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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
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