MPM: a locoregional cancer disease.

Bevacizumab 15mg/kg plus cisplatin pemetrexedpemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM): Results of the IFCT GFPC 0701 MAPS randomized phase 3 trial EUDRACT N : 2007 002574 63 N ClinicalTrials.gov : NCT00651456 Gérard ZALCMAN, Julien MAZIERES, Jacques MARGERY, Laurent GREILLER, Clarisse AUDIGIER VALETTE, Denis MORO SIBILOT, Olivier MOLINIER, Romain CORRE, Isabelle MONNET, Valérie GOUNANT, Henri JANICOT, Radj GERVAIS, Chrystèle LOCHER, Bernard MILLERON, Quan TRAN, Marie Paule LEBITASY, Franck MORIN, Christian CREVEUIL, Jean Jacques PARIENTI & Arnaud SCHERPEREEL, on behalf of the French Cooperative Thoracic Intergroup (IFCT). MPM: a locoregional cancer disease. originating from parietal pleura without any curative treatment and an abyssal median OS from 8.5 (first generation regimens) 1 to 13 months (pemetrexed based doublet) 2. No improvement achieved in the last decade 1 Muers MF et al. Lancet. 2008;371(9625):1685-94 2 Vogelzang NJ et al. Clin Oncol. 2003;21(14):2636-44. 1

Beyond its role as the main endothelial GF, VEGF is an autocrine growth factor for mesothelioma cells control VEGF VEGF-R1/FLT1 VEGF-R2/KDR Mesothelioma highly express VEGF & VEGF-R Strizzi L et al. J. Pathol. 2001; 193:468-73 rhumab anti VEGF (bevacizumab) Avastin : humanized monoclonal antibody directed against VEGF recombinant synthetic protein 7 % murine : hypervariable region binding VEGF antigenic peptide 93% human: Fc part responsible for species immunogenicity Binding all VEGF isoforms (ABCDE) 1/2 terminal life : 17 to 21 days Approved for seven mcrc 2 nd L mcrc Recurrent or Adv. CRC Japan NSCLC mcrc Breast m with CT 1 st or 2 nd L NSCLCm Japon Relapsing GBM China Breast m Japan Ovary K TML Ovary K 2 nd L Adv.. cervix K Adv. cervix K types of cancers 1 12 2004 2005 2006 2007 2008 2009 2010 2011 2012 2014 2015 1. Sandler A et al. NEJM 2006 Dec 14;355:2542 50; 2. Reck M et al. JCO 2009;27:1227 34; 3. Hurwitz H et al. NEJM 2004;350:2335 42; 4. Giantonio BJ et al. JCO 2007 ;25:1539 44; 5. Escudier B et al. Lancet 2007;370:2103 11; 6. Miller K et al. NEJM 2007 ;357:2666 76; 7. Gray R et al. JCO 2009;27:4966 72; 8. Miles DW et al. JCO 2010 ;28:3239 47; 9. Friedman HS et al. JCO 2009;27:4733 40; 10. Burger RA et al. NEJM 2011;365:2473 83; 11. Perren TJ et al. NEJM 2011;365:2484 96; 12.Tewari KS et al. NEJ M 2014; 370:734 743 2

IFCT-GFPC-0701 trial: MAPS Mesothelioma Avastin cisplatin Pemetrexed Study IFCT-sponsored, open-label, multi-centre randomized phase II-III trial Roche supplied bevacizumab Malignant Pleural Mesothelioma (MPM) Histologically proven PS= 0-2 No cardiovascular comorbidity Chemonaive R 1:1 A B Pemetrexed 500 mg/m 2 D1 Cisplatin 75mg/m 2 D1 6 cycles, Q21D Pemetrexed 500 mg/m 2 D1 Cisplatin 75mg/m 2 D1 Bevacizumab 15 mg/kg D1 6 cycles, Q21D Surveillance No cross-over allowed Maintenance Bevacizumab 15 mg/kg D1, Q21D until progression CT scan Q 3 cycles in both arms. Response assessed with modified RECIST criteria for mesothelioma Stratification: center, histology (epithelioid vs. sarcomatoid/mixed), PS (0-1 vs. 2), smoking status (ever smoker vs. never-smoker) Objectives Phase 2, Primary: Disease control rate at 6 months 1 Phase 2, Secondary: Toxicity Phase 3, Primary: Overall Survival Phase 3, Secondary: PFS, QOL, Ancillary Biomarkers studies, (PET-CT, Biology), Pharmacoeconomics 1 As centrally determined by an expert panel, according to modified RECIST-meso (after 6 cycles) Byrne M.J. & Nowak A. Ann. Oncol. 2004; 15: 257 260 3

