1. FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in patients with initially resectable metastatic colorectal cancer. A GERCOR Randomized Phase III study (MIROX) M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet, J.L. Dutel, M. Ychou, J.L. Legoux, M. Mabro, R. Faroux, D. Auby, D. Brusquant, A. Khalil, S. Truant, A. Hadengue, F. Bonnetain, FR. Pruvot, C. Dalban, A. de Gramont

2. CONFLICT OF INTEREST DISCLOSURE No conflict of interest to declare

3. Liver is the main metastatic site in patients with colorectal cancer Metastases are initially resectable in 15-20 % patients Perioperative FOLFOX chemotherapy is active (EORTC study) RATIONALE Nordlinger B, et al. Lancet 2008, 371:1007-16 HR= 0.73 [CI: 0.55-0.97] P=0.025 Surgery only Periop FOLFOX4 33.2% 42.4% (years) 0123456 0 10 20 30 40 50 60 70 80 90 100 PFS in resected patients (%) 3-yr PFS + 9.2%

4. Role of Irinotecan ? Ychou M, et al. Ann Oncol 2009, 20:1964-70 FOLFIRI x12cy postop LV5FU2 x12cy postop RANDOMIZATIONRANDOMIZATION DFS OS RATIONALE

5. Two questions May sequential administration of FOLFOX followed by FOLFIRI improve results ? Why should the chronology be imposed ? RATIONALE

6. MIROX strategy for resectable metastases 6FOLFOX7 (oxa. 130mg/m²) followed by 6FOLFIRI  To reduce occurrence of oxaliplatin-related neuropathy,  To increase efficacy (absence of cross resistance) Perioperative OR postoperative chemotherapy  Personalized strategy  To limit selection bias Prior phase II study in patients with resectable MCRC  N=47 (periop, N=22 ; postop, N=25)  No grade 3 neurotoxicity  Survivals : 2-yr DFS 47%, and 2-yr OS 89% Taïeb J, et al. J Clin Oncol 2005, 23:502-9 RATIONALE

7. DESIGN OF THE PHASE III STUDY FOLFOX7 – FOLFIRI (N=142) FOLFOX4 (N=142) RANDOMIZATIONRANDOMIZATION 4-6 preop cycles recommended Surgery N=284 From May 2004 to June 2010

8. INCLUSION CRITERIA Histologically documented colorectal adenocarcinoma Resected or resectable metastases Only one metastatic site: liver, lung, ovary, or peritoneum Age : 18-75 PS: 0-2 In case of prior adjuvant FOLFOX after resection of the primary: interval > 12 months required

9. Primary endpoint : Disease-free survival (DFS) Secondary endpoints : –Overall survival –Objective response rate with perioperative chemotherapy, –Resection rate (R0, R1, R2) with perioperative chemotherapy, –Safety (NCI CTC v2) –Health related Quality of Life (EORTC QLQ C-30) Sample Size - Superiority study, power of 80%, 2-sided test  = 0.05, - Δ 2-yr DFS rate : from 30% (FOLFOX4) to 45% (FOLFOX7-FOLFIRI) 284 patients to be enrolled 188 events required ENDPOINTS

10. STRATIFICATION CRITERIA Periop vs. postop chemotherapy Surgery alone vs. radiofrequency ablation +/- surgery Blumgart’s score (0-1 vs. 2-3 vs. 4-5) Disease-free interval (months)<12≥12 Primary tumorN+N0 Number of metastase(s)≥11 Largest met. size (cm)>5≤5 Preop CEA level>200≤200 Fong Y, et al. Ann Surg 1999, 3:309-21

11. CONSORT DIAGRAM FOLFOX4 arm Randomized: N=284 Treatment allocation Median follow-up : 50.4 months FOLFOX7 – FOLFIRI arm N=142 Treated N=140 N=142 ITT analysis N=140N=142

