Trial Comparison: ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98

Trial design and patient recruitment

9366 patients recruited from 381 centres in 21 countries ATAC trial: Belgium 192 Czech Republic 84 France 366 Germany 121 Hungary 243 Ireland 41 Italy 654 Netherlands 195 Poland 107 Portugal 74 Slovakia 33 Spain 417 Sweden 291 Turkey 53 UK

Combination n=3125 Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm Regular follow-up 9366 postmenopausal women with invasive breast cancer: mean age 64 years; 84% hormone receptor-positive; 61% node negative; 64% with tumour  2 cm in diameter Surgery  radiotherapy  chemotherapy Randomisation 1:1:1 for 5 years Anastrozole n=3125 Tamoxifen n=3116 Primary trial endpoints: Disease-free survival Safety / tolerability Secondary trial endpoints: Incidence of contralateral breast cancer Time to distant recurrence Overall survival Time to breast cancer death ATAC trial design

ATAC Completed Treatment Analysis Data cut-off 31 March 2004, based on at least 704 deaths in the two monotherapy arms combined 68 months’ median follow-up – beyond completion of treatment 59 months’ median treatment duration Only 8% of patients remain on treatment – the great majority of these nearing completion ATAC Trialists’ Group. Lancet 2005; 365: 60-62

8028 postmenopausal women with ER+ disease Median age 61 years 52% node negative 63% tumour  2 cm in diameter Tamoxifen BIG 1-98 trial design RANDOMISERANDOMISE Letrozole Tamoxifen LetrozoleTamoxifen Letrozole 025 A B C D Arm A vs B: March 1998 – March 2000; (n=1835) A vs B vs C vs D; September 1999 – May 2003; (n = 6193) BIG = Breast International Group ER+ = estrogen receptor-positive Time (years) 134 Adapted from Thürlimann B. St Gallen presentation 2005

Total number of DFS events (monotherapy arms)1226 <11–<22–<33–<44–<5>5>5 Duration of follow-up (years) Patients (%) ATAC: 73% of patients have been followed-up for 5 years or more Updated analysis (median follow-up 47 months) Treatment completion analysis (median follow-up 68 months) DFS = disease-free survival

BIG 1-98: only 15% of patients have been followed-up for 5 years 11 22 33 44 55 Follow-up (years) Patients (%) Thürlimann B. St Gallen presentation 2005

Demographics

Patient characteristics BIG 1-98 (n=8010) ATAC (n=6291) Age (years) Primary treatment (%) mastectomy radiotherapy chemotherapy Mean Median ATAC Trialists’ Group. Lancet 2002; 359: Adapted from Thürlimann B. St Gallen presentation 2005

Baseline disease characteristics Tumour size  2 cm (%) Nodal status (%) node-positive node-negative unknown HR status (%) ER+/PgR+ ER+/PgR- ER+/PgR unknown ER-/PgR BIG 1-98 (n=8010) ATAC (n=6291) ATAC Trialists’ Group. Lancet 2002; 359: Adapted from Thürlimann B. St Gallen presentation 2005

Efficacy analyses

Definition of disease-free survival differs ATAC –loco-regional recurrence or new contralateral breast cancer (invasive or DCIS) –distant recurrence or death (for any reason) BIG 1-98 –breast cancer recurrence (local, regional and distant) or invasive contralateral breast cancer –non-breast cancer deaths (deaths without recurrence) –non-breast cancer second primaries Time to recurrence is similar for both trials DCIS = ductal carcinoma in situ ATAC Trialists’ Group. Lancet 2002; 359: Thürlimann B et al. The Breast 2005;14; S3. Abstract S4

Definition of time to distant recurrence appears to differ ATAC - time to distant recurrence (TTDR) –distant recurrence or any death following a loco-regional recurrence (including ipsilateral new breast cancer) or breast cancer death –~45% of first events were distant events –~18% of first events were locoregional BIG time to distant metastasis (TTM) –breast cancer recurrence (excluding local or regional recurrences, and contralateral breast cancer) –censoring for non-breast cancer deaths –~65% of first events* were distant events –~12% of first events* were local or regional ATAC Trialists’ Group. Lancet 2005; 365: Thürlimann B et al. The Breast 2005;14; S3. Abstract S4 *excluding second primary events

A T ATAC: disease-free survival (HR-positive population) p value HR 0.83 A vs T 95% CI (0.73, 0.94) At risk: Follow-up time (years) Anastrozole (A) Tamoxifen (T) Absolute difference: 1.6%2.6%2.5%3.3% Patients (%) CI, confidence interval Howell A. SABCS presentation 2004

