ETOP 2-11 BELIEF - samo-workshop.ch · 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

Austria

• CECOG – Central EuropeanCooperative Oncology Group

• Translational Thoracic Oncology Lab

Belgium

• ELCWP – European Lung CancerWorking Party

• EORTC Lung Cancer

• Leuven Lung Cancer Group

• Oncologisch Centrum UZ Brussel

• Thoracic Oncology Unit, Department ofPulmonary Diseases, Heilig Hart ZiekenhuisRoeselare

• TOGA – Thoracale OncologieGroep Antwerpen

Czech Republic

• Czech Lung Cancer Cooperative Group

Denmark

• DLCG – Danish Lung Cancer Group

• DOLG – Danish Oncological LungcancerGroup

Norway

•NLCG – Norwegian Lung Cancer Group

Poland

•Polish Lung Cancer Group

•Medical University of GdanskTOP Group

Portugal

•GECP – Grupo de estudos docancro do pulmão

Spain

•SLCG – Spanish LungCancer Group

•CIBERES – Biomedical Research Center onRespiratory Diseases

Sweden

•Swedish Lung CancerStudy Group

Switzerland

•SAKK – Schweizerische

Outside Europe:

• Australia – Princess Alexandra Hospital

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

• China – Shanghai Chest Hospital

Group

France

• GFPC – Groupe Français dePneumo-Cancérologie

• ICO – Integrated Centers of Oncology

• IFCT – Intergroupe francophone deCancérologie thoracique

• IGR – Institut Gustave Roussy

Germany

• AOT – ArbeitsgemeinschaftOnkologische Thoraxchirurgie

• Arbeitsgruppe Thorakale Onkologieder Arbeitsgemeinschaft InternistischeOnkologie der DeutschenKrebsgesellschaft

• Lung Cancer Group Cologne

• Pius-Hospital Oldenburg

• Thoraxklinik am UniversitätsklinikumHeidelberg

Greece

• HeCOG – Hellenic Co-operative OncologyGroup

• HORG – Hellenic Oncology ResearchGroup

• Oncology Unit GPP, Athens School ofMedicine

Hungary

• Department of Pulmonology, SemmelweisUniversity

• Thoracic Oncology Program

Israel

• Israel Lung Cancer Group

• Tel-Aviv Medical Center

Italy

• AIOT – Associazione Italiana diOncologia Toracica

• GIMe – Italian group for the research andtherapy of Mesothelioma

• Medical Oncology, Azienda OspedalieraUniversitaria Integrata

• National Cancer Institute, Pascale Foundation

• Perugia Unviersity Hospital OncologyDepartment

•SAKK – SchweizerischeArbeitsgemeinschaft fuer KlinischeKrebsforschung

The Netherlands

•NVALT – Nederlandse Verenigingvan Artsen voor Longziekten enTuberculose

•ROTS - Rotterdam Thoracic Oncology StudyGroup

United Kingdom/Ireland

•Birmingham Group

•BTOG – British Thoracic Oncology Group

•ICORG – All Ireland Cooperative OncologyResearch Group

•London Lung Cancer Group

•Manchester Lung Cancer Group

•National Cancer Research Institute –Lung Cancer Clinical Study Group

ETOP 2-11 BELIEF

An open-label phase II trial of erlotinib and bevacizumab inpatients with advanced non-small cell lung cancer and

activating EGFR mutationsSample seize 102 patients, coordinating group SLCG

2 |

ETOP 5-13 SPLENDOUR3 |

A randomized phase III trial evaluating the addition of denosumab tostandard first-line anticancer treatment in advanced NSCLC

1000 randomized patients, coordinating group EORTC, partner groupsCECOG, SLCG, GFPC, and SAKK

All SAKK center

ETOP 4-13 STIMILI

A randomized phase II trial of consolidation ipilimumab vs placebo inlimited-stage SCLC after chemoradiotherapy

260 randomized patients, partner group IFCT

4 |

Clinical trials under discussion

• Afatinib in advanced disease NSCLC second or later line inpatients with HER2 mutation: Afatinib

