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Organisation des plateformes de génétiquemoléculaire du cancer

Frédérique Nowak – 11 octobre 2017

Journées du GFCO

Predictive biomarkers for targeted therapies’ prescription

Biomarker Cancer type Targeted therapiesPatients nb

in 2016

KIT mutations GIST Imatinib 1 218

HER2 amplification Breast and gastric cancersTrastuzumab, lapatinib, pertuzumab,

trastuzumab emtansine

10 832 (B)770 (G)

RAS mutations Colorectal cancer Panitumumab, cetuximab 21 923

EGFR mutations Lung cancer Gefitinib, erlotinib, afatinib, osimertinib 28 563

ALK translocations Lung cancer Crizotinib, ceritinib, alectinib 23 434

ROS1 translocations Lung cancer Crizotinib 17 680

BRAFV600 mutation MelanomaVemurafenib, dabrafenib, trametinib,

cobimetinib5 583

BCR-ABL translocationChronic Myeloid Leukaemia/

Acute Lymphoblastic LeukaemiaImatinib, nilotinib, dasatinib, ponatinib, bosutinib 9 570

17p deletion / TP53mutation

Chronic Lymphocytic Leukaemia Ibrutinib, idelalisib2 8571 808

BRCA mutation (somatic)

Ovarian cancer Olaparib 1 608

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France organisation of molecular centres for personalised medicine

Provides nationwide molecular diagnostic tests

� Perform molecular testing for all patients;

� Whatever the healthcare institution status (public hospitals, private hospitals…);

� Perform high qualitytests;

� leukemia, solidtumours

� Perform molecular testing for all patients;

� Whatever the healthcare institution status (public hospitals, private hospitals…);

� Perform high qualitytests;

� leukemia, solidtumours

Objectives

� Partnerships betweenseveral laboratorieslocated in Universityhospitals and cancer centers

� Regionalorganization

� Cooperation betweenpathologists and biologists

� Partnerships betweenseveral laboratorieslocated in Universityhospitals and cancer centers

� Regionalorganization

� Cooperation betweenpathologists and biologists

28 regional centres

�xThe program is operated by INCa/French Ministry of Health since 2006

Financements

� Financements INCa pour la mise en œuvre des tests moléculaires

� Structuration initiale (AAP 2006 et 2007)

� Tests KRAS

� Tests EGFR

� AAP anapath

� Biomarqueurs émergents

� Implémentation du NGS

� Essai PAOLA1 et déploiement BRCA

� Financements annuels récurrents de la DGOS

� Enveloppes MERRI ciblées par test

� Puis passage au RIHN

� Financements INCa pour le programme AcSé Moléculaire

� Financements INCa pour l’assurance qualité

RIHN

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Benefit & swift access to innovation for all patients

Ensure that all patiets actuallybenefit from molecular testing

… as soon as a new therapy is available

Lung cancer :

� June 2009 : gefitinib approval by EMA for

patients with activating EGFR mutations intheir tumour

� INCa started funding the 28 centres by

the end of 2009 (€1.7M)

Lung cancer :

� June 2009 : gefitinib approval by EMA for

patients with activating EGFR mutations intheir tumour

� INCa started funding the 28 centres by

the end of 2009 (€1.7M)

1269

2667

16834

20750

2199523336

2455826614 28563

0

10000

20000

30000

2008 2009 2010 2011 2012 2013 2014 2015 2016

nb

of

pat

ien

ts

EGFR screening / lung cancer

Elaboration of guidelines for :

� the detection of mutations in solid tumours ;

� the organisation of molecular testing ;

� reports of molecular tests

Implementation of national External Quality Assessmentrounds for the main tests in the 28 centers

Ensure the best quality for molecular tests

Implementation of a quality assurance programImplementation of a quality assurance program

�xTowards ISO 15189 accreditation

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Targeted NGS in routine practice

Routine use of targeted NGS

in all the molecular genetics centres

Routine use of targeted NGS

in all the molecular genetics centres

� Rolling out started

in 2015 in all the

molecular centres

� Progressive shift

from the standard

approach towards

targeted NGS for all

patients

� Rolling out started

in 2015 in all the

molecular centres

� Progressive shift

from the standard

approach towards

targeted NGS for all

patients

� Pilot phase launched in 2013 with 11 molecular genetic centres :

�develop the necessary skills to use this new

technology

� Monitoring led by INCa :�increase the sharing of experiences

�Draft guidelines

� 5 referent teams in bioinformatics :

�Validate & release existing data analysis

pipelines, or develop better ones

�support wet labs and their “embedded”

bioinformaticians through network animation

and training

� Economic impact of NGS evaluated at the same time

Implementation of targeted NGS in routine practice

Next challenge: use the additional information obtained by NGS to improve patients outcome

� Assess the clinical significance of new variants ;� Define a strategy of treatment ;� Enroll patients in clinical trials.

