Transcript BIG 1-98

Letrozole (Femara®) as Adjuvant
Endocrine Therapy for
Postmenopausal Women With
Receptor-Positive Breast Cancer
Results of IBCSG 18-98/BIG 1-98
BIG 1-98: Worldwide Collaborative
Argentina
123
New Zealand
157
Australia
667
Peru
51
Belgium
634
Poland
277
Brazil
17
Portugal
64
Canada
20
Russia
240
Chile
22
Slovenia
15
Czech Rep.
109
South Africa
187
Denmark 1396
Spain
70
France 1016
Sweden
64
Germany
113
Switzerland
611
Hungary
334
Turkey
54
Iceland
6
United Kingdom
401
Italy 1285
Uruguay
1
TOTAL
8028
The Netherlands
94
2
BIG 1-98: Study Background
 In March 1998, Novartis initiated a study comparing letrozole (Femara®)
with tamoxifen for 5 years in postmenopausal women with ER+/PgR+
resected breast cancer
 Study was known as FEMTA (Femara vs Tamoxifen, Adjuvant)
 To optimize potential treatment strategies in this setting, Novartis
collaborated with BIG
 Study was then modified and included a sequencing of both agents
 IBCSG, a member of BIG, then became responsible for the scientific
integrity, operations, and logistics of the trial
 Hence the trial was named BIG 1-98
BIG = Breast International Group; IBCSG = International Breast Cancer Study Group.
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
3
BIG 1-98: Trial Design
R
A
N
D
O
M
I
Z
E
A
Tamoxifen
n=2459
B
Letrozole (Femara®)
n=2463
8010 pts
C
Tamoxifen
Letrozole
n=1548
D
Letrozole
Tamoxifen
n=1540
0
2
5 Years
 Initiated 1998, completed May 2003
 8028 randomized (18 withdrew consent)
 Primary analysis compares letrozole vs tamoxifen and excludes events
and follow-up beyond switch for C & D
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
4
BIG 1-98: Primary Core Analysis
Randomized (N=8028 )
Withdrew Consent (no treatment/FU) (n=18)
Primary Core Analysis (n=8010)
4003 LET
vs
4007 TAM
133 (1.66%) ineligible cases included in primary core analysis
Median follow-up 25.8 months
FU = follow-up.
Thürlimann et al. N Engl J Med. 2005;353:2747.
5
BIG 1-98: Primary End Point—DFS
 Time from randomization to first:
– Invasive recurrence in

Ipsilateral breast

Chest wall

Regional site (internal mammary/axilla)

Distant site (including ipsilateral supraclavicular)
– Malignancy in contralateral breast (invasive)
– Secondary (nonbreast) malignancy
– Death without recurrence
DFS = disease-free survival.
Thürlimann et al. N Engl J Med. 2005;353:2747.
6
BIG 1-98: Secondary End Points