• PD-1 consolidation in stage III NSCLC treated with chemo-radiotherapy

5 |

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

6 | Lungscape project: Stepwise evolution

Step 1:Retrospective analysis at least 2400 completely resectedNSCLC with at least 3 years of follow-up from up to 18 sites:Mutation testing, immunohistochemistry, selected FISH onformalin-fixed, paraffin-embedded tumor tissue withstandardized protocolsstandardized protocols

• Step 2:Expansion to prospective study on biopsies from advanceddisease

• Further steps and issues under considerations:Enlargement of biobank, next generation sequencingsequencing, circulating biomarkers, technology platforms,resource utilization and health economics research

ETOP | Activities | March 5, 2013

Belgium

• Leuven:J. Vansteenkiste,E. Verbeken, C. Dooms

Denmark

• Aarhus:P. Meldgaard, H. Hager

Greece

• Frontier Science Hellas:U. Dafni

Ireland

• Dublin:

Outside of Europe

• China – Shanghai ChestHospital: S. Lu, Z. Jie

• USA – Roswell Park CancerInstitute: R. Cheney

Spain

• Barcelona:E. Felip, J. Hernandez-Losa, M. T. Salcedo, M.Canela

• Badalona:R. Rosell, M. Taron

• Valencia:C. Camps, M. Martorell,E. Jantus-Lewintre

Switzerland

• ETOP CoordinatingCenter:A. Hiltbrunner, S. Peters,R. Kammler, R. King,• Dublin:

K. O’Byrne, S. Finn,S. Gray

Italy

• Chieti:

A. Marchetti, S. Malatesta

• IEO Milano:,

Poland

• Gdansk:R. Dziadziuszko,W. Biernat, A. Sejda,A. Wrona

R. Kammler, R. King,R. Stahel

• Basel:L. Bubendorf, S. Savic

• Zurich:W. Weder, A. Soltermann

The Netherlands

• Amsterdam VU (E.Thunnissen, E. Smit

• Amsterdam NKI: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

Gemany

Heidelberg:T. Muley, A. Warth

Lungscape projects 2013/2014

• TNM outcome (2400 cases, submitted)

• ALK IHC and FISH (1000 cases, in revision)

• MET project (2600 cases)

• MET IHC on full sections

8 |

• MET IHC on full sections

• MET CISH on TMA

• PIK3CA project (2600 cases)

• PTEN IHC on TMA

• PIK3KI CISH on TMA

• Multiplex genetic testing (2400 cases)

• RANK/L

• PDL1

9 | Lungscape project: Stepwise evolution

Step 1:Retrospective analysis at least 2400 completely resectedNSCLC with at least 3 years of follow-up from up to 18 sites:Mutation testing, immunohistochemistry, selected FISH onformalin-fixed, paraffin-embedded tumor tissue withstandardized protocolsstandardized protocols

• Step 2:Expansion to prospective study on biopsies from advanceddisease

• Further steps and issues under considerations:Enlargement of biobank, next generation sequencingsequencing, circulating biomarkers, technology platforms,resource utilization and health economics research

ETOP | Activities | March 5, 2013

Lungscape step 2: SOAR-lung - Survival impact ofmolecular based treatment decisions inadvanced non-small cell lung cancer

Primary objective:

• Overall survival improvement of an advanced NSCLCprospective cohort with treatment decision based on tumormolecular characterization as compared to matched historical

10 |

molecular characterization as compared to matched historicalcohort

Design:

• Prospective cohort: 900 newly diagnosed patients, tested forsame biomarkers, optimal targeted therapy available ifappropriate, follow-up

• Retrospective cohort: 2:1 clinically matched from clinical trialdatabases

Cluster-design for future clinical trials11 |

TrialA

TrialB

TrialC

TrialD

TrialE

TrialF

Platform for molecular testing, shared by participating sites,supported by public-private partnership

