Day 2 Welcome Back ! 8.30 BIG 1-98 Issues 8.45 BIG 1-98 Syndicate The Case for Switching ITA & ARNO/ABCSG The Switch Call Video Statistics for Non-Statisticians ATAC Syndicate 12.15Arimidex/Zoladex in pre-menopausal Extended Adjuvant Data 1.00Lunch 1.45Differentiation Summary 2.00Marketing Tools 2.20Regional Marketing Syndicate 3.00Quiz and Close

BIG 1-98 Issues

Syndicate You are letrozole Product Manager at Novartis and you are very proud of your company pension, car and business card. You are slightly less happy about the latest data from BIG You are also very aware of the concerns being expressed due to the safety profile. New legislation allows you to make a direct-to- customer or direct-to-doctor television advert. You can mention other brands, and you MUST mention the side effect profile of your own brand. In your teams, please make a 2 minute advert for letrozole to show to the group. Please be as creative as you can !

Expand the Brand

Positioning / Strategic Drivers Arimidex is the first choice endocrine therapy for post-menopausal women with breast cancer Establish Arimidex as the standard of care for early breast cancer Expand use of Arimidex across the early disease segments Achieve strong positioning and differentiation relative to the other AI’s in early breast cancer Leverage meaningful value propositions with key stakeholders

Life Cycle Claims 2005/2006 Extended Adjuvant Giving Arimidex to patients who have completed their 5 years of TMX significantly reduces their risk of recurrence 2006/2007 Premenopausal Arimidex/Zoladex combination is more effective then TMX and Zoladex in reducing BC recurrence in premenopausal women 2009 DCIS/Prevention Giving Arimidex to patients at risk from developing early breast cancer is more effective than giving tamoxifen or no treatment.

EXPAND ARIMIDEX – the SWITCH Opportunity Patients already on tamoxifen: –Optimise ARNO/ABCSG/ITA data and prepare for new extended adjuvant data (ABCSG 6a)

The Switch Opportunity Switch offers the best opportunity for a quick return …… but there are risks to increasing the focus on switching patients Establishing 5 years of Arimidex as the standard of care remains the priority

Living through the breast cancer experience - expand the brand Diagnosis Initial treatment Patients who have been on 2-3yrs of tam Patients who have been on 5 years of tam Remission Patients WANT to be on the best treatment Clinicians WANT to do the best for their patients A Key driver: Mobilise patients to demand Arimidex

Treatment options for patients who have ALREADY been started on tamoxifen AnastrozoleLetrozoleExemestane Switching from tamoxifen Efficacy vs tamoxifen Tolerability ? Key Issues: Fragmented message Sequencing confused with switch Differentiation vs exemestane

Switch Data ITA / ARNO/ABCSG

How do we position the switch data? Switch message applies to patients ALREADY on tamoxifen Key messages: We know from ATAC that tamoxifen is inferior to ‘Arimidex’ use the best drug as early as possible because women will have their risk of recurrence significantly reduced if they are switched to ‘Arimidex’ Need to target switch business effectively on customer-by-customer basis

Switch vs. sequence

Newly diagnosed patients Newly diagnosed Surgery Chemotherapy (if given) Radiotherapy Adjuvant hormonal therapy PROSPECTIVE DECISION 5 yrs’ initial adjuvant tamoxifen OR 5 yrs’ initial adjuvant ‘Arimidex’ OR START WITH 2-3 yrs’ adjuvant tamoxifen FOLLOWED BY 2-3 yrs’ adjuvant ‘Arimidex’ SEQUENCING ? There are NO DATA for a strategy of PROSPECTIVELY sequencing adjuvant endocrine therapies In newly diagnosed patients

Existing patients Already completed 2-3 yrs’ adjuvant tamoxifen Continue on adjuvant tamoxifen OR Clinician convinced by data Patient has suffered an AE Patient at increased risk of an AE Patient request Change to adjuvant ‘Arimidex’ SWITCH For switch we DO have the data: ABSCG/ARNO ITA IES EVIDENCE BASED MEDICINE Switch NOT sequence

Aromatase Inhibitors in the adjuvant setting – reported trials EBCTCG Lancet 1998; 351:1451–1467 * Denotes time frame when randomisation to an AI occurs ATAC and BIG 1-98 * Recurrence- free survival (%) Years MA.17 * IES and ITA ABCSG8/ARNO These trials differ, not only in their design, but also in the characteristics of the enrolled patients due to differences in the timing of randomization

