A. Tsuji

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G)

BACKGROUND FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER UMIN000001396.

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05)

BACKGROUND In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. PATIENTS AND METHODS Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). RESULTS From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. CONCLUSION The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327.

No benefit from the addition of anti-EGFR antibody in all right-sided metastatic colorectal cancer?

Author Affiliations: Division of Medical Oncology, Showa University Northern Yokohama Hospital, 35-1, Chigasaki-chuo, Tsuzuki-ku, Yokohama, Kanagawa, 224-8503, Japan Department of Clinical Oncology, Kagawa University Faculty of Medicine Cancer Center, Kagawa University Hospital, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-machi, Itabashi-ku, Tokyo, 173-8610, Japan Division of Medical Oncology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, Japan

A genetic variant in Rassf1a predicts outcome in mCRC patients treated with cetuximab plus chemotherapy: results from FIRE-3 and JACCRO 05 and 06 trials.

The Hippo pathway is involved in colorectal cancer (CRC) development and progression. The Hippo regulator Rassf1a is also involved in the Ras signaling cascade. In this work, we tested single nucleotide polymorphisms within Hippo components and their association with outcome in CRC patients treated with cetuximab. Two cohorts treated with cetuximab plus chemotherapy were evaluated (198 RAS wild-type (WT) patients treated with first-line FOLFIRI plus Cetuximab within the FIRE-3 trial and 67 Ras WT patients treated either with first-line mFOLFOX6 or SOX plus Cetuximab). In these two populations, Rassf1a rs2236947 was associated with overall survival (OS), as patients with a CC genotype had significantly longer OS compared with those with CA or AA genotypes. This association was stronger in patients with left-side CRC (hazard ratio (HR): 1.79 (1.01–3.14); P=0.044 and HR: 2.83 (1.14–7.03); P=0.025, for Fire 3 and JACCRO cohorts, respectively). Rassf1a rs2236947 is a promising biomarker for patients treated with cetuximab plus chemotherapy.

Phase I study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PI)

Background The prognosis of locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, remains unsatisfactory, even with D2 gastrectomy followed by adjuvant chemotherapy. One promising approach is neoadjuvant chemotherapy. Combination chemotherapy with S-1 and oxaliplatin (SOX) is recognised as a potentially promising regimen for gastric cancer. However, the use of neoadjuvant chemotherapy consisting of SOX for locally advanced gastric cancer has not been reported. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose of preoperative chemotherapy combined with SOX for locally advanced gastric cancer. Methods Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1, as well as S-1 (80 mg/m2/day, twice daily) for 14 days, repeated every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph node dissection followed by adjuvant S-1 (80 mg/m2/day, twice daily) for 1 year. Escalation of oxaliplatin dose was planned (starting at level 0, oxaliplatin 100 mg/m2; level 1, 130 mg/m2). Results Six patients were enrolled. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with S-1 80 mg/m2/day twice daily could be administered with acceptable toxicity. Peripheral neuropathy was observed in all patients but with no functional disorders. No treatment-related death was observed and the incidence of operative morbidity was tolerable. Resection with curative intent was undertaken in all patients with R0 resection performed in five (83%) and R1 in one. Two of the six patients had a pathological complete response (33%). Conclusion Neoadjuvant chemotherapy with an SOX regimen was feasible in patients with locally advanced gastric cancer. The recommended phase II dose was determined to be oxaliplatin 130 mg/m2 in combination with S-1 80 mg/m2/day, twice daily.

625PRANDOMIZED PHASE II STUDY OF S-1 PLUS ORAL LEUCOVORIN (SL) VERSUS SL PLUS OXALIPLATIN (SOL) VERSUS S-1 PLUS CISPLATIN (SP) IN PATIENTS WITH ADVANCED GASTRIC CANCER (AGC):UPDATED OVERALL SURVIVAL DATA

