BIG 1-98 A study to evaluate Letrozole as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer

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Welcome and Introductions
Edith A. Perez, MD Director, Cancer Clinical
Study Unit Mayo Clinic Jacksonville, Florida
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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 OncologyUniversity of
NewcastleDirector, Department of Surgical
OncologyNewcastle Mater Misericordiae
HospitalNewcastle, Australia
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Outline

• 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 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
Netherlands 94 TOTAL 8028
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BIG 1-98 Design
R A N D O M I Z E
A
Tamoxifen
B
Letrozole
C
Letrozole
Tamoxifen
D
Letrozole
Tamoxifen
0
2
5
YEARS

• Compares Letrozole versus Tamoxifen
• Letrozole Arms B and D
• Tamoxifen Arms A and C
• Excludes events and FU beyond switch for C D

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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
4007 T
4003 L
versus
133 (1.66) ineligible cases included in primary
core analysis
Median Follow-Up25.8 months
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Patient/Tumor Characteristics
Letrozole Letrozole Tamoxifen
Median age Median age 61 61
Tumor size gt 2 cm Tumor size gt 2 cm 36.5 37.7
Node positive Node positive 41.5 41.2
Chemotherapy given Chemotherapy given 25.3 25.3
ER / PgR ER / PgR 63.5 62.7
ER / PgR- ER / PgR- 20.2 20.5
ER / PgR unk 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

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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
100
80
T
60
Percent Alive and Disease-Free
40
20
0
0
1
2
3
4
5
Years from Randomization
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Cumulative IncidenceBreast Cancer Event
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5-year diff (L-T) -3.4 (S.E. 1.2) Cum
incidence P0.0002
13.6
15
T
Proportion Failure ()
L
10
8.1
10.2
5
6.2
0
0
2
3
4
5
1
Years from Randomization
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Treatment Failures
Letrozole Tamoxifen P Letrozole Tamoxifen P Letrozole Tamoxifen P Letrozole 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
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
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 23 19
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Protocol Endpoints
DFS
0.81
OS
0.86
SDFS
0.83
1.0
0.5
0.75
1.33
2.0
Favors L
Favors T
Hazard Ratio (LT)
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Other Endpoints
DFS
0.81
OS
0.86
SDFS
0.83
DFS (w/o 2nd malignancy)
0.79
0.73
Time to distant recurrence
Time to recurrence
0.72
1.0
0.5
0.75
1.33
2.0
Favors L
Favors T
Hazard Ratio (LT)
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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 3651308
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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
1.0
0.5
0.75
1.33
2.0
Favors L
Favors T
Hazard Ratio (LT)
Based on local assessment
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Subgroup - OS
0.76
CT given (n2024)
0.90
CT not given (n5986)
1.0
0.5
0.75
1.33
2.0
Favors L
Favors T
Hazard Ratio (LT)
Based on local assessment
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Summary of Efficacy

• Letrozole significantly decreased
• overall risk of recurrence (19 P0.003)
• Letrozole significantly reduced the risk of
• distant metastases (27 P0.0012)
• Letrozole was associated with a non significant
  decreased risk of death (14 P0.16)
• The results are consistent with a similar effect
  in all subgroups examined

