Randomized phase III study of irinotecan (IRI) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial Ueda S, Hironaka S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I, Gastrointestinal Group of West Japan Oncology Group Thank you, chairmans. On behalf of West Japan Oncology Group, I thank ASCO scientific committee for giving us a great opportunity to present our randomized phase III study of irinotecan versus weekly paclitaxel for advanced gastric cancer refractory to combination chemotherapy of fluoropyrimidine plus platinum.

Background A combination chemotherapy (CT) of fluoropyrimidine and platinum (FP) has been regarded as the standard first-line treatment for AGC Two randomized phase III trials1,2 showed a survival benefit of second-line CT (docetaxel or irinotecan (IRI) ) compared with best supportive care However, no standard regimen has been established In Japan, wPTX3,4 has been used more commonly than docetaxel and IRI5 based on its tolerability Combination chemotherapy of Fluoropryrimidine and platinum has been regarded as the standard first-line treatment for advanced gastric cancer. Two randomized III trials showed a survival benefit of second-line chemotherapy compared with best supportive care, no standard regimen has been established. In Japan, weekly paclitaxel has been used more commonly than docetaxel and CPT-11 because of its tolerability 1 Thuss-Patience PC, Eur J Cancer 2011, 2 Kang JH, J Clin Oncol 2012, 3 Arai, Proc ASCO 2003, 4 Hironaka, Gastric Cancer 2006, 5 Futatsuki Gan to Kagaku Ryoho 1994

Study Scheme AGC refractory to prior FP confirmed by imaging Age 20-75, PS 0-2, No history of CPT-11 or Taxane RANDOMIZATION Stratified by Institution, PS 0-1/2, target lesion -/+ Patients with advanced gastric cancer refractory to prior FP were randomly assigned into weekly paclitaxel or irinotecan group. Stratification factors were institution, performance status and target lesion. Paclitaxel 80mg/m2 was administered weekly for consecutive three weeks with one-week rest. And irinotecan 150mg/m2 was administered bi-weekly. weekly Paclitaxel 80 mg/m2 d1, 8, 15 q4w IRI 150 mg/m2 d1, 15 q4w

Endpoints and Statistical Considerations Primary endpoint: Overall survival (OS) Secondary endpoints: Response Rate (RR) Progression Free Survival (PFS) Toxicity Proportion of third-line CT Statistical Consideration Assumed median OS: wPTX 5 months : reference IRI 7.5 months : investigational (Superiority) 2-sided alpha 5% and power 80% No planned interim analysis 220 pts were required. Primary endpoint was overall survival and secondary endpoints were response rate, progression free survival, toxicity and the rate of third-line chemotherapy. Sample size was calculated based on the assumption that median survival time was 5 months for weekly paclitaxel and 7.5 months for irinotecan with 2-sided alpha of 5% and power of 80%. Interim analysis was not planned. Thus, projected sample size was 220 patients.

Eligibility Criteria Histologically proven unresectable or recurrent gastric adenocarcinoma Refractory to prior combination CT with FP confirmed by imaging during treatment or within 1 month after last CT No prior CT with taxanes or IRI Age range 20-75 years PS (ECOG) of 0-2 Preserved organ functions Measurable or evaluable lesions No severe peritoneal dissemination Written informed consent This is eligibility criteria. Refractory to prior combination chemotherapy with FP by imaging, and no prior chemotherapy with taxanes or irinotecan.

Full Analysis Set (FAS) Safety Analysis Set (SAS) CONSORT Diagram Randomization 223 pts Assigned wPTX 111 pts Assigned IRI 112 pts 108 pts (3 pts excluded) Full Analysis Set (FAS) 111 pts (1 pt excluded) 108 pts (3 pts excluded) Safety Analysis Set (SAS) 110 pts (2 pts excluded) 106 pts (5 pts excluded) Per Protocol Set (PPS) 110 pts (2 pts excluded)

Patient Characteristics 1 wPTX (n=108) IRI (n=111) P Age Median (range) 64.5 (37-75) 65 (38-75) 0.72 Gender Male Female 84 24 87 1.00 PS 0-1 2 104 4 107 Gastrectomy + - 37 71 39 72 0.58 Prior CT S-1+CDDP Cape+CDDP S-1+Oxa 92 13 3 102 8 1 0.30 This is patient characteristics. 108 patients were assigned to weekly paclitaxel arm and 111 patients were assigned to irinotecan arm. The baseline patient characteristics were well-balanced between the arms. Majority of enrolled patients were performance status PS0-1. S-1 plus cisplatin therapy was predominantly used for first-line treatment in both treatment groups compared with capecitabine plus cisplatin. Fisher’s exact test FAS

Patient Characteristics 2 wPTX (n=108) IRI (n=111) P Target lesion + - 91 17 88 23 1.00 Histology* Intestinal Diffuse 54 57 0.97 Peritoneal mets 28 80 83 No. of metastatic sites <1 2< 51 64 47 0.59 * Lauren classification Fisher’s exact test FAS

Overall Survival IRI wPTX n 111 108 Median 8.4M 9.5M P 0.38 HR (95% CI) 1.13 (0.86-1.49) Log-rank test Probability (%) This is overall survival. There was no significant difference between two arms. Median survival time was 9.5 months for weekly paclitaxel and 8.4 months for irinotecan. Hazard ratio was 1.13 and p-value was 0.38. (Months) Number at risk wPTX IRI 108 111 80 75 36 29 10 2 3 1 1 FAS

