Transcript BIG 1-98 A study to evaluate Letrozole as adjuvant

Welcome and Introductions
Edith A. Perez, MD
Director, Cancer Clinical Study Unit
Mayo Clinic
Jacksonville, Florida
The Early Use of Adjuvant Aromatase
Inhibitors for Early Breast Cancer:
New Contributions from the
BIG 1-98 Letrozole Trial
John F. Forbes, MB, BS, MS, FRACS
Professor of Surgical Oncology
University of Newcastle
Director, Department of Surgical Oncology
Newcastle Mater Misericordiae Hospital
Newcastle, Australia
Outline
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Trial Design
Statistical Analyses
Population
Efficacy Endpoints
Subgroups
Safety
Conclusions
Perspective
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BIG 1-98 Worldwide Collaborative
8028 patients enrolled March 1998-May 2003
Argentina
123
New Zealand
Australia
667
Peru
Belgium
634
Poland
Brazil
17
Portugal
Canada
20
Russia
Chile
22
Slovenia
Czech Rep.
109
South Africa
157
51
277
64
240
15
187
Denmark
1396
Spain
70
France
1016
Sweden
64
Germany
113
Switzerland
Hungary
334
Turkey
Iceland
Italy
Netherlands
6
1285
94
United Kingdom
Uruguay
TOTAL
611
54
401
1
8028
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BIG 1-98 Design
R
A
N
D
O
M
I
Z
E
A
Tamoxifen
B
Letrozole
C Tamoxifen
Letrozole
Letrozole
Tamoxifen
D
0
•
•
•
•
2
YEARS
5
Compares Letrozole versus Tamoxifen
Letrozole: Arms B and D
Tamoxifen: Arms A and C
Excludes events and FU beyond switch for C & D
6
BIG 1-98

New since St. Gallen (January 2005)
- Medical review of all cerebrovascular, cardiac,
unclear AEs (538 cases) and all deaths without prior
cancer event (93 cases)

- Overall survival outcome by subgroups
- Identification of myalgia and arthralgia AEs
Still to come
- Central review of ER, PgR, Her-2
- Update of safety and efficacy
- Results of sequential treatment comparisons
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Primary Core Analysis
8028 Randomized
18 withdrew consent (no treatment / FU)
8010 Primary Core Analysis
4003 L
versus
4007 T
133 (1.66%) ineligible cases included in primary core analysis
Median Follow-Up=25.8 months
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Patient/Tumor Characteristics
Letrozole Tamoxifen
Median age
61
61
Tumor size > 2 cm
36.5%
37.7%
Node positive
41.5%
41.2%
Chemotherapy given
25.3%
25.3%
ER+ / PgR+
63.5%
62.7%
ER+ / PgR-
20.2%
20.5%
ER+ / PgR unk
14.5%
14.3%
Receptor positivity was a study requirement:
99.8% of patients had receptor positive tumors
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Primary End Point: DFS
Time from randomization to first of:
Invasive recurrence in
- Ipsilateral breast
- Chest wall
- Regional site (internal mammary/axilla)
- Distant site (including ipsi
supraclavicular)
Contralateral breast (invasive)
Second (non breast) malignancy
Death without prior cancer event
10
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 2nd non-breast cancer
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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
Percent Alive and Disease-Free
100
L
80
T
60
40
N
Events
HR (95% CI)
p
8010
779
0.81 (.70-.93)
0.003
20
0
0
No. at 4003
Risk 4007
1
3892
3896
2
3
Years from Randomization
2964
2926
1261
1238
4
5
892
866
567
544
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Cumulative Incidence
Breast Cancer Event
Proportion Failure (%)
20
5-year diff (L-T) = -3.4% (S.E. 1.2)
Cum incidence P=0.0002
13.6%
15
T
10
L
8.1%
10.2%
5
6.2%
0
0
1
2
3
4
5
Years from Randomization
13
Treatment Failures
Letrozole
Tamoxifen
P
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
Second (non breast) 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
First Failure Sites (DFS events)
*Regional includes axilla or internal mammary
**SDFS ignores local and contralateral events
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Deaths
Letrozole
Tamoxifen
Patients
4003
4007
Deaths
166
192
Deaths following cancer event
111
154
Deaths w/o prior cancer event
55
38
- Cerebro-vascular accident
7
1
- Venous thromboembolic
2
2
- Cardiac
13
6
- Sudden death (cause unk)
10
10
- Other
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19
15
Protocol Endpoints
0.81
DFS
0.86
OS
0.83
SDFS
0.5
0.75
Favors L
1.0
1.33
2.0
Favors T
Hazard Ratio (L:T)
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Other Endpoints
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
Favors L
1.0
1.33
2.0
Favors T
Hazard Ratio (L:T)
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Sub group Analyses
•
Subgroup analyses should concentrate on:
differences from the average overall treatment
effect (via tests of heterogeneity or interaction)
•
It is inappropriate to assess the effects of
treatment on a single subgroup by examination
of the 95% CI for that subgroup.