Do not confuse switch with sequence! Switching trials only provide evidence on the outcome of replacing tamoxifen with an AI in patients who have already been receiving tamoxifen for 2–3 years They give no information on what happened on tamoxifen in the 2 yrs prior to randomization It is not appropriate to extrapolate results from these studies and plan to use a sequencing strategy for newly- diagnosed patients who have yet to start adjuvant therapy: –Switching trials do not study the newly-diagnosed patient population –Switching trials do not account for patients who do not complete 2–3 years of tamoxifen due to relapse or withdrawal

This is not the perception in clinical practice! Views of the Breast Cancer Summit Audience (based on key pad voting), Sitges % would proactively sequence (initiate tamoxifen with the intention of switching)

Smoothed hazard rates for recurrence (ITT* population) Follow-up time (years) Annual hazard rates (%) 0 Patients selected out during First 2-3 years Note excess recurrences on tamoxifen ‘Arimidex’ Tamoxifen This equates to ~ 60 more patients who recurred on tamoxifen in the first 2.5 years of the trial

Don’t wait to start ‘Arimidex’ ! 5 yrs initial tamoxifen 0 % of patients without an event 5 Y 2-3 Y Switch Starts Treatment Period 100% But look at the number of patients who will recur if started on tamoxifen first! 5 yrs initial ‘Arimidex’ 2-3 yrs tamoxifen  ‘Arimidex’ Switching is superior to continuing on tamoxifen

‘Arimidex’Tamoxifen Venous thromboembolic1833 Ischaemic cerebrovascular 816 Endometrial cancer04 Vaginal bleeding4275 Vaginal discharge27113 Hot flushes398 Predefined adverse events/1000 patients first 2.5 years 342 Musculoskeletal events Fractures Difference This equates to ~ 350 more predefined adverse events on tamoxifen in the first 2.5 years of the trial

Assumptions for modelling Recurrences on tamoxifen –2.5% per year for 5 years –2% per year for next 5 years Initial aromatase inhibitor use leads to 25% relative reduction Delayed aromatase inhibitor use leads to 40% relative reduction from time of use Relative benefits maintained out to 10 years

Time (years) 5 years tamoxifen 5 years AI Switch to AI at 2 years Extend with AI at 5 years It’s always better to start with an AI

Summary - Evidence based medicine ATAC provides the only mature data comparing an AI with tamoxifen as initial adjuvant endocrine treatment Based on the data from the ITA, ABCSG/ARNO, BIG and MA-17 studies, it is reasonable to consider switching patients currently on tamoxifen to an AI after 2-3 years, or extending therapy for a further 5 years There are no data for a strategy of prospectively sequencing adjuvant endocrine therapies in newly diagnosed patients. ATAC data indicate it is even better to start treatment with 'Arimidex' than start with tamoxifen with the intention of switching to an AI Specifically, the higher rates of recurrence, adverse events, and treatment withdrawals associated with tamoxifen, and the substantial benefit of 'Arimidex' in the first 3 years, justify the approach of offering the most effective therapy at the earliest opportunity

Adjuvant trial designs 05 Time (years) Tamoxifen Aromatase inhibitor Sequencing trial Tamoxifen Aromatase inhibitor Randomisation Extended adjuvant trial Aromatase inhibitor Placebo 5 years’ prior tamoxifen Randomisation 2-3 years’ prior tamoxifen Switching trial Tamoxifen Aromatase inhibitor Randomisation Initial adjuvant trial Tamoxifen Aromatase inhibitor Randomisation

Primary adjuvant Time to recurrence in AI trials (hazard ratios) ATAC BIG 1-98 ITA IES ABCSG8/ARNO MA 17 Extended adjuvant versus placebo 0.58 Switching

Cross comparison of hazard ratios Inappropriate to cross compare trials Cross-trial comparisons of relative HRs are NOT informative. They relate to different: –Trials and patient numbers –Patient populations –Stages of endocrine therapy treatment –Patient demographics and baseline characteristics The HRs in favour of an AI for the switching trials are so much better than in ATAC. It must therefore be better to start with tamoxifen and switch at a later date

Cross comparison of hazard ratios Selected population The populations in the switching trials are a highly selected population of “hormone responders” –Many non-responders have been selected out through early recurrences –These patients are least likely to respond to ANY hormonal manipulation and would likely be spread evenly across both arms –Without these patients, the benefits of one hormonal manipulation over another becomes more pronounced Tamoxifen resistance Continued tamoxifen results in increased risk of resistance over time Switching to an AI removes this risk in half the trial population The AI is now compared with years 3-5 of tamoxifen therapy, where the effects of tamoxifen resistance are likely to be most apparent

