Les nouvelles cibles potentielles

Les nouvelles cibles potentielles Benjamin Besse, MD, PhD Responsable Pathologies Thoraciques 23 / 03 / 2013

DÉCLARATION DE CONFLITS D INTÉRÊTS J ai, ou ai eu durant les trois dernières années, une affiliation, des intérêts financiers (rémunération/ bourse/ honoraires) ou intérêts autres avec un organisme industriel ou commercial : de type : Investigateurs pour des essais cliniques ou bourse de recherche Eurocancer 2012 avec la (les) société(s) : Abbott, Amgen, AstraZeneca, Boehringer-Ingelheim, Lilly, Pfizer, Roche-Genentech, Sanofi-Aventis, Clovis, GSK 2

Median OS (months) OS in NSCLC patients 24 1L EGFR Mut+ Maintenance trials 1L trials Recruitment EGFR Mut+ NEJSG 002 16 First-SIGNAL 15 EURTAC 14 IPASS 12 OPTIMAL 13 18 12 All-comers Schiller 1 E4599 4 AVAiL8 Scagliotti 2 Gatzemeier 5 Giaccone 6 Alberola 3 Non-PD after 4 cycles Scagliotti 7 ATLAS 9 AVAPERL 10 PARAMOUNT 11 6 1995 2000 2005 2010 1. Schiller, et al. NEJM 2002; 2. Scagliotti, et al. JCO 2002; 3. Alberola, et al. JCO 2003; 4. Sandler, et al. NEJM 2006; 5. Gatzemeier, et al. JCO 2007 6. Giaccone, et al. JCO 2004; 7. Scagliotti, et al. Clin Cancer Res 2005; 8. Reck, et al. Ann Oncol 2010; 9. Kabbinavar, et al. ASCO 2010 10. Barlesi, et al. EMCC 2011; 11. Paz-Ares, et al. ASCO 2012; 12. Fukuoka, et al. JCO 2011; 13. Zhou, et al. ASCO 2012 14. de Marinis, et al. EMCC 2011; 15. Han, et al. JCO 2012; 16. Maemondo NEJM 2010 3

A.M.M. nouveaux agents Cible Hémat o Melanome Rein Sein CBNPC ORL Glivec (imatinib) C-kit / bcr X X Sprycel (dasatinib) Bcr X Tasigna (nilotinib) Bcr X Mabthera (rituximab) CD20 X Mabcampath (alemtuzumab) CD52 X Avastin (bevacizumab) VEGF X X X X Nexavar (sorafenib) VEGFR X X Sutent (sunitinib) VEGFR X Votrient (pazopanib) VEGFR X Torisel (Temsirolimus) mtor X Affinitor (everolimus) mtor X Vemurafemib BRAF BRAFmut X Erbitux (cetuximab) EGFR X X KRASwt Vectibix (panitumumab) EGFR X Tarceva (erlotinib) EGFR X X EGFRmut Iressa (gefitinib) EGFR X Herceptin (trastuzumab) HER2 X HER2+++ Tykerb (lapatinib) HER2 X Xalkori (Crizotinib) ALK ALK+ GI 4

Mutations activatrices, CBNPC EGFR Mutation found in 50% MET TOP1 FGFR1 BRAF HER2 PI3K FGFR4 NRAS PDK1 KDR ALKampl ALK STK11 KRAS No mutation No mutation detected 48% KRAS (24%) EGFR (11%) STK11( 7%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) FGFR1 (amplification) (1%) ALK amplification (2%) Planchard, ELCC 12 5

EURTAC erlotinib arm Rosell Lancet Oncol 12 6

A perspective on EGFR Clinical results Phase III: EURTAC Erlotinib approved 2/3rd line Phase III: BR21 Phase III: ipass Erlotinib approved based on EGFR mutation Gefitinib approved based on EGFR mutation Phase II erlotinib / gefitinib EGFR mutation described EGFR mutations EGFR mutation: a marker of sensitivity 7 7

