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Background Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). Patients and methods We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naive patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0−1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. Results Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4months with GC and 15.1months with GS, HR, 0.945; 90% confidence interval (CI), 0.78–1.15; P=0.046 for non-inferiority]. The median PFS was 5.8months with GC and 6.8months with GS (HR 0.86; 95% CI 0.70–1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. Conclusions GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. Clinical Trial number This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

Background This open-label study in Japan evaluated the safety and efficacy of an immune checkpoint inhibitor nivolumab (NIVO) alone or with gemcitabine-cisplatin (NIVO+GC) to treat biliary tract cancer (BTC). We present updated results for longer follow-up (minimum:493 days; median:679 days). Methods Patients with unresectable/recurrent BTC refractory or intolerant to gemcitabine-based treatment received NIVO (240 mg, 2-week intervals, N = 30). Chemonaive patients with unresectable/recurrent BTC received the same NIVO regimen + GC (N = 30). Primary objectives were tolerability and safety. Overall survival (OS) and centrally assessed progression-free survival (PFS) and objective response rate (ORR) were secondary efficacy endpoints. Results The most frequent drug-related adverse events with NIVO were decreased appetite (5/30, 17%), malaise (4/30, 13%), and pruritus (4/30, 13%), and with NIVO+GC w ere platelet count decreased (25/30, 83%) and neutrophil count decreased (25/30, 83%). In the NIVO cohort, median OS was 5.7 months (mo) (95% CI: 4.5, 8.7), median PFS was 1.4 mo (1.4, 1.4) and ORR was 10% (4, 23). Median OS was longer, and ORR higher, in the subgroup with programmed death-ligand 1 (PD-L1) ≥1% in tumor-associated immune cells (TAIC) (n = 19) than in those with PD-L1 Conclusion Longer follow-up of patients with unresectable/recurrent BTC confirmed NIVO was well tolerated, with a manageable safety profile. Further data may show an association between PD-L1 expression in TAIC and longer OS with NIVO.

Background A novel approach to differentiate somatic vs. germline BRCA1/2 mutations in cfDNA using a beta binomial model (AACR 2018, abst #4272) may enable identification of pts with advanced GI tumors who are likely to benefit from a PARP inhibitor. The results from the GOZILA study, the Nationwide Cancer Genome Screening Project utilizing Guardant360, are presented here. Methods Pts with advanced GI tumors who were appropriate for any systemic therapy and had progressed following at least one prior treatment were eligible. We investigated the prevalence of somatic vs. germline BRCA1/2 mutations and the association between BRCA1/2 mutations, TMB and MSI. Results From Jan 2018 to Mar 2019, 850 pts were prospectively enrolled among 26 major cancer centers in Japan. Of 40 (4.7%) actionable BRCA1/2 mutations, 14 were germline: esophagus (squamous cell carcinoma only), 2 pts (N = 62, 3.2%); stomach, 2 pts (N = 131, 1.5%); colorectum, 3 pts (N = 377, 0.8%); pancreas, 3 pts (N = 157, 1.9%); biliary tract, 4 pts (N = 77, 5.2%); and others, none (N = 31, 0%). Notably, the majority of BRCA1/2 mutations (75%) in pts with esophageal, pancreas and biliary tract cancers were germline, while 81% of BRCA1/2 mutations in pts with stomach and colorectal cancers were somatic (p = 0.001). Median TMB of pts with germline BRCA1/2 mutations was significantly lower than those with somatic BRCA1/2 mutations (p = 0.042). In addition, all pts with germline BRCA1/2 mutations were microsatellite stable, while 19% of pts with somatic BRCA1/2 mutations were MSI-high. Conclusions Analysis of cfDNA identified a unique subset of pts with germline BRCA1/2 mutations in advanced GI cancers. Given the association of these findings with efficacy of PARP inhibitor and immune-based therapies, these findings suggest that the identification of BRCA1/2 mutations and their germline-somatic origin may have future implications for therapy selection. Clinical trial identification UMIN000029315. Legal entity responsible for the study SCRUM-Japan GI-SCREEN. Funding Guardant Health, Ono Pharmaceutical. Disclosure Y. Kawamoto: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Daiichi Sankyo Co., Ltd.; Honoraria (self): Takeda Pharmaceutical Co., Ltd.; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Merck Biopharma Co., Ltd.; Honoraria (self): Eli Lilly Japan K.K.. Y. Nakamura: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho Pharmaceutical. M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Yakult; Advisory / Consultancy: Otsuka Pharmaceutical; Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Honoraria (self): EA Pharma; Honoraria (self): MSD; Advisory / Consultancy, Research grant / Funding (institution): ASLAN Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nano Carrier; Honoraria (self): Gilead. H. Bando: Honoraria (self): Taiho Pharmaceutical company; Honoraria (self): Eli Lilly; Research grant / Funding (self): Sysmex; Research grant / Funding (self): AstraZeneca. T. Esaki: Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self): Chugai; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Eli Lilly; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Novartis. M. Ueno: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Shire; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): MSD; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): ASLAN Pharmaceuticals. T. Nishina: Honoraria (self), Research grant / Funding (institution): Taiho pharmaceutinal; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Suibb; Honoraria (self): Nihonkayaku; Honoraria (self), Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Diichi Sankyo. E. Oki: Speaker Bureau / Expert testimony: Taiho Pham; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Chugai Pham; Speaker Bureau / Expert testimony: Takeda Pharm; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Bayer. T. Denda: Speaker Bureau / Expert testimony: DAIICHI SANKYO COMPANY, LIMITED. T. Mizukami: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly Japan; Advisory / Consultancy: Bristol-Myers Squibb Company; Speaker Bureau / Expert testimony: Takeda Pharmaceutical; Research grant / Funding (institution): TAIHO Pharmaceutical. N. Okano: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Eisai; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Yakult Honsha; Honoraria (self): Takeda; Honoraria (self): J-Pharma; Honoraria (self): Kyowa Hakko Kirin. M.I. Lefterova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. J.I. Odegaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. H. Taniguchi: Honoraria (self): Chugai; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): Taiho; Honoraria (self): Eli Lilly; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Sysmex. C. Morizane: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Yakult Honsha; Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (institution): Nobelpharma; Honoraria (self): Fujifilm; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Eisai; Advisory / Consultancy: Abbvie; Research grant / Funding (institution): ONO PHARMACEUTICAL; Research grant / Funding (institution): J-Pharma. T. Yoshino: Research grant / Funding (self): Novartis Pharma K.K.; Research grant / Funding (self): MSD.K.K.; Research grant / Funding (self): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (self): CHUGAI PHARMACEUTICAL Co., Ltd.; Research grant / Funding (self): Sanofi K.K.; Research grant / Funding (self): DAIICHI SANKYO Co., Ltd.; Research grant / Funding (self): PAREXEL International Inc.; Research grant / Funding (self): ONO PHARMACEUTICAL Co., Ltd. All other authors have declared no conflicts of interest.

