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

‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis. Surgery  radiotherapy  chemotherapy. Tamoxifen n=3116. ‘Arimidex’ n=3125. Combination n=3125. ATAC trial design. 9366 Postmenopausal women with invasive breast cancer

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

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

  2. Surgery  radiotherapy  chemotherapy Tamoxifen n=3116 ‘Arimidex’ n=3125 Combination n=3125 ATAC trial design 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 â â Randomization 1:1:1 for 5 years å æ â Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm â Regular follow-up â • Secondary trial endpoints: • Incidence of contralateral breast cancer • Time to distant recurrence • Overall survival • Time to breast cancer death • Primary trial endpoints: • Disease-free survival • Safety / tolerability

  3. First analysis – Dec 2001 Median follow-up : 33 months1 Updated analysis – November 2002 Median follow-up : 47 months2 Treatment Completion analysis – November 2004 Median follow-up : 68 monthsWomen years’ follow up: 49,941Total events: 1867 1. The ATAC Trialists’ Group. Lancet 2002; 359: 2131–2139 2. The ATAC Trialists’ Group. Cancer 2003; 98: 1802 – 1810 3. The ATAC Trialists’ Group. Lancet 2005; 365: 60-62 ATAC trial analysis history

  4. 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

  5. Efficacy analysis

  6. At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 Disease-free survivalCurves shown for HR+ patients 17% RR HR# 0.83 0.87 95% CI (0.73–0.94) (0.78-0.97) p-value 0.005 0.01 25 HR+* 20 ITT** 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 Absolute difference: 1.6% 2.6% 2.5% 3.3% 0 0 1 2 3 4 5 6 Follow-up time (years) *ITT = Intention-to-treat population; **HR+ = Hormone receptor-positive patients; #A vs T

  7. HR 0.74 0.79 95% CI (0.64–0.87) (0.79-0.90) p-value 0.0002 0.0005 HR+ ITT A 2618 2540 2448 2355 2268 2014 830 Time to RecurrenceCurves shown for HR+ patients 26% RR 25 20 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 Absolute difference: 1.7% 2.4% 2.8% 3.7% 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: T 2598 2516 2398 2304 2189 1932 774

  8. 3.0 2.5 2.0 1.5 1.0 0.5 0 Smoothed hazard rates for recurrence (HR+ population) Annualhazardrates(%) ‘Arimidex’ (A) Tamoxifen (T) 0 1 2 3 4 5 6 Follow-up time (years)

  9. ‘Arimidex’ (A) Tamoxifen (T) A 2618 2550 2464 2386 2309 2051 845 Time to Distant RecurrenceCurves shown for HR+ patients 25 HR 0.84 0.87 95% CI (0.70–1.00) (0.74-0.99) p-value 0.06 0.04 HR+ 20 ITT 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 At risk: T 2598 2533 2438 2361 2257 2005 816

  10. T 2598 2549 2502 2430 2333 2080 855 Overall Survival* Curves shown for HR+ patients HR 0.97 0.97 95% CI (0.83–1.14) (0.85-1.12) p-value 0.7 0.7 25 HR+ 20 ITT 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2566 2505 2437 2377 2117 867 * Includes non breast cancer deaths

  11. A 2618 2566 2505 2437 2377 2117 867 Time to Breast Cancer DeathCurves shown for HR+ patients HR 0.87 0.88 95% CI (0.70–1.09) (0.74-1.05) p-value 0.2 0.2 25 HR+ 20 ITT 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: T 2598 2549 2502 2430 2333 2080 855

  12. Incidence of new (contralateral) breast primaries in HR+ population HR 95% CI p-value A vs T 0.47 (0.29–0.75) 0.001 Number of cases 60 54 50 40 30 26 20 10 0 ‘Arimidex’ (A) (n=2618) Tamoxifen (T) (n=2598)

  13. Efficacy analysis – ITT and HR+ populations ITT population Disease-free survival HR+ population Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer 0.2 0.4 0.6 0.8 1.0 1.2 2.0 1.5 Hazard Ratio (A:T) and 95% CI ‘Arimidex’ (A) better Tamoxifen (T) better *ITT= intent-to-treat *HR+=hormone receptor-positive

  14. Nodal status +ve -ve unknown Tumour size ≤2 cm >2 cm unknown* Receptor status +ve -ve unknown Previous chemotherapy yes no 0.60 ‘Arimidex’ better Tamoxifen better Analysis of time to recurrence for subgroups of the ITT* population All patients 0.40 0.80 1.00 1.25 1.50 1.75 Hazard ratio (A:T) and 95% CI *Confidence limit extends beyond plot

  15. 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)

  16. ‘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

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

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

  19. 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 !

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

  21. Tolerability analysis

  22. 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 'Arimidex' (%)(n=3092) 11.1 6.5 33.3 4.7 3.3 0.2 Tamoxifen (%)(n=3094) 14.3 8.9 36.0 5.9 3.6 0.3 p-value 0.0002 0.0005 0.03 0.04 0.6 0.5 *Adverse events on treatment or within 14 days of discontinuation

  23. p-value <0.0001 <0.0001 <0.0001 0.02 0.03 0.0004 0.02 <0.0001 <0.0001 Pre-defined adverse events* Completion analysis A 35.7 5.4 3.5 0.2 2.0 2.8 1.6 35.6 11.0 T 40.9 10.2 13.2 0.8 2.8 4.5 2.4 29.4 7.7 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)

  24. 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

  25. Summary

  26. 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

  27. 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

  28. Daily Mail Evening Standard Daily Mirror Independent Daily Mirror The Times Big News !UK Headlines 08 Dec 2004

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