L T At risk: Follow-up time (years) N=8010 Letrozole Tamoxifen p value HR 0.81 L vs T 95% CI (0.70, 0.93) BIG 1-98: disease-free survival Yearly DFS % L T Adapted from Thürlimann B. St Gallen presentation 2005

ATAC: recurrence (HR-positive population) A T Anastrozole (A) Tamoxifen (T) p value HR 0.74 A vs T 95% CI (0.64, 0.87) Follow-up time (years) At risk: Absolute difference: 1.7%2.4%2.8%3.7% Patients (%) ATAC Trialists’ Group. Lancet 2005;365:60-62

BIG 1-98: breast cancer relapse (Time to recurrence) Cumulative incidence Proportion failure (%) year difference (L-T) = -3.4  1.2% p= (based on CI) 6.2% 10.2% 8.1% 13.6% Letrozole (L) Tamoxifen (T) Years from randomisation Thürlimann B. St Gallen presentation 2005

A T ATAC: time to distant recurrence (HR-positive population) p value 0.06 HR 0.84 A vs T 95% CI (0.70, 1.00) Anastrozole (A) Tamoxifen (T) Follow-up time (years) At risk: Patients (%) Howell A. SABCS presentation 2004

A T ATAC: overall survival (HR-positive population) p value 0.7 HR 0.97 A vs T 95% CI (0.83, 1.14) Anastrozole (A) Tamoxifen (T) Follow-up time (years) At risk: Patients (%) Howell A. SABCS presentation 2004

Hazard ratio (A:T) and 95% CI Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer ATAC: efficacy summary (HR-positive population) Anastrozole (A) betterTamoxifen (T) better Hazard ratio ATAC Trialists’ Group. Lancet 2005;365:60-62

ATAC: efficacy analysis (ITT and HR +ve) HR (A:T) and 95% CI Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer ITT population HR +ve population Anastrozole (A) betterTamoxifen (T) better ATAC Trialists’ Group. Lancet 2005;365: ITTHR

Time to distant recurrence Time to recurrence BIG 1-98: efficacy summary Disease-free survival Systemic disease-free survival Disease-free survival (without 2nd primary) Hazard ratio (L:T) and 95% CI Letrozole (L) betterTamoxifen (T) better Overall survival Hazard ratio Adapted from Thürlimann B. St Gallen presentation BIG 1-98ATAC

BIG 1-98: sites of first failure Failures (DFS events) local contralateral breast regional* distant second (non-breast) malignancy death without recurrence Deaths Systemic failures** Letrozole (%)Tamoxifen (%)p value *Regional includes axilla or internal mammary **SDFS ignores local and contralateral events Thürlimann B. St Gallen presentation 2005

ATAC vs BIG 1-98 efficacy summary Anastrozole is more effective than tamoxifen in reducing the risk of recurrence, distant recurrence and contralateral breast cancer –absolute difference between anastrozole and tamoxifen continues to increase over time, and extends beyond completion of treatment Letrozole demonstrates DFS benefits and early benefits in distant recurrence –BIG 1-98 has a comparatively higher number of patients per arm, resulting in a higher number of events per unit time –patient population in BIG 1-98 has a slightly worse prognosis –Absolute differences at 5 years for BIG 1-98 data are projected out to 5 years and are calculated from immature data hence liable to change

Sub-group analysis

ATAC: time-to-recurrence by subgroup Intent-to-treat population Hazard ratio (A:T) and 95% CI Nodal status+ve -ve All patients Tumour size≤ 2 cm >2 cm Receptor status+ve -ve Previous chemotherapy yes no Anastrozole (A) betterTamoxifen (T) better Howell A. SABCS presentation 2004

Intent-to-treat population Hazard ratio (L:T) and 95% CI Nodal status+ve -ve All patients Previous chemotherapy yes no Letrozole (L) betterTamoxifen (T) better Previous radiotherapy yes no BIG 1-98: disease-free survival by subgroup Adapted from Thürlimann B. St Gallen presentation 2005

ATAC vs BIG 1-98 subgroup summary (1) Anastrozole demonstrated advantages over tamoxifen for all subgroups examined –no heterogeneity of subgroups –no significant interaction with any baseline prognostic factor, including prior chemotherapy or nodal status –more effective than tamoxifen in overall HR+ve group  even greater improvement in ER+PgR- subgroup Subgroup analyses must be interpreted with caution –should not be used as a basis for making clinical decisions

