Disclosure Information Relationships Relevant to this Session Maria Di Bartolomeo Nordic Pharma Please note, all disclosures are reported as submitted to ASCO, and are always available at chicago2012.asco.org

ITACA-S Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach Comparison of a sequential treatment with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer E.Bajetta, I.Floriani, M.Di Bartolomeo, R.Labianca, A.Santoro, R.Casaretti, E.Pasquini, F.Di Fabio, G.Pinotti, P.Bidoli, G.Rosati, A.Mambrini, A.Ciarlo, S.Ricci, L. Frassinetti, F.Di Costanzo, AM.Bochicchio on behalf of ITACA-S group PRESENTED BY MARIA DI BARTOLOMEO

Background The standard recommendation for resectable gastric cancer was surgery (D1 dissection) Meta-analysis of literature data showed a small but significant benefit with chemotherapy1 Large, patient-level meta-analysis2 confirmed that 5-FU- based chemotherapy is associated with a statistically significant benefit: OS HR 0.82 (95% CI 0.76-0.90; P< .001) DFS HR 0.82 (95% CI 0.75-0.90; P< .001) Our choice of 5-FU/LV regimen as control arm was based on the results of meta-analysis of randomized clinical trials (1 Mari, Ann Oncol,2000; 2GASTRIC, JAMA 2010) ITACA-S

Italian contribution Bajetta, Cascinu, Di Costanzo, De Vita, Stage Ann Oncol, 2002 Cascinu, JNCI, 2007 Di Costanzo, JNCI, 2008 De Vita, Ann Oncol, 2007 Stage T3-4/N+ I-IIIB Pts 137/137 196/201 128/130 112/113 Experimental Arm EAPFU/LV PELFwk PELF ELFE Control arm Follow-up FU/LV HR 0.93 0.95 0.90 0.91 5-y OS control arm 49% 50% 48.7% 43.5% ITACA-S

Rationale for Experimental arm FOLFIRI -> less hematological, renal and neurological toxicity and less stomatitis than cisplatin combinations Docetaxel (TXT), CDDP and 5-FU regimen is active in terms of objective response and OS, but several grade 3-4 AEs Treatment sequence FOLFIRI TXT/CDDP Minimize AEs by considering each drug toxicity profile Feasibility of the sequence was documented in the ITMO trial2 Could more active drugs improve the benefit of FU/LV chemotherapy in patients radically resected with extended lymph nodes dissection? (1 Di Bartolomeo, Oncology 2006;) ITACA-S

Study Design Randomization Independent, not for profit, multicenter, randomized, superiority trial Control arm 5-FU:400-600mg/m2d1,2-14 LV:100mg/m2d1,2-14 9 cycles Randomization Adenocarcinoma of the stomach or GEJ CPT-11:180mg/m2d1-14 5-FU:400/600mg/m2d1,2-14 LV:100mg/m2d1,2-14 Experimental arm TXT:75mg/m2d1-21 CDDP:75mg/m2d1-21 Q2wks, 4 administrations 4 cycles 3 cycles Stratification for: Center Lymph-node involvement (N-/N+) ITACA-S

Eligibility criteria Histologically proven carcinoma of the stomach or gastroesophageal junction Total/subtotal gastrectomy with at least D1 dissection (D2 recommended ) pN+ or pT2b-3-4 No previous radiation and/or chemotherapy Complete recovery from surgery. The first infusion administered 3 to 8 weeks after surgery ITACA-S

Statistical considerations Primary endpoint: Disease-Free Survival (DFS) 636 events (1100 patients) required: to detect a 20% relative reduction of recurrence/death (HR 0.80) assuming 3-year DFS in control arm to be 50% to provide 80% power with 5% two-sided significance level Interim analyses for monitoring study conduction ITACA-S

Recruitment 1106 Randomized 541 control arm 565 experimental arm Feb/2005-Aug/2009 6 excluded for major violations: 3 control arm 3 experimental arm 1100 ITT population 538 control arm 562 experimental arm 6 crossed group 4 control-> experimental 2 experimental -> control 28 never started treatment: 16 control arm 12 experimental arm 1072 Safety population 520 control arm 552 experimental arm ITACA-S

Baseline characteristics Total (n.1100) Experimental arm (n.562) Control arm (n.538) Age (yrs) % median (range) > 70 yrs 62 (24-77) 16 62 (30-76) 17 61 (24-77) 15 Sex % Male 63 62 65 ECOG % 1 90 10 91 9 88 12 Histology (acc. Lauren) % Diffuse Intestinal Mixed Other classification (WHO) 40 35 11 14 36 ITACA-S

Surgical report Characteristics Total (n.1100) Experimental arm (n.562) Control arm (n.538) Node dissection % D1 D2 D3 25 72 3 24 73 27 71 2 Examined node % median <15 15-24 > 25 11 33 56 12 55 26 32 57 Tumor site % GE junction Proximal Distal Multicenter 59 13 ITACA-S

TNM stage Total (n.1100) Experimental arm (n.562) Control arm (n.538) Stage (UICC6th) % Ib II IIIa IIIb IV 8 32 27 14 17 25 19 31 29 N (UICC7th) % N0 N1(1-2) N2 (3-6) N3a (7-15) N3b (>15) 9 26 30 16 10 28 20 ITACA-S

Treatment compliance Experimental arm Control arm Completed: 76% - per protocol: 17% - modified: 59% Discontinued: 24% - Adverse events 15% - Death 1% - Withdrawal 7% - Progressive disease 1% Completed: 86% - per protocol: 36% - modified: 50% Discontinued: 14% - Adverse events 6% - Death 1% - Withdrawal 4% - Progressive disease 3% ITACA-S

