Translational research in NSCLC

- the role of ETOP and ESMO

Austria

• CECOG – Central European

Cooperative Oncology Group

• Translational Thoracic Oncology Lab

Belgium

• ELCWP – European Lung Cancer

Working Party

• EORTC Lung Cancer

• Leuven Lung Cancer Group

• Oncologisch Centrum UZ Brussel

• Thoracic Oncology Unit, Department of

Pulmonary Diseases, Heilig Hart Ziekenhuis

Roeselare

• TOGA – Thoracale Oncologie

Groep Antwerpen

Czech Republic

• Czech Lung Cancer Cooperative Group

Denmark

• DLCG – Danish Lung Cancer Group

• DOLG – Danish Oncological Lungcancer

Group

Norway

•NLCG – Norwegian Lung Cancer Group

Poland

•Polish Lung Cancer Group

•Medical University of Gdansk

TOP Group

Portugal

•GECP – Grupo de estudos do

cancro do pulmão

•Centro Hospitalar do Porto

Spain

•SLCG – Spanish Lung

Cancer Group

•CIBERES – Biomedical Research Center on

Respiratory Diseases

Sweden

•Swedish Lung Cancer

Study Group

Switzerland

Outside Europe:

• Australia – Princess Alexandra Hospital

• U.S.A. – Roswell Park Cancer Institute

• China – Shanghai Chest Hospital

Group

Finland

• Finnish Lung Cancer Study Group

France

• GFPC – Groupe Français de

Pneumo-Cancérologie

• ICO – Integrated Centers of Oncology

• IFCT – Intergroupe francophone de

Cancérologie thoracique

• IGR – Institut Gustave Roussy

Germany

• AOT – Arbeitsgemeinschaft

Onkologische Thoraxchirurgie

• Arbeitsgruppe Thorakale Onkologie

der Arbeitsgemeinschaft Internistische

Onkologie der Deutschen

Krebsgesellschaft

• Lung Cancer Group Cologne

• Pius-Hospital Oldenburg

• Thoraxklinik am Universitätsklinikum

Heidelberg

Greece

• HeCOG – Hellenic Co-operative Oncology

Group

• HORG – Hellenic Oncology Research

Group

• Oncology Unit GPP, Athens School of

Medicine

Hungary

• Department of Pulmonology, Semmelweis

University

• Thoracic Oncology Program

Israel

• Israel Lung Cancer Group

• Tel-Aviv Medical Center

Italy

• AIOT – Associazione Italiana di

Oncologia Toracica

• GIMe – Italian group for the research and

therapy of Mesothelioma

• Medical Oncology, Azienda Ospedaliera

Universitaria Integrata

• National Cancer Institute, Pascale Foundation

• Perugia Unviersity Hospital Oncology

Department

Switzerland

•SAKK – Schweizerische

Arbeitsgemeinschaft fuer Klinische

Krebsforschung

The Netherlands

•NVALT – Nederlandse Vereniging

van Artsen voor Longziekten en

Tuberculose

•ROTS - Rotterdam Thoracic Oncology Study

Group

United Kingdom/Ireland

•Birmingham Group

•BTOG – British Thoracic Oncology Group

•ICORG – All Ireland Cooperative Oncology

Research Group

•London Lung Cancer Group

•Manchester Lung Cancer Group

•National Cancer Research Institute –

Lung Cancer Clinical Study Group

ETOP Group Offices3 |

ETOP Office Zürich

ETOP Coordinating Office ETOP Coordinating Office

Bern

ETOP Scientific Coordinator

Lausanne

ETOP Statistical Office Athens

3rd ETOP meeting November 20104 |

SPLENDOUR

NICHEBELIEFiBiobank

Lungscape

ETOP clinical trials: activated

• EMPHASIS: Phase III second line erlotinib versus docetaxel in

advanced squamous NSCLC stratified by VeriStrat Good vs

VeriStrat Poor

• BELIEF: Phase II study on first line therapy in EGFR mutated

5 |

• BELIEF: Phase II study on first line therapy in EGFR mutated

NSCLC stratified according to T790M status as determined by

sensitive methods (SLCG coordinating group)

• SPLENDOUR: Phase III study on first line chemotherapy in

NSCLC with or without denosumab stratified according to

histology, bone involvement and region (EORTC, CECOG,

SLCG, SAKK)