� Organisation of molecular tumour boards (MTB)

� Initially designed in the context of genomic driven clinical trials ;

� Implementation of MTB in routine practice started in 2015 in some centres.

� Need to create shared databases to collect information about rare mutations in relation to

patients’ follow up.

� Development of new types of clinical trials with a large access on the territory : AcSé

programme

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The Biomarker France study is a cohort of #17,500 patients of French lung cancer patients who were routinely screened for EGFR mutations during a 1-year period (from April, 2012 to April, 2013).

It collected :

� Clinical data

� Molecular data

� The impact on treatment(s)’ decision and patients’ outcomes

A national database in lung cancer:The Biomarker France Study

� Only 3% of patients in this database were enrolled in clinical trials

- ELÉMENTS FONDATEURS & PRINCIPES -

Patients porteurs d’un cancer

au stade métastatique ou

réfractaires aux traitements

validés:

* cible identifiée dans leur

tumeur,

* une molécule disponible en

pré-AMM ou AMM mais dans

une indication différente

Prescriptions hors cadre réglementaire, donc non maitrisée,

non sécurisée

A PROSCRIRE!

PROGRAMME AcSé - Accès sécurisé aux thérapies ciblées

2

� SÉCURITÉ DU PATIENT et recueil des données scientifiques.

La RECHERCHE BIOMÉDICALE permet :

� D’évaluer objectivement l’efficacité et les effets secondaires ;� D’arrêter un traitement non efficace dans une indication donnée ;

� Une organisation optimale pour la communauté scientifique, les patients

et les autorités de santé.

� EGALITÉ D’ACCÈS SUR LE TERRITOIRE (centres autorisés en cancérologie avec

acticité de recherche)

� OUVERT à tous les âges notamment AUX ENFANTS et adolescents si des données

de phase I sont disponibles

� NE PAS SE SUBSTITUER A LA RECHERCHE DE DEVELOPPEMENT:

� Si le patient est éligible pour un essai clinique de développement ouvert

en France il est dirigé préférentiellement vers celui ci

� La France doit rester attractive pour la recherche industrielle

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PHASE II

CLINICAL TRIALS

PHASE II

CLINICAL TRIALS

MOLECULAR SCREENING

MOLECULAR SCREENING

Molecular Genetic Centers (Routine

molecular

diagnosis)

Molecular Genetic Centers (Routine

molecular

diagnosis)

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DRUGS (Provided by

pharmaceutica

l firms

DRUGS (Provided by

pharmaceutica

l firms

THERAPEUTIC

NEED

DRUG (S) PROJECTS

THERAPEUTIC

NEED

DRUG (S) PROJECTS

Research of specific molecular alterations of the drug(s) target

ALK, ROS1, MET

BRAF V600

ONE DRUG PROJECT (FOCUSED ON A DRUG)MULTI-DRUGS PROJECT

(FOCUSED ON THE TARGETED POPULATION)

Targeted Therapies Immunotherapies

Research of a molecular

alteration in an identified cohort

(biomarkers potentially

predictive of efficacy )

MSI on non-colorectal

cancer diagnosis

Screening in two centersNATIONAL SCREENING COORDINATED AND FUNDED BY INCA

AcSé-TRIALSAcSé-TRIALS

Sponsor

Founder(s)

No molecular screening

Molecular matching

trial at relapse

PHRC-K

Molecular matching

trial at relapse

PHRC-K

PI

21

3Pangenomic research

programme / Extensive molecular analysis

Extensive targeted therapies (for Pediatrics population)

MAPPYACTS PROJECT

PROGRAMME ACSÉ au 10/10/2017 LES DIFFÉRENTS ESSAIS AcSé

Multi-agent from multi company

Since July 2016

Nivolumab Pembrolizumab

Nivolumab Pembrolizumab

Crizotinib Vemurafenib

Since October 2014Since July 2013

B. GEOERGERA. MARABELLE C. MASSARDJY. BLAYG. VASSAL

Since June 2017Since May 2017

- LE 1er ESSAI - -CRIZOTINIB

ALK, MET, RON , ROS110 000 – 18 000 patients

14 000 – 25 000 tests

ALK, MET, RON , ROS110 000 – 18 000 patients

14 000 – 25 000 tests

2013 20152014 2016

12 528 patients « AcSé Crizo » dans la base de données (juil. 2017)

