Day 2 Welcome Back !

8.30 BIG 1-98 Issues8.45 BIG 1-98 Syndicate10.00 The Case for Switching

ITA & ARNO/ABCSG10.30 The Switch Call Video11.00 Statistics for Non-Statisticians11.15 ATAC Syndicate12.15 Arimidex/Zoladex in pre-menopausal12.30 Extended Adjuvant Data1.00 Lunch1.45 Differentiation Summary2.00 Marketing Tools2.20 Regional Marketing Syndicate3.00 Quiz 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 slightlyless happy about the latest data from BIG 1-98.You are also very aware of the concernsbeing 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 ownbrand.

In your teams, please make a 2 minute advertfor 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

DiagnosisInitial

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

Switch DataITA / 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

PROSPECTIVEDECISION

5 yrs’ initial adjuvant tamoxifen

OR

5 yrs’ initial adjuvant ‘Arimidex’

OR

START WITH 2-3 yrs’ adjuvant

tamoxifen

FOLLOWED BY2-3 yrs’ adjuvant

‘Arimidex’

SEQUENCINGSEQUENCING?

There are NO DATA for a strategy of PROSPECTIVELY sequencing

adjuvant endocrine therapies In newly diagnosed patients

Existing patients

Already completed2-3 yrs’ adjuvant

tamoxifen

Continue onadjuvant

tamoxifen

OR

Clinician convinced by data

Patient has suffered an AE

Patient at increased risk of an AE

Patient request

Change toadjuvant

‘Arimidex’

SWITCHSWITCH

For switch we DO have the data:

ABSCG/ARNOITAIES

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

*

60

70

80

90

100

0 5 10

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 2005

17

42

41 Undecided

Best First

Sequencing

• 41% would proactively sequence (initiate tamoxifen with the intention of switching)

Smoothed hazard rates for recurrence (ITT* population)

0.5

1.0

1.5

2.0

2.5

3.03.0

0 1 2 3 4 5 6Follow-up time (years)

Annualhazardrates(%)

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

% o

f p

atie

nts

wit

ho

ut

an e

ven

t

5 Y2-3 YSwitch 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 thromboembolic 18 33

Ischaemic cerebrovascular 8 16

Endometrial cancer 0 4

Vaginal bleeding 42 75

Vaginal discharge 27 113

Hot flushes 398

Predefined adverse events/1000 patients first 2.5 years

342

Musculoskeletal events 265 195

Fractures 3254

Difference

15

8

4

86

56

7022

202

92

33

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 

0

.05

.1

.15

.2

.25

0 2 4 6 8 10

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 97-02 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

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 thecall including

data used, techniques used, objections raised and handledhow 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-hardto encourage then to use Arimidex first-linein EBCGroup 2 – Please describe to the group howyou would explain the tolerability profile of Arimidexto a tamoxifen die-hard.

PremenopausalStrategy

Arimidex and Zoladex

Rationale for Zoladex + Arimidex

Tumour growth

Pituitary gland

OestrogensOvary

Adrenalglands

Androgens

Aromatase enzyme

Pituitary gland

OestrogensOvary

Adrenalglands

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; 590-594

What data do we have?

Advanced breast cancerEarly breast cancer

Zoladex + tamoxifen

Zoladex + Arimidex

Zoladex plus Arimidex: trial design

• 16 premenopausal women

Disease progression*

*Advanced disease

Forward et al 2004; BJC 90; 590-594

Oestradiol suppression with Zoladex + Arimidex

Forward et al 2004; BJC 90; 590-594

0

50

100

150

200

250

Baseline Zoladex +tamoxifen

Me

an

se

rum

oe

stra

dio

l (p

mo

l/L)

p<0.0001

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? O

estr

adio

l (p

g/m

l)O

estr

adio

l (p

g/m

l)

‘‘Zoladex’ 3.6mg depotZoladex’ 3.6mg depot

11 22 33 44 55 66

300300

250250

200200

150150

100100

5050

00

00 11 22 33 44 55 66 77 88 1212 1616 2020

Time (weeks)Time (weeks)

((nn=7)=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 1st 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 DataMA17