ATAC vs BIG 1-98 subgroup summary (2) Letrozole demonstrated benefits over tamoxifen –node positive patients  no apparent benefit in node negative patients –prior chemotherapy patients  slightly worse prognosis, more patients received prior chemotherapy (25% vs 20%) No apparent difference between ER+/PgR+ and ER+/PgR- subgroups for letrozole and tamoxifen –tamoxifen does not appear to be performing in line with expectations  previous studies demonstrate that ER+/PgR- patients on tamoxifen have a higher rate of recurrence than ER+/PgR+ Subgroup analyses must be interpreted with caution –should not be used as a basis for making clinical decisions

Tolerability analysis

BIG 1-98: safety analysis Included all patients that had received at least 1 treatment dose Protocol-specified only ‘targeted’ adverse event data was collected every 6 months Number of patients experiencing at least 1 serious adverse event: –587 vs 643 (letrozole vs tamoxifen)

ATAC: overview of adverse events* All adverse events Adverse events leading to withdrawal Drug-related adverse events leading to withdrawal All serious adverse events Serious adverse events leading to withdrawal Serious adverse events leading to death Drug-related serious adverse events leading to death p value Tamoxifen (%) (n=3094) Anastrozole (%) (n=3092) *Adverse events on treatment or within 14 days of discontinuation Howell A. SABCS presentation 2004

T A Completion analysis (%) p value < < Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer** Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures*** *Adverse events on treatment or within 14 days of discontinuation; **Excludes patients with prior hysterectomy and includes on- and off-therapy AEs; ***Fractures occurring at anytime prior to recurrence (includes patients no longer receiving treatment) ATAC: pre-defined adverse events* ATAC Trialists’ Group. Lancet 2005;365:60-62

T L Primary core analysis (%) Hot flushes Vaginal bleeding Night sweats Nausea Thromboembolic events Vomiting CVA/TIA Other cardiovascular Bone fracture Hypercholesterolemia BIG 1-98: targeted adverse events Adapted from Thürlimann B. St Gallen presentation 2005 No arthralgia/joint symptoms or osteoporosis data are available from BIG 1-98 Endometrial cancer shows no significant difference between L and T

ATAC vs BIG 1-98 : bone fractures Patients with bone fracture340 vs 237 (11.0% vs 7.7%) 1.49, p< ATAC (A vs T) BIG 1-98 (L vs T ) Patients 228 vs 162 (5.8% vs 4.1%) 1.44, p= Odds ratio, p value 2.2 vs 1.5 (per 100 patient years) 2.3 vs 1.6 (per 100 patient years) Bone fracture rate Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ; Thürlimann B. St Gallen presentation 2005

ATAC: fracture risk is predictable and manageable Years Arimidex Tamoxifen Number at risk Years since randomisation *Calculated using Kaplan-Meier estimates Annual rates, %* Anastrozole 1 mg od Tamoxifen 20 mg od 0 Howell A. SABCS presentation 2004

ATAC vs BIG 1-98 : endometrial cancer Patients with endometrial cancer 5 vs 17 (0.2% vs 0.8%) 0.29, p=0.02 ATAC (A vs T) BIG 1-98 (L vs T ) Patients 6 vs 15 (0.2% vs 0.4%) 0.40, p=0.078 Odds ratio, p value Adapted from ATAC Trialists’ Group. Lancet 2005;365:60-62 ; Thürlimann B. St Gallen presentation 2005

BIG 1-98: Grade 3-5 cardiovascular events CVA/TIA Thromboembolic Other cardiovascular 46 (1.2%) 30 (0.8%) 143 (3.6%) Letrozole (n=3965) Tamoxifen (n=3984) Patients 42 (1.1%) 79 (2.0%) 101 (2.5%) Thürlimann B. St Gallen presentation 2005 There is a significantly higher number of other cardiovascular events on letrozole compared with tamoxifen (p=0.006)

BIG 1-98: death without recurrence Cumulative incidence Years from randomisation 5-year difference (L-T) = 1.3  0.6% p=0.08 (based on CI) 1.4% 1.8% 0.8% 3.1% Proportion failure (%) 0 Letrozole (L) Tamoxifen (T) Thürlimann B. St Gallen presentation 2005

BIG 1-98: deaths without recurrence (non-breast cancer deaths) Total CVA thromboembolic cardiac other Overall p value based on cumulative incidence Letrozole (n=4003) Tamoxifen (n=4007) Patients Adapted from Thürlimann B. St Gallen presentation 2005 In ATAC, the numbers of cardiovascular deaths are comparable between anastrozole and tamoxifen (49 vs. 46, respectively)