12 528

5

229

2017

PI : G. Vassal

Autorisé – mai 2013

1er patient – Août 2013

21 cohortes, 463 patients, 3 ans d’inclusion

Durée totale de l’essai : 5-6 ans

Au 5 septembre 2017, 82 sites recruteurs (185

sites ouverts), 229 inclusions

PI : G. Vassal

Autorisé – mai 2013

1er patient – Août 2013

21 cohortes, 463 patients, 3 ans d’inclusion

Durée totale de l’essai : 5-6 ans

Au 5 septembre 2017, 82 sites recruteurs (185

sites ouverts), 229 inclusions

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BRAF V60010 000 – 18 000 patients

14 000 – 25 000 tests

BRAF V60010 000 – 18 000 patients

14 000 – 25 000 tests

- LE 2ème ESSAI - -VEMURAFENIB

1791 patients testés pour BRAF dans la base de données (juil. 2017)

1791

HORS cancers du poumon,

cancers colorectaux et

mélanomes

⇒ routine diagnostique

6

174

PI : JY. Blay

Autorisé – Août 2014

1er patient – Octobre 2014

11 cohortes, 500 patients, 3 ans d’inclusion

Durée totale de l’essai : 5-6 ans

Au 6 septembre 2017, 66 sites recruteurs (115

sites ouverts), 174 inclusions

PI : JY. Blay

Autorisé – Août 2014

1er patient – Octobre 2014

11 cohortes, 500 patients, 3 ans d’inclusion

Durée totale de l’essai : 5-6 ans

Au 6 septembre 2017, 66 sites recruteurs (115

sites ouverts), 174 inclusions

Targeted therapies

Molecular analysis of

tumour cells

Change of paradigm in cancer treatment : a fast evolving scientific and medical environment

PARP inhibitors

Germline genetics analysis

2014 : Market autorisation of olaparib in

ovarian cancer for patients with BRCAmutations (either somatic or germline)

New challenges :

1. Patients information on the personal and familial impact of a positive BRCA test : ethics+++

2. Molecular tests integrating 3 complementary expertises : pathology, somatic genetics and

germline genetics

3. Complex samples circuit (blood & tumour) / turnaround time

⇒ Need to make current organisational framework evolve

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French organisational framework for germline genetics in oncology

���� Brest

���� Limoges

Clermont-Ferrand (2)����

Amiens ����Le Havre

�������� Rouen

La Rochelle

Niort����

Poitiers

Angoulême

���� Lille (2)Boulogne-sur-Mer

LensValenciennes

���� Nancy (2)

Metz

����

Tours Bourges

Orléans

����

Caen

Cherbourg

Bordeaux (2) ����

Bayonne Toulouse (3) ����

Rodez

���� Lyon (7)

Saint-Etienne �������� Grenoble (2)

���� Chambéry

Nîmes ����

Perpignan

Montpellier (2) ����

Béziers

���� Reims (4)

Charleville Mézières

Troyes

���� Angers

Le Mans

Cholet

���� Dijon

Auxerre

Mâcon

Chalon-sur-Saône

(2)����

Nantes(2)

���� Besançon

���� Colmar

���� Strasbourg (3)

���� Mulhouse

Thonon-les-Bains

Avignon����

���� Nice

Gap

Ajaccio

Aubagne

DraguignanAix-en-Provence

Marseille(3)

Bastia���� Toulon

����

ValenceAurillac

Martigues

Belfort-Montbéliard

(2)

(2)

���� Fort de France

Cayenne���� Sainte-Clotilde

Saint-Denis����

���� Saint-Pierre

Clichy ����

Saint-Cloud ����

���� Paris (13)

Bobigny����

Briis-sous-Forges

Levallois-Perret

���� Kremlin Bicêtre����

Villejuif

Lorient

Saint-Nazaire(2)

Bondy (2)

Tarbes

Corbeil-Essonnes

����Pointe à Pitre

Saint-Brieuc

���� Rennes (2)

Grasse

Bonifacio

Corté

����

Montargis����Vannes

����

CHU de Rennes ����

����

����

���� CHU de Lille

����

Centre François Baclesse, Caen

Institut Bergonié, Bordeaux ����

����

����

����

����

���� CHU d’Angers����

����

CHU de Nantes

CHU de Nancy

Centre Jean Perrin, Clermont-Ferrand

CHU-CLCC de Reims

CHU de Rouen

CHU de Montpellier

Centre Oscar Lambret, Lille

APHM

Institut Claudius Regaud, Toulouse

CHU de Lyoncancers non fréquents

CHU-CLCC de Lyoncancers fréquents

Centre Georges-François Leclerc,Dijon

���� ����

Centre Paul Strauss, Strasbourg

CHU de Strasbourg

����

Institut Paoli Calmettes, Marseille

���� Paris����

Institut Gustave Roussy, Villejuif

APHP Hôpitaux Universitaires La Pitié-Salpêtrière

APHP Hôpitaux Universitaires Paris Nord Val de Seine

APHP Hôpitaux Universitaires Paris Centre et Paris Ouest

Institut Curie

130 genetic counseling sites in 90 cities 25 laboratories for genetic testing

Perform genetic tests prescribed by clinical geneticists

Objectives :

� identify people with genetic predisposition to cancer

� offer specific prevention programmes including risk-adjusted screening, preventive surgery and

medicines.