• STIMULI: Randomizes phase II study in limited disease SCLC

treated with chemoradiotherapy with or without ipilimumab

consolidation (IFCT)

Resistance to EGFR TKI might be associated with

tumor and stromal VEGF activity

6 |

Naumov, CCR 2009; Cagnoni & Tamagnone. Oncogene 2014

ETOP 2-11 BELIEF

An open-label phase II trial of erlotinib and bevacizumab in

patients with advanced non-small cell lung cancer and

activating EGFR mutations

Sample seize 102 patients, coordinating group SLCG,

participating group SAKK

7 |

Tissue:

• EGFR

• del19: 63,6%

• L858R: 36,4%

• T790M: 55,45%

Preliminary laboratory data8 |

• T790M: 55,45%

• Material for:

• RNA: 70% (BIM, BRCA1, RAP80 mRNA; EML4-ALK

detected in 3 cases (4%))

• Stroma (HGF mRNA): 58,2%

Serum/plasma:

• at baseline, at time of response and at progression

Erlotinib plus bevacizumab versus erlotinib alone

first line mEGFR NSCLC

9 |

Atagi, APLCC 2014

SPLENDOUR: Phase III trial of denosumab

in patients with Stage IV NSCLC subgroup?

10 |

Stage IV

untreated

NSCLC

± bone

metastases

Stratify:

- Bone metastases

- Region

- ECOG PS

4−6 CT Q3W

+ BSC (zoledronic acic allowed)

• Primary objective: overall survival

• Secondary objectives: PFS (RECIST 1.1); safety (CTCAE v 4);

determination of biomarkers for translational research

metastases

(N∼1000)

- ECOG PS

- Histology4−6 cycles CT Q3W

+ denosumab 120 mgSC Q3 (−4) weeks†

†To be continued on tumour progression and concomitantly to subsequent lines of systemic

treatment.

CT, chemotherapy, ECOG, Eastern Cooperative Oncology Group; IV, intravenously; Q3W, every 3

weeks; SC, subcutaneously.

RANK and RANK Ligand expression observed

in primary human NSCLC samples

11 |

Adenocarcinoma (n = 16) Squamous cell carcinoma (n = 26)

RANK Ligand

75%

RANK

56%

RANK

34%

RANK Ligand

19%

Both 37% Both 8%

Proportion

of samples

Scaglotti, WCLC 2011

Requirement for NFkB signalling in a mouse model of

lung adenocarcinoma

12 |

Lentiviral inactivation of NFkB in KRAS/p53-mutated mice model

developing multiple lung adenocarcinoma (CT 15 days post infection)

Meylan E, Nature 2009

SPENDOUR translational research

Mandatory FFPE tissue (slides or block), serum and urine samples will be

collected at baseline (prior to the start of chemotherapy), on day 1 of cycle 3

and at progression.

Serum analyses by ELISA include:

13 |

Serum analyses by ELISA include:

osteopontin (OPN); bone sialoprotein (BSP); RANKL by ELISA kit designed for

the quantitative determination of total (free RANKL and RANKL complexed to

OPG) soluble RANKL in serum and osteoprotegerin (OPG) levels.

FFPE tumour samples will be accessed for correlative research. Evaluations

will include: IHC for RANKL & RANK; NFkB pathway components, and

potentially BSP and osteopontin (OPN) levels in primary tumour may

correlate with tumour aggressiveness.

STIMILI: A randomized phase II trial of consolidation

ipilimumab vs placebo in limited-stage SCLC after

chemoradiotherapy

14 |

Lungscape iBiobank

ETOP Annual Meeting, Vienna

•Belgium

• Leuven:

J. Vansteenkiste,

E. Verbeken, C. Dooms,

L.Vliegen

•Denmark

• Aarhus:

P. Meldgaard, H. Hager

•Greece

• Frontier Science Hellas:

U. Dafni

•Germany

• Heidelberg:

H.Dienemann, A. Warth,

T. Muley

• Switzerland

• ETOP Coordinating Office:

A. Hiltbrunner, S. Peters,

R. Kammler, T. Geiger, M.

Marbot, R. King, R. Stahel

• Basel:

L. Bubendorf, S. Savic

• Zurich:

W. Weder, V. Tischler, A.

Soltermann

• The Netherlands

• Amsterdam VUMC:

• E. Thunnissen, E. Smit

• Amsterdam NKI:

P. Baas, J. de JongT. Muley

• Ireland

• Dublin:

S. Finn, S. Gray, K. Gately

• Italy

• Chieti:

• A. Marchetti, F. Buttitta,

A. Di Lorito

• Poland

• Gdansk:

R. Dziadziuszko,

W. Biernat, A. Sejda,

A. Wrona

P. Baas, J. de Jong

• Maastricht:

A.-M. Dingemans,

E-J.M. Speel

•United Kingdom

• Aberdeen:

K.M. Kerr, N. Price,

M. Nicolson

• Manchester:

F. Blackhall, D. Nonaka,

R. Peck, L. Priest

• Spain

• Barcelona:

E. Felip, J. Hernandez-Losa, M. T.

Salcedo, M. Canela

• Badalona:

R. Rosell, M.A. Molina

• Valencia:

C. Camps, M. Martorell,

M.C. Calabuig, E. Jantus-Lewintre

•Beyond Europe:

•China

• Shanghai Chest Hospital:

S. Lu, Z. Jie, Q. Tan

•USA

• Roswell Park Cancer Institute:

A. Adjei, R. Cheney, M. Reid

17 | LUNGSCAPE project: General objective

• The LUNGSCAPE program aims to address challenges of

studying the molecular epidemiology of lung cancer

– by coordinating and harmonizing the procedures of a group of

lung cancer specialists working in translational research

across Europe,

ETOP | Lungscape | Project description | Zurich, December 9, 2010

across Europe,

– and facilitating analysis of larger series of cases.

• This will expedite

– knowledge of the prevalence and context of current and

emerging molecular biomarkers with clinical significance,

– facilitate more rapid translation of biomarker knowledge to the

clinic,

– and provide a platform for future marker-driven ETOP studies

18 | Stepwise evolution

• Step 1: Lungscape (initiated 2011)

Retrospective analysis of completely resected NSCLC from

different sites. Fully annotated clinical data and local tissue

repository for immunohistochemistry, FISH and mutation

testing on formalin-fixed paraffin embedded tissue

• Step 2: SPECTAlung (initiated 2014 in collaboration with

EORTC)

Prospective multiplex analysis and expansion to biopsies from

advanced disease. Development of a masterprotocol

• Step 3: Prognostic signature (EU grant submitted 2014)

Center Adeno. Squamous Other Total

University Hospital Leuven, Belgium 90 100 10 200

University Hospital Basel, Switzerland 60 90 16 166

University Hospital Zurich, Switzerland 166 124 19 309

Shanghai Lung Cancer Center, China 111 7 19 137

Universitätsklinikum Heidelberg, Germany 50 49 3 102

Aarhus University Hospital, Denmark 184 124 28 336

University Hospital Valencia, Spain 22 23 1 46

Vall d'Hebron University Hospital Barcelona, Spain 80 57 33 170Vall d'Hebron University Hospital Barcelona, Spain 80 57 33 170

Royal Infirmary Aberdeen, UK 75 65 17 157

Lung Cancer Group Manchester, UK 53 24 2 79

St James' Hospital Dublin, Ireland 119 144 18 281

Ospedale Clinicizzatto Chieti, Italy 107 59 1 167

The Netherlands Cancer Institute Amsterdam, NL 38 26 12 76

Free University Medical Center Amsterdam, NL 41 48 13 102

University Medical Centre Maastricht, NL 44 43 6 93

Medical University Gdansk, Poland 86 109 5 200

Roswell Park Cancer Institute Buffalo, USA 51 25 12 88

Total 1377 1117 215 2709

Lungscape iBiobank

NSCLC FFPE blocks

1377 Adenocarcinoma,

1117 Squamous Cell,

2709 2702

2056

ETOP | Lungscape iBiobank | ESBB RBYC | Leipzig, Oct 23, 2014

1117 Squamous Cell,

215 Other,

Total: 2709

FFPE Tumor BlocksTMA's Extracted DNA

Lungscape achievments 201421 |

Agreement between FISH & IHC results in ALK status

determination (n=237)22 |

•Blackhall and Peters, JCO in press

OS according to ALK status23 |

•Blackhall and Peters, JCO in press

Lungscape achievments 201424 |

Lungscape | Name Project | Title Presentation | Zurich, July 27, 2009

Time to relapse according to pathological stage25 |

•Peters, JT0 2014

Lungscape achievments 201426 |

• Assessing standardization of molecular testing for

NSCLC: Results of a worldwide EQA scheme for

EGFR mutation testing.

