PRACTICE CHANGING BIG

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Pre-IMPAKT Training Course , May 6th 2009,
Brussels
PRACTICE CHANGING BIG CLINICAL TRIALS
Martine J. Piccart-Gebhart, MD, PhD Jules Bordet
Institute, Brussels, Belgium Université Libre de
Bruxelles EORTC, President Breast International
Group (BIG aisbl), Chair
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TAILORED / PERSONALIZED THERAPY

The right treatment for the right patient at
the right time
Increased quality-adjusted survival and cost
savings
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HERA study design
HER2-positive early breast cancer(IHC 3 and /
or FISH)n5102
Surgery (neo)adjuvant chemotherapy
radiotherapy
Herceptin q3w x 1 year
Herceptin q3w x 2 years
Observation
Option to cross over to Herceptin (after IA 2005)
IHC, immunohistochemistry FISH, fluorescence in
situ hybridisation
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Recruitment exceeding all expectations
registration of trastuzumab for early bc within
5 yrs of trial start
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BIG Record of Recruitment

• HERA trial (480 centers in 39 countries)
• Dec 01 to June 05 5,000 HER2 () patients
• Year 1 100 pts/mo.
• Year 2 3 175 pts/mo.
• Year 4 200 pts/mo
• ALTTO trial (1226 center in 43 countries)
• Adjuvant Lapatanib/Trastuzumab
• By Year 2 3 300 pts/mo
• June 07 to Feb 09 4400 patients

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Beginnings

• Reduce the wasteful duplication of effort /
  resources
• Respond to the exponential ? in new drugs

PAST PRESENT / FUTURE
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ADJUVANT USE OF TRASTUZUMAB (HERCEPTIN)
US 45,000 for one year treatment for one woman
BENEFIT
RISK
Risk of cardiac insufficiency (0.5 to 3.5)
 On average halving the risk of relapse  shown
by 5/6 clinical trials (N14.000 women)
but not all women derive benefit from
trastuzumab!
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THE CONTEXT OF TRASTUZUMAB RESISTANCE EARLY
DISEASE
HERA Trial
DFS ()
100
RESISTANT
80
EFFECTIVE
60
3-yearDFS
UNECESSARY
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Events
HR
95 CI
p value
218
0.63
0.53, 0.75
lt0.0001
80.6
20
316
74.0
0
0
Months from randomisation
No. at risk
1703
1591
1434
1127
742
383
140
1698
1533
1301
930
606
322
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Smith IE Lancet 2007
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SO FAR, MODEST SUCCESS RATES OF  TAILORED 
THERAPIES
The Economist, July 7th, 2007
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THE GREAT POTENTIAL OF THE  OMICS  ERA
TUMOR STROMA
Transcriptome microarray
CGH array
High-throughputtechnologies
Micro-RNA array
MultiplexRT-PCR
CIRCULATING TUMOR CELLS
Tissue-based expression array
si-RNA array
HOST DNA
Of Note Huge Bioinformatics / Statistical
Challenge!
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BIOLOGY-DRIVEN BIG / TRANSBIG TRIALS
QUESTION ASKED
1. MINDACT (BIG 3-04)
Who can be spared adjuvant chemotherapy ?
2. P53 (BIG 1-00)
Who benefits from a taxane ?
Can we improve upon trastuzumab?

• NeoAltto/Altto
• (BIG 1-06/BIG 2-06)

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TRANSBIG
microarray
Gene-expression profile
MINDACT - trial evaluating microarray
(Amsterdam 70-gene prognostic signature,
Mammaprint ) vs clinical testing to determine
chemotherapy or not after surgery for breast
cancer
Provide level 1 evidence for the utility of gene
signatures in daily clinical practice
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EORTC 10041 BIG 3-04 MINDACT Trial Design 6,000
Node - 1-3 N Women
Evaluate Clinical-Pathological risk and 70-gene
signature risk
55
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N780
N3300
Discordant cases
Clinical-pathological and 70-gene both LOW risk
Clinical-pathological and 70-gene both HIGH risk
Clin-Path HIGH 70-gene LOW
Clin-Path LOW 70-gene HIGH
R-T
N1920
Use Clin-Path risk to decide Chemo or not
Use 70-gene risk to decide Chemo or not
Chemotherapy
Endocrine therapy
Potential CT sparing in 10-15 pts
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LOGISTICS

• Strong inter-department collaboration
• Crucial role of research nurse
• Crucial role of NCC
• Investigators training meetings

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• BIG-TRANSBIG HQ Used with permission

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MINDACT CURRENT STATUS

• Enrolled 1087
• ER status positive 86
• negative 14
• HER2 status positive 13
• negative 83
• unknown 4

High risk by both methods
Discordant risk
Low risk by both methods
N 515 (47,4)
N 300 ( 28)
N 266 (24,5)
Predicted 50-60 !
Predicted 30
Predicted 10
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TAXANES AS ADJUVANT THERAPY
N 94,720
First generation of randomized trials
Second generation of randomized trials
Aimoptimizing their Administration N 48,763
Aimestablishing their role N 45,957
Increasing knowledge about Risk versus average
benefit
Lack of imagination in trial design
Minimal progress in understanding who benefits
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 p53 status and the efficacy of cancer therapy
in vivo  (Lowe et al Science 1994)