Overall survival (OS)
Systemic disease-free survival (SDFS)*
Distant disease-free survival (DDFS)†
Safety
*Excluding locoregional and contralateral events.
†Excluding locoregional and secondary nonbreast cancer.
Thürlimann et al. N Engl J Med. 2005;353:2747.
7
BIG 1-98: Statistical Considerations
 Target sample size: 7935
 Target number of DFS events
–
647 for primary core analysis
–
80% power to detect a 20% reduction in risk of a
DFS event
 Actual accrual: 8028
 Actual number of patients in primary core analysis: 8010 (4003 letrozole; 4007
tamoxifen)
 Actual number of DFS events: 779
 Median follow-up at core analysis: 25.8 mo
Thürlimann et al. N Engl J Med. 2005;353:2747.
8
BIG 1-98: Baseline Patient/Tumor
Characteristics
Letrozole
(Femara®)
Median age (y)
Tamoxifen
61
61
Tumor size >2 cm (%)
36.5
37.7
N+ (%)
41.5
41.2
CT given (%)
25.3
25.3
ER+/PgR+ (%)
63.5
62.7
ER+/PgR- (%)
20.2
20.5
ER+/PgR unknown (%)
14.5
14.3
 Receptor positivity was a study requirement
 99.8% of patients had receptor-positive tumors
CT = chemotherapy.
Thürlimann et al. N Engl J Med. 2005;353:2747.
9
BIG 1-98: Follow-Up Time
Primary Core Analysis (Median FU 25.8 mo)
% of patients
100
99
76
80
60
33
40
24
15
20
0
≥1
≥2
≥3
≥4
≥5
Years
More than 1200 patients were followed for at least 5 years
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
10
BIG 1-98: Follow-Up Time (cont’d)
No. of patients
Primary Core Analysis (Median FU 25.8 mo)
8000
7000
6000
5000
4000
3000
2000
1000
0
7926
5735
2678
1915
1235
≥1
≥2
≥3
≥4
≥5
Years
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
11
BIG 1-98: Disease-Free Survival
97.7
97.6
Yearly
DFS (%)
95.1
93.4
90.5
89.0
86.8
84.6
84.0
81.4
% of pts alive and
disease-free
100
LET
TAM
80
60
40
20
N
HR (95% CI)
P Value
8010
0.81 (0.70-0.93)
0.003
0
0
1
2
3
4
5
892
866
567
544
Years from randomization
No. at
risk
4003
4007
3892
3896
2964
2926
1261
1238
HR = hazard ratio.
Thürlimann et al. N Engl J Med. 2005;353:2747.
12
BIG 1-98: DFS By Treatment Duration
Women surviving free
of breast cancer (%)
100
97.7 97.6
Letrozole (Femara®)
Tamoxifen
95.1
95
93.4
90.5
89.0
90
86.8
84.6
85
84.0
81.4
80
1
2
3
4
5
Years
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
13
BIG 1-98: Cumulative Incidence of
Breast Cancer Events*
Proportion failure (%)
20
5-y difference (LET – TAM) = –3.4%
P<0.001
15
13.6%
TAM
8.1%
LET
10
10.2%
5
6.2%
0
0
1
2
3
4
5
Years from randomization
*Breast cancer event defined as ipsilateral or distant recurrence, or new contralateral breast primary.
Thürlimann et al. N Engl J Med. 2005;353:2747.
14
BIG 1-98: Treatment Failures
Letrozole
(Femara®)
Tamoxifen
P
First failure sites (DFS events)
8.8%
10.7%
0.003
Local
0.5%
0.9%
0.034
Contralateral breast (invasive)
0.4%
0.7%
0.092
Regional*
0.3%
0.3%
0.842
Distant
4.4%
5.8%
0.005
Secondary (nonbreast) malignancy
1.7%
2.0%
0.288
Death without cancer event
1.4%
0.9%
0.077
Deaths
4.1%
4.8%
0.155
Systemic failures†
8.1%
9.6%
0.017
*Includes axilla or internal mammary.
†SDFS ignores local and contralateral events.
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
15
BIG 1-98: Protocol End Points
0.81
DFS
0.86
OS
0.83
SDFS
0.5
0.75
Favors LET
1.0
1.33
2.0
Favors TAM
Thürlimann et al. N Engl J Med. 2005;353:2747.
16
BIG 1-98: Other End Points
0.81
DFS
0.86
OS
0.83
SDFS
0.79
DFS (w/o 2nd malignancy)
0.73
Time to distant recurrence
0.72
Time to recurrence
0.5
0.75
1.0
Favors LET
1.33
2.0
Favors TAM
HR (LET:TAM)
Thürlimann et al. N Engl J Med. 2005;353:2747.
17
BIG 1-98: DFS by Subgroups—“Unique Benefit in
Node+* and CT†-Pretreated Patients”
0.70
CT given (n=2024)
0.85
CT not given (n=5986)
0.71
N+ (n=3311)
0.96
N- (n=4587)
0.84