PARP inhibitors : impact on the national organisational framework

Setting up a pilot phase within the framework of the European PAOLA1 clinical trial

o Five screening centres granted by INCa for BRCA testing

o The molecular screening started in May 2015

o In two years : 1100 patients screened for BRCA

� 18,7% germline mutations

� 6,3% somatic mutations

Rolling out in the molecular genetics centres in collaboration with the oncogenetics laboratories

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Towards a more integratedorganisational framework

Pathology Somatic

genetics

Germline

genetics

Moleculargeneticscentres

Oncogeneticprogramme :

geneticcounseling and

laboratories

Towards a more integratedorganisational framework

Pathology Somatic

genetics

Germline

genetics

Integrated organisational

framework

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Targeted therapiesMolecular analysis of tumour cells

PARP inhibitorsGermline genetics analysis

Change of paradigm in cancer treatment : a fast evolving scientific and medical environment

ImmunotherapyCheckpoint inhibitors : � Anti-CTLA4

� Anti-PD1 and anti-PDL1

Market authorization and ongoing clinical trials in melanoma,

lung cancer, mesothelioma, kidney cancer, bladder cancer….

=> Specific predictive biomarkers are under development and will enter soon into clinical practice

Change of paradigm in cancer treatment : immunotherapy

Blank et al. Science 2016 ; 352:658-660

MSI & déficience MMR: AcSé Nivolumab

Expression PD-l1AMM pembrolizumab, Cancer du poumon

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Towards next ajustment integrated of the organisational framework

Pathology Somatic

genetics

Germline

genetics

Immunotherapy

ADN tumoral circulant : AMM de l’Osimertinib

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ADN tumoral circulant : test EGFR

Déploiement du test dans les laboratoires

���� 3 697 tests réalisés au cours du 1er semestre 2017

4

3

31

32

Non prévu

En projet

En cours de

validation de

méthodePour des projets de

recherche

uniquementRésultats rendus en

routine clinique

19

14

9

42

2 2 1NGS

PCR digitale

PCR spécifique d'allèle

sondes Taqman

Mass Array

Analyse de fragments

Pyroséquençage

HRM

Techniques d’analyse utilisées

Launch of the Plan in June 2016

Objectives :

o integrate genomic medicine into the patient’s care pathway

o allow equal access to whole genome sequencing, first for rare diseases and cancers and then for common diseases, as new therapeutic indications are validated

o create a momentum for innovation in a number of areas

National « France Genomic Medicine Plan 2025 »

From targeted NGS to tumour genomesanalysis in clinical pratice

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Call for proposals launched by the Ministry of Health for the set up of the first two ultra high-throughput clinical sequencing facilities

⇒ Generic activity: rare diseases and cancer, then common diseases

⇒ Sizing : sequencing of the equivalent of 18,000 genomes per year

⇒ Access for all of the patients in France

⇒ Integration into the patient’s healthcare pathway and the existing healthcare networks

France Genomic Medicine Plan 2025

SEQOiA

AURAGEN

Two selected applications among the 10 submitted :

o SEQOiA : joint application of Assistance Publique-Hôpitaux de Paris

(APHP), Institut Curie and Institut Gustave Roussy

o AURAGEN : joint application of Hospices Civils de Lyon, CHU de

Grenoble, CHU de Saint-Etienne, CHU de Clermont-Ferrand, Centre Léon

Bérard, Centre Jean Perrin and Institut de cancérologie de la Loire

Conclusion

France’ organisational framework for precision medicine in oncology :

– has been operating for 8 years;

– offers an equal access to molecular testing for all patients in

France;

– shows that molecular stratification can be successfully integrated

into the healthcare system;

– shows that such a national organisation has to be continuously

adjusted in a context of a fast evolving scientific, medical and

technological environment

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Institut national du cancer ● 52, avenue André Morizet ● 92513 Boulogne-Billancourt Cedex ● France ● Tél. +33 (0) 1 41 10 50 00 ● e-cancer.fr

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