• Transplantable fibrosarcoma tumors in athymic
  nude mices
• Tumors primarily either Wt or Mut p53

Wt p53 (/)
Mut p53 (-/-)
T vol (cm3)
A
A
A
A

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Sensitivity of FWL (wt p53) and CA 46 (mut p53)
cells to radiation and Taxol
Fan et al Clin Cancer Res 1998
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EORTC 10994 - BIG 00-01 STUDY DESIGN
Large operable Locally adv./Infl.
1st sample standard fixation
Trucut biopsy
p53 in yeast
2nd sample snap frozen
Arrays
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EORTC 10994 BIG 00-01Statistical
HypothesisOutcome of taxane arm ? DFS by 20
in p53 tumors
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THE BIG 01-00/EORTC 10994 TRIAL RESULTS OF P53
TESTING
Bonnefoi et al SABCS 2008
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THE BIG 01-00/EORTC 10994 TRIAL RESULTS OF P53
TESTING
Bonnefoi et al SABCS 2008
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EORTC p53 translational research substudiesRNA
DNA (from ER negative samples)
DNA predictive signatures
Hybrid RNA/DNA predictive signatures
RNA predictive signatures

• Validation of 2 RNA
• in vitro signatures
• (Duke University)
• for the prediction of pcR
• to FEC
• to taxane/ET
• (PPV 70, NPV gt 90)
• accuracy 78

Work in progress
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NEOADJUVANT SETTING ATTRACTIVE MODEL FOR CLINICAL
/ TRANSLATIONAL RESEARCH
Preoperative therapy
Postoperative therapy
Diagnosis
Surgery
Biopsy Fine molecular characterization
Molecular imaging Blood
Intermediate By Early read-out of efficacy
Molecular imaging Blood
Pathology at Sx Mid-term read-out of efficacy
In vivo assessment of response !
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BREAST CANCER CLASSIFICATION USING GENE
EXPRESSION PROFILING
Basal-like
Luminal A
HER-2/ER-
Luminal B
Normal

• Breast cancer
• At least 4 distinct diseases!

Sorlie T et al, PNAS 2001
Courtesy of Lisa CAREY
M.J. Piccart
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THE BIG-TBCI COLLABORATION IN TAILORED CLINICAL
TRIALS
NEO-ALTTO ALTTO
n 8000 women
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NEO-ALTTO LAPATINIB RANDOMIZED PHASE III TRIAL
R ANDOMIZA T I O N
Trastuzumab x 34 weeks
Trastuzumab x 6 weeks
Trastuzumab paclitaxel x 12 weeks
S U R G ERY
HER2 3 Tumors gt 2 cm (N450)
Lapatinib x 34 weeks
Lapatinib paclitaxel x 12 weeks
Lapatinib x 6 weeks
Trastuzumab lapatinib x 34 weeks
Trastuzumab
Trastuzumab lapatinib
paclitaxel x 12 weeks
Lapatinib x 6 weeks
Translational research
pCR rate
Disease-free survival
Biopsy (Pet Scan)
Week 2 Biopsy (Pet Scan)
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THE ALTTO TRIAL
8000 women with HER2 positive breast cancer
Design 1 sequential administration
Design 2 concomitant administration
CHEMOTHERAPY
Trastuzumab combined with lapatinib
Trastuzumab x 1y
Lapatinib x 1y
Trastuzumab ? then lapatinib
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ALTTO TRIAL - PRE-DEFINED SUBGROUP ANALYSES
Molecular marker
Distribution
Hypothesis
c-Myc co-amplified30
Exquisitely sensitive to trastuzumab
c-Myc
Group where L benefits more likely(80 power for
any pair-wise comparison to detect DFS HR 0.754)
c-Myc not co-amplified70
Resistant to trastuzumab
Loss / reduced expression in 40
PTEN
Group where L benefits more likely(80 power for
any pair-wise comparison to detect DFS HR 0.72)
Resistant to trastuzumab
Group where L benefits more likely(80 power for
any pair-wise comparison to detect DFS HR 0.638)
p95HER2
Seen in 10
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MOVING FORWARD COUPLING BIOMARKER AND NEW
DRUG DEVELOPMENT
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BIG

• NEO-BIG
• A network of cancer centers of excellence aimed
  to be at the forefront of translational research
  in preoperative/neoadjuvant trials for breast
  cancer

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NEO-BIG years 2009-2014
Tailored neo-adjuvant trials involving targeted
drugs
Luminal non-A
Neoadjuvanttrial 1
SURGERY
Neoadjuvanttrial 2
Basal-like
HER2-positive
Neoadjuvanttrial 3
PIK3CA mutation
Neoadjuvanttrial 4
FGFR amplification
Neoadjuvanttrial 5
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CANCER CLINICAL TRIALS OF THE FUTURE
Clinical Cancer Research Networks EORTC BIG Others

• Basic Research Scientists
• Cancer centers
• Research centers

Governments Regulatory agencies

• Clinical Research Scientists
• Cancer centers

Pharma Industry
Transforming the dream of tailored cancer therapy
into reality