ER+/PgR+ (n=5055)‡
0.83
ER+/PgR- (n=1631)‡
0.5
0.75
1.0
Favors LET
1.33
2.0
Favors TAM
* Preplanned stratified analysis.
†Preplanned exploratory analysis.
‡Based on local assessment.
Thürlimann et al. N Engl J Med. 2005;353:2747.
HR (LET:TAM)
18
BIG 1-98: Overall Survival By
Subgroups
0.76
CT given (n=2024)
0.90
CT not given (n=5986)
0.82
N+ (n=3311)
0.88
N- (n=4174)
1.00
ER+/PgR+ (n=5055)*
0.79
ER+/PgR- (n=1631)*
0.5
0.75
1.0
Favors LET
1.33
2.0
Favors TAM
HR (LET:TAM)
*Based on local assessment.
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
19
BIG 1-98: DFS by Central Pathologic
Review of ER, PgR, and HER2 Status
 In BIG 1-98 primary core analysis, the DFS benefit with letrozole
(Femara®) vs tamoxifen was comparable in ER+/PgR+ and ER+/PgRsubsets1
– Subset analysis was based on local pathologic assessments
 BIG 1-98 ER and PgR status was reassessed by central pathologic
review2
– 4399 patients were centrally reviewed; 3330 (75.7%) confirmed as
ER+/PgR+ and 832 (18.9%) as ER+/PgR– ER+/PgR+: IHC staining in ≥10% of tumor cells
– HER2 status was also centrally reviewed (HER2+: IHC+, confirmed
as FISH+)
1. Thürlimann et al. N Engl J Med. 2005;353:2747.
2. Update of Viale et al. Breast Cancer Res Treat. 2005;94(suppl 1):S13. Abstract 44.
20
BIG 1-98: DFS by Centrally Reviewed
PgR Status
ER+/PgR+
100
Letrozole (Femara®)
% of patients
80
ER+/PgR-
100
80
Tamoxifen
60
60
Interaction P=0.32
40
40
20
n
Events
HR (95% CI)
3330
215
0.67 (0.51-0.88)
20
n
Events
HR (95% CI)
832
70
0.88 (0.55-1.41)
0
0
0
1
2
3
4
0
Years
1
2
3
4
Years
Update of Viale et al. Breast Cancer Res Treat. 2005;94(suppl 1):S13. Abstract 44.
21
BIG 1-98: DFS by Central Pathologic
Assessment—PgR Status
0.71
All patients (n=4399)
0.67
ER+/PgR+ (n=3330)
0.88
ER+/PgR- (n=832)
0.5
0.75
Favors LET
1.0
1.25
1.5
Favors TAM
Hazard Ratio (LET:TAM)
Update of Viale et al. Breast Cancer Res Treat. 2005;94(suppl 1):S13. Abstract 44.
22
BIG 1-98: DFS by Central Pathologic
Assessment—HER2 Status
0.71
All patients (n=4399)
0.72
ER+/HER2- (n=3971)
0.68
ER+/HER2+ (n=234)
0.5
0.75
Favors LET
1.0
1.25
1.5
Favors TAM
Hazard Ratio (LET:TAM)
Update of Viale et al. Breast Cancer Res Treat. 2005;94(suppl 1):S13. Abstract 44.
23
BIG 1-98: DFS by Central Review of
ER, PgR, and HER2—Conclusions
 By central review, a letrozole (Femara®) benefit was seen in
all ER+ patients, irrespective of PgR or HER2 status
 There was no evidence of tamoxifen resistance in
ER+/PgR- tumors
 Because of small numbers of ER+/HER2+ tumors in this
study, any possible resistance of these tumors to endocrine
therapy will require further evaluation
 BIG 1-98 is the only adjuvant AI trial to centrally
reassess ER and PgR status
Update of Viale et al. Breast Cancer Res Treat. 2005;94(suppl 1):S13. Abstract 44.
24
BIG 1-98: Trial Design vs ATAC Trial
 While cross-trial comparisons are controversial, they are
often necessary to guide clinical decision-making
 Tamoxifen was used as the reference arm in both BIG 1-98
and ATAC
 Notably, definitions of end points differed between trials1,2
– DFS in BIG 1-98 included secondary cancers; ATAC did not
– BIG 1-98 included only invasive contralateral breast cancer
1. Thürlimann et al. N Engl J Med. 2005;353:2747.
2. Baum et al. Lancet. 2002;359:2131.
25
BIG 1-98: All End Points—
Comparison With ATAC
ATAC HR+
68 mo1
33 mo2
-
0.81
DFS
0.97
-
0.86
OS
0.93
-
0.73
Distant DFS
0.83
0.78
0.79
DFS (w/o 2nd malignancy)
0.84
-
0.73
Time to distant metastasis
0.74
0.73
0.72
Time to recurrence
0.5
HR = hormone receptor.
1. Howell et al. Lancet. 2005;365:60.
2. Baum et al. Lancet. 2002;359:2131.
Thürlimann et al. N Engl J Med. 2005;353:2747.
0.75
Favors LET
1.0
1.33
2.0
