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A Phase III trial of 5-FU/l-leucovorin/
irinotecan (FOLFIRI) versus irinotecan/S-1
(IRIS) as second-line chemotherapy for
metastatic colorectal cancer
FIRIS study
Ken Kato, Kei Muro, Hirofumi Yasui, Akihito Tsuji,
Shinichi Sameshima, Hideo Baba, Taroh Satoh,
Tadamichi Denda, Kenji Ina, Kenichi Sugihara
On behalf of the FIRIS study group
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.
Biochemical action of S-1
S-1 = Tegafur + CDHP + Oxo
Tegafur
Liver and Tumor
(CYP 2A6)
Neurotoxicity
Tumor
5-FU
CDHP
Antitumor
activity
FdUMP
GI toxicity
FdUMP
Myelotoxicity
GI tract
DPD
F-β-Ala
FdUMP
OPRT
Oxo
Bone marrow
Degradation
Phosphorylation
OPRT, orotate phosphoribosyltransferase
FIRIS Study Design
Metastatic CRC
FOLFIRI (n=213)
Age 20-75y
2nd line
PS 0-1
No prior Irinotecan
n=426
Accrual：2006.1-2008.2
Stratification factors:
・PS (0/1)
・Prior chemotherapy
(with/without L-OHP)
・Institution
R
Irinotecan: 150 mg/m2 d1, 15
l-LV: 200mg/m2 d1, 15
5-FU: 400mg/m2 bolus d1, 15
5-FU: 2,400mg/m2 46 hr civ d1,2,
&d15,16
repeated every 4 wks
IRIS (n=213)
Irinotecan: 125mg/m2 d1, 15
S-1: 80-120mg*/body d1-14
repeated every 4 wks
*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
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 characteristics
Male / Female
Median Age, years (range)
ECOG PS 0/1
FOLFIRI
(n=213)
IRIS
(n=213)
123/90
120/93
63 (32-75)
61 (29-75)
160/53
158/55
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
Histologic Type
Well differentiated
Moderately
differentiated
Poorly differentiated
Other
Undetermined
88/124
PFS (ITT population)
FOLFIRI
(n=213)
Proportion of patients
1
IRIS
(n=213)
Progression, n 194
195
Median, months 5.1
5.8
Adjusted HR
1.077
(95% CI)
0.879 to 1.319
0.75
Upper limit below < 1.333
(non inferiority margin)
p=0.039
0.5
0.25
FOLFIRI
IRIS
5.1 5.8
0
No. pts at risk
FOLFIRI 213
IRIS
213
3
6
9
12
15
18
21
24
Progression-Free Survival (months)
147
149
86
89
54
43
35
20
19
10
11
5
8
4
3
1
OS (ITT population)
FOLFIRI
(n=213)
Proportion of patients
1
IRIS
(n=213)
Events, n
117
110
Median, months 18.2
19.5
Adjusted HR
0.909
(95% CI)
0.699 to 1.181
0.75
0.5
0.25
FOLFIRI
IRIS
Median-follow-up time:12.9
18.2
0
3
No. patients at risk
FOLFIRI 213
IRIS
213
208
202
6
9
12
15
18
19.5
21
24
50
47
24
24
Survival Time (months)
179
180
160
155
126
125
99
92
78
67
Response rate
(of the patients who had >1 measurable lesion)
(%)
20
18.8%
16.7%
(95%CI :13.4-25.2)
(95%CI :11.5-23.1)
10
0
FOLFIRI
(n=174)
RECIST1.0 (investigator assessed)
IRIS
(n=181)
Adverse events
(safety analysis population)
Adverse event
CTC-AE v3.0
FOLFIRI (n=211)
IRIS (n=210)
Grade 3-4
Grade 3-4
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
Subgroup analysis : PFS
No. of
Patients
P value for
interaction
Male
Female
243
183
0.23
<65
65-75
252
174
0.76
122
257
21
24
0.93
0
1
Prior chemotherapy with oxaliplatin
Yes
No
318
108
0.88
257
169
0.03
ITT population
426
Subgroup
Sex
Age
Histologic type
Well differentiated adeno.
Moderate differentiated adeno.
Poorly differentiated adeno.
Other
ECOG PS
IRIS better
.3 .5 .7 1
2 3 4 FOLFIRI better
PFS and OS according to prior CTx
(with or without L-OHP)
L-OHP(+)
PFS
1
0.75
mPFS
FOLFIRI n=128
3.9M
IRIS n=129
5.7M
0.5
HR 0.876
(0.677 -1.133)
0.2
5
0
3
6
9
12
15
18
21
Proportion of patients
Proportion of patients
L-OHP(+)
24
OS
1
0.75
0.5
FOLFIRI n=128
0.25
0
IRIS n=129
3
L-OHP(-)
1
PFS
0.75
FOLFIRI n=85
IRIS n=84
0.5
6.0M
HR 1.490
(1.079 -2.059)
0.25
0
mPFS
7.8M
3
6
9
12
15
18
21
24
Progression-Free Survival (months)
9
12
15
18
21
24
Survival Time (months)
Proportion of patients
Proportion of patients
Progression-Free Survival (months)
6
HR 0.781
(0.571 -1.067)
L-OHP(-)
1
OS
0.75
0.5
HR 1.302
(0.806 -2.104)
FOLFIRI n=85
0.25
0
IRIS n=84
3
6
9
12
15
18
21
Survival Time (months)
24
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.
FIRIS Study Group
Participant institutions
Aichi Cancer Center Hospital
Shizuoka Cancer Center
National Cancer Center Hospital
Kochi Health Sciences Center
Gunma Cancer Center
Kumamoto University
Kinki University School of Medicine
Chiba Cancer Center
Nagoya Memorial Hospital
Shikoku Cancer Center
Saitama Cancer Center
Osaka Medical College Hospital
National Kyushu Cancer Center
Osaka City General Hospital
Gunma University Hospital
Hokkaido University Hospital
Kyoto Medical Center
Keio University Hospital
Kansai Rosai Hospital
Tokyo Medical and Dental University
Board members
Osaka Medical Center for Cancer and
Cardiovascular Disease
Aomori Prefectural Central Hospital
Showa University Toyosu Hospital
Minoh City Hospital
Saiseikai Kumamoto Hospital
Toyama University Hospital
Kagoshima Medical Center
Tonan Hospital
Kanagawa Cancer Center
Niigata Cancer Center Hospital
Saku Central Hospital
Hyougo Cancer Center
Hiroshima University Hospital
Tomakomai Nisshou Hospital
Aichi Cancer Center Aichi Hospital
Nagoya Medical Center
Kobe University Hospital
Yamagata Prefectural Central Hospital
Yokohama City University Hospital
Kitasato University Hospital
• 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
This study was sponsored by TAIHO and Daiichi Sankyo