Updated results, multivariate and subgroups analysis confirm improved activity and

efficacy for FOLFOXIRI vs FOLFIRI in the G.O.N.O. randomized phase III study in

metastatic colorectal cancer.

Updated results, multivariate and subgroups analysis confirm improved activity and

efficacy for FOLFOXIRI vs FOLFIRI in the G.O.N.O. randomized phase III study in

metastatic colorectal cancer.

2007 A.S.C.O. Annual MeetingChicago (USA), June 1-5

A. Falcone1,3, M. Andreuccetti1, I. Brunetti2, S. Ricci2, C. Barbara1, W.

Evangelista4, V. Passeri5, S. Chiara6, G. Allegrini1, G. Masi1

1 U.O. Oncologia Medica, Azienda USL-6, Livorno; 2 U.O. Oncologia Medica, Ospedale S. Chiara, Pisa; 3 Università degli Studi di Pisa, 4 Centro Oncologico ed Ematologico Subalpino, Ospedale S. Giovanni Battista Le Molinette, Torino, 5 Dipartimento di Medicina Sperimentale e Patologia, Oncologia Medica, Università la Sapienza, Roma, 6 Istituto Nazionale per la Ricerca sul Cancro, GenovaITALY

ABSTRACTABSTRACTBackground: As previously reported (ASCO 2006) the G.O.N.O. conduced a phase III study comparing FOLFIRI to FOLFOXIRI in 244 patients (pts) with not resectable MCRC. At a median follow-up of 18.4 months (mos) we reported significant improvements in response-rate (RR), R0 resection of metastases (mts), PFS and OS for FOLFOXIRI. Methods: Results have been updated (median follow-up of 36.2 mos) and 14 variables were tested as possible prognostic factors for response, R0 resection, PFS and OS. Results: At this updated analysis 225 (111 vs 114) pts have progressed and 180 (84 vs 96) have died. Results confirm the significant improvements for FOLFOXIRI in terms of confirmed RR (60% vs 34% p<0.001), R0 resection of residual mts (15% vs 6% p=0.033 and 36% vs 12% p=0.017 for pts with liver only mts), PFS (median 9.8 vs 6.9 mos p<0.001) and OS (median 23.6 vs 16.7 mos p=0.042) at the cost of a modest and acceptable increase in toxicity. In the logistic regression multivariate analysis treatment with FOLFOXIRI was the only independent predictive factor for response (HR:2.9, p<0.001) and for achieving an R0 surgical resection of mts (HR:3.1, p=0.018). The Cox’s multivariate analysis demonstrates that independent prognostic factors for improved time to progression were treatment with FOLFOXIRI (HR:0.64, p<0.001), and ECOG PS = 0 (HR:0.73, p=0.02) and for time to death were treatment with FOLFOXIRI (HR:0.74, p=0.04) and liver involvement < 25% (HR:0.57, p=0.006). The benefits of FOLFOXIRI was consistent across all subgroups, including those with unfavorable prognosis such as pts with time from diagnosis to randomization < 3 mos, multiple site of disease or liver involvement > 25%. Conclusions: FOLFOXIRI confirms to be the first combination demonstrated to be superior to an infusional 5FU containing doublet as FOLFIRI in terms of RR, R0 resections, PFS and OS. FOLFOXIRI represents a new treatment option in MCRC and its use and study is of particular interest in a neoadjuvant strategy, in pts with few chances to achieve a three-drug exposure in a sequential strategy and in combination with targeted agents. Partially supported by Fondazione ARCO.