Favors TAM
Hazard ratio (LET:TAM)
26
BIG 1-98 in Comparison:
Efficacy Results
 The risk of distant metastases was reduced by 27% with letrozole
(Femara®) in BIG 1-98 but did not reach any significant difference with
anastrozole in the ATAC trial*
 Risk of death was reduced by 14% with letrozole vs 3% with
anastrozole. Both results were nonsignificant
 Letrozole showed a significant DFS advantage in
– Patients who received chemotherapy
– Patients who were N+
 Within ATAC, anastrozole showed no significant advantage over
tamoxifen in these subgroups
*HR+ population (Howell et al. Lancet. 2005;365:60).
Thürlimann et al. N Engl J Med. 2005;353:2747.
27
BIG 1-98: Evaluation of Adverse
Events
 Safety population included patients who took at
least 1 dose of study treatment (n=7949)
 Protocol-specified targeted adverse events were
recorded on CRFs every 6 mo
 SAEs similar in 2 treatment groups
– LET = 587, TAM = 643 patients with at least 1 SAE
CRF = case report form.
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
28
BIG 1-98: Key Adverse Events,
Any Grade
General
Gynecol
CV/lipids
Musculoskeletal
Hot flushes
Night sweats
Vaginal bleeding
Endometrial biopsies
Invasive endometrial
cancer
Hypercholesterolemia*
Thromboembolic
CVA/TIA
Cardiac
Bone fracture
Muscle
Joint pain
Letrozole (%)
Tamoxifen (%)
33.5
13.9
3.3
1.9
38.0
16.2
6.6
7.2
0.2
0.5
43.5
1.5
1.0
4.1
5.7
6.4
20.3
19.1
3.5
1.0
3.8
4.0
6.1
12.3
*>80% were grade 1 (grade 1 events: LET 35.1%/TAM 17.3%); steady decline while on treatment up to 72
months (TAM 12%/LET 0%-2%).
CVA = cerebrovascular accident; TIA = transient ischemic attack.
Thürlimann et al. N Engl J Med. 2005;353:2747.
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BIG 1-98: Lipid Data
 As a check-listed adverse event, hypercholesterolemia
was noted in 43% of patients on letrozole (Femara®) and
19% of patients on tamoxifen:
– The vast majority (>80%) were categorized as grade 1
hypercholesterolemia (<300 μg/mL)
– Measurements reflect nonfasting lipid levels; single
pathologic measurements sufficed to qualify as an event
– No change in median total cholesterol from baseline in letrozole
group vs median decrease of 12% in tamoxifen group
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
Thürlimann et al. N Engl J Med. 2005;353:2747.
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BIG 1-98: Cholesterol Levels Remained
Stable— Analysis by Novartis
Post-Text Figure 10.2–1
Box Plot of Total Cholesterol (mmol/L) Over Time by
Treatment Safety Population
Total cholesterol (mmol/L)
25
20
15
10
5
0
M:0
L-2952
T-2962
M:6
2606
2599
M:12
2660
2671
M:18
2546
2588
Treatment:
M:24
2264
2255
M:30
1716
1679
Letrozole
M:36
1255
1226
M:42
863
831
M:48
698
695
M:54
527
519
M:60
455
425
Tamoxifen
Boxes represent median and interquartile range.
Whiskers (lines) represent 5th and 95th percentiles.
Symbols represent outliers.
31
BIG 1-98: Deaths
No. of Patients
Letrozole
(Femara®)
(n=4003)
Tamoxifen
(n=4007)
Deaths
166
192
Deaths following cancer event
111
154
Deaths w/o prior cancer event
55
38
CVA
7
1
Venous thromboembolic
2
2
Cardiac
13
6
Sudden death (cause unknown)
10
10
Other
23
19
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
32
BIG 1-98: Cardiovascular Events,
Grades 3-5
% of Patients
Letrozole
(Femara®)
(n=3975)
Tamoxifen
(n=3988)
P Value
CVA/TIA
1.0
1.0
1.0
Thromboembolic
0.8
2.1
<0.0001
Cardiac
2.1
1.1
0.0003
Ischemic heart disease
1.1
0.6
0.013
Cardiac failure
0.5
0.1
0.006
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
33
BIG 1-98: Summary of Efficacy
 Letrozole (Femara®) significantly decreased
– Overall risk of recurrence by 19% (P=0.003)
– Risk of recurrence