Patton et al. BJC 111(2): 413-20.

• ESMO 2014 Poster Discussion Prevalence and

clinical outcomes for patients with NSCLC expressing

MET protein: Results from the ETOP Lungscape

Project. Bubendorf, Finn et al.

ETOP | Lungscape iBiobank | ETOP AM 2014| Vienna

Current Lungscape projects (about 2700 cases)

• ALK project: RT/PCR

• MET project: IHC and SISH

• PIK3CA project: CISH

27 |

• PTEN project: IHC

• Multiplex genetic testing: 14 genes, over 150 mutations

• RANK/L: IHC

• PDL1: IHC

ETOP

CO

•Contract

Site Activation

Checks and Balances

Study

Lead

ETOP

CO

EQA Clinical Specimens

ETOPdata

(clinical DB)

L U

•Contract

•Protocols

•EC/IRB docs

•ECs/IRBs

N CG S

•EQA

L U N G S C

•Staining & Scoring

•Clinical Specimens

L U N G S C A P E

29 | Stepwise evolution

• Step 1: Lungscape (initiated 2011)

Retrospective analysis of completely resected NSCLC from

different sites. Fully annotated clinical data and local tissue

repository for immunohistochemistry, FISH and mutation

testing on formalin-fixed paraffin embedded tissue

• Step 2: SPECTAlung (initiated 2014 in collaboration with

EORTC)

Prospective multiplex analysis and expansion to biopsies from

advanced disease. Development of a masterprotocol

• Step 3: Prognostic signature (EU grant to be submitted

2014)

SPECTAlung (screening platform for efficient clinical

trials access)

30 |

Inclustion criteria

•Pathologically confirmed, any stage

• lung cancer (including NSCLC and SCLC)

• malignant pleural mesothelioma

• thymoma or thymic carcinoma;• thymoma or thymic carcinoma;

•Availability of HBM:

• FFPE tissue and liquid biopsy;

•Written informed consent according to ICH/GCP and

national/local regulations

Belgium

• EORTC, Brussels

• Jean-Paul Sculier, Insitute

Jules Bordet, Brussels

• Johan Vansteenkiste, Institute

KU Leuven, Leuven

Denmark

• Peter Meldgaard, Henrik

Hager, Aarhus, Denmark - tbc

France

• Benjamin Besse, Institute

Gustave Roussy, Paris

• Julien Maiser, Hôpital

Italy

• Silvia Novello, AOU San

Luigi Gonzaga, Orbassano

Torino

Poland

• Rafal Dziadziuszko, Medical

University of Gdansk,

Gdansk

United Kingdom

• Sanjay Popat, Royal

Marsden Hospital, Sutton

• Sanger Institute, Hinxton,

SPECTAlung

• Julien Maiser, Hôpital

Larrey, Toulouse

Germany

• Thomas

Gauler, Universitätsklinikum

Essen Innere Klinik, Essen

• Martin Reck, Center of

Pneumology and Thoracic

Surgery, Grosshansdorf

Ireland

• Steven Finn, St James

Institute, Dublin

Spain

• Enriqueta Felip, Vall

d‘Hebron University Hospital,

Barcelona

Switzerland

• Rolf Stahel, University

Hospital Zurich, Zurich

• Solange Peters, CHUV,

Lausanne

The Netherlands

• Egbert Smit, VU University

Medical Center, Amsterdam

Sanger clinical NGS panel – V232 |

1438

968

1102

kinases (93)

SNP cytoscape

SNP introns

Some examples:

- EGFR

- ALK

- ROS 1

- RET

- KIT

- PIK3CA

- HER-2

- BRAF

- DDR2

- Trk

- TP53

1222

851

1794

344

tumour suppressor genes (79)

transcription factors (55)

