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.).

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*A. Falcone*, , G. Masi, I. Brunetti, G. Benedetti, O. Bertetto, V.

Picone, S. Chiara, M. Merlano, S. Vitello, S. Ricci.

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

* Dept. of Oncology of Livorno and University of Pisa, ITALY

FOLFOXIRI RATIONALEFOLFOXIRI 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 RATIONALESTUDY 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 DESIGNSTUDY DESIGN

FOLFIRI*FOLFIRI*CPT-11 180 mg/m2 1-h d.1L-LV 100 mg/m2 2-h d.1,25FU 400 mg/m2 bolus d.1,25FU 600 mg/m2 22-h d.1,2 q. 2 wks x 12 cycles

FOLFOXIRI**FOLFOXIRI**CPT-11 165 mg/m2 1-h d.1LOHP 85 mg/m2 2-h d.1L-LV 200 mg/m2 2-h d.15FU 3200 mg/m2 48-h CI d.1q. 2 wks x 12 cycles

StratificationCenterPS 0/1-2Adjuvant CT

RANDOM

In pts progressed after FOLFIRI a second-line CT with an LOHP

containing regimen (FOLFOX) was recommended

* Douillard Lancet 2000

** Masi Ann Oncol 2004

Falcone A. – ASCO 2006

FOLFOXIRI SCHEDULEFOLFOXIRI SCHEDULE

5-FU infusion3200mg/m2

LV 200 mg/m2

Oxaliplatin 85 mg/m2

2 hours

Repeated every 14 days

CPT-11165 mg/m2

48 hours

Day 1 Day 2 Day 3

1 hour

Falcone A. – ASCO 2006

STUDY OBJECTIVESSTUDY OBJECTIVES

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

STATISTICAL CONSIDERATIONSSTATISTICAL 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 CRITERIAMAIN 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 CHARACTERISTICSPATIENTS CHARACTERISTICS

Caracteristc Total n n

All Patients 244 122 122

PS (ECOG)

0

1-2

148

96

74

48

74

48

Age

<65 yr

≥65 yr

147

97

66

56

81

41

Gender

Male

Female

144

100

69

53

75

47

Primary

ColonRectum

17668

9527

8141

Previous adjuvant CT

YesNo

58185

2993

2993

Time from diagnosis to randomization

< 3 months

≥ 3 months

15886

7943

7943

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

Caracteristc Total n n

All patients 244 122 122

LDH

≤UNL>UNLn.a.

1205965

561335

642830

CEA

<100≥100n.a.

1427428

703814

723614

Liver mts only

yes

no

81

163

42

80

39

83

N° organ involvement

1

>1

132

112

67

55

65

57

Liver involvement

<25%>25%

83 102

4054

4348

Falcone A. – ASCO 2006

47%41%

55%

29%34%

55%

45%

68%

40% 38%

0%

25%

50%

75%

100%

Diarrhea Vomiting Nausea Stomatitis Asthenia

FOLFIRI

FOLFOXIRI

NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT

NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT

(N=122)

(N=122)

P=0.079

P=0.064

HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT

HEMATOLOGICAL TOXICITY (NCI) GRADE 1-2 PER PATIENT

31%

6%

49%

33%

24%

62%

0%

25%

50%

75%

100%

Neutropenia Thrombocytopenia Anemia

FOLFIRI

FOLFOXIRI

(N=122)

(N=122)

Falcone A. – ASCO 2006

P=0.0003

P=0.07

12%

2% 3% 3% 0%

20%

7% 5% 6%

20%

0%

25%

50%

75%

100%

Diarrhea Vomiting Stomatitis Asthenia Neurotoxicity

FOLFIRI

FOLFOXIRI

NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT

NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT

(N=122)

(N=122)

p < 0.0001

** Grade 2-3**

Falcone A. – ASCO 2006

p = 0.08 p = 0.10

28%

3% 1% 1%

50%

5% 2% 3%

0%

25%

50%

75%

100%

Neutropenia Febrile Neutropenia Thrombocytopenia Anemia

FOLFIRI

FOLFOXIRI

HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT

HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT

(N=122)

(N=122)

p =0.0006

Falcone A. – ASCO 2006

FOLFIRI(122 pts)

FOLFOXIRI(122 pts)

S.A.E., total 20% 18%

S.A.E. for toxicity 7% 11%

S.A.E. for other reasons 13% 7%

Toxic deaths 0 0

Deaths within 60 days 1.6% (2pts) 1.6% (2 pts)

S.A.E. & TOXIC DEATHSS.A.E. & TOXIC DEATHS

Falcone A. – ASCO 2006

DOSE-INTENSITYDOSE-INTENSITY

FOLFIRI FOLFOXIRI

Cycles

Total 1056 1083

Median 10 11

Range 1-16 1-16

Oxaliplatin - 83%

Relative DI CPT-11 87% 82%

5-FU 86% 82%

G-CSF was used in:

• 2% of FOLFIRI cycles

• 6% of FOLFOXIRI cycles

Falcone A. – ASCO 2006

FOLFIRI(122 pts)

FOLFOXIRI(122 pts)

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% 2%

*P= 0.0002

RESPONSES (ITT analysis)RESPONSES (ITT analysis)