ATAC: deaths Median follow-up 68 months All deaths non-breast cancer deaths cerebrovascular cardiac Anastrozole (n=3125) Tamoxifen (n=3116) Patients A detailed review found that the non-breast cancer deaths in the anastrozole arm were due to a variety of apparently unrelated causes, with no link to anastrozole ATAC Trialists’ Group. Lancet 2005 ;365:60-62 ATAC Trialists’ Group. Lancet 2005 In Press

Comparison of safety between ATAC and BIG 1-98 L NS    ?   ? A  NS   Endometrial cancer Risk of stroke Venous thromboembolic events Cardiovascular deaths Joint symptoms Fractures Hot flushes Vaginal bleeding Vaginal discharge Hysterectomy Compared with tamoxifen ? – not reported

ATAC: tolerability and safety summary vs tamoxifen Compared with tamoxifen, anastrozole is associated with significantly fewer: –SAEs, treatment-related AEs and withdrawals due to SAEs or AEs –potentially life-threatening AEs such as endometrial cancer, thromboembolic and cerebrovascular events No new safety concerns have emerged with long-term follow- up. There is no issue with cardiovascular safety Anastrozole now has a known, predictable and manageable safety profile The ATAC Trialists’ Group. Lancet 2005; 365: 60-62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 AEs = adverse events; SAEs = serious AEs Only anastrozole has a tolerability profile of this robustness and maturity, as it covers more than 5-years’ follow-up

BIG 1-98: tolerability and safety summary vs tamoxifen Serious safety concerns about letrozole have emerged in this first analysis –increased incidence of stroke and cardiovascular events –increase in number of cerebrovascular and cardiovascular deaths No significant reduction in the incidence of endometrial cancer was observed The long-term safety profile of letrozole is unknown at this stage –cardiovascular effects of letrozole require further evaluation BIG 1-98 has raised serious safety concerns for letrozole at this early stage

Summary

Conclusions (1) The ATAC completed treatment analysis extends and strengthens the evidence that 5 years of anastrozole is significantly more effective and better tolerated than 5 years of tamoxifen The efficacy benefit continues to increase with time and extends beyond the completion of therapy These data support using anastrozole as initial adjuvant therapy The higher rates of recurrence, adverse events, and withdrawals from treatment with tamoxifen and the substantial benefit of anastrozole over the first 3 years justify the approach of offering the most effective therapy at the earliest opportunity

Conclusions (2) BIG 1-98 provides further evidence that tamoxifen should no longer be the standard of care for EBC No overall efficacy benefits have emerged for letrozole in BIG 1-98 that have not already been demonstrated for anastrozole in the ATAC trial There appear to be marked differences emerging in the safety of the aromatase inhibitors in the adjuvant setting –women treated with letrozole have a greater risk of stroke and cardiac events The ATAC completed treatment analysis demonstrates that the overall benefit:risk profile remains clearly and consistently in favour of anastrozole Only anastrozole has established efficacy and safety with >5 years’ long-term follow-up data

Back-up slides

ATAC: patient characteristics Tamoxifen (n=3116) Anastrozole (n=3125) Mean age (years) Receptor status (%) positive negative unknown Primary treatment (%) mastectomy radiotherapy chemotherapy ATAC Trialists’ Group. Lancet 2002; 359:

BIG 1-98: patient characteristics Tamoxifen (n=4007) Letrozole (n=4003) Median age (years) Primary treatment (%) chemotherapy Surgery/RT group (%) BC with RT BC without RT mastectomy with RT mastectomy without RT BC = breast conservation; RT = radiotherapy Adapted from Thürlimann B. St Gallen presentation 2005

ATAC: baseline disease characteristics Primary tumour size (%) T1 (  2 cm) Nodal status (%) node-positive node-negative node-unknown HR status (%) ER+/PgR+ ER+/PgR- ER+/PgR unknown ER-/PgR Tamoxifen (n=3116) Anastrozole (n=3125) HR = hormone receptor; ER = oestrogen receptor; PgR = progesterone receptor ATAC Trialists’ Group. Lancet 2002; 359:

BIG 1-98: baseline disease characteristics Tumour size  2 cm (%) Nodal status (%) node-positive node-negative unknown HR status (%) ER+/PgR+ ER+/PgR- ER+/PgR unknown ER-/PgR Tamoxifen (n=4007) Letrozole (n=4003) Adapted from Thürlimann B. St Gallen presentation 2005

