HR ~2.0–~2.25 p = 0.027 p = NS p = NS
N+disease
N–disease
*Statistically significant benefit of letrozole
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• Recent guidelines recommend • ASCO 2004: a minimum of 2.5 years of extended letrozole
consistent with median follow-up of MA.17• NCCN 2006: 5 years of letrozole following 5 years of tamoxifen• St Gallen: switch to AI (letrozole) after 5 years of tamoxifen
• Ingle et al. study shows that, at least to about 48 months, longer duration of letrozole is associated with greater benefit
• Based on these data* extended adjuvant letrozole therapy should be for at least 4 years
Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At:
www.nccn.org/professionals/physician_gls/PDF/breast.pdf; *Ingle et al. Breast Cancer Res Treat Mar 2006 published online
Increasing benefit of letrozole with longer duration of treatment:
conclusions
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Late extended adjuvant therapy Analysis post-unblinding
Tamoxifenn = 5187 Placebo n = 2594
5 years
Letrozole n = 2593 Letrozole (Let) n = 2457
No Letrozole (Plac) n = 613
Letrozole (Plac–Let) n = 1655
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Purpose: compare placebo–letrozole vs placebo to determine benefits/safety of starting letrozole after prolonged periods (1–5 years) off tamoxifen
Median F/U (months)
30 54Unblinding
0–3 mo
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Significantly different baseline characteristics (all p < 0.01)
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
92
49 49
66
96
57
33
80
0
20
40
60
80
100
120
Age < 70 years ECOG = 0 N– Prior CTx
Pe
r ce
nt
Plac–Let
Plac
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Time from randomization (months)
DFSAdjusted HR: 0.31 (0.18–0.55); p < 0.0001
0
20
40
60
80
100
0 20 40 60 80
Plac–LetPlac
Per
cen
tag
e d
isea
se-f
ree
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Late extended adjuvant therapy analysis post-unblinding: DFS
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Late extended adjuvant therapy analysis post-unblinding
p < 0.0001p = 0.002
p = 0.05
p = 0.012
Haz
ard
rat
io(p
lace
bo
–let
rozo
le v
s p
lace
bo
)
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Summary of efficacy
0.310.28
0.53
0.23
0
0.1
0.2
0.3
0.4
0.5
0.6
DFS Distant DFS OS CBC
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Plac–Let Plac
p = 0.60
p = 0.007
p = 0.84
Inci
den
ce (
%)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Fracture New osteoporosis CV disease
Update of Goss et al. Breast Cancer Res Treat 2005;94:S10(abstract 16)
Late extended adjuvant therapy analysis post-unblinding
Adverse events
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MA.17: updated analysis safety conclusions
• Letrozole associated with low-grade estrogen depletion symptoms • Overall QoL unaffected (in ~3600 women)
• No changes in CV events or lipid profiles• Mild decreases in bone density, but no significant
increase in fracture risk • Bone density changes can be easily monitored
and corrected
• AEs with letrozole after unblinding similar to those in the main trial for osteoporosis, fractures, and CV disease
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MA.17: updated analysis efficacy conclusions
• Letrozole significantly increased DFS and distant DFS (all patients) and OS (patients with N+ disease)
• Benefit with letrozole increased with treatment duration
• Late extended adjuvant letrozole (after prolonged treatment-free interval) significantly improved all outcomes
• Women with long tamoxifen-free periods should be considered for letrozole therapy
• International guidelines*: based on MA.17 findings postmenopausal women with HR+ EBC finishing 5 years of tamoxifen should consider treatment with letrozole
• Updated analysis suggests extended adjuvant letrozole therapy should be for at least 4 years
*Winer et al. J Clin Oncol 2005;23:1609–10; Goldhirsch et al. Ann Oncol 2005;16:1569–83; National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – v.2.2006, Breast Cancer. At:
www.nccn.org/professionals/physician_gls/PDF/breast.pdf
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MA.17R re-randomization study
5 15100
Years post-surgery
Tamoxifen
Placebo
Letrozole*
MA.17+
Non-study patients
n = 900
n = 900MA.17R
*Women remaining disease-free
Non-study patients
MA.17 n= 800
Goss et al. Proc Am Soc Clin Oncol 2004;23:87(abstract 847) and oral presentation