ATU?? Exemple EGFRmut Absence 52 Exon 18 mut (silence) 1 Ppolymorphisme exon 20 73 Del l exon 19 10 Double mutation exon 18 (E709K) et exon 21 (L858R) 1 Double mutation exon 18 (I706Y) et exon 21 (L858R) 1 Double mutation exon 18 (T725M) et exon 21 (L858R) 1 Double mutation exon 19 et 20 1 Double mutation exon 20 (S768I et V774M) 1 Double mutation exon 21 (L858R et L858M) + polymorphisme exon 20 1 Double mutation exon 21 (L858R et V834L) 1 Mutation de l exon 21 (A864T) et polymorphisme exon 20 1 Mutation de l exon 21 (L858R) et polymorphisme exon 20 2 Mutation exon 19 et 20 1 Mutation exon 20 (Q787Q) 1 Mutation exon 20 (T790M) et délétion de l exon 19 1 Mutation exon 21 1 HKI-272 Mutation exon 21 (L858R) 7 Mutation exon 21 (L861Q) 1 Polymorphisme R836R exon 21 1 Not done (no tissue, not enought cells ) 44 8 Sequist, JCO 10

Mutations activatrices, CBNPC EGFR Mutation found in 50% MET TOP1 FGFR1 BRAF HER2 PI3K FGFR4 NRAS PDK1 KDR ALKampl ALK STK11 KRAS No mutation No mutation detected 48% KRAS (24%) EGFR (11%) STK11( 7%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) FGFR1 (amplification) (1%) ALK amplification (2%) Planchard, ELCC 12 9

Decrease or increase from baseline (%) EML4-ALK : efficacité du crizotinib Inhibiteur ALK & c-met/hgfr - PF-02341066 50 (phase I) Best percent change in tumor size Taux 20 de réponse : 59% (IC 95%: 39-76%) 10 40 70 100-30% PD SD PR CR N=82 Y.Bang ASCO 2010 10

A perspective on ALK Clinical results First results crizotinib in ALK+ patients Approval (US) crizotinib in ALK+ patients 4 years EML4-ALK translocation discribed in NSCLC ALK Translocation 11

Mutations activatrices, CBNPC EGFR Mutation found in 50% MET TOP1 FGFR1 BRAF HER2 PI3K FGFR4 NRAS PDK1 KDR ALKampl ALK STK11 KRAS No mutation No mutation detected 48% KRAS (24%) EGFR (11%) STK11( 7%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) FGFR1 (amplification) (1%) ALK amplification (2%) Planchard, ELCC 12 12

A perspective on KRAS Clinical results Cetuximab approval in CCR restricted to K-RASwt pt 1 st publication on K-RASmut & cetuximab cetuximab approved in CCR Panitumumab in K-RASwt pt 26 years mutation K-RAS: 1/3 of CCR mutation K-RAS described KRAS Mutations K-RAS mutation: a marker of resistance 13

K-RAS mutation and smoking status % 35 30 25 20 15 10 5 0 Riely 481 (100% ADK) Sugio 322 (100% ADK) Sequist 546 (78% ADK) Ortiz 331 (85% ADK)* Never Smoker Former smoker Current smoker Studies > 100 patients * approx Riely et al. Clin Can Res 2008; Sugio et al. Br J Cancer 2006; 14 Ortiz #7517 ASCO 2011, Sequist #7518 ASCO 2011

K-RAS mutation and smoking status Riely et al. Clin Can Res 2008 15

Meta-Analysis Prognostic Significance of K-RAS All NSCLC (n=2631) HR:1.40; CI 95% 1.18 1.65. Adenocarcinoma (n=1170) HR=1.50; CI 95% 1.26 1.80 Heterogeneity P=0.03 Heterogeneity P=0.10 Univariate analysis Clinical heterogeneity between studies for stage (I-IV) and treatment received Mascaux et al. Br J Cancer, 2005 16

Incidence of single driver mutations Mutation found in 52% BRAF HER2 MET TOP1 ALK NRAS PDK1 KDR PI3K FGFR4 STK11 EGFR KRAS No mutation Squamous cell carninoma (18pts) mutation in 22% -1 KRAS mut -1 STK11 mut -1 PDK1 mut -1 FGFR1 amplification No mutation detected 48% KRAS (24%) EGFR (11%) STK11( 7%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) FGFR1 (amplification) (1%) ALK amplification (2%) 17

