1. 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

5. Which subset? Which target? Which agents?

6. Towards a major fragmentation
of nosological entities
Damien Hirst
« 1-bromoadamantane »
« Acivicin »
« Arginosuccinic acid »

7. 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-----------------------

8. 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

9. Are we running at the same speed?
• Gene expression profile Mindact EORTC 10041

10. Which subset? Which target? Which agents?
New molecular trials

11. Clinical
Research
Translational
research
Basic
research

12. 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

13. 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

14. 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

15. 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

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. 19

20. 20

22. Stroma
(immune cells…)
Molecular
typing
Histology
A new vision of the disease

23. Stroma
(immune cells …)
Molecular
typing
Histology
Trials on genotype?
e.g. CREATE
Trials on subsets
of histotypes
A new vision of the disease

24. 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

25. 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

29. To address major scientific questions
1900
2000
17/23 solved
1/7 solved
Oncology research … a « hard science »
with multidimensional complexity

30. 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