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Adverse Events, Any Grade
Letrozole
Tamoxifen
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
Letrozole Letrozole Tamoxifen
Patients 3975 3975 3988 P
CVA/TIA gr 3-5 CVA/TIA gr 3-5 1.0 1.0 1.0
Thromboembolic gr 3-5 Thromboembolic gr 3-5 0.8 2.1 lt 0.0001
Cardiac gr 3-5 Cardiac gr 3-5 2.1 1.1 0.0003
Ischemic heart disease gr 3-5 Ischemic heart disease gr 3-5 1.1 0.6 0.013
Cardiac failure gr 3-5 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
Patients 3975 3988
Bone fractures 244 164
Patients w/ bone fracture 225 (5.7) 159 (4.0)
Bone fracture rate (fracture/100 patient-years) 2.2 1.5
Risk ratio, p-value (LT) 1.42 p0.0006 1.42 p0.0006
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Endometrial Events
Letrozole Tamoxifen
Patients 3089 3157
Endometrial biopsies (pts) 72 (2.3) 288 (9.1)
Invasive endometrial cancer 6 (0.2) 15 (0.5)
Invasive endometrial cancer Risk ratio, p-value (LT) 0.40, p0.087 0.40, p0.087
Excludes 1717 patients with hysterectomy at
baseline
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Perspective
Interpretation Predictions
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EBCTCG 2000 (2005) Mortality
EBCTCG 2000 (2005) Recurrence
11.7 HR 0.44
0.70 7.9
0.74 9.2
0.70 3.6
HR Abs RRn
0.64 13.7
0.74 11.8
HR Abs RRn
0.57 10.4
14.8
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
2.5
Annual HR HR
2.0
1.5
1.0
Anastrozole
? Acquired Tamoxifen resistance developing at
2-3 years
0.5
Tamoxifen
0
0
1
2
3
4
5
6
Follow-up time (years)
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Fracture rates over time
3
2.5
2
Annual rates
1.5
1
Anastrozole Tamoxifen
0.5
0
1
2
3
4
5
6
0
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 ComparisonsBIG 1-98 and ATAC
ATAC HR
68 mo1
33 mo2
DFS
0.81
-
-
OS
0.86
0.97
-
SDFS
0.83
-
-
DFS (w/o 2nd malignancy)
0.79
0.83
0.78
0.73
0.84
-
Time to distant metastasis (DDFS)
Time to recurrence
0.72
0.73
0.74
1.0
0.5
0.75
1.33
2.0
Favors TAM
Favors LET
1. Lancet. Jan 7, 2005. 2. Lancet. June 22, 2002.
Hazard ratio (LETTAM)
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Subgroups OS
0.76
CT given (n2024)
0.90
CT not given (n5986)
0.82
N-positive (n3311)
0.88
N-negative (n4174)
1.00
ER / PgR (n5055)
0.79
ER / PgR- (n1631)
1.0
0.5
0.75
1.33
2.0
Favors L
Favors T
Hazard Ratio (LT)
Based on local assessment
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Retrospective analysis of time to recurrence for
ER/PgR subgroups
Patient group HR ERPgR
ERPgR- Hazard ratio 0.79
0.84 0.43
25
20
ER/PgR-
15
Patients ()
10
5
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
451
435
417
400
390
347
124
T
429
412
375
353
327
276
96
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ATAC Ischemic CV Disease and Deaths
ATAC (68 month F/U) ANA (n2618) TAM (n2598)
Overall Deaths 296 301 NS
Breast Cancer Deaths Cardiac Deaths 152 172 NS
Ischemic Cardiovascular Disease 127 (4.1) 104 (3.4) NS
Data from HR patients Distler W, St. Gallen
2005, poster P128 Howell A, St Gallen 2005,
poster P127
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IES MI and Deaths
IES (37.4 month F/U) EXE (n2352) TAM (n2372)
All MIs 20 (0.9) 8 (0.4) NS
MIs on Treatment 14 (0.7) 6 (0.3) NS
Deaths, All 152 187 NS
Deaths, Vascular 15 7
Deaths, Cardiac 13 12
Coombes RC et al, SABCS 2004, Abstract 3 (Oral
Presentation)
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Protective Effect of Tamoxifenon cholesterol?

• Cardiovascular risk substantially and
  progressively increases in women age gt65
  (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
199531197780 3) Rutqvist LE et al.J Natl
Cancer Inst 1993851398406, 4) Bradbury BD et
al, Cancer March 2005, 5) Reis SE et al. J Natl
Cancer Inst 2001, Vol 93, No 1, Jan 316-21
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EBCTCG 2000 (2005) Mortality
EBCTCG 2000 (2005) Recurrence
11.7 HR 0.44
0.70 7.9
0.74 9.2
0.70 3.6
HR Abs RRn
0.64 13.7
0.74 11.8
HR Abs RRn
0.57 10.4
14.8
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
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Lipid Data

• BIG 1-98 revealed an increase in
  hypercholesterolemia measured in the letrozole
  arm vs tamoxifen
• - The majority (gt80) were categorized as grade 1
  hypercholesterolemia, lt 300 ug/mL
• Measurements reflect non-fasting lipid levels,
• single pathologic measurements sufficed to
  qualify as an event
• Further review to be completed

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Conclusions

• Letrozole significantly prolongs DFS compared
  with tamoxifen for postmenopausal women with
  endocrine-responsive breast cancer (especially
  reducing relapse in distant sites).
• Compared with tamoxifen in postmenopausal women,
  more skeletal and grade 3-5 cardiac events and
  less venous thromboembolic and endometrial events
  occurred with letrozole.

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Conclusions

• Letrozole can now be considered part of standard
  adjuvant therapy for postmenopausal women with
  endocrine-responsive breast cancer.
• Longer follow-up of this study will provide
  assessment of the role of sequential endocrine
  agents compared with endocrine monotherapy.

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The Use of Adjuvant Aromatase Inhibitors In Post
Menopausal Early Breast Cancer New Contributions
from BIG 1 98
Professor John F Forbes IBCSG / ANZ
BCTG Newcastle Mater Hospital University of
Newcastle
Coordinated by the International Breast Cancer
Study Group International Study Chair Dr Beat
Thürlimann