1. 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

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 R A N D O M Stratification Center PS 0/1-2 Adjuvant CT
FOLFIRI*
CPT 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 mg/m2 1-h d.1
LOHP 85 mg/m2 2-h d.1
L-LV 200 mg/m2 2-h d.1
5FU 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 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

6. 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

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 yrs
ECOG PS 0-2 (ECOG PS=0 for pts 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
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

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

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

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

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

14. 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

15. 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

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

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

18. 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

19. (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

20. 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: )
log-rank P value =
TREATMENT
months
Falcone A. – ASCO 2006

21. 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
PS (ECOG)
1-2
148 96 74 48
8.0
5.5
9.9
0.67
0.58
Age
<65 yr
≥65 yr
147 97 66 56
5.3
7.9 81 41
9.6
10.2
0.53
0.70
Gender
Male
Female
144
100 69 53 75 47
9.4
0.62
Primary
Colon
Rectum
176 68 95 27
6.8
0.65
0.61
Previous adjuvant CT
Yes No 58
185 29 93
7.7
11.3
0.50
Time from diagnosis to randomization
< 3 months
≥ 3 months
158 86 79 43
6.7
9.5
10.5
0.64
0.60 HR
Falcone A. – ASCO 2006

22. 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
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
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
Liver mts only
yes no 81
163 42 80
6.8 39 83
9.2
0.75
0.57
N° organ involvement 1
>1
132
112 67 55 57
0.71
0.51
Liver involvement
<25%
>25%
102 40 54
8.7
6.7 43 48
10.5
9.4 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
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

25. OVERALL SURVIVAL FOLFIRI 122 pts FOLFOXIRI Died 81 65 Median OS 16,7 m
HR: 0.70 (95%CI: )
log-rank P value = 0.032
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. 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