l’imagerie médicale à l’institut gustave roussy · bresson, vladimir lazar. gustave roussy...
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WINTHER Study
Jean-Charles Soria,
Razelle Kurzrock, Josep
Tabernero, Apostolia
Tsimberidou, Jordi Rodon,
Raanan Berger, Amir Onn,
Gerald Batist, Eitan Rubin,
Yohann Loriot, Catherine
Bresson, Vladimir Lazar
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WINTHER:
A study to select rational therapeutics
based on the analysis of tumor and
matched normal tissue biopsies in
subjects with advanced malignancies
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Position of the problem
and clinical challenges
to be addressed
Tumor Biopsy
Match with
targeted therapies
Personalized
Medicine
Today
Relevant DNA
structural
changes
30 to 40% of pts Standard
Protocols
DNA
investigations
Standard
Pathology
How can we improve
cancer care
for 60 to 70% of pts ?
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State of the Art
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State of the Art Patient with metastatic cancer
TUMOR BIOPSY
MOLECULAR PROFILING
Histology Control
CGH
% of cancer
cells
Mutational aberrations
TREATMENT BASED ON DNA BIOLOGICAL INVESTIGATIONS OF THE TUMOR
Deep sequencing
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WINTHER
concept
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Patient with metastatic cancer
TUMOR BIOPSY
MOLECULAR PROFILING
Histology Control
CGH Transcriptomic
Aberrations
% of cancer
and normal
cells
Mutational aberrations
& MATCHED NORMAL TISSUE BIOPSY
WINTHER concept
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Patient with metastatic cancer
TUMOR BIOPSY
MOLECULAR PROFILING
Histology Control
CGH Transcriptomic
Aberrations
% of cancer
and normal
cells
Mutational aberrations
& MATCHED NORMAL TISSUE BIOPSY
WINTHER concept
1. Novelty: use of matched normal
and tumoral biopsies from strictly
the same patient.
2. Goal is to assess the
genetic distance between
tumor and normal by profiling
of mRNAs
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2
Individual
Drug efficacy
Scoring
Statement
Doctor’s
decision
3. Genetic distance converted into
drugs scoring
Computational
tools – Algorithm
and genes_drugs
database
WINTHER concept
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2
Individual
Drug efficacy
Scoring
Statement
Doctor’s
decision
3. Genetic distance converted into
drugs scoring
Computational
tools – Algorithm
and genes_drugs
database
WINTHER concept
RATIONAL TREATMENT BASED ON HOLISTIC BIOLOGICAL INVESTIGATIONS
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Example of WINTHER predictive scoring , that ranks drugs depending on
estimated efficacy
4
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WINTHER Study
Main components
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WINTHER Participants
Gustave Roussy [France]
Jean-Charles Soria, Coordinating PI
MD Anderson Cancer Center [USA]
Lia Tsimberidou, PI
VHIO [Spain]
Jordi Rodon, PI
Chaim Sheba Medical Center [Israel]
Rannan Berger, PI
McGill Segal Cancer Center [Canada]
Wilson Miller
UCSD Moores Cancer Center [USA]
Razelle Kurzrock
Cancer Centers Technology Partners
Foundation Medicine
Gary Palmer
NGS
Ben Gurion University
Eitan Rubin
WINTHER Data Analysis
Agilent Technologies
V Lazar
Gene Expression, miRNA
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Actionable DNA aberrations
Est. 30-40% of patients
NO Actionable DNA aberration
Est. 60-70% of patients
Enroll 200 patients with metastatic cancer
Tumor and matched normal tissue biopsies from each patient
Histology Control
Next Generation Sequencing
(mutational and CNV aberrations)
WINTHER ARM A:
Patient matched with
existing targeted
therapies or included in
Phase 1 trials
WINTHER ARM B:
Choice of therapy guided by WINTHER
drug efficacy predictive scoring derived
from
tumor vs. normal RNA investigations
Recruitment goals
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Estimated repartition of patients
200 patients
Arm A :
80 patients
Labeled Targeted Therapies:
20 patients
Targeted Therapies in Clinical Trials:
60 patients
Arm B :
120 patients
Standard of care:
20 patients
Off label drugs (non clinical
trials):
100 patients
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WINTHER study main objectives
Better identification of
actionable DNA
aberrations in patients
(today limited to 30%),
by using NGS
PFS2/PFS1 > 1.5 in 50%
of patients
WINTHER ARM B:
Offer a solution guided by each
patient’s individual biology to the
vast majority of patients without
actionable DNA aberrations
Prove the efficacy of using
