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