The Study Chair – Has no financial interest in Novartis– Has not received compensation from Novartis– Is not on an advisory board for letrozole

Letrozole as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer

First results of IBCSG 18-98/BIG 1-98

Beat Thürlimannfor the BIG 1-98 Collaborative

Coordinated by the International Breast Cancer

Study Group

Trial Coordinated by IBCSG

• IBCSG: Study design• IBCSG: Database and data management• IBCSG: DSMC and Ethics Committee• IBCSG: Medical review• IBCSG: Statistical analysis• IBCSG: Coordination and communication• Novartis: Drug distribution• Novartis: Financial support

ArgentinaArgentina 123123 New ZealandNew Zealand 157157AustraliaAustralia 667667

IcelandIceland 66 United KingdomUnited Kingdom 401401

PeruPeru 5151BelgiumBelgium 634634 PolandPoland 277277BrazilBrazil 1717 PortugalPortugal 6464CanadaCanada 2020 RussiaRussia 240240ChileChile 2222 SloveniaSlovenia 1515Czech Rep.Czech Rep. 109109 South AfricaSouth Africa 187187DenmarkDenmark 13961396 SpainSpain 7070FranceFrance 10161016 SwedenSweden 6464GermanyGermany 113113 SwitzerlandSwitzerland 611611HungaryHungary 334334 TurkeyTurkey 5454

ItalyItaly 12851285 UruguayUruguay 11Netherlands 94 TOTAL 8028

BIG 1-98 Worldwide Collaborative

BIG 1-98 Design

RANDOMIZE

2-Arm Option3/98 to 3/001835 pts

4-Arm Option9/99-5/036193 pts

TamoxifenA

LetrozoleB

Tamoxifen LetrozoleC

Letrozole TamoxifenD

0 2 5YEARS

BIG 1-98 Timeline

Start Database lock

2-Arm Accrual (1835)

4-Arm Accrual (6193) Follow-Up

Follow-Up

1998 1999 2000 2001 2002 2003 2004 2005DSMC interim efficacy

DSMC safety

Primary Core Analysis• Compares Letrozole versus Tamoxifen• Includes all patients• Letrozole: Arms B and D • Tamoxifen: Arms A and C• Excludes events and FU beyond switch for C & D

Tamoxifen

Letrozole

Tamoxifen Letrozole

Letrozole Tamoxifen

2-Arm Option

4-Arm Option

A

B

C

D

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 cancer event

Statistical Considerations

• Target sample size: 7935– 2-arm option: 1835– 4-arm option: 6100

• Actual accrual: 8028• Target number of DFS events:

– 647 for primary core analysis– 80% power to detect a 20% reduction in

the risk of a DFS event• Actual number of DFS events: 779

Primary Core Analysis

8028 Randomized

18 withdrew consent (no treatment / FU)

8010 Primary Core Analysis

versus4003 L 4007 T

133 (1.66%) ineligible cases included in primary core analysis

Follow-Up Time

99

77

46

28

15

99

76

3324

15

0

20

40

60

80

100

>=1 >=2 >=3 >=4 >=5

Years of Follow-Up

Perc

ent

Overall (median FU 35.5 mos.)Primary core (median FU 25.8 mos.)

Patient/Tumor Characteristics

Letrozole TamoxifenMedian age 61 61N+ 41.5% 41.2%N- (including sentinel) 52.0% 52.3%Nx / unknown 6.5% 6.5%Tumor size > 2 cm 36.5% 37.7%Prem at diagnosis 2.3% 2.5%

Patient/Tumor Characteristics

Letrozole TamoxifenER+ / PgR+ 63.5% 62.7%ER+ / PgR- 20.2% 20.5%ER+ / PgR unk 14.5% 14.3%ER- / PgR+ 1.5% 2.1%

Receptor positivity was a study requirement:99.8% of patients had receptor positive tumors

Treatment for Breast Cancer

Letrozole TamoxifenChemotherapy given 25.3% 25.3%Surgery / RT group

BC with RT 53.3% 54.0%BC without RT 2.8% 3.3%Mastectomy with RT 18.3% 17.6%Mastectomy without RT 25.4% 24.8%