Melanome V600E BRAF mut et Vemurafenib PFS : 1.6 vs 5.3 months Flaherty, NEJM 10 18

Erlotinib & NSCLC EGFRmut Crizotinib & NSCLC ALK+ Vemurafenib & melanoma BRAFmut Kwak, NEJM 10, Chapman, NEJM 11, Shaw ASCO 2012, Rosell Lancet Oncol 12 19

How are the «BRAFmut patients» N=18 of 687pts Paik JCO 12 20

How are the «BRAFmut patients» N=18 of 687pts Paik JCO 12 21

BRAF mutation s ½ of BRAF mutations Which prognosis? N=18 of 687pts Paik JCO 12 22

Mutations activatrices, CBNPC EGFR Mutation found in 50% MET TOP1 FGFR1 BRAF HER2 PI3K FGFR4 NRAS PDK1 KDR ALKampl ALK STK11 KRAS No mutation No mutation detected 48% KRAS (24%) EGFR (11%) STK11( 7%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) FGFR1 (amplification) (1%) ALK amplification (2%) Planchard, ELCC 12 23

MET mutations in human solid tumours 24 Ma et al. Genes Chromosomes Cancer 2008;47:1025-37

MET gene mutations and c-met overexpression are well documented in NSCLC MET mutation* Adenocarcinoma (%) 1.6 3.3 10 Squamous cell carcinoma (%) Large cell carcinoma (%) MET gain/ amplification c-met expression IHC HGF expression IHC * Somatic mutations 1.4 4.1 21 67 69 39 57 57 57 Transcriptional regulation of MET controlled by PAX8 in NSCLC MET amplification correlates with Paxillin expression IHC, immunohistochemistry Ma et al. Cancer Res 2005;65:1479-88 Beau-Faller et al. J Thorac Oncol 2008;3:331-9 Onitsuka et al. J Thorac Oncol 2010;5:591-6 Tanizaki et al. Br J Cancer 2011;105:807-13 Onozato et al. J Thorac Oncol 2009;4:5-11 Sattler et al. Ther Adv Med Oncol 2011;3:171-84 25

Activation par HGF/MET 26 Gherardi E., Nat. Rev. Cancer 2012

Mutations activatrices, CBNPC EGFR Mutation found in 50% MET TOP1 FGFR1 BRAF HER2 PI3K FGFR4 NRAS PDK1 KDR ALKampl ALK STK11 KRAS No mutation No mutation detected 48% KRAS (24%) EGFR (11%) STK11( 7%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) FGFR1 (amplification) (1%) ALK amplification (2%) Planchard, ELCC 12 27

HER2 mutation Mazières, ELCC 12 28

Decrease or Increase From Baseline (%) ROS/crizotinib et RET ASIAN (n= 412) Summary of Tumor Responses in Patients with Advanced ROS1+ NSCLC (N=14*) 100 Unknown 25% EGFR 56% 80 60 Response Rate 57% 40 20 0 20 40 60 80 100 15+ 16+ 18+ 4+ PD SD PR CR *Response-evaluable population. Tumor ROS1 FISH-positive, but negative for ROS1 fusion gene expression. Crizotinib held for >6 wks prior to first scans which showed PD. 12+ 8+ 22+ 18 44+ 20+ 35+ 48+ KIF5B-RET 2.3% CD74-ROS 0.7% BRAF 1% HER2 3% EML4-ALK 7 % KRAS 5% Shaw ASCO 2012, Capelletti M ASCO 2012 29

Carcinomes épidermoïdes Perez-Moreno P et al CCR 2012 30

FGFR family FGFR1, 2, 3, 4 18 ligands Transmembrane tyrosine kinases MAPK activation 31 Turner N, Nature Reviews Cancer, 2010

FGFR1 amplification: 10% of SCC patients 32

Candidate drugs: non selective FGFR inhibitors 33

Antitumor activity of EOS3810 Soria, TAT, 2012 34

Lung SCC at 100 mg BJG398: PR baseline day 28 baseline day 56 Confirmed PR at D56 patient presently in 7 th cycle of treatment Wolf et al. AACR 2012 35

