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