RATIONALERATIONALE

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)

FOLFOXIRI RATIONALEFOLFOXIRI 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)

STUDY RATIONALESTUDY RATIONALE

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

FOLFOXIRI SCHEDULEFOLFOXIRI SCHEDULE

5FU flat continuous infusion3200mg/m2

L-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

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

PATIENTS CHARACTERISTICSPATIENTS CHARACTERISTICS

*Accrual from November 2001 to April 2005

FOLFIRI(122 pts)

FOLFOXIRI(122 pts)

Age, median (range) 64 (21-75) 62 (27-75)

Sex (M/F) 69/53 75/47

ECOG PS 0 / 1-2 61% / 39% 61% / 39%

Previous adjuvant CT 24% 24%

Synchronous mts 65% 65%

Multiple sites of disease 45% 47%

Liver mts only 34% 32%

Liver involvement ≥ 25% 57% 53%

LDH >UNL 25% 23%

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**

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

FOLFIRI122 pts

FOLFOXIRI122 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

FOLFIRI122 pts

FOLFOXIRI122 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)

Logistic regression multivariate analysis of predictive factors for Response

Logistic regression multivariate analysis of predictive factors for Response

Covariate P value HR (95% CI)

Treatment

FOLFIRI 1.0

FOLFOXIRI <0.001 2.9 1.7-4.9

Variables tested: Treatment, sex, age, PS, primary, N. organs involv., sites of mts,% liver involv., time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

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)

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)

Logistic regression multivariate analysis of predictive factors for secondary R0-SurgeryLogistic regression multivariate analysis of predictive factors for secondary R0-Surgery

Covariate P value HR (95% CI)

Treatment

FOLFIRI 1.0

FOLFOXIRI 0.018 3.1 1.2-7.9

Liver only metastases

Yes 1.0

No 0.054 0.27 0.1-1.0

Variables tested: Treatment, Sex, age, PS, primary, N. organs involv., Sites of mts,% liver involv., Time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

FOLFIRI

122 pts

FOLFOXIRI

122 pts

Progressed 114 111

Median PFS 6.9 m 9.9 m

HR: 0.65 (95%CI: 0.47-0.83)

log-rank P value = 0.0009

PROGRESSION FREE SURVIVALPROGRESSION FREE SURVIVAL

0 6 12 18 24 30 36 420

20

40

60

80

100

months

Perc

en

t su

rviv

al

Cox’s multivariate analysis of prognostic factors for Progression Free Survival

Cox’s multivariate analysis of prognostic factors for Progression Free Survival

Covariate p value HR (95% CI)

Treatment

FOLFIRI 1.0

FOLFOXIRI <0.001 0.64 0.49-0.83

ECOG PS

> 1 1.0

0 0.02 0.73 0.55-0.95

Gender

Female 1.0

Male 0.054 0.77 0.59-1.0

Variables tested: Treatment, sex, age, PS, primary, N. organs involv., sites of mts,% liver involv., time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

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 9.9 0.65 0.43-0.83

PS (ECOG) 0

1-2

148

96

74

48

8.2

5.6

74

48

9.9

9.6

0.68

0.59

0.47-0.94

0.36-0.87

Age <65 yr

≥65 yr

147

97

66

56

5.2

7.9

81

41

9.6

10.4

0.58

0.70

0.38-0.79

0.46-1.06

Gender Male

Female

145

99

69

53

6.9

6.9

76

46

10.2

9.4

0.62

0.67

0.42-0.88

0.43-1.01

Primary Colon

Rectum

176

68

95

27

7.0

6.6

81

41

9.4

10.4

0.70

0.55

0.50-0.94

0.29-0.90

Previous adjuvant CT Yes

No

58

186

29

93

7.5

6.7

29

93

11.2

9.8

0.81

0.60

0.46-1.40

0.43-0.80

Time from diagnosis to randomization

< 3 months

≥ 3 months

158

86

79

43

6.8

7.4

79

43

9.8

10.5

0.62

0.72

0.43-0.84

0.45-1.11

LDH ≤UNL

>UNL

n.a.

120

59

65

56

31

35

6.9

6.8

6.7

64

28

30

10.2

9.7

9.4

0.53

0.69

0.89

0.32-0.73

0.39-1.16

0.53-1.48

FOLFIRI FOLFOXIRI

0.1 10.5 5

Caracteristcs Totaln

Mediann

Median HR 95% CI

All patients 244 122 6.9 122 9.8 0.63 0.47-0.81

CEA <100

≥100

n.a.

142

74

28

70

38

14

7.4

5.4

5.4

72

36

14

10.2

8.7

10.9

0.63

0.76

0.52

0.43-0.87

0.46-1.21

0.20-1.12

HGB <11

≥11

n.a.