ATAC vs BIG 1-98 demographics Patients in the ATAC trial had an improved prognosis compared with patients in BIG 1-98 –fewer patients in ATAC had node positive disease –fewer patients in ATAC had received prior radiotherapy –fewer patients in ATAC had received prior chemotherapy

Definition of further ATAC endpoints Time to recurrence (TTR) –loco-regional recurrence (including ipsilateral new breast cancer) or new contralateral breast cancer –distant recurrence or death due to breast cancer Overall survival (OS) –death (for any reason) Time to breast cancer death (TTBCD) –any death following a loco-regional (including ipsilateral new breast cancer) or distant recurrence –breast cancer death

Definition of further BIG 1-98 endpoints Time to recurrence (TTR) –breast cancer recurrence or new contralateral breast cancer (excluding non-breast cancer second primaries*) –censoring for non-breast cancer deaths Overall survival (OS) –death (for any reason) DFS without second primary events –as DFS (excluding non-breast second primaries*) Systemic disease-free survival (SDFS) † –regional or distant recurrence (not including local and contralateral) –non-breast second primaries –non-breast cancer death Thürlimann B et al. The Breast 2005;14; S3. Abstract S4 *allows comparison with ATAC † no ATAC equivalent

ATAC: efficacy analysis (ITT and HR +ve) HR (A:T) and 95% CI Disease-free survival Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer ITT population HR +ve population Anastrozole (A) betterTamoxifen (T) better ATAC Trialists’ Group. Lancet 2005;365: ITTHR

ATAC: recurrence in ER+/PgR- patients At risk: A T Follow-up time (years) Anastrozole (A) Tamoxifen (T) Patients (%)

ATAC: recurrence in ER+/PgR+ patients Follow-up time (years) Anastrozole (A) Tamoxifen (T) Patients (%) At risk: A T

ATAC: retrospective analysis of HR subgroups Anastrozole was more effective than tamoxifen in the overall HR+ group The improvement with anastrozole in the ER+PgR+ subgroup was comparable to that for the HR+ group There was even greater improvement with anastrozole in the ER+PgR- subgroup The relative benefit for anastrozole over tamoxifen appears to be larger in patients with ER+PgR- tumours than in those with ER+PgR+ tumours, but prospective studies are needed to confirm this Patient group HR+ ER+/PgR+ ER+/PgR- Hazard ratio

BIG 1-98: DFS in ER/PgR* subgroups Hazard Ratio (A:T) and 95% CI ER+ PgR+ (n=5055) ER+ PgR- (n=1631) ER+ PgR unknown (n=1154) Letrozole betterTamoxifen (T) better *Based on local assessment Thürlimann B. St Gallen presentation 2005

Introduction to ‘best first’ The risk of recurrence is highest in the first five years after surgery, with a peak at 2 years Patients deserve to receive the best treatment first in order to reduce the risk of breast cancer recurrence

When to treat? Recurrence rates in early breast cancer are highest in the first 5 years after surgery, with a peak at 2 years, regardless of baseline prognostic factors Tamoxifen is associated with higher rates of recurrence, AEs and withdrawals than anastrozole Substantial benefit with anastrozole in the first 3 years justifies offering the most effective therapy at the earliest opportunity

Recurrence rate/year (%) Year Saphner et al JCO 1996; 14: Most recurrences occur within the first 5 years of primary therapy Need to give most effective treatment first to reduce risk of recurrence

Annual risk of recurrence: ECOG data Hazard of recurrence by yearly interval (%) Time (years) Total Positive nodes (0) Positive nodes (>4) Postmenopausal Premenopausal ER +ve ER -ve Tumour size (>3 cm) Tumour size (<1 cm) ECOG = Eastern Cooperative Oncology Group Saphner T et al. J Clin Oncol 1996;14:

Timing of recurrence in the first 10 years post-diagnosis Adapted from EBCTCG meta–analysis EBCTCG, Lancet 1998; 351; %61% Node +ve Node -ve 38% 0-5 years5-10 years 39% Proportion of recurrence (%)

ATAC: smoothed hazard rates for recurrence ( HR-positive population ) Follow-up time (years) Annual hazard rates (%) Anastrozole Tamoxifen

Patients deserve the best treatment first Recurrence rates in early breast cancer are highest in the first 5 years after surgery, with a peak at 2 years, for all patients (irrespective of risk) Anastrozole demonstrated substantial benefits over tamoxifen throughout the entire 5-year follow-up period in the ATAC trial, regardless of baseline prognostic factors –the peak of recurrences at years’ 1-3 is suppressed by anastrozole All patients deserve the best treatment available at the earliest opportunity in order to reduce the risk of recurrence