12. PATIENT’S CHARACTERISTICS FOLFOX4 (N=142) FOLFOX7-FOLFIRI (N=142) Age <70, %7782 Male, %6470 ECOG PS 0-1, %93 Liver met. Site, %8384 One metatasis, %5152 Largest met. Size <5cm, %8685 Synchronous met., %5559 Primary : node positive, %5857 Prior adjuvant chemo, %2328 Preop CEA level, mean ratio (V/ULN)9.98.1

13. TREATMENTS FOLFOX4 (N=142) FOLFOX7-FOLFIRI (N=142) Treated patient142140 Median oxaliplatin dose (mg)13851218 Median oxaliplatin or irinotecan- base cycles912 Peri-operative chemotherapy, n (%)85 (60)83 (58) Response rate after pre-operative chemo, n (%)42 (49)41 (50) Met. Surgery after pre-operative chemo, n %68 (80)73 (88) R0 resection after pre-operative chemo, n %61 (90)61 (84)

14. TOXICITY NCI CTCAE v2, grade 3-4 (%)FOLFOX4 (N=142) FOLFOX7-FOLFIRI (N=142) Neutropenia3222 Anemia20 Thrombocytopenia59 Febrile neutropenia2<1 Nausea39 Vomiting22 Mucositis / Stomatitis12 Diarrhea1021* Cutaneous0<1 Alopecia (Gr. 2)66 Neurotoxicity2416

15. Arm2-yr rate, % Median [95% CI] HR [95% CI] P value FOLFOX448.222.4 [17.9-36.2] FOLFOX7-FOLFIRI49.323.0 [19.7-35.6] 0.97 [0.72-1.31] 0.856 DFS DISEASE-FREE SURVIVAL

16. Arm2-yr rate, % Median [95% CI] HR [95% CI] P value FOLFOX487.5NR FOLFOX7-FOLFIRI90.2NR1.07 [0.68-1.70] 0.764 OS NR, not reached OVERALL SURVIVAL

17. Arm2-yr rate, % Median [95% CI] Postoperative60.539.9 [26.9-NR] Perioperative40.323.0 [15.2-22.4] DFS NR, not reached DFS POSTOP VS PERIOP

18. Arm2-yr rate, % Median [95% CI] Postoperative60.539.9 [26.9-NR] Perioperative40.323.0 [15.2-22.4] DFS NR, not reached DFS POSTOP VS PERIOP Populations not comparable 39.6% synchronous mets 66.0% synchronous mets

19. MIROX strategy is not superior to FOLFOX4. Results in both arms were better than expected, with a 2y-DFS over 45%, and a 4-yr survival over 70%. Survival difference between perioperative and postoperative schedules mainly explained by differences in patient’s profiles. Planned: Multivariate analysis focusing on known prognostic factors, and chronology of chemotherapy. Overall survival update. CONCLUSIONS

20. Acknowlegments PATIENTS AND THEIR FAMILIES, INVESTIGATORS AVIGNON: Laurent Mineur BEAUVAIS: Jean-Yves Dutel BORDEAUX: Denis Smith BRIEY: Patrick Brucker CALAIS: Zoher Merad DIJON: Michel Flesch LA ROCHE/YON: Roger Faroux LIBOURNE: Dominique Auby LILLE: Mohamed Hebbar, Eric Vaillant, Philippe Martin, Stéphanie Truant, François-René Pruvot, Christophe Mariette, Jean-Pierre Triboulet MONTPELLIER: Marc Ychou, Eric Assenat PARIS: Aimery de Gramont, Thierry André, Christophe Louvet, Christophe Tournigand, Frédérique Maindrault-Goëbel, Mostepha Bennamoun, Ahmed Khalil, Julien Taïeb PESSAC: Jean-Louis Legoux SENLIS: Elisabeth Carola SURESNES: May Mabro BIOSTATISTICIANS : CGFL (Dijon) Cécile Dalban, Franck Bonnetain GERCOR (Paris) Benoist Chibaudel, David Brusquant, Alexandra Hadengue, Dominique Notelet … SANOFI-AVENTIS Youssef Yataghene