INVESTIGATORS’ASSESSMENT

INVESTIGATORS’ASSESSMENT

Falcone A. – ASCO 2006

FOLFIRI(122 pts)

FOLFOXIRI(122 pts)

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% 8%

*P< 0.0001

EXTERNALLYREVIEWED

EXTERNALLYREVIEWED

RESPONSES (ITT analysis)RESPONSES (ITT analysis)

Falcone A. – ASCO 2006

FOLFIRI(122 pts)

FOLFOXIRI(122 pts)

R0 6%*(7 pts) 15%*(18 pts)

R1 1% 2%

Explorative 8% 1%

* P=0.033

POST-CT SURGICAL RESECTIONS(all patients)

POST-CT SURGICAL RESECTIONS(all patients)

Falcone A. – ASCO 2006

FOLFIRI(42 pts)

FOLFOXIRI(39 pts)

R0 12%*(5 pts) 36%*(14 pts)

* P=0.017

POST-CT SURGICAL RESECTIONS(patients with liver mts only)

POST-CT SURGICAL RESECTIONS(patients with liver mts only)

Falcone A. – ASCO 2006

FOLFIRI

122 pts

FOLFOXIRI

122 pts

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

PROGRESSION FREE SURVIVALPROGRESSION FREE SURVIVAL

0 6 12 18 24 300

25

50

75

100

Time

Per

cen

t su

rviv

al

Falcone A. – ASCO 2006

18% vs 45% p<0.0001

months

TREATMENT

Hazard ratios for risk of progression in subgroups (1)

Hazard ratios for risk of progression in subgroups (1)

Caracteristcs Totaln

Mediann

Median HR 95% CI

All Patients 244 122 6.9 122 9.8 0.63 0.47-0.81

PS (ECOG)

0

1-2

148

96

74

48

8.0

5.5

74

48

9.9

9.8

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

6.9

6.9

75

47

10.2

9.4

0.62

0.67

0.42-0.88

0.43-1.01

Primary

ColonRectum

17668

9527

6.86.9

8141

9.49.8

0.650.61

0.46-0.880.32-1.00

Previous adjuvant CT

YesNo

58185

2993

7.76.8

2993

11.39.6

0.500.67

0.25-0.820.48-0.90

Time from diagnosis to randomization

< 3 months

≥ 3 months

15886

7943

6.77.7

7943

9.510.5

0.640.60

0.45-0.890.36-0.93

FOLFIRI FOLFOXIRI

0.1 10.5 5

HR

Falcone A. – ASCO 2006

Caracteristcs Totaln

Mediann

Median HR 95% CI

All patients 244 122 6.9 122 9.8 0.63 0.47-0.81

LDH

≤UNL>UNLn.a.

1205965

561335

5.94.1

10.0

642830

9.99.59.5

0.580.470.89

0.36-0.830.24-0.750.52-1.05

CEA

<100≥100n.a.

1427428

703814

7.95.45.6

723614

10.18.8

10.6

0.660.670.46

0.45-0.940.41-1.060.16-0.98

Liver mts only

yes

no

81

163

42

80

6.9

6.8

39

83

9.2

10.0

0.75

0.57

0.46-1.20

0.39-0.77

N° organ involvement

1

>1

132

112

67

55

6.9

6.8

65

57

9.8

9.8

0.71

0.51

0.48-1.02

0.31-0.72

Liver involvement

<25%>25%

83 102

4054

8.76.7

4348

10.59.4

0.670.66

0.40-1.070.42-0.97

FOLFIRI FOLFOXIRI

0.1 10.5 5

Hazard ratios for risk of progression in subgroups (2)

HR

Falcone A. – ASCO 2006

0

20

40

60

80

100

120

0 4 8 12 16 20 24 28

Time From Treatment Start (weeks)

QO

L S

co

re A

vera

ge

FOLFIRI

FOLFOXIRI

EVOLUTION OVER TIME OF GLOBAL HEALTH STATUS (EORTC QLQ-C30 vers 3.0)

EVOLUTION OVER TIME OF GLOBAL HEALTH STATUS (EORTC QLQ-C30 vers 3.0)

Falcone A. – ASCO 2006

FOLFIRI FOLFOXIRI

Progressed pts 112 104

Second-line CT 73% 76%

FOLFOX 67% 12%

FOLFIRI 3,5% 22%

FOLFOXIRI 0% 14%

Mitomycin-C 0% 14%

Other* 2,5% 14%

SECOND-LINE CHEMOTHERAPYSECOND-LINE CHEMOTHERAPY

* Cetuximab: 1 pt in arm A and 2 pts in arm B

Falcone A. – ASCO 2006

FOLFIRI

122 pts

FOLFOXIRI

122 pts

Died 81 65

Median OS

16,7 m 22,6 m

HR: 0.70 (95%CI: 0.50-0.97)

log-rank P value = 0.032

OVERALL SURVIVALOVERALL SURVIVAL

0 6 12 18 24 300

25

50

75

100

Time

Per

cen

t su

rviv

al

Falcone A. – ASCO 2006months

34%

21%

CONCLUSIONSCONCLUSIONS 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

InvestigatorsInvestigators

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

GruppoOncologicoNord Ovest

Falcone A. – ASCO 2006