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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. 29 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. 30 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. 34 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 cancerspecific survival FSH = follicle-stimulating hormone; LH = luteinizing hormone. 38