Atlanta (Georgia) - June 2-6, 2006 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

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

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

STUDY DESIGN R A N D O M Stratification Center PS 0/1-2 Adjuvant CT FOLFIRI* CPT-11 180 mg/m2 1-h d.1 L-LV 100 mg/m2 2-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

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

STUDY OBJECTIVES PRIMARY SECONDARY 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

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

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

PATIENTS CHARACTERISTICS Caracteristc Total n All Patients 244 122 PS (ECOG) 1-2 148 96 74 48 Age <65 yr ≥65 yr 147 97 66 56 81 41 Gender Male Female 144 100 69 53 75 47 Primary Colon Rectum 176 68 95 27 Previous adjuvant CT Yes No 58 185 29 93 Time from diagnosis to randomization < 3 months ≥ 3 months 158 86 79 43 Caracteristc Total n All patients 244 122 LDH ≤UNL >UNL n.a. 120 59 65 56 13 35 64 28 30 CEA <100 ≥100 142 74 70 38 14 72 36 Liver mts only yes no 81 163 42 80 39 83 N° organ involvement 1 >1 132 112 67 55 57 Liver involvement <25% >25% 102 40 54 43 48 *Accrual from November 2001 to April 2005 Falcone A. – ASCO 2006

NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT Falcone A. – ASCO 2006

HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT Falcone A. – ASCO 2006

NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT ** ** Grade 2-3 Falcone A. – ASCO 2006

HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT Falcone A. – ASCO 2006

S.A.E. & TOXIC DEATHS FOLFIRI FOLFOXIRI S.A.E., total 20% 18% (122 pts) FOLFOXIRI S.A.E., total 20% 18% S.A.E. for toxicity 7% 11% S.A.E. for other reasons 13% Toxic deaths Deaths within 60 days 1.6% (2pts) 1.6% (2 pts) Falcone A. – ASCO 2006

DOSE-INTENSITY FOLFIRI FOLFOXIRI Cycles Total 1056 1083 Median 10 11 Range 1-16 Oxaliplatin - 83% Relative DI CPT-11 87% 82% 5-FU 86% G-CSF was used in: 2% of FOLFIRI cycles 6% of FOLFOXIRI cycles Falcone A. – ASCO 2006

RESPONSES (ITT analysis) FOLFIRI (122 pts) FOLFOXIRI Complete 6% 8% Partial 35% 58% Complete + Partial 41%* 66%* 95% Confidence Interval 0.32-0.50 0.56-0.74 Stable 33% 21% Progression 24% 11% Not evaluable 2% INVESTIGATORS’ ASSESSMENT *P= 0.0002 Falcone A. – ASCO 2006

RESPONSES (ITT analysis) FOLFIRI (122 pts) FOLFOXIRI Complete 6% 7% Partial 28% 53% Complete + Partial 34%* 60%* 95% Confidence Interval 0.25-0.43 0.51-0.68 Stable 34% 21% Progression 24% 11% Not evaluable 8% EXTERNALLY REVIEWED *P< 0.0001 Falcone A. – ASCO 2006

POST-CT SURGICAL RESECTIONS (all patients) FOLFIRI (122 pts) FOLFOXIRI R0 6%*(7 pts) 15%*(18 pts) R1 1% 2% Explorative 8% * P=0.033 Falcone A. – ASCO 2006

(patients with liver mts only) POST-CT SURGICAL RESECTIONS (patients with liver mts only) FOLFIRI (42 pts) FOLFOXIRI (39 pts) R0 12%*(5 pts) 36%*(14 pts) * P=0.017 Falcone A. – ASCO 2006

PROGRESSION FREE SURVIVAL 18% vs 45% p<0.0001 FOLFIRI 122 pts FOLFOXIRI Progressed 112 104 Median PFS 6,9 m 9,8 m HR: 0.63 (95%CI: 0.47-0.81) log-rank P value = 0.0006 TREATMENT months Falcone A. – ASCO 2006