TrialA

TrialB

TrialC

TrialD

TrialE

TrialF

Cost efficacy of shared mutation platform

• Separation of costs for screening and clinical trial

• Shared costs for screening and mutation platform

• Coordination

12 |

• Coordination

• Informed consent and regulatory affairs

• Shippments of samples

• Analyses

• Data capturing

• Separate costs for clinical trials

A Phase II Genotype-Based Multi-agent Study inAdvanced NSCLC

13 |


14 |


15 |

EORTCEORTC protocolprotocol 13351335

SPECTAlung: Screening ProgramSPECTAlung: Screening Programfor Efficient Clinical Trial Accessfor Efficient Clinical Trial Access

in Thoracic Tumorsin Thoracic Tumorsin Thoracic Tumorsin Thoracic Tumors

Study CoordinatorStudy Coordinator Benjamin BesseBenjamin Besse

EORTCEORTC –– ETOP collaborationETOP collaboration

Primary objective

Establish a platform for screening patients with thoracic cancer andefficiently allocate them to biomarker-driven clinical trials

Secondary objectives

Identify or validate new molecularly defined subgroups of tumors;

Objectives and Endpoints

Investigate the prevalence of novel biomarkers to plan futureclinical trials;

Perform exploratory/future research;

Facilitate the establishment of quality-assured and validated testsfor thoracic cancer biomarkers.

• Pathologically confirmed

lung cancer (including NSCLC and SCLC)

malignant pleural mesothelioma

thymoma or thymic carcinoma;

• Availability of HBM:

FFPE tissue sample from the primary tumor, recurrent tumor, metastasis, PD site,liquid biopsy at time of primary diagnosis, liquid biopsy at time of recurrence, liquidbiopsy at regular timing during FU, liquid biopsy at time of PD.

Inclusion criteria

biopsy at regular timing during FU, liquid biopsy at time of PD.

• Age ≥ 18 years;

• Written informed consent according to ICH/GCP and national/local regulations;

• Absence of exclusion criteria like active hepatitis B/C or HIV, secondmalignancies, no severe organ dysfunction or other comorbidities that mayprevent inclusion into clinical trials

• Life expectancy > 3 months

Genetic alterations in lung cancer

Genetic alterations in advanced NSCLC

Gene Type of alteration Adenok SCC

KRAS Mutation 15-20% 6%

EGFR Mutation 10-15% <5%

ALK Rearrangement 6-8% 1%

MET Amplification 2-15% 2-15%

BRAF Mutation 2-4.9% 2%

Genetic alterations in advanced SCLC

Gene Type of alteration Prevalence (%)

p53 Mutation 75 to 90

PTEN Mutation 10

FGFR1 Amplification 6

HER-2 Mutation 2.8% 1%

PIK3CA Mutation 1.5-2.6% 4%

ROS1 Rearrangement 1.2-2.6% Unknown

RET Rearrangement 1.2-1.9% Unknown

FGFR1 Amplification 1% 20%

PTEN Mutation 2% 10%

AKT1 MutationVeryrare

6%

DDR2 Mutation 2% 4%

SOX2 Amplification 27

PLF-MYCL1

Rearrangement 9

RB1 Rearrangement 40

MYC Amplification 20

Status of SPECTAlung project and questions

• Platform protocol development:

• EORTC Benjanim Besse, Rafal Dziadziuszko DenisLacombe

• ETOP Rolf Stahel, Solange Peters, Stephen Finn

• Masterprotocol:

21 |

• Masterprotocol:

• Developed by Thanyan Reungwettana, senior fellow withAlex Adjei

• Now to be adapted by Rafal Dziadziuszko and SolangePeters

• Questions to pathologist:

• Pathology review?

• Block versus slides

Centers (hubs) asked for interest of participation

• Enriqueta Felip, Vall d'Hebron University Hospital (Barcelona, Spain);

• Benjamin Besse, Institute Gustave Roussy (Paris, France);

• Julien Maiser, Hôpital Larrey (Toulouse, France);

• Rolf Stahel University Hospital Zurich (Zurich, Switzerland) or SolangePeters, (CHUV)

• Thomas Gauler, Universitätsklinikum Essen Innere Klinik (Essen, Germany);

• Martin Reck, Center of Pneumology and Thoracic Surgery (Grosshansdorf,

22 |

Germany);

