A Phase III trial of 5-FU/l-leucovorin/ irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic

colorectal cancer

Ken Kato, Kei Muro, Hirofumi Yasui, Akihito Tsuji, Shinichi Sameshima, Hideo Baba, Taroh Satoh, Tada

michi Denda, Kenji Ina, Kenichi Sugihara

On behalf of the FIRIS study group

FIRIS study

Background

• S-1(tegafur,CDHP,Oxo) is an oral “DPD inhibitory fluoropyrimidine (DIF)” widely used for various solid tumors in Japan.

• Several phase II studies of irinotecan plus S-1 combination therapy (IRIS) have shown promising efficacy and safety for metastatic colorectal cancer (mCRC).

• This phase III trial was conducted to examine whether IRIS is non-inferior to FOLFIRI as second-line chemotherapy for mCRC.

DPD

CDHP

Neuro- toxicity

Liver and Tumor (CYP 2A6)

5-FU

Oxo

Tumor

GI tract

Bone marrow

FdUMP

FdUMP

FdUMPAntitumor activity

GI toxicity

Myelo- toxicity

Tegafur

OPRT

Degradation Phosphorylation

F-β-Ala

Biochemical action of S-1

OPRT, orotate phosphoribosyltransferase

S-1 = Tegafur + CDHP + Oxo

FIRIS Study Design

Stratification factors: ・ PS (0/1) ・ Prior chemotherapy (with/without L-OHP) ・ Institution

Metastatic CRC Age 20-75y2nd linePS 0-1No prior Irinotecan

FOLFIRI (n=213)Irinotecan: 150 mg/m2 d1, 15l-LV: 200mg/m2 d1, 15 5-FU: 400mg/m2 bolus d1, 155-FU: 2,400mg/m2 46 hr civ d1,2, &d15,16repeated every 4 wks

FOLFIRI (n=213)Irinotecan: 150 mg/m2 d1, 15l-LV: 200mg/m2 d1, 15 5-FU: 400mg/m2 bolus d1, 155-FU: 2,400mg/m2 46 hr civ d1,2, &d15,16repeated every 4 wks

IRIS (n=213)Irinotecan: 125mg/m2 d1, 15S-1: 80-120mg*/body d1-14repeated every 4 wks

IRIS (n=213)Irinotecan: 125mg/m2 d1, 15S-1: 80-120mg*/body d1-14repeated every 4 wks

Rn=426

*According to body surface area, BSA < 1.25 m2, 80 mg/day, 1.25=<BSA <1.5, 100 mg/day; BSA >=1.5, 120 mg/day

Accrual ： 2006.1-2008.2

Endpoints and Statistical considerations

• Primary objective– Progression free survival

• Secondary objectives– overall survival, response rate, toxicity and

cost.

• Sample size– With 400 patients, this had 80% power to

detect non-inferiority of IRIS vs. FOLFIRI, defined by the upper limit of the 95% CI for the HR of ≤1.333

Main inclusion criteria• Histologically confirmed adenocarcinoma

• Inoperable mCRC

• No prior Irinotecan

• Failure to 1st line chemotherapy for mCRC or relapse during or within 6 months of adjuvant chemotherapy

• Age 20-75

• ECOG PS 0,1

• Adequate organ functions

• No prior radiotherapy for mCRC • Written informed consent

Baseline characteristicsFOLFIRI

(n=213)

IRIS

(n=213)

Male / Female 123/90 120/93

Median Age, years (range) 63 (32-75) 61 (29-75)

ECOG PS 0/1 160/53 158/55

Histologic 　 Type

Well differentiated

Moderately differentiated

Poorly differentiated

Other

Undetermined

62

124

13

13

1

60

133

8

11

1

Prior Chemotherapy with oxaliplatin

　 Yes/No 128/85 129/84

Number of metastatic sites

1/≥2 92/120 88/124

Pro

po

rtio

n o

f p

atie

nts

Progression-Free Survival (months)No. pts at risk

FOLFIRIIRIS

213213 89 20 5 1

86 35 11 3147 85443

1910149 4

5.85.1

0.25

0.5

0.75

1

0 3 6 9 12 15 18 21 24

PFS (ITT population)

FOLFIRI IRIS

FOLFIRI IRIS (n=213) (n=213)

Progression, n 194 195Median, months 5.1 5.8Adjusted HR 1.077 (95% CI) 0.879 to 1.319

Upper limit below < 1.333 (non inferiority margin)p=0.039

Survival Time (months)

Pro

po

rtio

n o

f p

atie

nts

92

No. patients at riskFOLFIRIIRIS

213213 180 125 67 24

179 126 78 24208 50160155

99202 47

0.25

0.5

0.75

1

0 3 6 9 12 15 18 21 24

18.2 19.5

OS (ITT population) FOLFIRI IRIS (n=213) (n=213)

Events, n 117 110Median, months 18.2 　 19.5 Adjusted HR 0.909 (95% CI) 0.699 to 1.181

