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 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 Antitumor activity GI toxicity Myelo- toxicity Tegafur OPRT DegradationPhosphorylation 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 20-75y 2 nd line PS 0-1 No prior Irinotecan FOLFIRI (n=213) Irinotecan: 150 mg/m 2 d1, 15 l-LV: 200mg/m 2 d1, 15 5-FU: 400mg/m 2 bolus d1, 15 5-FU: 2,400mg/m 2 46 hr civ d1,2, &d15,16 repeated every 4 wks FOLFIRI (n=213) Irinotecan: 150 mg/m 2 d1, 15 l-LV: 200mg/m 2 d1, 15 5-FU: 400mg/m 2 bolus d1, 15 5-FU: 2,400mg/m 2 46 hr civ d1,2, &d15,16 repeated every 4 wks IRIS (n=213) Irinotecan: 125mg/m 2 d1, 15 S-1: mg*/body d1-14 repeated every 4 wks IRIS (n=213) Irinotecan: 125mg/m 2 d1, 15 S-1: mg*/body d1-14 repeated every 4 wks R n=426 *According to body surface area, BSA =1.5, 120 mg/day Accrual ：

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 ECOG PS 0,1 Adequate organ functions No prior radiotherapy for mCRC Written informed consent

Baseline characteristics FOLFIRI (n=213) IRIS (n=213) Male / Female 123/90120/93 Median Age, years (range) 63 (32-75) 61 (29-75) ECOG PS 0/1 160/53158/55 Histologic Type Well differentiated Moderately differentiated Poorly differentiated Other Undetermined Prior Chemotherapy with oxaliplatin Yes/No 128/85 129/84 Number of metastatic sites 1/≥2 92/120 88/124

Proportion of patients Progression-Free Survival (months) No. pts at risk FOLFIRI IRIS PFS (ITT population) FOLFIRI IRIS FOLFIRI IRIS (n=213) (n=213) Progression, n Median, months Adjusted HR (95% CI) to Upper limit below < (non inferiority margin) p=0.039

Survival Time (months) Proportion of patients 92 No. patients at risk FOLFIRI IRIS OS (ITT population) FOLFIRI IRIS (n=213) (n=213) Events, n Median, months Adjusted HR (95% CI) to FOLFIRI IRIS Median-follow-up time:12.9

Response rate (of the patients who had >1 measurable lesion) RECIST1.0 (investigator assessed) (%) FOLFIRI (n=174) IRIS (n=181) 16.7% (95%CI : ) 18.8% (95%CI : )

FOLFIRI (n=211)IRIS (n=210) Grade 3-4 Adverse eventNo.% % Neutropenia Leukopenia Hemoglobin Thrombocytopenia Diarrhea Fatigue Febrile neutropenia Mucositis / Stomatitis Adverse events (safety analysis population) CTC-AE v3.0

Subgroup analysis : PFS P value for interaction ECOG PS Prior chemotherapy with oxaliplatin 257Yes 257 Moderate differentiated adeno. 21 Poorly differentiated adeno Histologic type 122 Well differentiated adeno. 169No 24 Other 252<65 Age 183Female 243Male Sex No. of Patients Subgroup ITT population 426 IRIS betterFOLFIRI better

Progression-Free Survival (months) FOLFIRI n= M IRIS n= M L-OHP(+) PFS Survival Time (months) Progression-Free Survival (months) Survival Time (months) Proportion of patients L-OHP(-) PFS L-OHP(+) OS L-OHP(-) OS PFS and OS according to prior CTx (with or without L-OHP) HR ( ) FOLFIRI n=128 IRIS n=129 FOLFIRI n=85 7.8M IRIS n=84 6.0M FOLFIRI n=85 IRIS n=84 HR ( ) HR ( ) HR ( ) mPFS

Cost analysis GroupMedian 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 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 This study was sponsored by TAIHO and Daiichi Sankyo 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 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