N. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group R andomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)

Background For advanced gastric cancer, there is no established standard chemotherapy. In our previous phase III study (JCOG9205), combination chemotherapy of 5-FU+CDDP did not show a survival benefit over 5-FU alone. (Ohtsu, J Clin Oncol 2003) Phase II studies of S-1 (oral fluoropyrimidine) alone and combination chemotherapy of CPT-11+CDDP showed promising activity and acceptable toxicities. (Sakata, Eur J Cancer 1998; Koizumi, Oncology 2000; Boku, J Clin Oncol 1999)

Primary endpoint ： Overall survival Secondary endpoints ： Time to treatment failure (TTF) Non-hospitalized survival (NHS) Adverse Events (NCI-CTC ver.2) Response rate (RECIST, central review) Compared to 5-FU continuous infusion (5-FUci) ・ Superiority of CPT-11+CDDP ・ Non-inferiority of S-1 Objectives

Inclusion Criteria 1) Histologically confirmed unresectable or recurrent gastric adenocarcinoma 2) Adequate oral intake 3) Age: > 20, < 75 4) PS (ECOG) ： 0, 1, 2 5) Preserved organ functions 6) No history of chemotherapy or radiation therapy except adjuvant chemotherapy completed 6 months before 7) Measurable lesion is not mandatory small metastatic disease detected by laparotomy is allowed 8) No severe peritoneal dissemination such as impaired bowel passage, ascites beyond pelvic cavity, wall deformity detected by barium enema 9) Written informed consent

S-1 40 mg/m 2, po, bid, days 1-28 q 6 weeks Stratified by (minimization) ・ Institution ・ PS 0/1/2 ・ Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx 5-FUci CPT-11 + CDDP S-1 Randomization 800 mg/m 2 /day, ci, days 1-5 q 4 weeks CPT mg/m 2, div, days 1&15 CDDP 80 mg/m 2, div, day 1 q 4 weeks Present Phase III Study (JCOG9912) Continued until disease progression, unacceptable toxicities, patient’s refusal BSA < mg/body/day 1.25 < BSA < mg/body/day 1.5 < BSA 120 mg/body/day

Statistical Considerations Study design Assumed 6-M, 1-Y survival rates of 5-FUci: 50-55%, 25-30% Expected superiority of CPT-11+CDDP: +10% Margin of non-inferiority of S-1: -5% (HR< 1.16) One-sided alpha 0.05, power 0.7 -multiplicity adjusted by modified Bonferroni (Holm’s method) Sample size: 450 (150/arm), planned accrual: 4 years -amended to 690 (230/arm) to achieve power= 0.8 (Mar. 2005) One interim analysis at accrual of 300 patients (Mar. 2004) using O’Brien & Fleming type alpha spending function Actual accrual 704 patients between Nov – Jan Final analysis (Feb. 2007) on intention-to-treat (ITT) basis

Background (Patient) Adjuvant Cx - / + Unresectable / Recurrent 0 / 1 / 2PS M / F Gender median (range)Age No. of patients 233/1 188/46 151/80/3 175/59 64 (39-75) 234* S-1 235/1 190/46 151/81/4 180/56 63 (32-75) 236 CPT-11+CDDP 233/1 189/45 152/79/3 176/58 63 (24-75) FUci * One patient was ineligible; adenosquamous cell carcinoma.

Background (Tumor) Target lesion - / + intestinal / diffuse Histological type ** 0 / 1,2 / 3,4,5 Macroscopic type * No. of patients Peritoneal metastasis 165/69 59/ /124 *** 5/68/ S-1 102/101/31 55/ /134 5/73/ CPT-11+CDDP 160/76 100/105/31 59/ /121 5/63/ FUci 147/87 103/90/41 No. of metastatic sites 0,1 / 2 / >3 - / + * Japanese Classification of Gastric Carcinoma ** Lauren classification, no data available in 2 pts ** 1 pt with adenosquamous type included

No. of patients Incidences(%) of Gr.>3 Adverse Events within 6 months (1) S-1CPT-11+CDDP5-FUci Treatment related death* Leukocytes Neutrophils Hemoglobin Platelets Infection without neutropenia Infection with Gr.3 or 4 neutropenia Febrile neutropenia * Judged by Data and Safety Monitoring Committee