Treatment received Experimental arm Control arm Treatment completed 76% 86% 9 cycles 8 cycles 90% 7 cycles 93% 6 cycles 83% 94% 5 cycles 89% 95% 4 cycles 92% 97% 3 cycles 98% 2 cycles 99% 1 cycle 100% CDDP +TXT FOLFIRI ITACA-S

Grade 3-4 hematological toxicity * * * * *All p<0.001 ITACA-S

Grade 3-4 non hematological toxicity * * * * * *All p<0.001 ITACA-S

Events and Relapses median follow up: 48 mos (range IQ35.5-62.2) Overall (n.1100) Experimental arm (n.562) Control arm (n.538) Relapse/Deaths % 558 (51) 283 (50) 275 (51) Deaths % 440 (40) 222 (39) 218 (40) Relapse site**: % locoregional both distant 10 8 82 9 81 7 83 **% calculated on the total of relapses ITACA-S

Disease-free survival HR:0.98 95%CI: 0.83-1.16 p=0.83 Median DFS: 41.3 months 5-year DFS: 44.8% ITACA-S 538 418 328 273 194 127 71 562 438 347 270 201 129 74 Control Experimental Disease Free Survival 10 20 30 40 50 60 0,0 0,2 0,4 0,6 0,8 1,0 Months from randomization Patients at risk Events 275 283 Totals 538 562

Overall survival HR:1.0 95%CI: 0.83-1.20 p=0.986 538 477 401 321 222 149 79 562 492 404 328 230 81 Control Experimental Overall Survival 10 20 30 40 50 60 0,0 0,2 0,4 0,6 0,8 1,0 Months from randomization Patients at risk Events 218 222 Totals 538 562 HR:1.0 95%CI: 0.83-1.20 p=0.986 Median OS: 69.8 months 5-year OS: 52.2% ITACA-S

Hazard Ratio for deaths Test for interaction Test for interaction p=0.371 p=0.371 p=0.602 p=0.733 p=0.928 ITACA-S

Conclusions ITACA-S is the largest western trial to compare two different types of adjuvant chemotherapy in gastric cancer Patients received adequate surgery and D2 dissection in more than 75% Sequential irinotecan/FU-CDDP/TXT is feasible in the adjuvant setting. However it is: - not more effective than FU/LV - more toxic than FU/LV According to these results there is no indication to use polychemotherapy regimen in adjuvant setting for any stage of gastric cancer ITACA-S

MG. Valsecchi, M. Tonato, E. Zucca Sponsor Istituto Farmacologico Mario Negri Milano Steering committee E.Bajetta (PI), B.Daniele, D.Nitti, R. Labianca, A.Martoni, E.Mini, F.Di Costanzo, A,Falcone, D. Amadori, G.Tortora, G.Comella DSMC MG. Valsecchi, M. Tonato, E. Zucca Financial Support by: Sanofi Aventis-Italy & Pfizer- Italy ITACA-S

Thanks to: ITMO GISCAD GONO SICOG IRST GOCCI GIRCG APRIC GOIRC Labianca, Bergamo Bidoli, Monza Foa, Milano Aitini, Mantova Barni, Treviglio Giordano, Como Martignoni, Milano Catalano, Pesaro Zaniboni, Brescia Aglietta, Candiolo Piazza, Milano Beretta, Brescia Menichetti, Senigallia Cortesi, Roma Silva, Fabriano Nardi, Reggio Calabria Cascinu, Ancona Luporini, Milano Ficarella, Urbino Falcone, Livorno Cantore, Carrara Di Leo, Prato Ricci, Pisa Magnanini, Arezzo Sozzi, Biella Fea, Cuneo Chiara, Genova Alabiso, Novara Fioretto, Antella Decensi, Genova Ciuffreda, Torino Barsani, lucca Bajetta, Milano Pinotti, Varese Rosati, Potenza Bordonaro, Catania Bochicchio, Rionero Fazio, Milano Marini, Brescia Buscarino,Catania Massidda, Cagliari Isa, Gorgonzola Bartolini, Sondrio Reguzzoni, Busto Arsizio Iop, Latisana Villa, Milano Ucci, Lecco Tumolo, Pordenone Frustaci, Aviano Lombardo, Pescara Sbalzarini, Casalpusterlengo Verusio, Saronno Bonetti, Legnago Monfadini, Padova Agostara, Palermo Bonciarelli, Este Marchetti, Roma Zagonel, Roma Cicero, Castrovillari Mantovani, Cagliari Duro, Como Oliani, Montecchio Maggiore Porcile, Alba Bobbio Pallavicini, Crema Gebbia, Palermo Repetto, Roma Casaretti, Napoli Farris, Sassari Filippelli, Paola Graco, Lamezia Terme Roselli , Roma Natale, Penne Buzzi, Terni Tafuto, Pozzuoli Masullo, Vallo della Lucania IRST Ravaioli, Rimini Amadori, Forlì Marangolo, Ravenna Gambi, Faenza Cruciani, Lugo GOCCI Fiorentini, Empoli Mazzanti, Firenze Fiorentini, Empoli Mazzanti, Firenze GIRCG APRIC Nitti, Padova Tiberio, Brescia De Manzoni, Verona GOIRC Montesarchio, Napoli Daniele, Benevento Genua, Ariano Irpino Santoro, Rozzano Boni, Reggio Emilia Di Costanzo, Firenze Cavanna, Piacenza Mattioli, Fano Pucci, Parma Bravi, Città di Castello Artioli, Carpi Passalacqua, Cremona Contu, Sassari Rossetti, Marsciano ONCOTECH GOAM De Placido, Napoli Cartenì, Napoli Martoni, Bologna Brandes, Bologna Lelli, Ferrara ……..the patients and their families ITACA-S