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FIRIS study

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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FIRIS study

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  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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

  7. Baseline characteristics

  8. 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

  9. 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

  10. 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)

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

  12. 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

  13. 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)

  14. Cost analysis ＊Included only medical direct cost

  15. 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.

  16. 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

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