DNA methylation (4)

histone modifications (11)

chromatin modifications (2)

miscellaneous (116)

gene fusions

SNP gwas

8023 regions

Roadmap for change: SPECTAlung and its

masterprotocol

33 |

Molecular Screening Platform

Standard treatment (no open trial)

Academia

investment

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009

First line Second line 3rd line trial

2nd line trialFirst line Third line

1st line trial Standard treatment

Standard treatment (no open trial)

Standard treatment (no open trial)

Industry

cooperation

Pan-European Collaborative

Molecular Screening

Platforms (CMSP):

Connecting for a

Data Driven

Personalised Medicine

Landscape

WP1 Coordination and Governance

WP

2 D

ata

coll

ect

ion

WP4

Bioinformatics &

data access

WP

7 I

mp

lem

en

tati

on

WP

6 I

mp

act

ass

ess

me

nt

WP

3 Q

A/Q

C

Landscape

•

WP

5 T

um

or

bo

ard

s

data access

WP

7 I

mp

lem

en

tati

on

WP

6 I

mp

act

ass

ess

me

nt

WP8 Education and Dissemination

WP

3 Q

A/Q

C

H2020 application, joint EORTC, ETOP, ESP2

ETOP clinical trials: contracted and in preparation

• NICOLAS: Feasibility of anti-PD1 nivolumab consolidation after

standard first line chemoradiotherapy in locally advanced stage

IIIA/B NSCLC

• NICHE: Afatinib in HER2 mutated NSCLC: Phase II Simon

35 |

• NICHE: Afatinib in HER2 mutated NSCLC: Phase II Simon

two-stage design with disease control rate as primary endpoint

methods

• SPECTAlung Masterprotocol

• PEARLS: Adjuvant anti-PD1 antibody in resected NSCLC.

Collaboration with EORTC

• MAPS: Anti-PD1 antibody in malignant pleural mesothelioma

NICOLAS: Feasibility of nivolumab after

chemoradiotherapy of stage III NSCLC

36 |

Stage

IIIA / B

NSCLC

Investi-

gator‘s

choice

Standard treatmentScreening, eligibility

and enrolment

Trial treatment

chemo

cycle 1

chemo

cycle 2

chemo

cycle 3

Radiotherapy

66Gy, 33 fractions

Radiotherapychemo chemo chemo

Anti PD-1 consolidation:

nivolumab 10mg/kg every 2

weeks

Whole body

FDG PET-CT

Chemotherapy: Cisplatin (or Carboplatin) doublet

Radiotherapy

66Gy,

24fractions

chemo

cycle 1

chemo

cycle 2

chemo

cycle 3

CT after

Radiotherapy

Year 1: CT every 8 weeks

Year 2: CT every 12 weeks

Primary endpoint: Grade ≥3 pneumonitis (CTCAE V4.0) up to 6 months post-

radiotherapy

Secondary endpoints: Time to first grade ≥3 pneumonitis; PFS, OS; response

(RECIST 1.1); time to treatment failure; Adverse events by CTCAE 4.0

NICHE: Phase II trial of afatinib in mHER2 NSCLC 37 |

Stage

IIIB / IV

NSCLC,

pretreated

HER2

mutation

confirmed

locally

Trial treatmentScreening, eligibili

ty

and enrolment

Afatinib 40mg daily p.o.

until PD or unacceptable toxicity

For 1 year

after

enroll-

ment of

last

patient

Progression Follow up

Primary endpoint: disease control (CR / PR / SD) lasting at least 12 weeks

Secondary endpoints: objective response; PFS; OS

Adverse events acc. CTCAE 4.0

CT T&A

CT or MRI

brain

CT week 20, then every 8

weeks until PD

33.

CT

week

6

CT

week

12

33.

Upcoming meetings

• 3rd Lungscape Pathologists Meeting:

February 6, 2015 in Zurich, Switzerland

• 4th ETOP Residential Workshop:

August 20-22, 2015 in Amsterdam, Netherlands

• ETOP Annual Meeting:

38 |

• ETOP Annual Meeting:

November 13-14, 2015 in Zurich, Switzerland

Thank you for listening!

ETOP | European Thoracic Oncology Platform | c/o IBCSG | Effingerstrasse 40 | 3008 Bern | www.etop-eu.org lungscape@etop-eu.org