Summary – Overcoming issues Start is better than switch – best treatment first Don’t start to switch – switch only those patients ALREADY on tamoxifen DON’T use tamoxifen to prevent or treat: Bone/joint disorders Lipids/cardiovascular events Use ‘Arimidex’ to prevent: Breast cancer recurrence Life-threatening side effects

Expand the Brand Syndicate We will watch the experts at work ! Members of the global team will act out a ‘Switch’ Call. We would like you to offer a critique of the call including data used, techniques used, objections raised and handled how would you do it better

Statistics for Non-Statisticians ……

ATAC Syndicate We will divide into 2 groups. Group 1 – Using the ATAC data please describe how to the group which efficacy data you would present to a Tamoxifen die-hard to encourage then to use Arimidex first-line in EBC Group 2 – Please describe to the group how you would explain the tolerability profile of Arimidex to a tamoxifen die-hard.

Premenopausal Strategy Arimidex and Zoladex

Rationale for Zoladex + Arimidex

Tumour growth Pituitary gland Oestrogens Ovary Adrenal glands Androgens Aromatase enzyme

Pituitary gland Oestrogens Ovary Adrenal glands Androgens ARIMIDEX Tumour regression ZOLADEX

What do we know to date? We know that: Combining an LHRHa and tamoxifen confers better efficacy than either agent alone in premenopausal patients with advanced disease Arimidex offers superior efficacy to tamoxifen in postmenopausal patients with advanced disease Tamoxifen is no longer the standard of care in the adjuvant treatment of breast cancer in postmenopausal patients

So… If a younger woman is made effectively postmenopausal with an LHRHa Should we treat her as a postmenopausal woman? Can we achieve the benefit seen in ATAC?

Postmenopausal status Postmenopausal women do not have functioning ovaries Hospital reference intervals for oestradiol are: –Premenopausal levels: >200pmol/L –Postmenopausal levels : < 110pmol/L Postmenopausal status is NOT defined by age Forward et al 2004; BJC 90;

What data do we have? Advanced breast cancer Early breast cancer

Zoladex + tamoxifen Zoladex + Arimidex Zoladex plus Arimidex: trial design 16 premenopausal women Disease progression* *Advanced disease Forward et al 2004; BJC 90;

Oestradiol suppression with Zoladex + Arimidex Forward et al 2004; BJC 90; BaselineZoladex + tamoxifen Mean serum oestradiol (pmol/L) p< Zoladex + Arimidex p<0.0001

Zoladex + Arimidex: clinical effects Clinical result objective response / static disease at 6 months in 12 (75%) patients median duration of remission >17 months Forward DP et al. Br J Cancer 2004; 90: 590-4

When should Arimidex be started? Oestradiol (pg/ml) ‘Zoladex’ 3.6mg depot Time (weeks) (n=7) Addition of Arimidex once postmenopausal E2 levels reached Postmenopausal threshold

Further Data Adjuvant trials involving overian function suppression + AI –ABCSG12, PROMISE, SOFT, TEXT, PERCHE Additional data in 1 st line ABC Data to come at ASCO Cheung et al (abstract only) –1st line ABC –Zoladex + Arimidex  60% CB rate Steger et al (abstract only) –ABC 1st – 4th line –Zoladex + Faslodex  overall CB 45%

Why might this approach be acceptable? Medically logical We have some data Supports current clinical thinking –KOL endorsed –Ongoing adjuvant trials

Who else thinks this is a good idea? ‘Although limited, there are both endocrine and clinical data suggesting that AIs will be of value in premenopausal women being treated with OFS.’ ASCO Tech Assessment 2004 Recommendation for recurrent disease: ‘Ovarian ablation or suppression plus hormonal therapy as for postmenopausal women.’ NCCN Guidelines 2005

Focus Group Feedback – St Gallen Zoladex + Arimidex concept is broadly accepted –Tam may be oestrogenic in patients treated with Zoladex An AI may theoretically be superior –Some consideration of comparability of chemical vs natural menopause Do endocrine difference impact on tumour and/or response to an AI Very comfortable with idea of using combination in ABC –Provides further endocrine options and potential QoL benefits vs chemotherapy –Impact on disease control/life expectancy more important than potential concerns on side effects

Focus Group Feedback In EBC wanted data –Bone effects, CV risk –Perceived benefit in addition to chemotherapy –Cost –BUT some doctors already using in selected patients (e.g. ER+/Her2+; ER+/PgR-)

By 2007… in Europe premenopausal women with ER+ disease will be treated with ovarian suppression plus an aromatase inhibitor Craig Jordan, St Gallen 2005

Extended Adjuvant Data MA17