FOLFIRI IRIS

Median-follow-up time:12.9

Response rate

20

10

0

(of the patients who had >1 measurable lesion)

RECIST1.0 (investigator assessed)

(%)

FOLFIRI(n=174)

IRIS(n=181)

16.7%(95%CI :11.5-23.1)

18.8%(95%CI :13.4-25.2)

FOLFIRI (n=211) IRIS (n=210)

Grade 3-4 Grade 3-4

Adverse event No. % No. %

Neutropenia 110 52.1 76 36.2

Leukopenia 33 15.6 38 18.1

Hemoglobin 14 6.6 21 10.0

Thrombocytopenia 2 0.9 0 0.0

Diarrhea 10 4.7 43 20.5

Fatigue 7 3.3 18 8.6

Febrile neutropenia 2 0.9 10 4.8

Mucositis / Stomatitis 1 0.5 6 2.9

Adverse events(safety analysis population) CTC-AE v3.0

Subgroup analysis : PFS

0.03

0.88

0.93

0.76

0.23

P value forinteraction

ECOG PS31801081

Prior chemotherapy with oxaliplatin257Yes

257Moderate differentiated adeno.

21Poorly differentiated adeno.

17465-75Histologic type

122Well differentiated adeno.

169No

24Other

252<65Age

183Female243Male

Sex

No. ofPatients

Subgroup

1 .7 .5 .3 2 3 4 ITT population 　　　　 　　

426IRIS better FOLFIRI better

Progression-Free Survival (months)

FOLFIRI n=128 　　　 3.9M 　 IRIS n=129 5.7M

L-OHP(+)

PFS

0.25

0.5

0.75

1

0 3 6 9 12 15 18 21 24Survival Time (months)

0.25

0.5

0.75

1

0 3 6 9 12 15 18 21 24

Progression-Free Survival (months) Survival Time (months)

Pro

po

rtio

n o

f p

ati

en

ts

Pro

po

rtio

n o

f p

ati

en

ts

Pro

po

rtio

n o

f p

ati

en

ts

Pro

po

rtio

n o

f p

ati

en

ts

0.25

0.5

0.75

1

0 3 6 9 12 15 18 21 24

0.25

0.5

0.75

1

0 3 6 9 12 15 18 21 24

L-OHP(-)

PFS

L-OHP(+)

OS

L-OHP(-)

OS

PFS and OS according to prior CTx (with or without L-OHP)

HR 0.876 (0.677 -1.133)

FOLFIRI n=128

IRIS n=129

FOLFIRI n=85 7.8M

IRIS n=84 6.0M

FOLFIRI n=85

IRIS n=84

HR 0.781 (0.571 -1.067)

HR 1.490 (1.079 -2.059)

HR 1.302(0.806 -2.104)

mPFS

mPFS

Cost analysis

Group Median cost per cycle*

FOLFIRI \214,092 (€1,647)

IRIS \134,774 (€1,037)

＊ Included only medical direct cost

Conclusions• This is the first phase III trial demonstrated

the non-inferiority of an oral FU derivative combination with irinotecan compared to FOLFIRI.

• Toxicities of both groups were manageable.

• IRIS can potentially replace FOLFIRI as second-line chemotherapy for mCRC.

Participant institutionsAichi Cancer Center HospitalShizuoka Cancer CenterNational Cancer Center HospitalKochi Health Sciences CenterGunma Cancer CenterKumamoto UniversityKinki University School of Medicine Chiba Cancer CenterNagoya Memorial HospitalShikoku Cancer CenterSaitama Cancer CenterOsaka Medical College HospitalNational Kyushu Cancer CenterOsaka City General HospitalGunma University HospitalHokkaido University HospitalKyoto Medical CenterKeio University HospitalKansai Rosai HospitalTokyo Medical and Dental University

This study was sponsored by TAIHO and Daiichi Sankyo

Osaka Medical Center for Cancer and Cardiovascular Disease

Aomori 　 Prefectural Central HospitalShowa University Toyosu HospitalMinoh City HospitalSaiseikai Kumamoto HospitalToyama University HospitalKagoshima Medical CenterTonan HospitalKanagawa Cancer CenterNiigata Cancer Center HospitalSaku Central HospitalHyougo Cancer CenterHiroshima University HospitalTomakomai Nisshou HospitalAichi Cancer Center Aichi HospitalNagoya Medical CenterKobe University HospitalYamagata Prefectural Central HospitalYokohama City University HospitalKitasato University Hospital

Board members• Steering Committee

–Kenichi Sugihara–Yoshito Komatsu–Yasuhiro Shimada–Hiroya Takiuchi–Narikazu Boku–Masahiko Watanabe

• Independent Data Monitoring Committee

–Yu Sakata–Yasuo Ohashi–Nobuyuki Yamamoto

• Independent Central Review Committee

–Atsushi Ohtsu–Yasuaki Arai–Junji Tanaka

• Medical Adviser

–Ichinosuke Hyodo• Statistical Adviser

–Satoshi Morita

FIRIS Study Group