448 Patients Randomized Inclusions by center Amiens Rouen Caen CRLCC Cherbourg Elbeuf Evreux From Feb. 2008 to Jan. 2014 42% of patients Included in 5 centers Caen CHU Lille CHU Marseille CHU Roubaix Rouen CHU Inter région NO= 30% des inclusions Toulouse CHU Gustave Roussy MAJOR RESPONSES OBSERVED Baseline Baseline 2 cycles of Pem-Cis Beva 2 cycles of Pem-Cis Beva 4

Efficacy: ITT Progression free Survival (PFS) median follow up= 39.4 mo [11.0 83.05] 1 0,9 rvival Probability Progression Free Su 0,8 0,7 06 0,6 0,5 0,4 0,3 Median PFS: 7.48 mo, 95%CI: [6.79 8.13] Median PFS: 9.59 mo, 95%CI: [8.49 10.59] Stratified HR=0.61; 95%CI [0.50 0.75] p<0.0001 0,2 0,1 0 0 10 20 30 40 50 60 Time (months) No. At risk CT(PEM+CIS) CT(PEM+CIS)+Beva 225 67 17 4 1 1 1 223 105 37 16 10 3 3 IFCT 0701 MAPS randomized phase 3 trial Efficacy: ITT Overall Survival (OS) median follow up= 39.4 mo [11.0 83.05] 1 Survival Pro obability 0,9 0,8 0,7 0,6 0,5 Median Overall Survival: 16.07 mo, 95%CI: [14.00 17.93] Median Overall Survival: 18.82 mo, 95%CI: [15.90 22.62] Stratified HR=0.76; 95%CI [0.61 0.94] p=0.0127 0,4 0,3 0,2 0,1 CT(PEM+CIS) CT(PEM+CIS)+Beva 0 No. At 0 risk Time (months) 10 20 30 40 50 60 225 166 77 36 16 10 7 223 171 91 45 20 8 8 IFCT 0701 MAPS randomized phase 3 trial 5

MAPS trial conclusions Adding bevacizumab 15 mg/kg to Pemetrexed cispla n doublet significantly increased both PFS (by 2 months) andos(by 2.75 months) at the cost of a slight, manageable increase of toxicity; QOL was preserved in both arms and beva did not show a detrimental effect on QOL, despite the higher toxicity. In this study, standard arm patients had a longer OS than historical series, or patients in previous trials, possibly because of eligibility criteriafor bevacizumab The triplet Pemetrexed, cisplatin and bevacizumab is a new treatment paradigm for pleural mesothelioma patients eligible for bevacizumab, not amenable to curative surgery Statistical Group F. CHAILLOT C. CREVEUIL A.D. PHAM JJ PARIENTI Clinical Research Unit B. MILLERON, A LANGLAIS, F. MORIN E. AMOUR, Q.TRAN & M.P. LEBITASY Programme Hospitalier de Recherche Clinique (PHRC) National 2007 UMR 1086 Cancers & Prévention Biomarkers ancillary studies G. LEVALLET, E. CHEVALLIER, S. BROSSEAU, G. ZALCMAN (Caen) A. SCHERPEREEL (Lille) ROCHE France: Drug supplying Research grant on biomarkers 6

UMR 1086 Cancers & Prévention Bio MAPS Marqueurs Plasmatiques (Pr. A. Scherpereel, Institut Pasteur, Lille): VEGF, Endocan, Fibuline 3, Mésothéline, ostéopontine Marqueurs ADN (Pr. G. Zalcman, Dr. G. Levallet, U1086, Caen): Mutations BAP 1 & c met, Méthylation gènes voie hippo (RASSF1A, RASSF2A, MST1, MST2 ), WIF 1 Marqueurs mir: 15 mir (mir21, 200c, 155 etc.) Marqueurs IHC: VEGFR2, VE Statin, c met, P cmet, NF2, p16, CD44, AREG, HIF1, CD34, TUBB3, YAP/TAZ. 260 blocs paraffine /448 inclusions (100 en attente) 380 plasma / 448 inclusions 7

UMR 1086 Cancers & Prévention Bio MAPS Biologie cellulaire: la voie Hippo/YAP dans le modèle mésothéliome cf. Posters : Elodie Chevalier (doctorante, UMR1086, Caen) Solenn Brosseau (M2R, UMR 1086, Caen & Service de Pneumologie) Etude TEP CT (FDG): Pr. Nicolas AIDE (CHU Caen) 8