• Jean-Paul Sculier, Insitute Jules Bordet (Brussels, Belgium);

• Johan Vansteenkiste, Institute KU Leuven (Leuven, Belgium);

• Egbert Smit, VU University Medical Center (Amsterdam, Netherlands);

• P. Meldgaard, H. Hager to be confirmed (Aarhus, Denmark)

• Sanjay Popat, Royal Marsden Hospital (Sutton, United Kingdom);

• Steven Finn, St James Institute (Dublin, Ireland);

• Silvia Novello, AOU San Luigi Gonzaga (Orbassano [TO], Italy)

• Rafal Dziadziuszko, Medical University of Gdansk (Gdansk, Poland).

CLIA whole exome plus whole

CTIG clinical NGS laboratory

Bringing the power and depth of comprehensive integrated

genomic analysis to patients in a clinical timeframe

CTIG’s clinical cancer genomics laboratory

SAN FRANCISCO, CA CLIA whole exome plus whole

transcriptome tumor analysis

Follow patients longitudinally from

diagnosis throughout patient’s life,

defining therapeutic targets at

each point along clinical course

Rapid turnaround

Lung cancer focused

CTIG clinical NGS laboratoryCTIG comprehensive cancer genomics analysis

Case reviewDetailed review of medical history and microscopic evaluations of tumor

histopathology.

Somatic mutation analysisDeep whole exome sequencing (21,522 genes) at an average coverage of

200x

COMPREHENSIVE CANCER GENOMICS ANALYSIS (CCGA) SUMMARY

Copy number analysisHigh resolution amplification and deletion detection across entire genome

using low pass whole genome sequencing.

Fusion gene detection Known and novel cancer fusion gene detection.

Whole transcriptomeUltra-deep total RNA-sequencing enabling comprehensive gene expression

analysis including mutant allele expression.

Pathway analysisComprehensive cancer pathway analysis integrated with somatic mutation,

copy number and fusion gene data.

Therapeutic annotationDetailed discussion of therapeutic implications of analysis with information

regarding available drugs and relevant clinical trials.

CTIG clinical NGS laboratoryCTIG CCGA tissue requirements and processing

TISSUE REQUIREMENTS

Tissue options Amount required Processing information

Frozen tissue 10 mg or 2 needle corebiopsies

Snap freeze tissue in 2ml cryovial andstore at -80C until prearranged pickup byCTIG courier service.

Tumor and matched normal tissue needed for analysis:

NORMAL

TUMOR

Frozen tissue

biopsies CTIG courier service.

Collect blood in lavender top tube andstore at -80C until prearranged pickup byCTIG courier service.

FFPE block or unstained slides shouldbe delivered via express service (FedEx,DHL, UPS, etc) to CTIG.

Snap freeze tissue in 2ml cryovial andstore at -80C until prearranged pickup byCTIG courier service.

FFPE block or unstained slides shouldbe delivered via express service (FedEx,DHL, UPS, etc) to CTIG.

10 mg or 2 needle corebiopsies

FFPE

Peripheral blood

FFPE

FFPE block or 15-20unstained sections

FFPE block or 15-20unstained sections

3 ml

Thank you for listening!

www.etop-eu.org

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

28 | ETOP meetings

• March 26-29, 2014 Geneva:ETOP investigators meetings for SPLENDOUR and STIMULIduring ELCC,starting 2015 ETOP is official partner at ELCC

• August 27-29, 2014 Gdansk:Third ETOP residential courseThird ETOP residential course

• November 14-15, Vienna7th ETOP meeting

Genetic landscape of clinical resistance to

EGFR inhibition in EGFR-mutant NSCLC

Petros Giannikopoulos,1 John A. St. John,1 Joel S. Parker,2 Oscar Westesson,1 Nick Hahner,1 Niki Karachaliou,3

Carlota Costa,3 Cristina Texeido,3 Aleah F. Caulin,1 Urvish Parikh,1 Mitchell E. Skinner,1 Catherine K. Foo,1 KimberlyCarlota Costa,3 Cristina Texeido,3 Aleah F. Caulin,1 Urvish Parikh,1 Mitchell E. Skinner,1 Catherine K. Foo,1 Kimberly

Lung,1 Jeffrey Catalano,1 Maria D. Lozano,4 Santiago Viteri,3 Jose L. Perez-Gracia,4 Alessandra Curioni,5 Alex

Soltermann,5 Martina Storz.5 Maria Eloisa Jantus-Lewintre,6 Carlos Camps,6 Alain Vergnenegre,7 Radj Gervais,8

Jonathan Barry,1 George W. Wellde Jr.,1 Rolf Stahel,5 Andrés F. Cardona,9 Jonathan S. Weissman,1,11,13 William R.