Background A family and personal history of breast (B), ovarian(O), and pancreatic(P) cancer was reported to be a predictive marker in patients with pancreatic adenocarcinoma (PA) treated with platinum-based chemotherapy. We planned a prospective phase II trial to evaluate the efficacy and safety of platinum-based chemotherapy in this population. Method Eligible patients had chemotherapy-naive metastatic PA, had one or more of the followings: 1) at least one family history of P/B/O/prostate (PR) cancer in a first-degree relative, 2) at least two family members with history of P/B/O/PR cancer within third-degree relatives, and 3) at least one personal history of B/O/PR cancer.Patient suitable for FOLFIRINOX or gemcitabine plus nab-paclitaxel were ineligible unless patient refuse those regimens. Patients received gemcitabine 1000mg/m2and oxaliplatin 100 mg/m2 every two weeks (GEMOX). The primary endpoint was the one-year survival rate and 44% were desired. The sample size was calculated to be 43 pts, with a one-sided alpha of 5% and a power of 80%. Results A total of 45 pts were enrolled. First 43 pts were included in primary analysis. One-year survival rate was 27.9 [90%CI;17.0-41.3]% and didn’t met pre-planned boundary. Response rate was 27.9%. Tendency of prolonged survival was observed in patients with two or more family histories of P/B/O/PR cancer (HR 0.65, 95%CI [0.34-1.23]). Family history or personal history with B/O/PR cancer tended to be associate with better response and prolonged survival. In this study, patient with family history of pancreatic cancer seemed to be associate with poor response. The most common adverse events of grade 3 or higher were neutropenia (36%), leukopenia (27%), thrombocytopenia (23%) and elevated level of ALT (20%). Treatment related death was not observed. Conclusion GEMOX did not show expected efficacy in patients with metastatic PA with family history or personal history of P/B/O/PR cancer.

Aim: No standard salvage chemotherapy regimens has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a phase I/II clinical trial of FGS was conducted, the number of patients enrolled was small and the efficacy and safety of FGS is still not well known. Methods: We retrospectively reviewed 67 patients who received FGS as salvage chemotherapy at our institution from March 2009 to Mach 2014. The selection criteria in this study was progressive disease under gemcitabine-based chemotherapy, ECOG performance status Results: Sixty-six patients were selected for the analysis. Twenty-two patients of them had received FGS as third line treatment. The overall responce rate was 12% and the disease control rate was 45%. The median progression-free survival time was 2.7 months and the median overall survival time was 6.0 months. The common grade 3/4 toxicities were leukopenia (11%), neutropenia (15%), diarrhea (3%), anorexia (2%) and fatigue (2%). Univariate analysis showed that performance status of >0, presence of ascites, serum carcinoembryonic antigen level of > 10 ng/ml, serum albumin level of 500 IU/L and serum C-reactive protein level of > 1.0 mg/dl were significantly associated with a poor prognosis. Multivariate analysis identified serum C-reactive protein level of > 1.0 mg/dl and serum albumin level of Conclusions: FGS as salvage chemotherapy for patients with gemcitabine-refractory advanced pancreatic cancer is marginally effective and well tolerated in a practical setting. These results suggest FGS is of value to be further investigated in a clinical trial in patients with gemcitabine-refractory pancreatic cancer. Disclosure: All authors have declared no conflicts of interest.