Cuzick J 1982; Lancet 2005 365:1308
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Sub group Analyses
Two types of error can occur
1. Attribution of an effect to a subgroup
when there is no overall effect and no
evidence for heterogeneity (more common)
2. To claim a lack of effect in a subgroup
when the overall effect is significant
Cuzick J 1982; Lancet 2005 365: 1308
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Sub group Analyses
•
Confidence intervals in subgroups are always wider than
those for the main effect because of smaller numbers.
•
If the interval for a subgroup crosses the no effect point,
this is widely misinterpreted as a lack of effect in the
subgroup even when the overall effect is significant.
•
The correct approach is to determine whether the effect
size for different subgroups varies significantly from the
main effect by a test for heterogeneity.
Cuzick J 1982; Lancet 2005 365: 1308
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Subgroups - DFS
0.70
CT given (n=2024)
0.85
CT not given (n=5986)
0.71
N-positive (n=3311)
0.99
N-negative (n=4174)
0.84
ER+ / PgR+ (n=5055)*
0.83
ER+ / PgR- (n=1631)*
0.5
0.75
Favors L
1.0
1.33
2.0
Favors T
Hazard Ratio (L:T)
* Based on local assessment
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Subgroup - OS
0.76
CT given (n=2024)
0.90
CT not given (n=5986)
0.82
N-positive (n=3311)
0.88
N-negative (n=4174)
1.00
ER+ / PgR+ (n=5055)*
0.79
ER+ / PgR- (n=1631)*
0.5
0.75
Favors L
1.0
1.33
2.0
Favors T
Hazard Ratio (L:T)
* Based on local assessment
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Summary of Efficacy
•
•
•
•
Letrozole significantly decreased
overall risk of recurrence (19% P=0.003)
Letrozole significantly reduced the risk of
distant metastases (27% P=0.0012)
Letrozole was associated with a non significant
decreased risk of death (14% P=0.16)
The results are consistent with a similar effect
in all subgroups examined
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Adverse Events, Any Grade
1.0
1.0
1.5
CVA/TIA
Thromboembolic
Letrozole
3.5
Vaginal bleeding
4.1
3.8
5.7
4.0
3.3
6.6
Muscle
6.4
6.1
Cardiac
Bone fracture
Tamoxifen
20.3
Joint
12.3
43.5
Hyperchol*
19.1
33.5
Hot flushes
38.0
13.9
16.2
Night Sweats
0
25
50
Percent of Patients
*Grade 1: 35.1% L, 17.3% T; Grade 2+: 8.5% L, 1.9% T
Serial cholesterol levels are being reviewed.
