Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment of advanced gastric cancer ( The SPIRITS trial ) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment of stomach cancer H. Narahara 1, W. Koizumi 2, T. Hara 3, A. Takagane 4, T. Akiya 5, M. Takagi 6, K. Miyashita 7, T. Nishizaki 8, O. Kobayashi 9, S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group; 1 Osaka Medical Center for Cancer and CV Diseases, Osaka, JAPAN, 2 Kitasato University East Hospital, Kanagawa, JAPAN, 3 Kouseiren Takaoka Hospital, Toyama, JAPAN, 4 Iwate Medical University, Iwate, JAPAN, 5 Gunma Prefectural Cancer Center, Gunma, JAPAN, 6 Shizuoka General Hospital, Shizuoka, JAPAN, 7 National Hospital Organization Nagasaki Medical Center, Nagasaki, JAPAN, 8 Matsuyama Red Cross Hospital, Ehime, JAPAN, 9 Kanagawa Cancer Center, Kanagawa, JAPAN.

F-  -Ala Neuro Toxicity GI toxicity Myelotoxicity 5-FU Anti-tumoractivity Background-1  S-1 is : an oral fluoropyrimidine widely used for AGC in Japan. an oral fluoropyrimidine widely used for AGC in Japan. an oral formulation of Tegafur, CDHP, and Oxo at a molar an oral formulation of Tegafur, CDHP, and Oxo at a molar ratio 1:0.4:1. ratio 1:0.4:1. observed high RR and MST of % and days observed high RR and MST of % and days in two independent phase II trials 1,2 in two independent phase II trials 1,2 1: Y Sakata et al. Eur J Cancer 1998; 34: : W Koizumi et al. Oncology 2000; 58: DPD Tegafur CDHP OPRT Oxo inhibit inhibit

Background-2 regimenptsRR(%)PFS(M)OS(M) P value(OS) 5FUUFT+MMC5FU+CDDP(FP) NS  JCOG9205 1) 1): A. Ohtsu et al. J Clin Oncol 2003; 21:54-59 FP arm demonstrated significantly longer PFS FP arm demonstrated significantly longer PFS than 5FU arm. (P<0.001) than 5FU arm. (P<0.001) There were no significant differences between There were no significant differences between the arms with respect to OS the arms with respect to OS In Japan, recommended regimen for AGC was In Japan, recommended regimen for AGC was 5-FU alone

Background-3  JCOG FU S-1 CPT-11+CDDP Non-inferiority Boku et al. ASCO2007 abstract#: LBA4513

Background-4  S-1+CDDP Phase I/II Study 1) S mg BID for 3wks Day 1 Day 8 Day 15 Day 22 Day 29 Day 36 CDDP 60mg/m 2 on Day 8 S-1regimenPts(RD)RR(%)TTP(Day)MST(Day)S-1+CDDP : W Koizumi et al. Br J Cancer 2003; 89: Dosage of S-1 was based on patient’s body surface area (BSA) Dosage of S-1 was based on patient’s body surface area (BSA) BSA < 1.25 : 40 mg BID BSA < 1.25 : 40 mg BID < 1.50 : 50 mg BID < 1.50 : 50 mg BID < BSA : 60 mg BID < BSA : 60 mg BID

Study Design AGC No prior Chemo. R S-1 alone S-1: mg BID for 28 days q6wks S-1 + CDDP S-1: mg BID for 21 days q5wks CDDP: 60 mg/m 2 iv on day 8 Central Randomization (dynamic balancing) (dynamic balancing) Adjustment Factors: Institute PS PS Unresectable vs Recurrent Unresectable vs Recurrent

Endpoints  Primary Endpoint Overall Survival Overall Survival Estimated OS (S-1/S-1+CDDP) : 8/12 months Estimated OS (S-1/S-1+CDDP) : 8/12 months N=142 in each arm for 90% power to establish N=142 in each arm for 90% power to establish superiority in OS (Two-sided log-rank  =0.05). superiority in OS (Two-sided log-rank  =0.05). Follow up: 2 years Follow up: 2 years  Secondary Endpoints Progression Free Survival Progression Free Survival Time to Treatment Failure Time to Treatment Failure Overall Response Overall Response Safety Safety 142 pts in each arm

Inclusion Criteria  Histologically confirmed gastric adenocarcinoma (unresectable/recurrent gastric cancer) (unresectable/recurrent gastric cancer)  No prior chemotherapy  PS (ECOG scale) 0-2  Age  Expected survival > 3 months  Adequate organ function (bone marrow, liver, renal function) (bone marrow, liver, renal function)  Written informed consent

Patient Characteristics -1  Randomized : 305 pts (S-1/S-1+CDDP : 152/153) between Mar/2002 and Nov/2004 between Mar/2002 and Nov/2004  FAS : 298 pts (S-1/S-1+CDDP : 150/148) No. of pts S-1S-1+CDDPP-value Gender M / F 116 / / Age, years Median (range) 62.0 (28 – 74) 61.5 (33 – 74) ECOG PS, 0 / 1 / / 39 / / 38 / Primary lesion - / + - / + 58 / /

Patient Characteristics -2 No. of pts S-1S-1+CDDPP-value Diagnosis Unresectable Unresectable Recurrent Recurrent Adjuvant chemotherapy Adjuvant chemotherapy - / + - / + 23 / 8 20 / Histology Diffuse Diffuse Intestinal Intestinal Unknown Unknown No. of organs involved 1 / 2 / >3 1 / 2 / >3 39 / 54 / / 36 / Metastasis of peritoneum - / + - / / /

Months Estimated probability (%) Overall Survival S-1S-1+CDDP No. of pts MST yr survival 46.7 % 54.1 % 2 yr survival 15.3 % 23.6 % Log-rank p-value: HR: [ 95% CI: – 0.985] Median follow-up time (M): 34.6