Polkinghorn,1,10 Rafael Rosell,1,3,12,13 Trever G. Bivona1,14

AFFILIATIONS:

1. Cancer Therapeutics Innovation Group, San Francisco, CA, New York, NY. 2. University of North Carolina, Chapel Hill, NC. 3. Pangaea

Biotech S.L, Quirón Dexeus University Hospital, Barcelona, Spain. 4. Clínica Universidad de Navarra, Pamplona, Spain. 5. University Hospital

Zurich, Zurich, Switzerland. 6. Hospital General Universitario de Valencia, Valencia, Spain. 7. Service de Pathologie Respiratoire, Hôpital du

Cluzeau, Limoges, France. 8. Centre François Baclesse, Caen, France 9. Oncology Institute Fundación Santa Fe de Bogota, Bogota,

Colombia. 10. Memorial Sloan-Kettering Cancer Center, New York, NY. 11. Howard Hughes Medical Institute. 12. Catalan Institute of Oncology,

Barcelona, Spain. 13. Molecular Oncology Research (MORe) Foundation, Barcelona, Spain. 14. University of California, San Francisco, San

Francisco.

Pre-treatment

EGFRTKI

Acquired resistance

Background

Mechanisms of resistance

NF-KB

AKT

PIK3CA

MEK

ERK

AXL

EGFR

EMT

HER2

AXL

MAPK1

MET

PIK3CA

T790M

Mechanisms of resistanceto EGFR TKIs (NSCLC)

METHER2

P

GAS6

20-25%upregulated

5%amp

>50%T790M

12%amp

5% amp

5%mutated

PP

PP

PP

Mechanisms of resistanceto EGFR TKIs (NSCLC)

PATIENTGENDER

(M/F)AGE AT

DIAGNOSISSMOKINGSTATUS

EGFR STATUSBEFORE TKI

TKIPRE-TREATMENT

HISTOPATHOLOGY

ANATOMIC SITE OF BIOPSIESHISTOPATHOLOGY

TRANSITIONTTP

(MONTHS)