DDR2 Discoidin domain receptor 2 (DDR2) is a tyrosine kinase binds collagen as its endogenous ligand, And when activated interacts with Src Dasatinib, imatinib, nilotinib, and ponatinib target BCR/ABL, SRC, c-kit, and multiple Eph kinases, and also inhibit DDR1 and DDR2 Dasatinib has limited activity in NSCLC, but some cases with impressive ORR have been observed (is DDR2 mutation the reason => ongoing trial) 36

37 PI3K Pathway Inhibitors Isoform-specific Inhibitor Pan-PI3K Inhibitor Dual PI3K/mTOR Inhibitor mtor Inhibitor α α β γ Akt δ α β γ δ α β γ δ Isoform-specific PI3K inhibitors block signaling through one particular isoform of PI3K 1,2 Pan-PI3K inhibitors block signaling through all PI3K isoforms 1,2 mtorc1 Akt mtorc2 Dual PI3K/mTOR inhibitors block 1,2 : All PI3K isoforms Both mtorc1 and mtorc2 as mtor catalytic site inhibitors mtorc1 mtorc2 Allosteric mtor inhibitors such as rapamycin mainly inhibit mtorc1, but may have some efficacy against mtorc2 3,4 37

PD-L1 Topalian NEJM 12 38

Nouvelles cibles potentielles : déjà une routine? 39

28 French molecular genetics centres Lille Brest Rennes Caen Rouen Reims Nancy Strasbourg/ Mulhouse/ Colmar Angers Tours Nantes Poitiers Dijon Besançon Bordeaux Limoges Clermont Lyon Ferrand St Etienne Grenoble Toulouse Montpellier/ Nîmes Marseille Nice St Cloud/ Paris (2) : AP-HP, Curie Versailles Villejuif 40

Molecular screening activity in 2012 for lung cancer Biomarker Number of patients EGFR mutations 21,921 KRAS mutations 21,025 BRAF mutations 13,376 PI3KCA mutations 13,713 HER2 mutations 14,466 ALK translocation FISH IHC 13,858 8,696 tests 11,550 tests 41

Mutation rate in lung cancer 30% 27% 20% 10% 0% 10% 2% 2% 1% EGFR act KRAS BRAF PI3KCA HER2 ALK translocation rate : IHC : 4.2% FISH : 6.3% ~250 pts! 42

MSN : un essai thérapeutique biologique Plateformes INCa Mutations EGFR, KRAS BRAF, HER2, PI3KCA FISH ALK Financement INCa Plateforme IGR CGH +/- FISH HER2 FGFR1 MET Financement IGR + partenariat Industrie Plateforme IGR Mutations MET, AKT1, FGFR2, FGFR3, CTNNB1, NRAS, TOP1,TOP2A, STK11, PTEN, FLT3, FCGR2A, FGFR4, FGFR2, TSC1, TSC2, PTEN, ERCC1, ERBB4, KDR, ALK, PDPK1 Financement IGR + Europe (FP6) 43

MSN enrollment as of May Consented patients n=250 Pending analysis Study Group n=100 09/01/2010 to 06/01/2011 incomplete genomic analysis insufficient tumor cells or poor quality DNA 9pts 91 Multiplex mutation testing 44

Baseline Patients characteristics Sex Histology Stage Smoking status Patients Characteristics N (%) Median age (range) 60 (33-79) Male 64 (64%) Female 36 (36%) Adenocarcinoma 70 (70%) Squamous cells 18 (18%) Others 12 (12%) II 4 (4%) III 21 (21%) IV 75 (75%) never smoker 15 (15%) Former smoker 68 (68%) Current smoker 17 (17%) 45

OS and PFS 46

Tumor samples Source of diagnosis Bronchoscopy 48 CT scan guided biopsy 39 Surgical biopsy 4 Other 9 Squamous Cell Ca Adenocarcinoma Necrosis Fibrosis Adequate Biopsies Inadequate Biopsies 47

