20 3 14
Avancées et nouveaux
paradigmes en recherche
clinique
JY Blay
Lyon,
LYRIC INCa 4664, NetSARC, RREPS
Eurosarc FP7 2...
Which subset? Which target? Which agents?
Towards a major fragmentation
of nosological entities
Damien Hirst
« 1-bromoadamantane »
« Acivicin »
« Arginosuccinic aci...
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...
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
–  …
•...
Heinrich et al. Hum Pathol. 2002;33:484; Science
2003,
Corless et al. Proc AACR. 2003
KIT and PDGFRα are mutated in GIST
M...
Median PFS
(months)
6 / 19
3-year
estimate (%)
5 / 17
P value
(logrank test)
0.017
KIT exon 9 mutants (10% of patients)
KI...
Tumor heterogeneity
à Molecular heterogeneity at progression
– After imatinib
Debiec Rychter et al, Heinrich et al 2006
–...
Three situations
•  Initial molecular event
–  KIT in GIST
–  Loss NF1, TSC
–  Translocations
–  Mdm2 amplification
–  …
•...
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 v...
Program to Establish the Genetic and Immunologic
Profile of Patient's Tumour for All Types of Advanced
Cancer (PROFILER)
*...
My Own Specific Treatment
(MOST)
•  Design: two-period, national,
multicentre, randomised, open-label,
phase II study usin...
To address major scientific questions
1900
2000
17/23 solved
1/7 solved
Oncology research … a « hard science »
with multid...
Conclusions
Avancées et nouveaux paradigmes en
recherche clinique
•  Comprendre la biologie de la maladie
•  Importance du...
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique
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Avancées et nouveaux paradigmes en recherche clinique - Jean-Yves BLAY - Rencontres de la Recherche Clinique

  1. 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
  2. 2. Which subset? Which target? Which agents?
  3. 3. Towards a major fragmentation of nosological entities Damien Hirst « 1-bromoadamantane » « Acivicin » « Arginosuccinic acid »
  4. 4. 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-----------------------
  5. 5. 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
  6. 6. Are we running at the same speed? •  Gene expression profile Mindact EORTC 10041
  7. 7. Which subset? Which target? Which agents? New molecular trials
  8. 8. Clinical Research Translational research Basic research
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. 19
  15. 15. 20
  16. 16. Stroma (immune cells…) Molecular typing Histology A new vision of the disease
  17. 17. Stroma (immune cells …) Molecular typing Histology Trials on genotype? e.g. CREATE Trials on subsets of histotypes A new vision of the disease
  18. 18. 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
  19. 19. 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
  20. 20. To address major scientific questions 1900 2000 17/23 solved 1/7 solved Oncology research … a « hard science » with multidimensional complexity
  21. 21. 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

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