RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin, irinotecan and oxaliplatin) VS GEMCITABINE AS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC ADENOCARCINOMA Prodige 4 - ACCORD 11/0402 trial: final results T. Conroy, F. Desseigne, M. Ychou, M. Ducreux, O. Bouché, R. Guimbaud, Y. Bécouarn, C. Montoto-Grillot, S. Gourgou-Bourgade, A. Adenis, FNCLCC-FFCD Prodige group Centre Alexis Vautrin, Nancy; Centre Léon Bérard, Lyon; Centre Val d'Aurelle, Montpellier; Institut Gustave Roussy, Villejuif; Centre Hospitalier R. Debré, Reims; Institut Claudius Regaud, Toulouse; Institut Bergonié, Bordeaux; Fédération Nationale des Centres de Lutte Contre le Cancer - BECT, Paris; Centre Oscar Lambret, Lille; FRANCE

Background Metastatic pancreatic ductal adenocarcinoma: incurable disease few good treatment options Gemcitabine as single agent: cornerstone of treatment median survival: 6 to 7 mo. Gemcitabine-based combinations generally failed to increase survival Some trials suggested a possible benefit from combination chemotherapy in good performance status patients

Background Folfirinox regimen assessed in a phase II study (n=35) promising regimen in good PS patients with M1 disease median survival of 9.5 months A phase II-III randomized study comparing Folfirinox regimen to gemcitabine alone was launched Results of phase II randomized study step (n=88) were presented during ASCO 2007: 31.8% RR in the Folfirinox arm vs 11.4% in the gemcitabine arm Due to these encouraging interim results, the trial continued as a phase III study. Conroy T et al. J Clin Oncol 2005;23:1228-36 Ychou M et al. J Clin Oncol 2007;25:18S:201s

Prodige 4 - ACCORD 11 trial design 6 months of chemotherapy recommended CT scans: obtained every 2 months for both arms: R A N D O M I Z E Folfirinox Metastatic pancreatic cancer Gemcitabine Stratification : center performance status: 0 versus 1 location of the tumor: head versus other location of the primary

Inclusion Criteria Histologically/cytologically confirmed pancreatic adenocarcinoma ECOG performance status of 0 or 1 Measurable metastases No prior cytotoxic chemotherapy No prior abdominal radiotherapy Age 18-75 years Adequate hematopoietic, hepatic and renal function Bilirubin < 1.5 UNL No unstable angina or myocardial infarction within 12 months before entry Written informed consent

Non Inclusion Criteria Non ductal pancreatic cancer (endocrine, acinar cell…) Adenocarcinoma of the ampulla of Vater Unresectable locally advanced pancreatic cancer without distant metastases (stage III) Central Nervous System metastases Chronic diarrhea Other previous or concomitant malignant disease

Experimental Arm: FOLFIRINOX Oxaliplatin 85 mg/m2 over 2 hours, Leucovorin 400 mg/m2 over 2 hours, Irinotecan 180 mg/m2 in 90 mn infusion, 5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 on 46-h infusion. 1 cycle = 14 days Bolus 5-FU 400 mg/m2 2 h Oxaliplatin 85 mg/m2 Leucovorin 400 mg/m2 Continuous 5-FU 2.400 mg/m2 Irinotecan 180 mg/m2 2 h 46 h 1 h 30 q2wks

Reference Arm: Gemcitabine 1000 mg/m2 over 30 minutes given weekly x 7/8 and then weekly x 3/4 1 cycle = 14 days Burris AH et al. J Clin Oncol 1997;15:2403-13

Endpoints Primary: overall survival Secondary: objective response rate (RECIST) toxicity (NCI-CTC version 3.0 grading) progression-free survival (PFS) quality of life (EORTC QLQ-C30 v 3.0)

Statistical considerations Hypothesis: Study designed to have 80% power to detect an increase in median overall survival from 7 to 10 months (HR 0.70) Sample size: 360 patients required to reach 250 events for final analysis, based on the use of the log-rank test with a two-sided significance level of 5% Planned interim analysis after observation of 167 events Intent to treat analysis (ITT)

Trial progress Recruitment: January 2005-October 2009 IDMC meeting, 30 September, 2009: Preplanned interim analysis after 192 events Recommendation to stop accrual: preplanned primary objective met (p <0.001) Final accrual of 342 patients Current analysis database frozen: 16 April, 2010 Number of deaths observed: 273 (73.4% of the sample size)