Incidence of single driver mutations Mutation found in 52% BRAF HER2 MET TOP1 ALK NRAS PDK1 KDR PI3K FGFR4 STK11 EGFR KRAS No mutation Squamous cell carninoma (18pts) mutation in 22% -1 KRAS mut -1 STK11 mut -1 PDK1 mut -1 FGFR1 amplification No mutation detected 48% KRAS (24%) EGFR (11%) STK11( 7%) ALK -EML4 (2%) NRAS (2%) BRAF (2%) PDK1 (2%) HER2 (1%) KDR (1%) MET (1%) PI3K (1%) TOP1 (1%) FGFR4 (1%) FGFR1 (amplification) (1%) ALK amplification (2%) 48

Concurrent mutations EGFR-EGFR 4 PDK1-MET 3 2 KRAS-PI3K 1 PDK1-KRAS 0 BRAF-HER2 STK11-KRAS STK11-NRAS 49

Treatment 91 Multiplex mutation testing Druggable Target KRAS mut Class MEKi Pi3Ki Drug GSK1120212 PF-04691502 BRAF V600E RAFi Pi3Ki GSK2118436 PF-04691502 48 (52%) Driver mutations found HER2 mut/ampl NRAS HER2i Pi3Ki MEKi PF-00299804 BIBW2992 PF-04691502 GSK1120212 PTEN Pi3Ki BKM120 20 (42%) Received therapy targeted to Specific mutation PI3KCA1 or PDPK1 FGFR mut/ampl LKB1 or STK11 ALK MET mut/ampl Pi3Ki Pi3Ki FGFRi LKB1i Meti METi PF-04691502 BKM120 AZD4547 CC-223 PF 02341066 ARQ197 Crizotinib 10 - erlotinib/gefitinb 10 - clinical trial of agent for identified mutation April 2012 Protocols linked to specific molecular lesions detected 50

Identification accidentelle d une nouvelle cible : que faire? 51

www.i-o-t.fr 52

Qu est qu une RCP moléculaire? RCP : réunion de concertation pluridisciplinaire Acteurs : Oncologues, radiothérapeutes, biologisteschercheurs, pharmaciens et anatomopathologistes. Compte rendu : meilleur traitement médical individualisé Patients atteints de cancers du poumon non à petites cellules avancés ou métastatiques, ayant déjà reçu un ou plusieurs traitements médicaux. Une réunion par mois 53

Attente patients/société Proposer des alternatives thérapeutiques justifiées Essais cliniques ATU Générer des hypothèses Recherche de transfert Nouveaux essais Limites thérapeutiques Accès traitement Application à la chirurgie, à la radiothérapie RCP Moléculaire RCP moléculaire Coût Tumeur dispo. Consommables Temps d analyse Rigueur scientifique 54

Homme 68 ans Tabagisme 60 P/A Urologue Mut BRAF V600E 31/05/12 Janvier à Octobre 2010 Pemetrexed Cisplatine Bevacizumab 6 cycles Pemetrexed Bevacizumab maintenance 55

Vemurafenib started 03/06/12 + 4 kg 31/05/12 19/06/12 SaO2 89% to 96% 56

MOSCATO I trial (PI: JC Soria) Prospective evaluation of integrated biology for treatment decision Institut Gustave Roussy Biopsy of metastatic sites Frozen sample CGH/hot spot mutations (96 amplicons) N=600 TUMOR BIOSPY SEQCan CGHarray Agilent Target discovery 14 working days to get the results! Clinical trials Phase I trials Primary endpoint MOSCATO PFS1/2 ratio > 1,3 = test the hypothesis that high throughput technologies improve outcome 57

MOSCATO M15 62 years old patient Castration resistant prostate cancer Bone and lymph nodes mets Previous Rx: agoniste LHRH, docetaxel, Inhibitor of androgen biosynthesis 01/2012: LN and bone progression Mutation TP53 Amp FGFR1, MYC, AR and PTEN loss Prostate cancer biology >50% 4 trials at IGR, SITEP 58

Les nouvelles cibles Le portrait moléculaire est une réalité Déjà 3 AMM en thoracique, 2 en 1 ère ligne Autre Impact potentiel La chimiothérapie La stratégie Les traitements locaux Aujourd hui 2 marqueurs, demain des milliers Trop d info tue l info Accès à la maladie micrométastatique Adjuvant, restons classique La chimiothérapie n est pas morte Efficace quelque soit le portrait Revival de l immothérapie Quelle place sur l échiquier moléculaire? 59