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

Transcription

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

2 Letrozole as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer First results of IBCSG 18-98/BIG 1-98 Beat Thürlimann for the BIG 1-98 Collaborative Coordinated by the International Breast Cancer Study Group

3 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

4 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 Netherlands 94 TOTAL 8028

5 BIG 1-98 Design R A N D O M I Z E A B C D Tamoxifen Letrozole Tamoxifen Letrozole Letrozole Tamoxifen 2-Arm Option 3/98 to 3/ pts 4-Arm Option 9/99-5/ pts YEARS

6 BIG 1-98 Timeline Start Database lock 2-Arm Accrual (1835) 4-Arm Accrual (6193) Follow-Up Follow-Up DSMC interim efficacy DSMC safety

7 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 A B C Tamoxifen Tamoxifen Letrozole Letrozole 2-Arm Option 4-Arm Option D Letrozole Tamoxifen

8 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

9 Statistical Considerations Target sample size: arm option: 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

10 Primary Core Analysis 8028 Randomized 18 withdrew consent (no treatment / FU) 8010 Primary Core Analysis versus 4003 L 4007 T 133 (1.66%) ineligible cases included in primary core analysis

11 Follow-Up Time Overall (median FU 35.5 mos.) Primary core (median FU 25.8 mos.) Percent >=1 >=2 >=3 >=4 >=5 Years of Follow-Up

12 Patient/Tumor Characteristics Letrozole Tamoxifen Median age N+ 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%

13 Patient/Tumor Characteristics Letrozole Tamoxifen ER+ / 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

14 Treatment for Breast Cancer Letrozole Tamoxifen Chemotherapy 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%

15 Percent Alive and Disease-Free Yearly DFS % Disease-Free Survival N HR (95% CI) p ( ) L T No. at Risk Years from Randomization

16 Sites of First Failure Letrozole Tamoxifen P Failures (DFS events) 8.8% 10.7% 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% Deaths 4.1% 4.8% Systemic Failures** 8.1% 9.6% *Regional includes axilla or internal mammary **SDFS ignores local and contralateral events

17 20 Cumulative Incidence Breast Cancer Event Proportion Failure (%) year diff (L-T) = -3.4% (S.E. 1.2) Cum inc P= % 6.2% 13.6% T L 10.2% Years from Randomization

18 20 Cumulative Incidence Second (non-breast) malignancy Proportion Failure (%) year diff (L-T) = -0.5% (S.E. 0.6) Cum inc P= % 3.2% T L 0 1.9% 2.7% Years from Randomization

19 20 Cumulative Incidence Death without Cancer Event Proportion Failure (%) year diff (L-T) = 1.3% (S.E. 0.6) Cum inc P= % 0.8% 3.1% 1.8% L T Years from Randomization

20 Deaths Letrozole Tamoxifen Patients Total deaths Total death w/o cancer event CVA Thromboembolic 3 2 -Cardiac Other Overall p-value based on cumulative incidence P=0.08

21 Hazard Ratio (L:T) Protocol Endpoints DFS OS SDFS Favors L Favors T

22 Hazard Ratio (L:T) Other Endpoints DFS OS SDFS DFS (w/o 2 nd malignancy) 0.73 Time to distant recurrence 0.72 Time to recurrence Favors L Favors T

23 ATAC HR+ 68 mos.* 33 mos.** Other Endpoints DFS OS SDFS DFS (w/o 2 nd malignancy) Time to distant recurrence Time to recurrence *Lancet Jan **Lancet June Favors L Hazard Ratio (L:T) Favors T

24 Subgroups-DFS CT given (n=2024) CT not given (n=5986) N-positive (n=3311) N-negative (n=4174) RT given (n=5744) RT not given (n=2258) Favors L Favors T Hazard Ratio (L:T)

25 * Based on local assessment ER/PgR* Subgroups-DFS ER+ / PgR+ (n=5055) ER+ / PgR- (n=1631) ER+ / PgR unk (n=1154) Favors L Favors T Hazard Ratio (L:T)

26 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 treatments L=587, T=643 patients with at least 1 SAE

27 Targeted AEs, any grade CVA/TIA Letrozole Thromboembolic Tamoxifen Other cardiovasc Bone fracture Vaginal bleeding Nausea Vomiting Percent Incidence

28 Targeted AEs, any grade Hyperchol* Hot flushes Night Sweats Letrozole Tamoxifen Percent Incidence *Grade 1: 35.1% L, 17.3% T

29 Bone Fractures Letrozole Tamoxifen Patients Bone fractures Patients w/ bone fracture 228 (5.8%) 162 (4.1%) Bone fracture rate (fracture/100 patient-years) Odds ratio, p-value (L:T) 1.44, p=0.0006

30 Endometrial Events Letrozole Tamoxifen Patients Endometrial 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

31 Cardiovascular Events Letrozole Tamoxifen Patients CVA/TIA grade (1.2%) 42 (1.1%) Thromboembolic gr (0.8%) 79 (2.0%) Other cardiovascular gr (3.6%) 101 (2.5%)

32 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

33 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

34 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 M. Castiglione, Switzerland A. Martoni, Italy A. Coates, Australia L. Mauriac, France T. Cufer, Slovenia H. Mouridsen, Denmark J. Forbes, Australia K. Price, USA P. Dodion, Novartis D. Evans, Novartis W. Hackl, Novartis M. Lassus, Novartis R.D. Gelber, USA M. Rabaglio, Switzerland E. Raman, Novartis A. Goldhirsch, Italy A. Santoro, Italy A. Hiltbrunner, Switzerland I. Smith, U.K A. Robertone, Novartis E. Waldie, Novartis C. Straehle, Belgium

35 IBCSG Core Offices Coordinating Center Statistical Center Data Management Center Manuela Rabaglio Aparna Keshaviah Lynette Blacher Tara Heckman-Scolese Monica Castiglione Richard Gelber Shauna Bancroft Richard Krall Anita Hiltbrunner Karen Price Michelle Belisle Sandra Lippert Gerda Egli Leslie Somos Mary Caporale Jennifer Meshulam Bettina Cliffe Central Pathology Joie Celano Leslie Mundy Sabrina Hofmann Barry Gusterson Laura Dalfonso Anya Pavlov-Shapiro Florence Munarini Giuseppe Viale Laurie Dooley Karolyn Scott Eva Marbot Scientific Comm Susan Fischer Margaret Scott Nadia Munarini Aron Goldhirsch Kim Galloway Jocelyn Swick Alan Coates John Gould Lois Uhteg Danita Harrison Rita Hinkle Dawn Weinbaum Cynthia Westby Theresa Zielinski

36