In patients who had received chemotherapy by 30%
(P=0.01)
In patients with N+ disease by 29% (P<0.001)
 Letrozole significantly reduced the risk of distant
metastases by 27% (P=0.001)
 Letrozole decreased risk of death by 14% (P=0.16)
Thürlimann et al. N Engl J Med. 2005;353:2747.
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BIG 1-98: Summary of Safety
 Letrozole (Femara®) was generally well tolerated
 Serious adverse events were similar with letrozole and
tamoxifen
 Overall, more deaths occurred with tamoxifen
 Fewer venous thromboembolic and endometrial events
occurred in the letrozole group
 More skeletal and cardiac grades 3-5 events occurred in the
letrozole group
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
Thürlimann et al. N Engl J Med. 2005;353:2747.
35
BIG 1-98: Clinical Implications
 Breast cancer recurrence remains a significant and ongoing risk
throughout the entire treatment of breast cancer regardless of lymph
node status
 Recurrence at distant sites leads to poor and often fatal outcomes
 First trial to demonstrate an increase in distant DFS in initial adjuvant
setting in hormone receptor+ postmenopausal women
 First trial to demonstrate benefit of initial adjuvant letrozole (Femara®)
over tamoxifen in N+ patients and patients who received CT
 Letrozole is effective as initial adjuvant therapy. Further follow-up is
needed to determine whether sequential therapy is superior to initial
letrozole therapy
Update of Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.
Thürlimann et al. N Engl J Med. 2005;353:2747.
36
FACE: Femara® vs Anastrozole Clinical
Evaluation
 Unanswered key medical question: Selecting the
better AI to benefit high-risk patients
 Strong message to the scientific community
 Differentiation of Femara® from anastrozole based
on subset analyses in BIG 1-98, MA.17, and ATAC
trials
 Supporting launch of adjuvant indication
37
FACE: Phase IIIb Head-to-Head
Comparison—Study Design
EBC
• ER+
• Postmenopausal
• Node+
• Postmenopausal
FSH/LH/E2 levels
• De novo adjuvant
ET
R
A
N
D
O
M
I
Z
E
Femara® 2.5 mg/qd
N=4000
Anastrozole 1 mg/qd

Primary end point
–
About 46% of all
adjuvant ER+
postmenopausal
patients are node+

DFS
Secondary end points
–
Safety
–
OS
–
Time to distant metastasis
–
Time to contralateral disease
–
Breast cancerspecific survival
FSH = follicle-stimulating hormone; LH = luteinizing hormone.
38