alternative investigations based on
functional genomics of the RNA on
a dual biopsy of tumor and
matched normal tissue to identify
relevant aberrations in patients
PFS2/PFS1 > 1.5 in 40% of patients
WINTHER Arm A:
RATIONAL TREATMENT BASED ON HOLISTIC BIOLOGICAL INVESTIGATIONS
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Statistical design of the study
Objective of WINTHER:
achieve 1.5 ratio in 50% of patients in arm A
achieve 1.5 ratio in 40% of patients in arm B
30 % being the average oncologist threshold
PFS 1 PFS 2
PFS1
PFS 2 > 1,5 Relevant Molecular Targeted Agent
(WINTHER) Standard Therapy
Tumor
Progression
Tumor
Progression
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MOLECULAR SCREENING
NGS-CNV-CGH-gene expression
CLINICAL
DECISION
Max 6 working weeks
FRESH TUMOR
BIOPSY PATHOLOGICAL
CONTROL
TREATMENT
• Multi-disciplinary trial
WINTHER Workflow
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WINTHER Study
Initial achievments
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Recruitment
Rapid Accrual
Currently 2-3 pts / week
July April June May
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WINTHER
From April 16 to July 2, 2013
32
Consents
5 Screening
Fails
1 pt included in another therapeutic
clinical study
1 pt with rapid worsening condition
1 pt withdraw consent
2 pts with normal tissue not
obtainable
8 biopsies yet to
be performed
19 Biopsies
3 biopsies July 2, 2013
9 Analyzed
7 Logistical Failures
1 inappropiate choice of normal
tissue
6 Tumor tissues < 60% of T cells
IGR-1011 Breast cancer
IGR-1012 Oral squamous cell carcinoma
IGR-1013 Colon cancer
IGR-1016 Lung ADK
IGR-1019 Kidney cancer
IGR-1027 Oral squamous cell carcinoma
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Patients characteristics
0
1
2
3
4
5
6
7
8
head andneck
breast lung sarcoma kidney colon/rectum
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0%
10%
30%
50%
100%
70%
90%
80%
20%
60%
40%
Not reliable
NGS + CGH
Pe
rcen
tage o
f C
ells
WINTHER
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WINTHER
9 sent
DNA structural alterations
N=5
Transcriptomic
alterations
N=3
8 reports
ARM A ARM B
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Target characteristics
DNA alterations
0
1
2
3
4
5
6
Mutation
Deletion
Amplification
Gene fusion
0
1
2
MET VEGFA HER3
Transcriptome-based targets
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WINTHER
9 sent
DNA structural alterations
N=5 transcriptomic alterations
N=3
8 reports
ARM A ARM B
HER2 amp Still on 1st line chemo
FGFR1 amp Included in EOS-3810 study
MET amp On screening (MET inhibitor)
TSC1 mut On everolimus therapy
RET gene fus On sorafenib therapy
Target MET
Target VEGF-A
Target HER-3
On screening
On screening
Still on treatment
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IGR-1004 Head & Neck SCC FM: MDM2 ampl, P53 mut BGU: MET
ARM B 1/ SAR125844 (Met inhibitor)
2/ cabozantinib
IGR-1007 Lung ADK FM: KRAS G12D BGU: HER3, HER2
ARM B 1/ MM-141 phase I
2/ capecitabine + trastuzumab
IGR-1006 uterine Leiomyosarcoma FM: TSC1 mut
ARM A: Everolimus
IGR-1010 Lung Carcinosarcoma FM: RET transl, MYC ampl
ARM A 1/ sorafenib
2/ switch to another RET TKI with better IC50
TC 20130625
IGR-1004
IGR-1007
IGR-1006
IGR-1010
WINTHER - Pr SORIA
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IGR-1005 Lung ADK FM: EGFR and MET amp ARM A: SAR-MET trial
IGR-1014 Kidney cancer FM: VHL mut BGU: VEGFA ARM B: bevacizumab
IGR-1001 Breast carcinoma FM: FGFR1 ampl, FGF3 ampl, FGF4ampl ARM A: lucitanib phase I
IGR-1002 Head & Neck SCC FM: HER2 and EGFR ampl ARM A: Paclitaxel + Trastuzumab
TC 20130521
TC 20130702
IGR-1001
IGR-1002
IGR-1005
IGR-1014
WINTHER - Pr SORIA
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Summary: Why is WINTHER different?
• Includes all patients, with or without actionable genetic aberrations
• Investigates both DNA and RNA
• Includes a variety of different technologies: Next Generation Sequencing,
Copy Number Variations, gene expression, Comparative Genomic
Hybridization
• Based on a dual biopsy of tumor and matched normal tissue of same
histology, which enables:
• Evaluating the genetic distance between tumor and normal
• Disregarding variability factors between individuals
• Limiting the number of irrelevant aberrations and noise
• Increasing the statistical factor of the study by 16
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Thank you Gustave Roussy:
- Fabienne Dufour, Maud Ngo Camus
- Aurélie Abou Lauverne
- Catherine Richon
- Nathalie Auger, Valerie Kouby, Ludovic Lacroix
- Philippe Vielh
- Thierry De Baere
- Gilles Vassal