Flow Chart Folfirinox Gemcitabine Total Total randomized 171 342 Did not fulfill all eligibility criteria 8* 7* 15 (4%) Untreated patients 4 2 6 (2%) ITT population 342 (100%) Safety population 167 169 336 (98%) *Folfirinox arm : 2 patients > 76 years; one patient PS=2; 5 patients with high bilirubin, high creatinine or low platelets *Gemcitabine arm: 7 patients with high bilirubin, high creatinine or low platelets

Patients characteristics Folfirinox N=171 Gemcitabine p Median age (yrs) [range] 61 [25-76] [34-75] NS Sex Male Female 106 (62%) 65 (38%) 105 (61.4%) 66 (38.6%) Baseline PS 1 2 64 (37.4%) 106 (62.0%) 1 (0.6%) 0 (0.0%) Location of primary Head Other 62 (36.3%) 109 (63.7%) 60 (35.1%) 111 (64.9%)

Disease characteristics Folfirinox N=171 Gemcitabine p Synchronous metastases Metachronous metastases 156 (91.2%) 15 (8.8%) 161 (94.2%) 10 (5.8%) NS Median nr. of involved sites CA19-9  59 ULN 2 (1-6) 68 (41.5%) 77 (46.7%) Measurable site Liver Pancreas Nodes Lungs Peritoneal 149 (88.2%) 89 (52.7%) 48 (28.4%) 33 (19.5%) 150 (87.7%) 91 (53.2%) 39 (22.8%) 49 (28.7%) 32 (18.7%) 0.049

Safety: hematological AEs AE, % per patient Folfirinox N=167 Gemcitabine N=169 p All Grade 3/4 Neutropenia 79.9 45.7 54.8 18.7 0.0001 Febrile Neutropenia 7.2 2.4 0.6 0.009 Anemia 90.4 7.8 94.6 5.4 NS Thrombocytopenia 75.2 9.1 0.008 5.4 42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm One toxic death occurred in each arm AE, adverse event

Safety: main non-hematological AEs AE, % per patient Folfirinox N=167 Gemcitabine N=169 p All Grade 3/4 Infection without neutropenia 6 1.2 7.1 1.8 NS Peripheral neuropathy 70.5 9 0.6 0.0001 Vomiting 61.4 14.5 43.2 4.7 0.002 Fatigue 87.3 23.2 78.7 14.2 0.036 Diarrhea 73.3 12.7 30.8 Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) ALT 64.8 7.3 83.8 0.0022 18.6

Objective Response Rate Folfirinox N=171 Gemcitabine p Complete response 0.6% 0% Partial response 31% 9.4% 0.0001 CR/PR 95% CI [24.7-39.1] [5.9-15.4] Stable disease 38.6% 41.5% Disease control CR+PR+SD 70.2% 50.9% 0.0003 Progression 15.2% 34.5% Not assessed 14.6% Median duration of response 5.9 mo. 4 mo. ns

Progression-Free Survival Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

Overall Survival Median survival 11.1 mo. 6.8 mo. <0.0001 0.57 Median follow up: 26.6 months [95% CI: 20.5 – 44.9] Folfirinox N=171 Gemcitabine p HR Median survival [CI 95%] 11.1 mo. [ 9 - 13.1] 6.8 mo. [ 5.5 - 7.6] <0.0001 0.57 1-yr. survival 48.4% 20.6% 18-mo. survival 18.6% 6%

Overall Survival

Time to definitive QoL degradation

Conclusions Folfirinox treatment resulted in a higher frequency of gr. 3/4 febrile neutropenia (5.4%), emphasizing the need for vigilant patient selection, education, monitoring, and active management Folfirinox regimen: is more toxic but has manageable toxicity Significantly improves PFS: reduced risk of disease progression by 53% Delays QoL degradation Significantly improves overall survival (HR 0.57, p<0.0001) : median survival 11.1 mo. Folfirinox recommended as new worldwide standard of care for patients with metastatic pancreatic cancer, bilirubin <1.5 UNL and PS 0-1 This combination will be tested in adjuvant setting

Thank you ! To our very brave and wonderful patients and their families who trust us. To enthusiastic CRA (M. Torres-Macque, F. Nait-Atmane, S. Prigent, S. Levêque), Anne-Chantal Le Gall, and safety department (J. Genève, MD, and collaborators) who also trust us... but check everything! To our remarkably efficient data-managers (A. Pommier and S. Louveau) To all investigators of the 48 active centers, their pharmacists and research staff for quick accrual and excellent quality of the data To very talented physicians and statisticians who helped to plan and execute this trial To IDMC members (B. Asselain, MD; E. François, MD; Pr E. Gamelin, MD; Pr C. Louvet, MD) for their sound advice. Trial supported by two Clinical Research Hospital Program grants (PHRC 2004 and 2007) from the French Ministry of Health. sanofi-aventis and Pfizer for oxaliplatin and irinotecan supply. Grants from Amgen and from the French National League Against Cancer.