37

198

9

20

96

6

7.3

6.7

7.6

17

102

3

10.4

9.8

10.5

0.70

0.63

0.94

0.35-1.33

0.45-0.83

0.22-3.96

GB <8000

≥8000

n.a

123

111

10

61

54

7

7.5

6.4

4.4

62

57

3

10.2

9.2

10.5

0.67

0.58

0.81

0.45-0.96

0.37-0.84

0.21-3.19

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

7.1

6.4

65

57

9.8

10.0

0.80

0.48

0.55-1.13

0.28-0.65

Liver involvement <25%

>25%

n.a.

83

102

59

40

54

31

7.4

6.9

6.8

43

48

28

11.8

9.1

10.5

0.54

0.79

0.67

0.32-0.82

0.52-1.16

0.36-1.17

FOLFIRI FOLFOXIRI

Hazard ratios for risk of progression in subgroups (2)

0.1 10.5 5

FOLFIRI FOLFOXIRI

Progressed pts 114 111

Second-line CT 78% 73%

FOLFOX 87% 15%

FOLFIRI 5% 23%

FOLFOXIRI 1% 20%

Mitomycin-C 0% 17%

Infusional 5FU 3% 11%

Cetuximab 1% 7%

Bevacizumab 0% 0%

Other 3% 6%

SECOND-LINE CHEMOTHERAPYSECOND-LINE CHEMOTHERAPY

OVERALL SURVIVALOVERALL SURVIVAL

FOLFIRI

122 pts

FOLFOXIRI

122 pts

Died 96 84

Median OS

16.7 m 23.6 m

HR: 0.74 (95%CI: 0.55-0.99)

log-rank P value = 0.042

19%13%

0 12 24 36 48 600

20

40

60

80

100

months

Perc

en

t su

rviv

al

Median follow up: 36.2 months

Cox’s multivariate analysis of prognostic factors for Survival

Cox’s multivariate analysis of prognostic factors for Survival

Covariate P value HR (95% CI)

Treatment

FOLFIRI 1.0

FOLFOXIRI 0.041 0.74 0.55-0.99

Liver involvement

> 25% 1.0

< 25% 0.001 0.51 0.34-0.77

no 0.61 0.43-0.85

Variables tested: Treatment, Sex, age, PS, primary, N. organs involv., Sites of mts,% liver involv., Time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

Hazard ratios for risk of OS in subgroups (1)Hazard ratios for risk of OS in subgroups (1)

Caracteristcs Total n

Mediann

Median HR 95% CI

All Patients 244 122 16.7 122 23.6 0.74 0.55-0.98

PS (ECOG) 0

1-2

148

96

74

48

17.6

14.1

74

48

24.2

20.8

0.70

0.80

0.47-1.01

0.50-1.26

Age <65 yr

≥65 yr

147

97

66

56

13.4

20.2

81

41

23.9

23.6

0.58

1.02

0.38-0.82

0.63-1.67

Gender Male

Female

145

99

69

53

17.1

16.7

76

46

27.3

17.2

0.60

1.02

0.44-0.87

0.65-1.62

Primary Colon

Rectum

176

68

95

27

16.7

14.9

81

41

23.4

24.1

0.74

0.77

0.52-1.05

0.42-1.37

Previous adjuvant CT

Yes

No

58

186

29

93

20.9

15.4

29

93

23.8

23.6

1.05

0.66

0.56-1.97

0.47-0.92

Time from diagnosis to randomization

< 3 months

≥ 3 months

158

86

79

43

15.3

19.9

79

43

23.6

24.1

0.66

0.92

0.46-0.93

0.54-1.56

LDH ≤UNL

>UNL

n.a.

120

59

65

56

31

35

16.5

19.4

14.9

64

28

30

24.1

20.8

27.1

0.70

0.82

0.81

0.45-1.06

0.45-1.46

0.45-1.42

FOLFIRI FOLFOXIRI

0.1 10.5 5

Caracteristcs Totaln

Mediann

Median HR 95% CI

All patients 244 122 16.7 122 23.6 0.74 0.55-0.98

CEA <100

≥100

n.a.

