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

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Presentation Transcript
slide1

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, Tadamichi Denda, Kenji Ina, Kenichi Sugihara

On behalf of the FIRIS study group

FIRIS study

background
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.

slide3

5

-

FU

Biochemical action of S-1

S-1 = Tegafur + CDHP + Oxo

Tegafur

Liver and Tumor

(CYP 2A6)

Tumor

Antitumor activity

FdUMP

GI tract

DPD

Neuro- toxicity

OPRT

F-β-Ala

GI toxicity

FdUMP

CDHP

Oxo

Myelo- toxicity

FdUMP

Bone marrow

Degradation

Phosphorylation

OPRT, orotate phosphoribosyltransferase

firis study design
FIRIS Study Design

Metastatic CRC Age 20-75y

2nd line

PS 0-1

No prior Irinotecan

FOLFIRI (n=213)

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

R

n=426

Accrual:2006.1-2008.2

Stratification factors:

・PS (0/1)

・Prior chemotherapy

(with/without L-OHP)

・Institution

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
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
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

slide8

PFS (ITT population)

FOLFIRI

IRIS

FOLFIRI IRIS

(n=213) (n=213)

Progression, n 194 195

Median, months 5.1 5.8

Adjusted HR 1.077

(95% CI) 0.879 to 1.319

1

0.75

Proportion of patients

Upper limit below < 1.333

(non inferiority margin)

p=0.039

0.5

0.25

5.1

5.8

0

3

6

9

12

15

18

21

24

Progression-Free Survival (months)

No. pts at risk

FOLFIRI

213

147

86

54

35

19

11

8

3

IRIS

213

149

89

43

20

10

5

4

1

slide9

FOLFIRI

IRIS

OS (ITT population)

1

FOLFIRI IRIS

(n=213) (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

Proportion of patients

0.5

0.25

Median-follow-up time:12.9

18.2

19.5

0

3

6

9

12

15

18

21

24

Survival Time (months)

No. patients at risk

FOLFIRI

213

208

179

160

126

99

78

50

24

IRIS

213

202

180

155

125

92

67

47

24

response rate
Response rate

(of the patients who had >1 measurable lesion)

(%)

18.8%

(95%CI :13.4-25.2)

20

16.7%

(95%CI :11.5-23.1)

10

0

IRIS

(n=181)

FOLFIRI

(n=174)

RECIST1.0 (investigator assessed)

slide12

Subgroup analysis : PFS

Subgroup

No. of

Patients

P value for

interaction

Sex

Male

243

0.23

Female

183

Age

<65

252

0.76

65-75

174

Histologic type

Well differentiated adeno.

122

0.93

257

Moderate differentiated adeno.

Poorly differentiated adeno.

21

Other

24

ECOG PS

0

318

0.88

1

108

Prior chemotherapy with oxaliplatin

Yes

257

0.03

No

169

426

ITT population

IRIS better

FOLFIRI better

4

.3

.5

.7

2

3

1

slide13

1

1

0.75

0.75

FOLFIRI n=1283.9M

FOLFIRI n=128

FOLFIRI n=85

FOLFIRI n=85 7.8M

IRIS n=129 5.7M

IRIS n=84 6.0M

IRIS n=129

IRIS n=84

0.5

0.5

0.25

0.25

0

3

6

9

12

15

18

21

24

24

0

3

6

9

12

15

18

21

1

1

0.75

0.75

0.5

0.5

0.25

0.25

0

3

6

9

12

15

18

21

24

0

3

6

9

12

15

18

21

24

PFS and OS according to prior CTx

(with or without L-OHP)

L-OHP(+)OS

L-OHP(+)PFS

mPFS

Proportion of patients

Proportion of patients

HR 0.876

(0.677 -1.133)

HR 0.781

(0.571 -1.067)

Progression-Free Survival (months)

Survival Time (months)

L-OHP(-)OS

L-OHP(-)PFS

mPFS

Proportion of patients

Proportion of patients

HR 1.302

(0.806 -2.104)

HR 1.490

(1.079 -2.059)

Progression-Free Survival (months)

Survival Time (months)

cost analysis
Cost analysis

*Included only medical direct cost

conclus ions
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

FIRIS Study Group
  • 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

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

This study was sponsored by TAIHO and Daiichi Sankyo