PRE-TKI RESISTANCE

1 M 57 Unknown Exon 19 del Erlotinib AdenocarcinomaLeft cervicallymph node

Skin None 16.0

2 F 39 Never smoker Exon 19 del Erlotinib Adenocarcinoma Lung Lung None 9

3 F 67 non-smokerExon 19 del p. L747-

A750Erlotinib Adenocarcinoma

Subcarinal lymphnode

Left adrenal gland None 40.0

4 F 49 Never smokerExon 19 del p.

747L_751TErlotinib Adenocarcinoma

Lung, leftlower lobe

Brain None 9.0

5 F 46 Former smokerExon 19:del p.

746E_750AErlotinib Adenocarcinoma

Lung, rightupper lobe

Left supraclavicularlymph node

None 34.0

6 F 58 Former smokerExon 19 del p.

746E_750AErlotinib Adenocarcinoma

Bone, lumbarvertebra

Right supraclavicularlymph node

None 10.1

Clinical and pathological characteristics of patient cohort

6 F 58 Former smoker746E_750A

Erlotinib Adenocarcinomavertebra lymph node

None 10.1

7 F 61 Unknown Exon 21 p.L858R Erlotinib Adenocarcinoma Lung Brain None 15.1

8 F 49 Never smoker Exon 19 del Erlotinib Adenocarcinoma Lung, primary Liver metastasis None 9.6

9 F 62 Never smoker Exon 19 del Erlotinib Adenocarcinoma Lung, primary Lung metastasis None 16.2

10 M 61 Former smokerExon 20 c.G>A

p.Q787QErlotinib Adenocarcinoma Lung Cerebellum None 14.7

11 M 75 Never smokerExon 19 p.A750P;

Exon 19 del

p.L747_E749Erlotinib Adenocarcinoma

Lung, left lowerlobe

Lung, left lowerlobe

None 12.0

12 F 74 Never smoker Exon 21 p.L858R Erlotinib Adenocarcinoma Lung Lung None 3.8

13 M 49 Unknown Exon 21 p.L858R Gefinitib Adenocarcinoma Lung Brain None 16.0

14 F 59 Smoker Exon 21 p.L858R Gefinitib Adenocarcinoma Lung Lung None 9

15 F 47 SmokerExon 19 del

p.L747_T751Gefinitib Adenocarcinoma Lung Lung None 7.0

16 M 46 Never smoker Exon 21 p.L858R Erlotinib Adenocarcinoma Lung, left Brain None 25.0

Average age: 56.2 Average time to progression: 15.4

PAT BIOPSYEGFRT790M

GENES WITHSOMATIC

MUTATIONS

FUSIONGENES

COPY NUMBER ALTERED GENES EXPRESSION CHANGE UPON RESISTANCE

AMPLIFICATION DELETION AXL DUSP6 ERBB2 GAS6 MAPK1 MET FGFR1

1Pre-treatment

Yes YesPost-resistance Present KIT, KRAS, PDGFRA,

PIK3CA, SMOEGFR BRCA2, FLT3, GAS6

2Pre-treatment KRAS

Yes Yes YesPost-resistance Present

3Pre-treatment MET

No RNA-seq dataPost-resistance Present MYH11, RXRA MET

4Pre-treatment

YesPost-resistance Present EGFR, SMO, MET

5Pre-treatment EGFR BRCA2, FLT3, FGFR1

Yes YesPost-resistance Present

6Pre-treatment TP53, GAS6, RXRA, FLT3,

BRCA2

***

Somatic variants, CNAs, and expression changes acrosscohort for genes of interest and known MORs

6Pre-treatment

BRCA2 No RNA-seq dataPost-resistance Present SMO, MET TP53

7Pre-treatment EGFR

YesPost-resistance MLL RXRA

8Pre-treatment EML4-ALK

YesPost-resistance EML4-ALK

9Pre-treatment

Yes Yes YesPost-resistance KRAS

10Pre-treatment BRCA2

Yes Yes YesPost-resistance FLT3, RXRA

11Pre-treatment MYH11

Yes Yes YesPost-resistance TPM3-ROS1

12Pre-treatment

Yes Yes YesPost-resistance

13Pre-treatment

Yes Yes Yes YesPost-resistance CTNNA2

14Pre-treatment

Yes Yes Yes Yes YesPost-resistance FGFR1

15Pre-treatment EGFR

No RNA-seq dataPost-resistance EGFR

16Pre-treatment

Yes YesPost-resistance SMAD4

*

**

FGFR1 in resistance:

ERBB2 in resistance:

Patients

1 2 7 10 1113 12 14 45 8916

ERBB2BCR

ADCY9

ITPR3AKT2

PDPK1

ADCY6NRG2

PLCG1

HRAS

PHLPP1

AKT1

PRKCA

NRG1BAD

Patient #:1 271011 1312 14458 916

T790M - :

T790M + :

WSB2CKS18

PAICS

RRM1

HATQ

PCNA

CDK4GINS2

SNRPB

HIST1H4CPTMA

SLBP

PA2G4

MAD2L2

TMX1

MLF1P

MGAT2

STMN1

CDC6

Patient #:

Gene set analysis of post-resistance versus pre-treatmentgene expression profiles