Progression-Free Survival Log-rank p-value: < HR: [ 95% CI: – 0.734] Estimated probability (%) Months S-1S-1+CDDP No. of pts PFS4.06.0

Time to Treatment Failure Log-rank p-value: HR: [ 95% CI: – 0.912] Estimated probability (%) Months S-1S-1+CDDP No. of pts TTF3.94.8

Overall Response No. Response Overall RR CRPRSDPDNE S % S-1+CDDP %  Criteria : RECIST (Extramural Review) Fisher’s Exact Test p-value:

Adverse Drug Reactions-1 S-1 N = 150 S-1+CDDP N = 148 All Gr. N (%) Gr. 3/4 N (%) All Gr. N (%) Gr. 3/4 N (%) Haematological Leucopenia Leucopenia 57 (38) 3 (2) 104 (70) 17 (12) Neutropenia Neutropenia 63 (42) 16 (11) 110 (74) 59 (40) Anemia Anemia 49 (33) 6 (4) 100 (68) 38 (26) Thrombocytopenia Thrombocytopenia 27 (18) 0 (0) 72 (49) 8 (5) Non-haematological T-bil T-bil 30 (20) 2 (1) 36 (24) 1 (1) AST AST 17 (11) 3 (2) 15 (10) 0 (0) ALT ALT 14 (9) 1 (1) 18 (12) 0 (0) ALP ALP 8 (5) 1 (1) 8 (5) 1 (1) Creatinine Creatinine 3 (2) 0 (0) 32 (22) 0 (0) Criteria : NCI-CTC ver. 2.0

Adverse Drug Reactions-2 S-1 N = 150 S-1+CDDP N = 148 All Gr. N (%) Gr. 3/4 N (%) All Gr. N (%) Gr. 3/4 N (%) General Fatigue Fatigue 49 (33) 2 (1) 84 (57) 6 (4) Gastrointestinal Anorexia Anorexia 55 (37) 9 (6) 107 (72) 45 (30) Nausea Nausea 39 (26) 2 (1) 99 (67) 17 (12) Vomiting Vomiting 21 (14) 3 (2) 54 (37) 6 (4) Diarrhea Diarrhea 34 (23) 5 (3) 51 (35) 6 (4) Stomatitis Stomatitis 32 (21) 0 (0) 43 (29) 1 (1) Skin Pigmentation Pigmentation 60 (40) 0 (0) 53 (36) 0 (0) Rash Rash 28 (19) 2 (1) 32 (22) 3 (2) Hand-foot syndrome Hand-foot syndrome 18 (12) 0 (0) 14 (10) 0 (0) No treatment-related death was observed No treatment-related death was observed Criteria : NCI-CTC ver. 2.0

Phase III trials in AGC GroupregimenptsRR(%)PFS(M)OS(M) P value (OS) SPIRITSS-1S-1+CDDP E Van Cutsem, et al 1) (2006)CFDCF *5.6* D Cunningham, et al 2) (2006) ECFEOFECXEOX NS YK Kang, et al 3) (2006)FPXP NS *TTP 3) Proc ASCO 2006; Vol 24, No. 18S: LBA4018 1) J Clin Oncol 2006; 24: 4991 – ) Proc ASCO 2006; Vol 24, No. 18S: LBA4017

Conclusions The OS of S-1+CDDP is superior to S-1 alone  The OS of S-1+CDDP is superior to S-1 alone 11.0 M, The median survival time of S-1 was 11.0 M, 13.0 M moreover, that of S-1+CDDP was 13.0 M  S-1+CDDP is well tolerated and no treatment- related death was observed  S-1+CDDP regimen can be regarded as the first-line standard treatment for AGC

Future Perspectives In Red : FP vs S-1+CDDP (FLAGS: on-going) In Red : FP vs S-1+CDDP (FLAGS: on-going) In Yellow : S-1 vs S-1+CDDP (SPIRITS) In Yellow : S-1 vs S-1+CDDP (SPIRITS) In near future, the clinical characteristics of S-1+CDDP for AGC will become clear

Acknowledgements Participating Inst. Kitasato University East Hospital Osaka Medical Center for Cancer and CV Diseases Kouseiren Takaoka Hospital Iwate Medical University Gunma Prefectural Cancer Center Shizuoka General Hospital National Hospital Organization Nagasaki Medical Center Matsuyama Red Cross Hospital Kanagawa Cancer Center (Department of Gastrointestinal Surgery) Hiroshima City Asa Hospital National Hospital Organization Kyushu Cancer Center Aso Iizuka Hospital Kanagawa Cancer Center(Department of Gastroenterology) Aichi Cancer Center Wakayama Medical University Saga Prefectural Hospital KOSEIKAN National Hospital Organization Tokyo Medical Center Osaka Saiseikai Nakatsu Hospital Aichi Cancer Center Aichi Hospital The Fraternity Memorial Hospital University of Tokai School of Medicine Gifu Municipal Hospital Toranomon Hospital Kumamoto Rosai Hospital Showa University Northern Yokohama Hospital Kobe City Medical Center General Hospital Kawaguchi Municipal Medical Center Nara Prefectural Nara Hospital Chikushi Hospital, Fukuoka University Kanto Medical Center, NTT EC Kyoto University Kinki University School of Medicine Yamagata Prefectural Central Hospital National Hospital Organization Fukuoka-Higashi Medical Center Kouri Hospital, Kansai Medical University Sendai Kousei Hospital Tokyo Women's Medical University Medical Center East Kokura Memorial Hospital Niigata City General Hospital This study was sponsored by TAIHO Pharmaceutical, co. ltd.