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Cardiovascular Events, Grade 3-5
Patients
Letrozole
Tamoxifen
3975
3988
P
CVA/TIA gr 3-5
1.0%
1.0%
1.0
Thromboembolic gr 3-5
0.8%
2.1%
< 0.0001
Cardiac gr 3-5
2.1%
1.1%
0.0003
Ischemic heart disease gr 3-5
1.1%
0.6%
0.013
Cardiac failure gr 3-5
0.5%
0.1%
0.006
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Summary: Cardiovascular Events
•
Compared with tamoxifen
- AIs reduce the risk of thromboembolic adverse events
- Adjuvant treatment with AIs has been associated with some increase in
the risk of CV events
•
Current information is conflicting and insufficient to fully determine the
longer-term effect of AIs on CV health
•
It is not possible at present to assign different cardiovascular risk
profiles to the individual AIs
•
Further analyses of ongoing AI trials is required
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Bone Fractures
Letrozole
Tamoxifen
3975
3988
Bone fractures
244
164
Patients w/ bone fracture
225 (5.7%)
159 (4.0%)
Patients
Bone fracture rate
2.2
1.5
(fracture/100 patient-years)
Risk ratio, p-value (L:T)
1.42
p=0.0006
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Endometrial Events
Patients*
Endometrial biopsies (pts)
Invasive endometrial cancer
Letrozole
Tamoxifen
3089
3157
72 (2.3%)
288 (9.1%)
6 (0.2%)
15 (0.5%)
Invasive endometrial cancer
Risk ratio, p-value (L:T)
0.40, p=0.087
*Excludes 1717 patients with hysterectomy at baseline
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Perspective
Interpretation
Predictions
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EBCTCG 2000 (2005)
Recurrence
EBCTCG 2000 (2005)
Mortality
11.7 HR 0.44
HR
0.57
Abs RRn 10.4
14.8
0.64
13.7
0.74
11.8
0.70
HR
Abs RRn 3.6
0.70
7.9
0.74
9.2
RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown:
15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+)
Lancet May 14 2005
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Smoothed hazard rates for recurrence
? Start Early or Switch
Letrozole: Prevention of early distant relapses
Should translate into mortality reduction
3.0
Annual 2.5
HR HR+
2.0
%
1.5
1.0
Anastrozole
Tamoxifen
? Acquired Tamoxifen resistance
developing at ~ 2-3 years
0.5
0
0
1
2
3
4
5
6
Follow-up time (years)
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Fracture rates over time
Annual rates %
3
2.5
2
1.5
1
Anastrozole
Tamoxifen
0.5
0
0
1
2
3
4
5
6
Years since randomization
Fracture rates per 1000 women years:
Anastrozole 22.6; Tamoxifen 15.6; P1 control 18.4; WHI control 19.1
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Cross trial Comparisons
Cross trial (indirect) comparisons may be unreliable:
- Different end-point definitions
- Different populations
- Different treatments
- Non randomised comparisons
They should be interpreted with caution both for
efficacy and side effects comparisons
But they may lead to new hypotheses
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Endpoint: Comparisons
BIG 1-98 and ATAC
ATAC HR+
68 mo1 33 mo2
-
0.81
DFS
0.97
-
0.86
OS
-
-
0.83
SDFS
0.83
0.78
0.79
DFS (w/o 2nd malignancy)
0.84
-
0.73
Time to distant metastasis (DDFS)
0.74
0.73
0.72
Time to recurrence
0.5
1. Lancet. Jan 7, 2005.
2. Lancet. June 22, 2002.
0.75
Favors LET
1.0
1.33
2.0
Favors TAM
Hazard ratio (LET:TAM)
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Subgroups: OS
0.76
CT given (n=2024)
0.90
CT not given (n=5986)
0.82
N-positive (n=3311)
0.88
N-negative (n=4174)
1.00
ER+ / PgR+ (n=5055)*
0.79
ER+ / PgR- (n=1631)*
0.5
0.75
Favors L
1.0
1.33
2.0
Favors T
Hazard Ratio (L:T)
* Based on local assessment
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Retrospective analysis of time to recurrence
for ER/PgR subgroups
Patient group
HR+
ER+PgR+
ER+PgR-
Hazard ratio
0.79
0.84
0.43
Patients (%)
25
Anastrozole (A)
Tamoxifen (T)
20
ER+/PgR-
15
10
5
0
0
At risk:
A
451
T
429
1
2
3
4
5
6
347
276
124
96
Follow-up time (years)
435
412
417
375
400
353
390
327
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Protective Effect of Tamoxifen
on cholesterol?


Cardiovascular risk substantially and progressively
increases in women age >65 (Framingham study)1
The cardio protective effect of tamoxifen has been
studied in several trials
–The data are conflicting, some studies showed
a
cardio protective effect2-4, others did not5.
1) http://www.nhlbi.nih.gov/about/framingham/index.html; 2) McDonald CC et al.: BMJ 1995;311:977–
80; 3) Rutqvist LE et al.:J Natl Cancer Inst 1993;85:1398–406, 4) Bradbury BD et al, Cancer March
2005, 5) Reis SE et al.; J Natl Cancer Inst 2001, Vol 93, No 1, Jan 3:16-21
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EBCTCG 2000 (2005)
Recurrence
EBCTCG 2000 (2005)
Mortality
11.7 HR 0.44
HR
0.57
Abs RRn 10.4
14.8
0.64
13.7
0.74
11.8
0.70
HR
Abs RRn 3.6
0.70
7.9
0.74
9.2
RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown:
15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+)
Lancet May 14 2005
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Questions and Answers