2006 A.S.C.O. ANNUAL MEETING Atlanta (Georgia) - June 2-6, 2006

1. 2006 A.S.C.O. ANNUAL MEETING Atlanta (Georgia) - June 2-6, 2006 The triplet combination of irinotecan, oxaliplatin, and 5FU/LV (FOLFOXIRI) versus the doublet of irinotecan and 5FU/LV (FOLFIRI) as first-line treatment of metastatic colorectal cancer (MCRC): Results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.). A. Falcone*, G. Masi, I. Brunetti, G. Benedetti,O. Bertetto, V. Picone, S. Chiara, M. Merlano, S. Vitello, S. Ricci. * Dept. of Oncology of Livorno and University of Pisa, ITALY

2. FOLFOXIRI RATIONALE • Preclinical synergism between CPT-11, LOHP and 5FU and different dose-limiting toxicities (Fischel, BJC 2001) • FOLFOXIRI can expose 100% of pts to all the 3 active agents (CPT-11, LOHP and 5-FU) while in a sequential strategy 25-50% of pts does not receive II line CT and therefore is not exposed to all the 3 agents (Grothey, JCO 2004) • FOLFOXIRI, if more active, may improve post-CT resection-rate of mts (Folprecht, Ann Oncol 2005) Falcone A. – ASCO 2006

3. STUDY RATIONALE • FOLFIRI was a reference standard combination in MCRC (Douillard, Lancet 2000) • FOLFOXIRI was a feasible regimen with manageable toxicities and promising activity in phase I-II studies (Falcone JCO 2002; Masi Ann Onc 2004) Falcone A. – ASCO 2006

4. STUDY DESIGN FOLFIRI* CPT-11 180 mg/m2 1-h d.1 L-LV 100 mg/m22-h d.1,2 5FU 400 mg/m2 bolus d.1,2 5FU 600 mg/m2 22-h d.1,2 q. 2 wks x 12 cycles R A N D O M • Stratification • Center • PS 0/1-2 • Adjuvant CT * Douillard Lancet 2000 FOLFOXIRI** CPT-11 165 mg/m2 1-h d.1 LOHP 85 mg/m2 2-h d.1 L-LV 200 mg/m2 2-h d.1 5FU 3200 mg/m2 48-h CI d.1 q. 2 wks x 12 cycles ** Masi Ann Oncol 2004 • In pts progressed after FOLFIRI a second-line CT with an LOHP containing regimen (FOLFOX) was recommended Falcone A. – ASCO 2006

5. FOLFOXIRI SCHEDULE Day 1 Day 2 Day 3 CPT-11 165 mg/m2 Oxaliplatin 85 mg/m2 5-FU infusion 3200mg/m2 LV 200 mg/m2 1 hour 2 hours 48 hours Repeated every 14 days Falcone A. – ASCO 2006

6. STUDYOBJECTIVES PRIMARY • Response-rate (WHO criteria) Confirmed by an external panel SECONDARY • Progression-free survival • Overall survival • Safety • Post-CT R-0 surgical resections • QoL (EORTC QLQ-C30) Falcone A. – ASCO 2006

7. STATISTICAL CONSIDERATIONS • Assuming a response-rate of 40% in the FOLFIRI arm and to demonstrate an improvement of 20% in the FOLFOXIRI arm (60%) with a power of 0.80 and an -error of 0.05 (two-sided) it was planned to randomize a total of 240 pts. • With this sample size, and assuming to observe the same results reported by Douillard (Lancet 2000) with FOLFIRI (mPFS of 6.7 mos), the study was also able to demonstrate by two-tailed log-rank test (-error=0.05, power 0.80) a prolongation in PFS of 3.1 months. Falcone A. – ASCO 2006

8. MAIN PATIENTS SELECTION CRITERIA • Metastatic and unresectable colorectal cancer • Measurable disease • Age 18-75 yrs • ECOG PS 0-2 (ECOG PS=0 for pts 71-75 yrs) • Adjuvant CT ended > 6 mos • Adequate renal, hepatic and bone-marrow functions • No previous CPT-11 or LOHP • No previous CT for metastatic disease Falcone A. – ASCO 2006

9. PATIENTS CHARACTERISTICS *Accrual from November 2001 to April 2005 Falcone A. – ASCO 2006

10. NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT (N=122) (N=122) P=0.064 P=0.079 Falcone A. – ASCO 2006

11. HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT (N=122) (N=122) P=0.07 P=0.0003 Falcone A. – ASCO 2006

12. NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT (N=122) (N=122) p < 0.0001 p = 0.08 p = 0.10 ** ** Grade 2-3 Falcone A. – ASCO 2006

13. HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT (N=122) (N=122) p =0.0006 Falcone A. – ASCO 2006

14. S.A.E. & TOXIC DEATHS Falcone A. – ASCO 2006

15. DOSE-INTENSITY • G-CSF was used in: • 2% of FOLFIRI cycles • 6% of FOLFOXIRI cycles Falcone A. – ASCO 2006

16. RESPONSES (ITT analysis) INVESTIGATORS’ ASSESSMENT *P= 0.0002 Falcone A. – ASCO 2006

17. RESPONSES (ITT analysis) EXTERNALLY REVIEWED *P< 0.0001 Falcone A. – ASCO 2006

18. POST-CT SURGICAL RESECTIONS (all patients) * P=0.033 Falcone A. – ASCO 2006

19. POST-CT SURGICAL RESECTIONS (patients with liver mts only) * P=0.017 Falcone A. – ASCO 2006

20. PROGRESSION FREE SURVIVAL 18% vs 45% p<0.0001 TREATMENT months Falcone A. – ASCO 2006

21. Hazard ratios for risk of progression in subgroups (1) FOLFIRI FOLFOXIRI HR Falcone A. – ASCO 2006

22. Hazard ratios for risk of progression in subgroups (2) FOLFIRI FOLFOXIRI HR Falcone A. – ASCO 2006

23. EVOLUTION OVER TIME OF GLOBAL HEALTH STATUS(EORTC QLQ-C30 vers 3.0) Falcone A. – ASCO 2006

24. SECOND-LINE CHEMOTHERAPY * Cetuximab: 1 pt in arm A and 2 pts in arm B Falcone A. – ASCO 2006

25. OVERALL SURVIVAL 34% 21% months Falcone A. – ASCO 2006

26. CONCLUSIONS • The FOLFOXIRI regimen is moderately more toxic than FOLFIRI, however it remains a very feasible and manageable combination • Response-Rate, Prevention of Early Progressions, Progression-Free-Survival, and Post-CT radical surgical resection of mts are significantly improved with FOLFOXIRI • Hazard ratios for risk of progression analyzed in several subgroups indicates similar reductions in risk with FOLFOXIRI • QoL is similar between patients receiving FOLFIRI and FOLFOXIRI • Overall Survival, although this was not the primary endpoint of the study and the total number of events is still low, seems also significantly improved with FOLFOXIRI Falcone A. – ASCO 2006

27. Gruppo Oncologico Nord Ovest Investigators Falcone A. – ASCO 2006