Progression Free Survival IRI wPTX n 111 108 Median 2.3M 3.6M P 0.33 HR (95% CI) 1.14 (0.88-1.49) 3.6 Probability (%) 2.3 Log-rank test This is progression free survival. There was no significant difference between two arms. Median progression free survival was 3.6 months for weekly paclitaxel and 2.3 months for irinotecan. Hazard ratio was 1.14 and p-value was 0.33.. (Months) Number at risk wPTX IRI 108 111 66 46 16 18 9 8 3 6 2 2 1 FAS

Response Rate n CR PR SD PD NE CR+PR P wPTX 91 19 38 32 2 21% 0.24 IRI 19 38 32 2 21% 0.24 IRI 88 1 11 28 45 3 14% RECIST 1.0 Fisher’s exact test

Hematological Toxicities (%Grade 3<) wPTX (n=108) IRI (n=110) P Leukocytes 20.4 19.1 0.87 Neutrophils 28.7 39.1 0.12 Hemoglobin 21.3 30.0 0.16 Platelets 0.9 1.8 1.00 This is Hematological toxicities. They were generally mild and tolerable in both arms. There was no significant difference between both arms. CTCAE 3.0 Fisher’s exact test SAS

Non-Hematological Toxicities (%Grade 3<) wPTX (n=108) IRI (n=110) P Nausea 1.9 4.5 0.45 Vomiting 2.8 0.9 0.37 Anorexia 7.4 17.3 0.04 Diarrhea 0.21 Hyponatremia 3.7 15.5 0.005 Neuropathy (Sens.) 0.003 Febrile Neutropenia 9.1 0.08 Treatment Related Death 3.6 1.00 This is non-Hematological toxicities. Grade 3 or 4 anorexia and hyponatremia were more frequent in irinotecan arm, whereas sensory neuropathy was observed in only paclitaxel arm. Other non-hematological toxicities were generally mild and tolerable. CTCAE 3.0 Fisher’s exact test SAS

Reasons for Treatment Discontinuation wPTX (n=106) IRI (n=110) Total (n=216) Disease Progression 93 ( 88%) 96 ( 87%) 189 Adverse Event 6 ( 6%) 10 ( 9%) 16 Withdraw 5 ( 5%) 2 ( 2%) 7 Death 1 ( 1%) Other This is reasons for treatment discontinuation. Most of patients discontinued study due to disease progression in both arms. PPS

Post-Study Chemotherapy (3rd line) wPTX (n=108) IRI (n=111) P Received 3rd line CT 97 (90%) 80 (72%) 0.001 CPT-11 containing 81 (75%) 5 ( 5%) Taxane containing 8 ( 7%) 67 (60%) Others Fisher’s exact test FAS

Summary Median OS was 9.5 months for wPTX and 8.4 months for IRI (HR 1.13, P=0.38) Median PFS was 3.6 months for wPTX and 2.3 months for IRI (HR 1.14, P=0.33) RR was 21% for wPTX and 14% for IRI (P=0.24) Toxicities were tolerable in both arms 90% of pts with wPTX and 72% with IRI received post- study CT (P=0.001) This is the summary of this trial.

Conclusion WJOG4007 trial failed to demonstrate the superiority of IRI to wPTX in OS wPTX can be adopted as a control arm of future phase III trials of second-line CT for AGC In conclusion; The WJOG4007 trial failed to demonstrate the superiority of CPT-11 to wPTX in overall survival. Thus, weekly paclitaxel can be adopted as a control arm of future phase III trials of second-line chemotherapy for advanced gastric cancer.

Acknowledgement We would like to express special thanks to all participating patients, Data and Safety Monitoring Committee, Audit Committee of WJOG, and WJOG Data Center (Ms Hirai Y, Mrs. Nonogaki K, Ms. Ozumi N and Dr. Nakamura S) 37 Participating Institutions Oita University Hosp. Osaka Medical college Osaka National Hosp. Osaka Red Cross Hosp. Ryugasaki Saiseikai Hosp. Saitama Cancer Center Shikoku Cancer Center Shizuoka Cancer Center Shizuoka General Hosp. St. Marianna University School of Medicine Hosp. Teikyo University Hosp. Tochigi Cancer Center Tohoku University Hosp. Tokai University Hosp. Tsukuba University Hosp. Tsuyama Chuo Hosp. Yamagata Prefectural Central Hosp. Yokohama City Hosp. Aichi Cancer Center Chiba Cancer Center Ibaraki Prefectural Central Hosp. Fujita Health University Hosp. Hiroshima Prefectural Hosp. Hyogo Cancer Center Jichi Medical University Kenseikai Dongo Hosp. Kinki University KKR　Sapporo Medical Center Tonan hospital Kobe University Hosp. Kochi Health Sciences Center Kouseiren Takaoka Hosp. Kushiro City General Hosp. Kyushu Cancer Center Kyushu University Hosp. Narita Red Cross Hosp. Niigata Cancer Center Osaka City General Hosp. Osaka Medical Center for Cancer and Cardiovascular Disease We would like to express special thanks to all participating patients and WJOG staff. Thank you for your attention.