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 |
A Phase II Genotype-Based Multi-agent Study inAdvanced NSCLC
14 |
A Phase II Genotype-Based Multi-agent Study inAdvanced NSCLC
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)
Unique post-Rxmutations (144)
Sharedmutations (85)
Unique pre-Txmutations (14)
Sharedmutations (148)
Unique post-Rxmutations (84)
Unique pre-Txmutations (55)
Sharedmutations (129)
Unique post-Rxmutations (8)
Unique pre-Txmutations (21)
Sharedmutations (107)
Unique post-Rxmutations (256)
Unique pre-Txmutations (275)
1.00
Sharedmutations (88)
Unique post-Rxmutations (23)
Unique pre-Txmutations (9)
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.