Transcript Slide 1

BIG 1-98/IBCSG 18-98
Henning Mouridsen
for the BIG 1-98 Collaborative Group
Authors: Sunil Verma
Date posted: December 22, 2008
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Background
• Previous reported data
– Primary Core Analysis (PCA)
• median follow up of 26 months
• Letrozole superior to Tamoxifen
– Statistically significant DFS and TTDR
– Monotherapy Arm Analysis
• Median follow up 51 months
• Letrozole superior to Tamoxifen
– Statistically significant improvement in DFS and TTDR
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Arm A: Tamoxifen x 5 years
R
Stratify
-Institution
-CT (Adj/NA)
prior
None
Concurrent
Arm B: Letrozole x 5 years
Arm C: Tamoxifen x 2 years followed by Letrozole
Arm D: Letrozole x 2 years followed by Tamoxifen
5 years of endocrine therapy
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BIG 1-98
Key Analysis
• Monotherapy update
– Median follow up 76 months
– Cross over effect
• 25.2% of patients randomized to Tam crossed over to
Letrozole once L>T results available in 2005
• Majority in year 3-5 with a median time on L of 18 months
• Sequential therapy vs. Letrozole
– Final efficacy analysis – October 2008 with a median
follow up of 71 months
– The trial was designed to show superiority of
sequential therapy over Letrozole
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BIG 1.98
Monotherapy Analysis
• n = 4,922 patients
• Two Analysis
– ITT
– Censoring at crossover
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BIG 1.98
Sequential vs. Letrozole
5 year DFS
L
L->T
T->L
87.9%
87.6%
86.2 %
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STUDY COMMENTARY
• This study results were much awaited to help determine the ideal
treatment strategy for HR positive post-menopausal women
• The results of the monotherapy arm are confounded by significant
cross over
• 25% of patients randomized to T crossed over to L
• No information was presented on which subjects crossed over
• One may hypothesize that those at higher risk or those
experiencing more toxicity on T were more likely to cross over
• The sequential arms were powered to look for superiority over L
monotherapy arm
• This is the final efficacy analysis
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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS
• Aromatase Inhibitors are superior to Tamoxifen
• This is the second key trial showing upfront AI use is superior to
Tamoxifen
• There is a trend towards improved survival seen with Letrozole
over Tamoxifen
• This may be confounded by significant cross over, however
the exact bias or effect may be difficult to elucidate
• The first two and half years are critical for disease recurrence
• An upfront therapy choice with an Aromatase Inhibitor may
therefore be optimal especially for those at high risk of recurrence
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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS
• There is a suggestion that Aromatase Inhibitor therapy may be
superior to the sequence of Tamoxifen to Aromatase Inhibitors
• This is the first trial to report a direct comparison between the two
strategies
• It is important to note that the trial was designed to show superiority of
sequence arm over Letrozole monotherapy, so all we can conclude is to
say that the sequence strategy is not superior to Letrozole monotherapy
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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS
• There is also a suggestion that patients receiving Letrozole for two
years and then switched over to Tamoxifen (reverse sequence arm)
did just as well as those receiving Letrozole monotherapy alone
- Again as this analysis was designed to
show superiority, a
lack of significant result
just means that the reverse
sequence arm
was not superior to Letrozole monotherapy
- Oncologists should be cautious to over interpret this result
as there may be a natural tendency to switch patients from
an Aromatase Inhibitor to Tamoxifen after two years or if they
develop toxicity
- We don’t have long term data on this
single arm of
an underpowered study
- Furthermore, we know that 5 years of an
AI is
associated with significant carry
over effect (ATAC
100), there is no such
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data for just two years of an
Aromatase
BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS
• Some important questions still remain to be answered
• Which is the most efficacious Aromatase Inhibitor?
• FACE and MA.27 trials should help address this
• What should be duration of endocrine therapy when using
an AI?
• What role does Tamoxifen play in the treatment of
postmenopausal HR positive breast cancer?
• Tamoxifen remains an effective drug but we need more
information on what population derives a benefit from
this drug
• Role of risk stratification
• Patient selection – prospective studies with
CYP2D6
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