T

0

20

40

60

80

100

0 1 2 3 4 5

Perc

ent A

live

and

Dis

ease

-Fre

e

Years from Randomization

Disease-Free Survival

L

97.797.6

YearlyDFS %

95.193.4

90.589.0

86.884.6

84.081.4

N HR (95% CI) p

8010 0.81 (.70-.93) 0.003

No. at Risk

38923896

29642926

12611238

892866

40034007

567544

Sites of First FailureLetrozole Tamoxifen P

Failures (DFS events) 8.8% 10.7% 0.0040.0470.1250.8450.0060.3240.0770.1760.020

Deaths 4.1% 4.8%Systemic Failures** 8.1% 9.6%

Local 0.5% 0.9%Contralateral Breast (invasive) 0.4% 0.7%Regional* 0.3% 0.3%Distant 4.4% 5.8%Second (non breast) malignancy 1.7% 2.0%Death without cancer event 1.4% 0.9%

*Regional includes axilla or internal mammary**SDFS ignores local and contralateral events

Years from Randomization

0 2 3 4 51

0

10

5

15

20

Pro

porti

on F

ailu

re (%

)

T

L

Cumulative IncidenceBreast Cancer Event

13.6%

10.2%8.1%

6.2%

5-year diff (L-T) = -3.4% (S.E. 1.2)Cum inc P=0.0002

0

10

5

15

20

Pro

porti

on F

ailu

re (%

)Cumulative Incidence

Second (non-breast) malignancy

LT

3.2%

2.7%

2.1%

1.9%

5-year diff (L-T) = -0.5% (S.E. 0.6)Cum inc P=0.29

0 1 2 3 4 5

Years from Randomization

0

10

5

15

20

Pro

porti

on F

ailu

re (%

)Cumulative IncidenceDeath without Cancer Event

1.8%

3.1%

0.8%

1.4%

5-year diff (L-T) = 1.3% (S.E. 0.6)Cum inc P=0.08

LT

0 1 2 3 4 5

Years from Randomization

Deaths

Letrozole Tamoxifen

Total deaths 166 192Patients 4003 4007

Total death w/o cancer event 55 38

- Other 19 22

- CVA 7 1- Thromboembolic 3 2- Cardiac 26 13

Overall p-value based oncumulative incidence

P=0.08

Protocol Endpoints

DFS

OS

SDFS

Favors L Favors T

0.81

0.86

0.83

0.5 0.75 1.0 1.25 1.5

Hazard Ratio (L:T)

Other Endpoints

DFS

OS

SDFS

Time to recurrence

DFS (w/o 2nd malignancy)

Favors L Favors T

0.81

0.86

0.83

0.79

0.73 Time to distant recurrence

0.72

0.5 0.75 1.0 1.25 1.5

Hazard Ratio (L:T)

Other EndpointsATAC HR+

68 mos.* 33 mos.**

- - 0.81 DFS

OS

SDFS

Time to recurrence

DFS (w/o 2nd malignancy)

Favors L Favors T

0.86

0.83

0.79

0.73

1.00.5 0.75 1.25 1.5

Hazard Ratio (L:T)

Time to distant recurrence

0.72

-0.97

--

0.83 0.78

-0.84

0.74 0.73

*Lancet Jan 7 2005**Lancet June 22 2002

Subgroups-DFS

CT given (n=2024)

CT not given (n=5986)

0.70

0.85

N-positive (n=3311)

N-negative (n=4174)

0.71

0.99

RT given (n=5744)

RT not given (n=2258)

0.82

0.77

0.5 0.75 1.0 1.25 1.5

Favors L Favors T

Hazard Ratio (L:T)

ER/PgR* Subgroups-DFS

ER+ / PgR+ (n=5055)

ER+ / PgR- (n=1631)

ER+ / PgR unk (n=1154)

Favors L Favors T

0.84

0.83

0.72

0.5 0.75 1.0 1.25 1.5

Hazard Ratio (L:T)

* Based on local assessment

Adverse Events

• Safety population includes pts who took at least 1 dose of trial treatment. N=7949

• CRFs collected protocol-specified targeted adverse events every 6 mos.