Stomatitis Nausea Diarrhea Anorexia Fatigue AST ALT Bilirubin Creatinine Hyponatremia Incidences(%) of Gr.>3 Adverse Events within 6 months (2) No. of patients S-1CPT-11+CDDP5-FUci

Progression-free Survival and Response rate Response rate - in pts with target lesion - 5-FUci CPT-11 +CDDPS-1 CR+PR n RR9%38%28% CR and PR were confirmed by central review M 234 < %C.I M M 236 HR Median n P-value † 1224 (months) 0 50 (%) 100 †: one-sided log-rank test (superiority) S-1 5-FUci CPT-11+CDDP PFS

< M234S P-value † %C.I. -2.3M2345-FUci M236CPT-11+CDDP HRMediann †: one-sided log-rank test (superiority) Time to Treatment Failure 1224 (months)0 50 (%) 100

Reasons for Treatment Failure Other Death Refusal not related to toxicity Refusal related to toxicity Toxicities Disease progression Continuing at final analysis No. of patients S CPT-11+CDDP FUci 234

(months)0 50 (%) 100 Overall Survival P-value † † %C.I %10.8M2345-FUci %11.4M234S %12.3M236CPT-11+CDDP HR1-yrMSTn †: one-sided log-rank test (superiority) non-inferiority <0.001 ‡: multiplicity adjusted by Holm’s method Significance level ‡

M234S %C.I. -7.2M2345-FUci M236CPT-11+CDDP HRMediann P-value † †: one-sided log-rank test (superiority) Non-hospitalized Survival (months)0 50 (%) 100 = overall survival time – hospitalized days

* type unknown were excluded from the analysis Subset Analysis for Overall Survival - Hazard Ratio to 5-FUci and 95% Confidence Interval - Hazard ratio Age <65 (n=372) >65 (n=332) PS 0 (n=454) 1,2 (n=250) Unresectable (n=567) Recurrent (n=137) Intestinal (n=323)* Diffuse (n=379) (-) (n=173) Target lesion (+) (n=531) No. of met sites 0,1 (n=305) >2 (n=399) Peritoneal mets (-) (n=472) (+) (n=232) All randomized (n=704) CPT-11+CDDPS-1

Subset Analysis of Overall Survival P-value † S-1 5-FUci (months) 0 50 (%) n P-value † 10.5M 9.0M 12.1M MST 3.8M 2.2M 4.8M PFS - Target Lesion (+) -- Target Lesion (-) M M M55 MSTn †: one-sided log-rank test (superiority) S-1 5-FUci CPT-11+CDDP 0 50 (%) (months)

Summary and Conclusion S-1 showed a significant non-inferiority to 5-FUci in survival mild toxicities favorable results of RR, TTF, NHS and PFS longer survival than 5-FUci in almost all subsets CPT-11+CDDP did not show superiority to 5-FUci in survival substantial toxicities causing treatment failure favorable results of RR, TTF, NHS and PFS longer survival than 5-FUci in the subset of TL (+) poor results in TL (-) and peritoneal mets (+) S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer.

Acknowledgement We would like to express sincere thanks to all participating patients, Data and Safety Monitoring Committee, Audit Committee of JCOG, and JCOG Data Center Support This study was mainly supported by the Grant-in-Aid for Cancer Research (11S-3, 14S-3, 17S-3, 11S-4, 14S-4, 17S-5) from the Ministry of Health, Labour and Welfare of Japan, and in part by the contract of periodical safety reports for S-1 to TAIHO PHARMACEUTICAL CO., LTD and for CPT-11 to Yakult Honsha Co., Ltd.

Investigators Y. Komatsu Y. Tsuji S. Saito A. Murakami T. Yoshioka H. Saito K. Amagai Y. Hamamoto K. Yamaguchi H. Endo T. Doi T. Denda A. Nakamura K. Shirao K. Kaneko K. Chin W. Koizumi S. Ohkawa Y. Hara K. Tanaka K. Hotta N. Boku H. Kawai H. Kojima H. Iwase S. Matsumoto H. Takiuchi T. Tamura H. Nishisaki M. Taniguchi J. Nasu A. Tsuji E. Baba M. Yoshida