ABSTRACT Aim: We have investigated the enhanced antitumor activity by oral leucovorin (LV) when added to S-1, and found optimized treatment schedule of S-1 plus LV (SL), 1 week (w) on and 1w off, as a platform regimen. In this treatment schedule, SL showed promising efficacy in previous phase II trials of colorectal and pancreatic cancer. Here, we evaluated the efficacy and the safety of SL and SL plus oxaliplatin (SOL) compared with S-1 plus cisplatin (SP) as a reference standard treatment in advanced gastric cancer (AGC). Methods: Patients who were previously untreated with chemotherapy for AGC were randomized equally to receive SL (S-1; 40-60 mg bid and oral LV; 25 mg bid for 1w, q2w), SOL (SL plus oxaliplatin; 85 mg/m2 on day 1, q2w), or SP (S-1; 40-60 mg bid for 3w and cisplatin; 60 mg/m2 on day 8, q5w). The primary endpoint was response rate (RR) by the independent review committee. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Clinical trial registration: JapicCTI-111635. Results: From Oct 2011 to Dec 2012, 145 patients were randomized, and 142 were included in the efficacy analysis (SL/SOL/SP, 47/47/48). The confirmed RR (%) of SL/SOL/SP was 43 (95% Cl: 28-58)/ 66 (51-79)/ 46 (31-61) (SL vs. SP, p = 0.837; and SOL vs. SP, p = 0.063). DCR (%) was 74/100/83 (SL vs. SP, p = 0.324; and SOL vs. SP, p = 0.0057). Median PFS was 4.2/8.3/5.6 months (SL vs. SP, HR = 1.08, p = 0.764; and SOL vs. SP, HR= 0.60, p = 0.054). Median OS was 15.4/21.6/12.6 months (SL vs. SP, HR = 0.83, p = 0.443; and SOL vs. SP, HR = 0.51, p = 0.011) after median follow-up of 18.8 months. Incidences (%) of grade 3/4 toxicities were neutropenia 6/26/35, anemia 8/15/24, lymphopenia 2/6/10, leucopenia 4/6/12, anorexia 13/28/20, diarrhea 4/17/0, stomatitis 4/13/0. Updated OS data 18 months after enrollment of the last patient will be presented at this meeting. Conclusions: In this randomized phase II study, SL showed a similar RR to SP, and SOL demonstrated promising efficacies with tolerable toxicities, suggesting the superiority to SP. A phase III trial of SOL versus SP is warranted. Disclosure: K. Yamaguchi: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb I have honoraria to disclose. Name of entity:Taiho Pharmaceutical Co., LTD., Bristol Myers Squibb; S. Hironaka: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha I have honoraria to disclose. Name of entity:Taiho Pharmaceutical Co., LTD., Yakult Honsha; N. Sugimoto: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha I have honoraria to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha; T. Moriwaki: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD. I have honoraria to disclose. Name of entity:Taiho Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; Y. Komatsu: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; T. Nishina: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; A. Tsuji: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD. I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; T.E. Nakajima: I have an advisory relationship and research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD. I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb;M. Gotoh: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Bristol Myers Squibb I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD; N. Machida: I have research funding and honoraria to disclose. Name of entity:Tahio Pharmaceutical Co., LTD; N. Fuse: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD; T. Esaki: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; Y. Emi: I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; Y. Takinishi: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; S. Matsumoto: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; N. Boku: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha; H. Baba: I have research funding to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb I have honoraria to disclose. Name of entity: Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb; I. Hyodo: I have an advisory relationship to disclose. Name of entity:Yakult Honsha I have research funding and honoraria to disclose. Name of entity:Tahio Pharmaceutical Co., LTD., Yakult Honsha, Bristol Myers Squibb.

631PIMPACTS OF PROGRESSION TYPE ON OVERALL SURVIVAL IN ADVANCED GASTRIC CANCER: RANDOMIZED PIII STUDY OF S-1 + OXALIPLATIN VS. S-1 + CISPLATIN

ABSTRACT Aim: Randomized phase III study for the first-line treatment of advanced gastric cancer (AGC) (G-SOX PIII) demonstrated the non-inferiority of S-1 plus oxaliplatin (SOX) for S-1 plus cisplatin (CS) on PFS (HR for SOX vs. CS 1.004, 95% confidence interval [CI] 0.840-1.199; Higuchi, JCO 2013;30:Suppl, Abstract 60) and on OS (HR 0.958, 95% CI 0.803-1.142). Reporting of separate analyses for individual progression types is recommended (European Medicines Agency. Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man). Thus, we aimed to assess the association between progression types and OS in this study. Methods: Tumor lesions were assessed every 6 weeks until disease progression and independently reviewed according to the RECIST v1.0. We applied the Cox regression including two time-dependent covariates, i.e., progressive disease with new lesions (PDNL) or without new lesions (PDwoNL) in each treatment group, and estimated their effects compared to no progression (Non-PD). Results: The results of analysis are shown in the table below. PDNL and PDwoNL were identified for 88 and 166 patients in SOX group (317 patients), and 95 and 146 patients in CS group (324 patients), respectively. The hazards of death in Non-PD were different between treatment groups (HR 0.582). However, association between progression types and OS were similar in both treatment groups. Both progression types were strong prognostic factors for OS, and greater effects were seen in PDNL (HR 8.277 in SOX, 5.997 in CS). Conclusions: The progression accompanied by new lesions gives a strong negative impact on OS in patients treated with S-1 and platinum for AGC. Examining progression types would be useful for evaluating efficacy of anticancer treatment on OS. HR (95%CI) P SOX vs. CS in Non-PD 0.582 (0.371-0.914) 0.019 in PDwoNL 1.111 (0.868-1.589) 0.403 in PDNL 0.803 (0.593-1.089) 0.158 SOX PDwoNL vs. Non-PD 5.447 (3.609-8.221) PDNL vs. Non-PD 8.277 (4.250-8.462) CS PDwoNL vs. Non-PD 2.854 (2.038-3.995) PDNL vs. Non-PD 5.997 (4.250-8.462) Disclosure: Y. Yamada: honoraria: Yakult Honsha, Taiho, Chugai, Pfizer, Takeda, Bristol-Myers, Dainippon Sumitomo, Johnson & Johnson, Novartis, Daiichi Sankyo Research Funding: Yakult Honsha, Otsuka, Chugai, Pfizer, Astra Zeneca, Novartis, Daiichi Sankyo, Bayer, Merck; K. Higuchi: I have received honoraria from Yakult Honsha; M. Gotoh: I have received honoraria from Yakult Honsha; N. Fuse: I have received honoraria from Taiho and research funding from Yakult Honsha and Taiho. N. Sugimoto: I have received honoraria and research funding from Yakult Honsha and Taiho; T. Nishina: I have received honoraria and research funding from Yakult Honsha and Taiho; A. Tsuji: I have received honoraria from Yakult Honsha and Taiho; K. Yamaguchi: I have received honoraria from Chugai, Bristol-Myers, Takeda, and Merck; H. Yasui: I have received honoraria from Yakult Honsha, Medicon, Chugai, Taiho, and Bristol-Myers. S. Hironaka: I have received honoraria from Yakult Honsha and Taiho; C. Hamada: I have received consultant fees and honoraria from Yakult Honsha, Taiho, and Chugai; I. Hyodo: I have held an advisory Role for Yakult Honsha and Taiho. I have received honoraria from Yakult Honsha and Taiho. All other authors have declared no conflicts of interest.