‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis

     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 Randomization 1:1:1 for 5 years ‘Arimidex’ n=3125 Tamoxifen n=3116 Combination n=3125  Regular follow-up  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 Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm ATAC trial design

ATAC trial analysis history First analysis – Dec 2001 Median follow-up : 33 months 1 1. The ATAC Trialists’ Group. Lancet 2002; 359: 2131–2139 Updated analysis – November 2002 Median follow-up : 47 months 2 2. The ATAC Trialists’ Group. Cancer 2003; 98: 1802 – 1810 Treatment Completion analysis – November 2004 Median follow-up : 68 months Women years’ follow up: 49,941 Total events: The ATAC Trialists’ Group. Lancet 2005; 365: 60-62

ATAC completed treatment analysis Data cut off: 31st March 2004: –prospectively defined based on at least 704 deaths in the two monotherapy arms combined Follow-up: –68 months’ median follow-up – i.e. extends beyond completion of treatment –59 months’ median treatment duration –Only 8% of patients remain on treatment – the great majority of these nearing completion

Efficacy analysis

Disease-free survival Curves shown for HR+ patients *ITT = Intention-to-treat population; **HR+ = Hormone receptor-positive patients; # A vs T At risk: A T Absolute difference: 1.6%2.6%2.5%3.3% ‘Arimidex’ (A) Tamoxifen (T) Patients (%) Follow-up time (years) HR # HR+* 95% CI (0.73–0.94) ( ) p-value ITT** 17% RR

At risk: A T Absolute difference: 1.7%2.4%2.8%3.7% Patients (%) Time to Recurrence Curves shown for HR+ patients HR HR+ 95% CI (0.64–0.87) ( ) p-value ITT Follow-up time (years) ‘Arimidex’ (A) Tamoxifen (T) 26% RR

Smoothed hazard rates for recurrence ( HR+ population ) Follow-up time (years) Annual hazard rates (%) ‘Arimidex’ (A) Tamoxifen (T)

At risk: A T Patients (%) HR HR+ 95% CI (0.70–1.00) ( ) p-value ITT Time to Distant Recurrence Curves shown for HR+ patients ‘Arimidex’ (A) Tamoxifen (T)

Overall Survival* Curves shown for HR+ patients At risk: A T Follow-up time (years) * Includes non breast cancer deaths HR 0.97 HR+ 95% CI (0.83–1.14) ( ) p-value 0.7 ITT Patients (%) ‘Arimidex’ (A) Tamoxifen (T)

Time to Breast Cancer Death Curves shown for HR+ patients At risk: A T Follow-up time (years) HR HR+ 95% CI (0.70–1.09) ( ) p-value 0.2 ITT Patients (%) ‘Arimidex’ (A) Tamoxifen (T)

Incidence of new (contralateral) breast primaries in HR+ population Tamoxifen (T) (n=2598) ‘Arimidex’ (A) (n=2618) 26 HR95% CIp-value A vs T 0.47(0.29–0.75)0.001 Number of cases

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 ITT population HR+ population *ITT= intent-to-treat *HR+=hormone receptor-positive Efficacy analysis – ITT and HR+ populations ‘Arimidex’ (A) betterTamoxifen (T) better

*Confidence limit extends beyond plot Analysis of time to recurrence for subgroups of the ITT* population Hazard ratio (A:T) and 95% CI Nodal status+ve -ve unknown All patients Tumour size≤ 2 cm >2 cm unknown* Receptor status+ve -ve unknown Previous chemotherapy yes no ‘Arimidex’ betterTamoxifen better

Summary of efficacy endpoints In the HR+ population, compared with tamoxifen, ‘Arimidex’ reduces the risk of : –all events: 17% (p=0.005) –recurrence: 26% (p=0.0002) –distant recurrence: 16% (p=0.06) –contralateral recurrence: 53% (p=0.001) There is also a (non-significant trend for a reduction in breast cancer mortality: 13% (p=0.2)

‘Arimidex’ demonstrates superior efficacy to tamoxifen ‘Arimidex’ is more effective than tamoxifen in reducing the risk of recurrence, distant recurrence and contralateral breast cancer The absolute difference between ‘Arimidex’ and tamoxifen continues to increase over time, and extends beyond completion of treatment As expected, overall survival is similar for both treatments, i.e. ‘Arimidex’ maintains the significant survival benefit already established for tamoxifen, with a trend in favour of ‘Arimidex’ for breast cancer death There are no significant subgroup interactions

Added benefit versus tamoxifen HR+ve population Reduction in risk of recurrence Reduction in risk of breast cancer mortality Reduction in risk of contralateral breast cancer EBCTCG Benefit for tamoxifen vs placebo 50% 28% 47%* ATAC Additional benefit of ‘Arimidex’ vs tamoxifen 26% 13% 53% *hormone receptor-positive and -negative patients EBCTCG = Early Breast Cancer Trialists’ Collaborative Group

Added benefit versus tamoxifen 38% risk of recurrence with no adjuvant treatment 50% risk reduction with tamoxifen Further 26% risk reduction with ‘Arimidex’

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 ‘Arimidex’ Substantial benefit with ‘Arimidex’ in the first 3 years justifies offering the most effective therapy at the earliest opportunity Best treatment first !

