20 3 14
Avancées et nouveaux paradigmes en recherche
clinique
JY Blay Lyon,
LYRIC INCa 4664, NetSARC, RREPS Eurosarc FP7 278742
French Sarcoma Group EORTC
Which subset? Which target? Which agents?
Towards a major fragmentation of nosological entities
Damien Hirst « 1-bromoadamantane » « Acivicin » « Arginosuccinic acid »
Empirism in drug development “Old school”1950-2010
1 2 3 4 5 6 7 8 9…
A
B
C
D
E
F
G
H…
Tumors
-------------------Drugs-----------------------
Novel strategies in drug development 2010’+
1 2 3 4 5 6 7 8 9…
A X X X X X X X X X
B X X X X X X X X
C X X X X X X X X
D X X X X X X X X X
E X X X X X X X X
F X X X X X X X X X
G X X X X X X X X X
H… X X X X X X X X
X
X
Are we running at the same speed?
• Gene expression profile Mindact EORTC 10041
Which subset? Which target? Which agents?
New molecular trials
Clinical Research
Translational research
Basic research
Three situations • Initial molecular event
– KIT in GIST – Loss NF1, TSC – Translocations – Mdm2 amplification – …
• Secondary event – VEGF production – Activation of mTOR pathway – ER expression in ESS
• Simple bystander – PDGFR expression in normal (and malignant) cells of connective
tissue
Heinrich et al. Hum Pathol. 2002;33:484; Science 2003,
Corless et al. Proc AACR. 2003
KIT and PDGFRα are mutated in GIST
Membrane
Cytoplasm
Exon 11 (67.5%)
Exon 9 (11%)
Exon 13,14 (1%)
Exon 17 (0.5%)
Exon 12 (0.9%)
Exon 18 (6.3%)
KIT PDGFRα • KIT & PDGFRA : 85%
• Other key genes involved:
• NF1, Raf, SDH, IGF1R
Exon 14 (0.3%)
Imatinib sensitive + Sunitinib sensitive
Median PFS (months) 6 / 19
3-year estimate (%) 5 / 17
P value (logrank test) 0.017
KIT exon 9 mutants (10% of patients)
KIT exon 9 mutants: 400 mg / 800 mg Other patients: 400 mg / 800 mg
0 1 2 3 4 5 0
10 20 30 40 50 60 70 80 90 10
0
Years
Dose Adjuvant
KIT Exon 11 Im 400 +
KIT exon 9 Im 800 +
PDGFRA
Non D842V Im 400 +
D842V: 0 0 KIT/PDGFR WT Im 400 +/?
NF1 ?/Im 400 +/?
SDHB ?/Im 400 +/?
Raf ? ?
Pediatric ? ?
GIST are at least 10 diseases GISTS : 10 different diseases
Tumor heterogeneity
à Molecular heterogeneity at progression
– After imatinib Debiec Rychter et al, Heinrich et al 2006
– After sunitinib Fletcher et al ECCO 2007
Exon 11 mutation
+ Exon 13 + Exon 14
+ Exon 17
Three situations • Initial molecular event
– KIT in GIST – Loss NF1, TSC – Translocations – Mdm2 amplification – …
• Secondary event – VEGF production – Immune response
• Simple bystander – PDGFR & EGFR expression
19
20
Stroma (immune cells…)
Molecular typing
Histology
A new vision of the disease
Stroma (immune cells …)
Molecular typing
Histology
Trials on genotype? e.g. CREATE
Trials on subsets of histotypes
A new vision of the disease
Program to Establish the Genetic and Immunologic Profile of Patient's Tumour for All Types of Advanced
Cancer (PROFILER)
*
Signed informed consent
Collection of tumour material Blood sample (PB, serum)
Clinical data
Genomic profiling of the tumour
Report of genomic and immunological profiling of the tumour
Molecular Board
Recommendation for a clinical trial, MOST protocol, or off-label treatment
• Design: non-randomised, multicentric, cohort study, combined with a biological sample collection, a retrospective clinical data collection and with a genetic and immunological biomarkers study
• Aim: genetic profiling and immune characterisation of circulating immune cells in patients with advanced solid or haematological tumours in advanced stage
• Start date: 28 February 2013
• Enrolment single center: n=414/2000 (June!)
• Adapting tools and manpower Reopening Oct 13
ClinicalTrials.gov identifier NCT01774409
My Own Specific Treatment (MOST)
• Design: two-period, national, multicentre, randomised, open-label, phase II study using a randomised discontinuation design
• Aim: to evaluate, in patients with advanced solid tumours after at least 1 prior systemic treatment regimen, the clinical benefit of a maintenance treatment in patients with stable disease after a 12-week induction treatment with a therapy targeting the molecular alterations identified in the patient’s tumour
• Start date: July 2013
To address major scientific questions
1900
2000
17/23 solved
1/7 solved
Oncology research … a « hard science » with multidimensional complexity
Conclusions Avancées et nouveaux paradigmes en
recherche clinique
• Comprendre la biologie de la maladie
• Importance du diagnostic moléculaire
• Fragmentations nosologiques
• Cibler les altérations primaires
• Comprendre les réponses inattendues (« empiriques »)
• Evaluation pharmacodynamique
• Collaborations internationales