Hazard ratios for risk of progression in subgroups (1) FOLFIRI FOLFOXIRI Caracteristcs Total n Median HR 95% CI All Patients 244 122 6.9 9.8 0.63 0.47-0.81 PS (ECOG) 1-2 148 96 74 48 8.0 5.5 9.9 0.67 0.58 0.46-0.94 0.32-0.85 Age <65 yr ≥65 yr 147 97 66 56 5.3 7.9 81 41 9.6 10.2 0.53 0.70 0.33-0.71 0.45-1.07 Gender Male Female 144 100 69 53 75 47 9.4 0.62 0.42-0.88 0.43-1.01 Primary Colon Rectum 176 68 95 27 6.8 0.65 0.61 0.46-0.88 0.32-1.00 Previous adjuvant CT Yes No 58 185 29 93 7.7 11.3 0.50 0.25-0.82 0.48-0.90 Time from diagnosis to randomization < 3 months ≥ 3 months 158 86 79 43 6.7 9.5 10.5 0.64 0.60 0.45-0.89 0.36-0.93 HR Falcone A. – ASCO 2006

Hazard ratios for risk of progression in subgroups (2) FOLFIRI FOLFOXIRI Caracteristcs Total n Median HR 95% CI All patients 244 122 6.9 9.8 0.63 0.47-0.81 LDH ≤UNL >UNL n.a. 120 59 65 56 13 35 5.9 4.1 10.0 64 28 30 9.9 9.5 0.58 0.47 0.89 0.36-0.83 0.24-0.75 0.52-1.05 CEA <100 ≥100 142 74 70 38 14 7.9 5.4 5.6 72 36 10.1 8.8 10.6 0.66 0.67 0.46 0.45-0.94 0.41-1.06 0.16-0.98 Liver mts only yes no 81 163 42 80 6.8 39 83 9.2 0.75 0.57 0.46-1.20 0.39-0.77 N° organ involvement 1 >1 132 112 67 55 57 0.71 0.51 0.48-1.02 0.31-0.72 Liver involvement <25% >25% 102 40 54 8.7 6.7 43 48 10.5 9.4 0.40-1.07 0.42-0.97 HR Falcone A. – ASCO 2006

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

SECOND-LINE CHEMOTHERAPY FOLFIRI FOLFOXIRI Progressed pts 112 104 Second-line CT 73% 76% FOLFOX 67% 12% 3,5% 22% 0% 14% Mitomycin-C Other* 2,5% * Cetuximab: 1 pt in arm A and 2 pts in arm B Falcone A. – ASCO 2006

OVERALL SURVIVAL FOLFIRI 122 pts FOLFOXIRI Died 81 65 Median OS 16,7 m HR: 0.70 (95%CI: 0.50-0.97) log-rank P value = 0.032 34% 21% months Falcone A. – ASCO 2006

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

Investigators Gruppo Oncologico Nord Ovest Centro Trial M. Andreuccetti, C. Barbara, C. Orlandini Alba G. Porcile, M. Boe Bologna L. Crinò, G. Benedetti, S. Bartolini, C. Calandri Caltanissetta S. Vitello Correggio S. Bagnulo Cuneo M. Merlano, C. Granetto, E. Fea Firenze L. Fioretto, A. Ribecco Genova R. Rosso, S. Chiara Livorno A. Falcone, G. Masi, G. Allegrini, L. Marcucci, E. Cerri, F. Loupakis Novara O. Alabisio, S. Miraglia, L. Forti Parma A. Ardizzoni, R. Camisa, F. Pucci Pisa S. Ricci, I. Brunetti, R. Murr, E. Pfanner Pistoia M. Di Lieto, A. Chiavacci Pontedera M. Filidei, S. Cupini Roma E. Cortesi, V. Picone, S. Ferraldeschi, G. D’Auria Torino O. Bertetto, L. Fanchini, W. Evangelista Falcone A. – ASCO 2006