• Serious Adverse Events (SAEs) similar in 2 treatmentsL=587, T=643 patients with at least 1 SAE

Targeted AEs, any grade

9.5

2.6

6.6

4.1

8.3

2.4

1.1

2.7

8.8

3.3

5.8

8.7

1.0

1.2

0 2 4 6 8 10

Vomiting

Nausea

Vaginal bleeding

Bone fracture

Other cardiovasc

Thromboembolic

CVA/TIA

Percent Incidence

Letrozole

Tamoxifen

Targeted AEs, any grade

16.2

38.1

19.2

14.0

33.6

43.6

0 15 30 45

Night Sweats

Hot flushes

Hyperchol*

Percent Incidence

Letrozole

Tamoxifen

*Grade 1: 35.1% L, 17.3% T

Bone Fractures

Letrozole TamoxifenPatients 3965 3984Bone fractures 247 167Patients w/ bone fracture 228 (5.8%) 162 (4.1%)Bone fracture rate (fracture/100 patient-years)

2.2 1.5

Odds ratio, p-value (L:T) 1.44, p=0.0006

Endometrial Events

Letrozole TamoxifenPatients 3965 3984Endometrial biopsies (pts) 74 (1.9%) 288 (7.2%)Invasive endometrial cancer 6 (0.2%) 15 (0.4%)Invasive endometrial cancer Odds ratio, p-value (L:T) 0.40, p=0.078

Cardiovascular Events

Letrozole TamoxifenPatients 3965 3984

CVA/TIA grade 3-5 46 (1.2%) 42 (1.1%)

Thromboembolic gr 3-5 30 (0.8%) 79 (2.0%)

Other cardiovascular gr 3-5 143 (3.6%) 101 (2.5%)

Conclusions• Letrozole significantly prolongs DFS compared

with tamoxifen for postmenopausal women with endocrine responsive breast cancer (especially reducing relapse in distant sites)

• Letrozole was associated with an increased risk of bone fractures and a decreased risk of venous thromboembolic side effects compared with tamoxifen

• Further investigation of cardiovascular side effects is required in trials evaluating aromatase inhibitors

• Longer follow-up of this study will allow assessment of the role of sequential endocrine agents compared with endocrine monotherapy

Thanks to…

• The patients participating in the trial• The principal investigators• The co-investigators, data managers,

nurses, study coordinators• The cooperative groups• The IBCSG Data and Safety Monitoring

Committee• The trial monitors/audit teams

BIG 1-98 Steering Committee

B. Thürlimann, Switzerland S. Holmberg, Sweden G. Viale, Italy

L. Blacher, USA A. Keshaviah, USA H.A. Chaudri-Ross, Novartis

P. Dodion, Novartis

D. Evans, Novartis

W. Hackl, Novartis

M. Lassus, Novartis

E. Raman, Novartis

A. Robertone, Novartis

E. Waldie, Novartis

C. Straehle, Belgium

M. Castiglione, Switzerland A. Martoni, Italy

A. Coates, Australia L. Mauriac, France

T. Cufer, Slovenia H. Mouridsen, Denmark

J. Forbes, Australia K. Price, USA

R.D. Gelber, USA M. Rabaglio, Switzerland

A. Goldhirsch, Italy A. Santoro, Italy

A. Hiltbrunner, Switzerland I. Smith, U.K

IBCSG Core Offices

Coordinating Center Statistical Center Data Management Center

Manuela Rabaglio Aparna Keshaviah Lynette Blacher Tara Heckman-Scolese

Shauna Bancroft Richard Krall

Sandra Lippert

Jennifer Meshulam

Leslie Mundy

Anya Pavlov-Shapiro

Karolyn Scott

Margaret Scott

Nadia Munarini Aron Goldhirsch Kim Galloway Jocelyn Swick

Alan Coates John Gould Lois Uhteg

Danita Harrison Dawn Weinbaum

Rita Hinkle Cynthia Westby

Theresa Zielinski

Michelle Belisle

Mary Caporale

Joie Celano

Laura Dalfonso

Laurie Dooley

Susan Fischer

Monica Castiglione Richard Gelber

Anita Hiltbrunner Karen Price

Gerda Egli Leslie Somos

Bettina Cliffe Central Pathology

Sabrina Hofmann Barry Gusterson

Florence Munarini Giuseppe Viale

Eva Marbot Scientific Comm