Annual hazard of recurrence peaks at 2 years regardless of baseline prognostic factors Adapted from Saphner et al, 1996 Need to give most effective treatment first to reduce risk of recurrence

Tolerability analysis

Overview of 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) 'Arimidex' (%) (n=3092) *Adverse events on treatment or within 14 days of discontinuation

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) Pre-defined adverse events*

Tolerability summary Compared with tamoxifen, 'Arimidex' is associated with significantly fewer: –SAEs, treatment-related AEs and withdrawals –potentially life threatening AEs such as endometrial cancer, thromboembolic, and cerebrovasular events No new safety concerns with long-term follow-up Only 'Arimidex' has a tolerability profile this robust and mature, covering the full 5 year treatment period 'Arimidex' now has a known, predictable and manageable safety profile Tolerability profile not only different but SUPERIOR

Summary

ATAC summary ATAC Completed Treatment Analysis extends and strengthens the evidence that 5 years of 'Arimidex' is significantly more effective and better tolerated than 5 years of tamoxifen Overall risk:benefit profile remains clearly in favour of 'Arimidex' The absolute benefits for 'Arimidex' over and above those of tamoxifen continue to increase with time and extend beyond the completion of therapy

ATAC in context 'Arimidex' is a more effective and better-tolerated adjuvant treatment than tamoxifen These findings provide a basis for establishing 'Arimidex' as the standard of care for the initial 5 years’ adjuvant treatment of postmenopausal women with hormone receptor-sensitive early breast cancer Howell, SABCS 2004

Big News ! UK Headlines 08 Dec 2004 Daily Mail Evening Standard Daily Mirror Independen t The Times

Big News ! UK Headlines 08 Dec 2004

Most successful international media campaign of all time….. ….. probably!

Most successful international media campaign of all time….. probably! To date over 800 articles have been printed in 24 markets …. ….. creating 260 million opportunities to see Over 60% contain > 1 of our key media messages regarding the role of 'Arimidex' in the adjuvant treatment of early breast cancer (as written by AZ) 83% contain a quote from an independent global and national key opinion leader as sourced by AstraZeneca Consumer key messages appeared in print and broadcast media directly as written in our own AZ press releases

How can we use these data in practice ?

Lancet publication

New Look Promotional Guide! Interactive CD Rom (Printer friendly Version also available)

Who are our Customers? Promotional Guide needs to meet the needs of the customer! Product Managers Nominated Signatories Marketing Companies INTERNAL Medical Community EXTERNAL End consumer (patient ) } Media

Promotional Guide to Suit the Customer How can we say it and to whom? Preferred Key Claims (medical & consumer) Are there any alternative ways to say it? Additional Claims (medical & consumer) What’s in it for the customer? Benefit Statements What’s the evidence for this? Supporting Data What do the experts say? Key Quotes How do the pieces fit together? Recommended Story Flow What do we need to say? Communication Objectives

Sales Story Flow Mature data from ATAC conclude that ‘Arimidex’ is the new standard of care for the primary adjuvant treatment of postmenopausal women with hormone-sensitive early breast cancer The primary goal in the adjuvant treatment of early breast cancer is to prevent disease recurrence with the aim of achieving a cure Need to use the most effective treatment first, as the risk of recurrence in early breast cancer is highest in the first 5 years, irrespective of baseline prognostic factors

Sales Story Flow ‘Arimidex’ has consistently demonstrated significant efficacy benefits over tamoxifen, reducing the risk of:  Recurrence  Contralateral breast cancer  Distant recurrence ‘Arimidex’ is significantly better tolerated than tamoxifen with mature, robust data supported by 68 months follow- up Due to pharmacological differences between AIs, the evidence from ATAC applies only to ‘Arimidex’

Any questions ?

Back-up slides

Definition of endpoints (1) Disease-free survival (DFS) –loco-regional recurrence (inc. ipsilateral new breast cancer) or new contralateral breast cancer –distant recurrence or death (for any reason) Time to recurrence (TTR) –loco-regional recurrence (inc. ipsilateral new breast cancer) or new contralateral breast cancer –distant recurrence or death due to breast cancer

Definition of endpoints (2) Overall survival (OS) –death (for any reason) Time to distant recurrence (TTDR) –distant recurrence or any death following a loco- regional recurrence (inc. ipsilateral new breast cancer) –breast cancer death Time to breast cancer death (TTBCD) –any death following a loco-regional (inc. ipsilateral new breast cancer) or distant recurrence –breast cancer death

ATAC: patient characteristics Tamoxifen (n=3116) 'Arimidex' (n=3125) Mean age (years) Mean weight (kg) Receptor status (%) positive negative unknown Primary treatment (%) mastectomy axillary surgery radiotherapy chemotherapy prior tamoxifen

ATAC: baseline disease characteristics Primary tumour size (%) T1 (  2 cm) T2 (  2 cm to  5 cm) T3 (  5 cm) Nodal status (%) node-positive Grading (%) well differentiated moderately differentiated poorly / undifferentiated not assessed / recorded Tamoxifen (n=3116) 'Arimidex' (n=3125)