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Aimery de Gramont

Aimery de Gramont.

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Aimery de Gramont

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  1. Aimery de Gramont Oxaliplatin/5-FU/LV in Adjuvant Colon Cancer: Updated Efficacy Results of the Mosaic Trial, Including Survival, with a Median Follow-up of 6 YearsAimery de Gramont, Corrado Boni, Matilde Navarro, Josep Tabernero, Tamas Hickish, Clare Topham, Andrea Bonetti, Philip Clingan, Christelle Lorenzato, Thierry André, and MOSAIC investigators

  2. Primary end-point: disease-free survival Secondary end-points: safety, overall survival • n=2246 • Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries) • Completely resected colon cancer • Stage II, 40%; Stage III, 60% • Age 18–75 years • KPS ≥60 • No prior chemotherapy (n=1123) FOLFOX4 (LV5FU2+ oxaliplatin 85 mg/m²) R LV5FU2 (n=1123) MOSAIC: Study Design LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

  3. Cut-off Dates for Efficacy Analyses 1. André, et al. N Engl J Med 2004;350:2343–2351

  4. Primary End-Point: Disease-Free Survival • “DFS allows to make more quickly a decision regarding the efficacy of a new treatment • Clinical trials can be completed more quickly • Drug development time can be shortened • Better therapy can be made available to patients more quickly • DFS can be considered as an endpoint of its own merit in decreasing the high cost, quality-of life impact and debilitating consequence of recurrent disease” 1. Sargent, et al. J Clin Oncol 2005;23:8664–8670

  5. Disease-free Survival Events = Relapse + Second Primary Colon Cancer + Death any cause 1. Andre, et al. N Engl J Med 2004;350:2343–2351

  6. 1.0 0.9 0.8 5.9% 0.7 0.6 0.5 Probability Events FOLFOX4 304/1123 (27.1%) LV5FU2 360/1123 (32.1%) HR [95% CI]: 0.80 [0.68–0.93] 0.4 FOLFOX4 LV5FU2 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 Disease-free survival (months) Disease-free Survival: ITT p=0.003 Data cut-off: June 2006

  7. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] p-value Stage II 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93] 0.005 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months Disease-free Survival: Stage II and Stage III Patients p=0.258 3.8% p=0.005 7.5% Data cut-off: June 2006

  8. Disease-free Survival: High-risk Stage II Patients 1.0 0.9 0.8 7.2% 0.7 FOLFOX4 n=286 LV5FU2 n=290 0.6 0.5 Probability 3-year 5-year FOLFOX4 85.4% 82.1% LV5FU2 80.4% 74.9% HR [95% CI]: 0.74 [0.52–1.06] High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion , <10 lymph nodes examined; Data cut-off: June 2006 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Disease-free survival (months) Exploratory analysis

  9. Summary: Disease-free SurvivalFinal Update Data cut-off: June 2006

  10. Secondary End-Point: Safety Toxicity per Patient (on Treatment) 1. André, et al. N Engl J Med 2004;350:2343–2351

  11. Long-term Safety Second cancer Peripheral Sensory Neuropathy Data cut-off: January 2007

  12. Secondary End-Point: Overall Survival Data cut-off: January 2007

  13. FOLFOX4 LV5FU2 Overall Survival: ITT 1.0 p=0.057 0.9 0.8 2.6% 0.7 0.6 0.5 Probability 0.4 Events FOLFOX4 243/1123 (21.6%) LV5FU2 279/1123 (24.8%) HR [95% CI]: 0.85 [0.72–1.01] 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall survival (months) Data cut-off: January 2007

  14. 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall survival (months) Overall Survival: Stage II and Stage III p=0.996 0.1% p=0.029 4.4% FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Data cut-off: January 2007

  15. Summary: Overall Survival Data cut-off: January 2007

  16. Hazard ratios for DFS and OS by sub group Favours FOLFOX4 Favours LV5FU2 Disease-free survival (DFS) Stage II High risk Stage II Stage III Overall survival (OS) Stage II High risk Stage II Stage III 1 0.5 0.7 0.9 1.1 1.3 1.5 Hazard Ratio

  17. Deaths other than Colon Cancer Exploratory analysis Data cut-off: January 2007

  18. Treatment for Recurrence * first-line Exploratory analysis Data cut-off: June 2006

  19. Time from Relapse to Death: ITT 1.0 0.9 0.8 0.7 FOLFOX4 n= 258 median 21 months LV5FU2 n=334 median 24 months 0.6 0.5 Probability 0.4 0.3 Patients alive with relapse (%) FOLFOX4 69 (6.1) LV5FU2 88 (7.8) 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time from relapse to death (months) Exploratory analysis

  20. Conclusions For FOLFOX4 vs LV5FU2: • The DFS benefit at 3 years was maintained at 5 years • Trend showing improved DFS in ‘high-risk’ stage II patients • Significant OS benefit in stage III patients • No increase in the rate of secondary cancers • Continued recovery from sensory neuropathy

  21. Acknowledgments Dr’s Abad A, Achille E, Agostara B, Albertsson M, Ales JE, Andersen OKD, André T, Anton A, Aranda E, Basser R, Beauduin M, Benavides M, Berger C, Bessel EM, Boaziz C, Bonetti A, Boni C, Boutan-Laroze A, Bridgewater J, Bruntsch U, Bumma C, Canon JL, Carlsson G, Carmichael J, Carola E, Carrato A, Cassidy J, Catane R, Cervantes A, Chauvenet L, Clarke S, Clingan P, Colin P, Colucci G, Cortes-Funes H, Craft P, Creemers GJ, Cumin I, Cunningham D, Dahl O, Davidson N, de Braud F, de Gramont A, Della-Fiorentina S, Demol J, Depisch D, Díaz-Rubio E, Dorval E, Erdkamp FLG, Facchini T, Fahlke C, Falk S, Figer A, Fillet G, Flesch M, Fountzilas G, Ganem G, Georgoulias V, Gervasio H, Glynne-Jones R, Green M, Guérin-Meyer V, Hansen J, Hawkins R, Heike M, Heikkilä R, Hendler D, Herben MG, Hickish T, Höhler T, Honhon B, Humblet Y, Isacson R, Izso J, James R, Janinis J, Janssen M, Kahan Z, Kalofonos H, Karina M, Kerger J, Landi B, Ledermann J, Lepoutre L, Lim R, Lledo G, Maartense E, Madoe V, Maigre M, Marcuello E, Marques F,Marti P, Massuti B, Mathijs R, Maughan T, Megyery E, Mejer J, Meurisse MP, Miccio-Belaiche A, Mignot L, Mineur L, Mitchell P, Monfardini S, Monfort L, Morvan F, Mousseau M, Muron T, Myint S, Nabico R, Navarro M, Noirclerc M, Nowacki M, Nylen U, Papamichael D, Pavlidis N, Piazza E, Pinotti G, Pinter T, Polus M, Raoul Y, Ridwelski K, Rinaldi Y, Rivera F, Rosenthal M, Roth A, Samantas E, Samuel L, Sanches E, Scheithauer W, Schrijvers D, Seymour M, Shani A, Simoens M, Singer J, Skosgaard T, Slancar M, Sleebom HP, Slevin M, Smit JM, Sörensen JB, Soyer P, Steger G, Steward W, Stuart NSA, Szanto J, Szucs M, Tabernero J, Topham C, Toumieux J, Tubiana-Mathieu N, Underhill C, van Deijk WA, van den Bossche L, van Eygen K, van Laethem JL, van Veelen H, Vandebroek J, Vilain C, Vindevoghel A, Wasan H, Westman G, Wilson C, Zaniboni A

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