Acknowledgements All investigators : Dr Françoise DESSEIGNE, Dr Christelle de la FOUCHARDIERE Centre Léon Bérard LYON ; Pr. Marc YCHOU Centre Val d'Aurelle MONTPELLIER ; Pr. Michel DUCREUX Institut Gustave Roussy VILLEJUIF ; Pr Olivier BOUCHE Centre Hospitalier R. Debré REIMS ; Pr Rosine GUIMBAUD Institut Claudius Regaud TOULOUSE ; Dr Yves BECOUARN Institut Bergonié BORDEAUX ; Pr. Antoine ADENIS Centre Oscar Lambret LILLE; Pr. Jean-Luc RAOUL Centre Eugène Marquis RENNES ; Pr Philippe ROUGIER Hôpital Ambroise Paré BOULOGNE-BILLANCOURT ; Dr Jaafar BENNOUNA Centre René Gauducheau NANTES - St HERBLAIN ; Dr Marie-Christine KAMINSKY, Dr Ivan KRAKOWSKI, Centre Alexis Vautrin, NANCY; Dr Faiza KHEMISSA-AKOUZ Centre hospitalier M. Joffre PERPIGNAN ; Dr Denis PÈRE-VERGÉ Hôpital de la Croix-Rousse LYON ; Dr Catherine DELBALDO CHU Henri Mondor CRETEIL ; Pr Bruno CHAUFFERT Centre François Leclerc DIJON; Pr Pierre MICHEL CHU ROUEN ; Dr Thierry N'GUYEN CHU Jean Minjoz BESANCON ; Dr Jean-Louis JOUVE CHU du Bocage DIJON ; Dr Gilles PIOT CMC Les Ormeaux Vauban LE HAVRE ; Dr Mohammed GASMI Hôpital Nord MARSEILLE ; Dr Patrick TEXEREAU Centre Hospitalier Général MONT DE MARSAN ; Dr Christian BOREL Centre Paul Strauss STRASBOURG ; Dr Frédérique CVITKOVIC Centre René Huguenin SAINT-CLOUD ; Dr Marie-Pierre GALAIS Centre François Baclesse CAEN ; Dr Thierry LECOMTE Centre hospitalier TOURS ; Dr Jean-Paul LAGASSE CHR ORLEANS ; Pr Françoise MORNEX Centre Hospitalier Lyon Sud PIERRE-BENITE ; Dr Dominique ARSENE Centre hospitalier universitaire CAEN ; Dr Yves RINALDI Hôpital Ambroise Paré MARSEILLE ; Dr Gaël DEPLANQUE Hôpital Saint Joseph PARIS  ; Pr Thomas APARICIO Hopital Bichat-Claude Bernard PARIS; Dr Vanessa PALASCAK-JUIF Hôpital Hautepierre STRASBOURG ; Dr Gaëtan DES GUETZ Hôpital Avicenne BOBIGNY ; Dr Cédric LECAILLE Polyclinique Bordeaux Nord Aquitaine BORDEAUX ; Dr Catherine LOMBARD-BOHAS Hôpital Edouard Herriot LYON; Dr Pierre-Luc ETIENNE Clinique Armoricaine de Radiologie SAINT-BRIEUC ; Dr Laurent CHARNEAU Hôpital Duchenne BOULOGNE sur MER ; Dr Serge FRATTE CH de Belfort-Montbéliard BELFORT ; Dr Gilles BREYSACHER Hôpitaux Civils de Colmar COLMAR ; Dr Ahmed AZZEDINE Centre Hospitalier Henri Duffaut AVIGNON ; Dr Jean-Paul JOLY CHU Amiens Picardie AMIENS ; Dr Laurent POINCLOUX CHU Hôtel Dieu CLERMONT-FERRAND ; Dr Anne-Marie QUEUNIET CHI Elbeuf-Louviers-Val de Reuil St AUBIN lès ELBEUF ; Dr Jean-Frédéric BLANC Hôpital Saint André BORDEAUX ; Dr Olivier DUBROEUCQ Institut Jean Godinot REIMS ; Dr Christophe DESAUW Hôpital Saint Vincent de Paul LILLE ; Pr Jean-François SEITZ CHU de la Timone MARSEILLE; Dr Christian PLATINI Hôpital Bon Secours METZ. FRANCE