Gene sets

ERBB2 signaling

FGFR in disease

Activated FGF

BAD

MATK

CUX1TRIB3

MLST8

PRKAR2AMAPKAP1

THEM4

FOXO4

FGF1

ADCY7

KL

PTENFGFR1OP2

CAMK4

PARKACBPDE1A

FGF2

FOXO1

FGF7

NRAS

CHUK

STAT1

CDC6

C16orf61TOPBP1

KIAA0090

ATP5G2

YY1PRMT5

FEN1

DAXXUNG

MCM3

CDK2PRKDC

LMNB1

CCNB2

GINS1WDR76

NUSAP1

CDT1RBL1

CDK1

EZH2

UMPSSLK

CDKL5

PCDHB15MARCH10

JPH2

SMAD3PCDHB4

SPAG17

SOX5

MST1C19orf11

Fold change

Log2 (Post/Pre)

1.6-1.6 -0.8 0 0.8

Gene sets associated with T790M+

Cell cycle

Genome integrity

Epigenetic

Gene sets associated with T790M-

Stem cell/de-differentiation

Fold change

Log2 (Post/Pre)

1.6-1.6 -0.8 0 0.8

Sharedmutations (132)

Unique post-Rxmutations (136)

Unique pre-Txmutations (153)













1.00




Greater clonal divergence and genome copy numberalteration in T790M+ vs. T790M- cases

Patientsp = 0.129

Div

erg

ence

sco

re

T790M -

2 4 5 15 11

0.00

0.25

0.50

0.75

T790M +6

yn

um

ber

alte

red

0.20

0.25

0.30T790M +

Patient 2

Patient 6

Patient 4

1 210 11 1312 14 4 58 9 16 7

T790M - :

T790M + :

REV1

POLL

PRKDC

Patient #:

Gene set analysis of post-resistance versus pre-treatmentgene expression profiles

p = 0.023

Pro

po

rtio

nofg

eno

me

copy

Pre-treatment Post-resistance

0.00

0.10

0.15

0.20

0.05

T790M -

Patient 5

Patient 2

Patient 16 (pre only)

Patient 11

Patient 7 (post only)

Patient 9

Patient 15

PCNA

FANCD2

MAD2L2

UNG

FEN1

POLE3

DNA repair associated gene sets

KEGG base excision repair

REACTOME DNA repair

KEGG mismatch repair

REACTOME DS break repair

REACTOME NE repair

Fold change

Log2 (Post/Pre)

1.6-1.6 -0.8 0 0.8

3

4

5

be

ra

lte

ratio

n

13

14

Am

RN

Ae

xp

ressio

n

15

Correlation of NFKBIA copy number and expressionwith EGFR TKI response

0 10 20 30 40

1

2

3

TTP (months)p = 0.0025

NF

KB

IAco

py

nu

mb

r = 0.89

0 10 20 30 40

10

11

12

TTP (months)p = 0.013

No

rma

lize

dN

FK

BIA

r = 0.66

• SPECTAlung: a standardized, quality-assured molecular screeningplatform for tumor characterization and storage of HBM forintegrating new biomarkers into clinical trials.

• HBM and clin/pathological data are collected from consenting pts.

• Molecular biomarkers are assessed to determine eligibility fortherapeutic biomarker-driven trials.

• Downstream trials may enroll pts at any stage of disease evolutionand treatment.

Concept overview

and treatment.

• Longitudinal patient FU and data collection for all SPECTAlung ptsuntil death or loss to FU will help

The matching process of eligible pts with clinical trials

Answer further research questions (e.g. comparison of first with secondprogression, survival beyond progression, sequencing of treatments, andsurvivorship issues)

Workflow

Laboratories

Structure of the screening platform

Participating sites - requirements Signature of the Consortium Agreement; Local or Central Ethics Committee approval; After patient's consent, sending appropriate HBM to central laboratories; Considering participation in downstream clinical trials; Maintaining updates of clinical and pathological database entries.

Laboratories Designated central laboratories for initial review of the quality of the obtained HBM

and confirmation of the histological diagnosis;

Local diagnostic laboratories that have performed biomarkers analysis underquality guidance;

Designated central diagnostic and research laboratories performing screeninganalyses, including non-EORTC academic or contracted commercial laboratories;

Research laboratories performing analyses within the frame of exploratory/futureresearch projects.

Documents

ETOP 2-11 BELIEF - samo-workshop.ch · 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