142

74

28

70

38

14

19.8

15.9

11.0

72

36

14

23.4

21.3

28

0.90

0.68

0.34

0.61-1.33

0.39-1.14

0.09-0.6

HGB <11

≥11

n.a.

37

198

9

20

96

6

16.7

15.9

14.3

17

102

3

18.4

23.4

27.2

0.85

0.73

0.91

0.41-1.73

0.52-1.01

0.19-4.26

GB <8000

≥8000

n.a.

123

111

10

61

54

7

19.1

14.8

11.9

62

57

3

29.3

21.3

27.3

0.75

0.71

0.78

0.49-1.15

0.46-1.09

0.18-3.30

Liver mts only yes

no

81

163

42

80

17.3

15.7

39

83

24.2

21.1

0.82

0.71

0.49-1.36

0.49-1.01

N° organ involvement

1

>1

132

112

67

55

19.8

13.9

65

57

24.3

21.1

0.96

0.53

0.64-1.45

0.34-0.79

Liver involvement <25%

>25%

n.a

83

102

59

40

54

31

18.0

15.7

24.1

43

48

28

24.8

20.8

25.2

0.91

0.53

1.02

0.55-1.52

0.47-0.81

0.52-1.01

FOLFIRI FOLFOXIRI

Hazard ratios for risk of OS in subgroups (2)

0.1 10.5 5

Survival of pts radically resected after FOLFOXIRI in phasae II and III GONO’s trials

Survival of pts radically resected after FOLFOXIRI in phasae II and III GONO’s trials

0 12 24 36 48 60 72 84 960

20

40

60

80

100

R0 patients

Months

Per

cen

t su

rviv

al

N. of pts: 37

N. of events: 18

Median Follow up: 55 months

Median Survival: 39.0+ months

5-years Survival: 40%

Falcone at al. J Clin Oncol 2002; Masi et al. Ann Oncol 2004; Falcone et al. J Clin Oncol 2007

Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.

Survival improves with availability Survival improves with availability of three active drugsof three active drugs

*“GONO” FOLFOXIRI

P=0.0001

Response rate

,9,8,7,6,5,4,3

Rese

ctio

n r

ate ,6

,5

,4

,3

,2

,1

0,0

Studies incl. selected pts.(liver metastases only, no extrahepat. disease) r=.96, p=.002

Studies incl. all patients with metastatic CRC (solid line) r=.74, p<.001

Phase III studies in metastatic CRC(dashed line) r=.67, p=.024

G Folprecht, A Grothey, S Alberts, HR Raab, and CH Köhne, Ann Oncol 2005

*

*

“GONO” FOLFOXIRI

“GONO” FOLFOXIRI

CORRELATION BETWEEN TUMOR CORRELATION BETWEEN TUMOR RESPONSE AND RESECTION RATESRESPONSE AND RESECTION RATES

Doublet + 1 biologic or Triplet Doublet + 1 biologic or Triplet in phase III studiesin phase III studies

Doublet + 1 biologic or Triplet Doublet + 1 biologic or Triplet in phase III studiesin phase III studies

Treatment IFL + BVNEJM ‘04

FOLFOX or XELOX + BV

ASCO-GI ‘07

FOLFOXIRIASCO‘07

N pts 402 700 122

RR (%) 44.8% 38.0% 60.0 %

R0 surgery < 2% ? 15%

PFS (months) 10.6 9.4 9.9

OS (months) 20.3 ? 23.6

CONCLUSIONSCONCLUSIONS

“GONO” FOLFOXIRI is the first studied combination, in a phase III study, that compared to an infusional doublet as FOLFIRI, although at the cost of a modest increase in toxicity, significantly improves ORR, post-CT resection of mts, PFS and OS

“GONO” FOLFOXIRI represents a new first-line option in metastatic colorectal cancer patients with similar characteristics to those included in this study

The study of FOLFOXIRI should be of particular interest in a neoadjuvant strategy, in pts with few chances to achieve a 3 drugs exposure in a sequential strategy and in combination with targeted agents

Thank you to all patients and investigators!

Thank you to all patients and investigators!

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, S. Bursi, 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