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Disclosure Information Relationships Relevant to this Session Maria Di Bartolomeo Nordic Pharma Please note, all disclosures are reported as submitted.

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Presentazione sul tema: "Disclosure Information Relationships Relevant to this Session Maria Di Bartolomeo Nordic Pharma Please note, all disclosures are reported as submitted."— Transcript della presentazione:

1 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

2 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 PRESENTED BY MARIA DI BARTOLOMEO on behalf of ITACA-S group

3 The standard recommendation for resectable gastric cancer was surgery (D1 dissection) The standard recommendation for resectable gastric cancer was surgery (D1 dissection) Meta-analysis of literature data showed a small but significant benefit with chemotherapy 1 Meta-analysis of literature data showed a small but significant benefit with chemotherapy 1 Large, patient-level meta-analysis confirmed that 5-FU- based chemotherapy is associated with a statistically significant benefit: Large, patient-level meta-analysis 2 confirmed that 5-FU- based chemotherapy is associated with a statistically significant benefit: OS HR 0.82(95% CI ; P<.001) OS HR 0.82(95% CI ; P<.001) DFS HR 0.82(95% CI ; P<.001) DFS HR 0.82(95% CI ; 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; 2 GASTRIC, JAMA 2010) ITACA-S

4 Bajetta, Ann Oncol, 2002 Cascinu, JNCI, 2007 Di Costanzo, JNCI, 2008 De Vita, Ann Oncol, 2007 StageT3-4/N+ I-IIIB Pts137/137196/201128/130112/113 Experimental Arm EAP  FU/LVPELFwkPELFELFE Control armFollow-upFU/LVFollow-up HR y OS control arm 49%50%48.7%43.5% ITACA-S

5 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 trial 2 Could more active drugs improve the benefit of FU/LV chemotherapy in patients radically resected with extended lymph nodes dissection? ITACA-S ( 1 Di Bartolomeo, Oncology 2006;)

6 Independent, not for profit, multicenter, randomized, superiority trial Independent, not for profit, multicenter, randomized, superiority trial Adenocarcinoma of the stomach or GEJ Adenocarcinoma of the stomach or GEJ Stratification for: Center Lymph-node involvement (N-/N+) Stratification for: Center Lymph-node involvement (N-/N+) Q2wks, 4 administrations Control arm 5-FU: mg/m 2 d1,2-14 LV:100mg/m 2 d1, cycles ITACA-S CPT-11:180mg/m 2 d FU:400/600mg/m 2 d1,2-14 LV:100mg/m 2 d1,2-14 TXT:75mg/m 2 d1-21 CDDP:75mg/m 2 d cycles Experimental arm 4 cycles

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

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

9 6 excluded for major violations: 3 control arm 3 experimental arm 1106 Randomized 541 control arm 565 experimental arm 1106 Randomized 541 control arm 565 experimental arm 1100 ITT population 538 control arm 562 experimental arm 1100 ITT population 538 control arm 562 experimental arm 1072 Safety population 520 control arm 552 experimental arm 1072 Safety population 520 control arm 552 experimental arm 28 never started treatment: 16 control arm 12 experimental arm 6 crossed group 4 control-> experimental 2 experimental -> control 6 crossed group 4 control-> experimental 2 experimental -> control ITACA-S

10 Total (n.1100) Experimental arm (n.562) Control arm (n.538) Age (yrs) % median (range) > 70 yrs 62 (24-77) (30-76) (24-77) 15 Sex % Male ECOG % Histology (acc. Lauren) % Diffuse Intestinal Mixed Other classification ( WHO) ITACA-S

11 CharacteristicsTotal (n.1100) Experimental arm (n.562) Control arm (n.538) Node dissection % D1 D2 D Examined node % median < > Tumor site % GE junction Proximal Distal Multicenter ITACA-S

12 Total (n.1100) Experimental arm (n.562) Control arm (n.538) Stage (UICC6th) % Ib II IIIa IIIb IV N (UICC7th) % N0 N1(1-2) N2 (3-6) N3a (7-15) N3b (>15) ITACA-S

13 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 Experimental arm Control arm

14 Experimental arm Control arm Treatment completed 76%86% 9 cycles86% 8 cycles90% 7 cycles76%93% 6 cycles83%94% 5 cycles89%95% 4 cycles92%97% 3 cycles94%98% 2 cycles97%99% 1 cycle100% FOLFIRI CDDP +TXT ITACA-S

15 *All p<0.001 * * * * ITACA-S

16 *All p<0.001 * * * * * ITACA-S

17 EventsOverall (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 median follow up: 48 mos (range IQ ) **% calculated on the total of relapses ITACA-S

18 HR: %CI: p=0.83 Median DFS: 41.3 months 5-year DFS: 44.8% ITACA-S Control Experimental Disease Free Survival ,0 0,2 0,4 0,6 0,8 1,0 Months from randomization Patients at risk Experimental Control Events Totals

19 ITACA-S Control Experimental Overall Survival ,0 0,2 0,4 0,6 0,8 1,0 Months from randomization Patients at risk Experimental Control Events Totals HR:1.0 95%CI: p=0.986 Median OS: 69.8 months 5-year OS: 52.2%

20 ITACA-S p=0.371 Test for interaction p=0.602 p=0.733 p=0.928 p=0.371 Test for interaction

21 ITACA-S is the largest western trial to compare two different types of adjuvant chemotherapy in gastric cancer 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% Patients received adequate surgery and D2 dissection in more than 75% Sequential irinotecan/FU-CDDP/TXT is feasible in the Sequential irinotecan/FU-CDDP/TXT is feasible in the adjuvant setting. However it is: 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 According to these results there is no indication to use polychemotherapy regimen in adjuvant setting for any stage of gastric cancer ITACA-S

22 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 ITACA-S Financial Support by: Sanofi Aventis-Italy & Pfizer- Italy

23 ITACA-S 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 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 Fiorentini, Empoli Mazzanti, Firenze Montesarchio, Napoli Daniele, Benevento Genua, Ariano Irpino Martoni, Bologna Brandes, Bologna Lelli, Ferrara Nitti, Padova Tiberio, Brescia De Manzoni, Verona De Placido, Napoli Cartenì, Napoli ITMOGISCAD GOIRC GONO ONCOTECH APRIC GOCCI GIRCG IRST SICOG GOAM 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 Fiorentini, Empoli Mazzanti, Firenze Casaretti, Napoli Farris, Sassari Filippelli, Paola Graco, Lamezia Terme Roselli, Roma Natale, Penne Buzzi, Terni Tafuto, Pozzuoli Masullo, Vallo della Lucania Ravaioli, Rimini Amadori, Forlì Marangolo, Ravenna Gambi, Faenza Cruciani, Lugo ……..the patients and their families


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