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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-naïve 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: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78–1.15; P  =   0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months 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. [ABSTRACT FROM AUTHOR]

Background In the NAPOLI-1 phase 3 trial, nal-IRI+5-FU/LV significantly increased median PFS (mPFS) vs 5-FU/LV (3.1 vs 1.5 months [mo], unstratified HR = 0.56, P = 0.0001) in pts with mPAC that progressed on prior gemcitabine-based therapy. This randomised phase 2 trial evaluated nalIRI+5FU/LV vs 5-FU/LV in Japanese pts with gemcitabine-refractory mPAC (NCT02697058). Table: 132P   nal-IRI+5-FU/ LV n = 40  5-FU/ LV n = 39  PFS, mo (investigator assessed)  Median  2.7  1.5  95% CI  1.5–5.0  1.4–1.6  HR  0.60  95% CI  0.37–0.98  P-value  0.039  PFS, mo (independently assessed)  Median  1.7  1.6  95% CI  1.5–3.6  1.4–1.6  HR  0.79  95% CI  0.47–1.32  P-value  0.376  Best overall response, n (%)  40 (100.0)  39 (100.0)  ORR  8 (20.0)  1 (2.6)  P-value  0.029  Disease control rate, n (%)  8 (20.0)  2 (5.1)  P-value  0.087  OS, mo  Median  6.3  NR  95% CI  5.2–NR  6.1–NR  HR  1.67  95% CI  0.88–3.16  P-value  0.110  TTF, mo  Median  1.7  1.5  95% CI  1.5–2.2  1.4–1.6  HR  0.70  95% CI  0.44–1.12  P-value  0.134  CA19-9 response rate,n/evaluable population (%)  5/28 (17.9)  1/28 (3.6)  P-value  0.193    nal-IRI+5-FU/ LV n = 40  5-FU/ LV n = 39  PFS, mo (investigator assessed)  Median  2.7  1.5  95% CI  1.5–5.0  1.4–1.6  HR  0.60  95% CI  0.37–0.98  P-value  0.039  PFS, mo (independently assessed)  Median  1.7  1.6  95% CI  1.5–3.6  1.4–1.6  HR  0.79  95% CI  0.47–1.32  P-value  0.376  Best overall response, n (%)  40 (100.0)  39 (100.0)  ORR  8 (20.0)  1 (2.6)  P-value  0.029  Disease control rate, n (%)  8 (20.0)  2 (5.1)  P-value  0.087  OS, mo  Median  6.3  NR  95% CI  5.2–NR  6.1–NR  HR  1.67  95% CI  0.88–3.16  P-value  0.110  TTF, mo  Median  1.7  1.5  95% CI  1.5–2.2  1.4–1.6  HR  0.70  95% CI  0.44–1.12  P-value  0.134  CA19-9 response rate,n/evaluable population (%)  5/28 (17.9)  1/28 (3.6)  P-value  0.193  Table: 132P   nal-IRI+5-FU/ LV n = 40  5-FU/ LV n = 39  PFS, mo (investigator assessed)  Median  2.7  1.5  95% CI  1.5–5.0  1.4–1.6  HR  0.60  95% CI  0.37–0.98  P-value  0.039  PFS, mo (independently assessed)  Median  1.7  1.6  95% CI  1.5–3.6  1.4–1.6  HR  0.79  95% CI  0.47–1.32  P-value  0.376  Best overall response, n (%)  40 (100.0)  39 (100.0)  ORR  8 (20.0)  1 (2.6)  P-value  0.029  Disease control rate, n (%)  8 (20.0)  2 (5.1)  P-value  0.087  OS, mo  Median  6.3  NR  95% CI  5.2–NR  6.1–NR  HR  1.67  95% CI  0.88–3.16  P-value  0.110  TTF, mo  Median  1.7  1.5  95% CI  1.5–2.2  1.4–1.6  HR  0.70  95% CI  0.44–1.12  P-value  0.134  CA19-9 response rate,n/evaluable population (%)  5/28 (17.9)  1/28 (3.6)  P-value  0.193    nal-IRI+5-FU/ LV n = 40  5-FU/ LV n = 39  PFS, mo (investigator assessed)  Median  2.7  1.5  95% CI  1.5–5.0  1.4–1.6  HR  0.60  95% CI  0.37–0.98  P-value  0.039  PFS, mo (independently assessed)  Median  1.7  1.6  95% CI  1.5–3.6  1.4–1.6  HR  0.79  95% CI  0.47–1.32  P-value  0.376  Best overall response, n (%)  40 (100.0)  39 (100.0)  ORR  8 (20.0)  1 (2.6)  P-value  0.029  Disease control rate, n (%)  8 (20.0)  2 (5.1)  P-value  0.087  OS, mo  Median  6.3  NR  95% CI  5.2–NR  6.1–NR  HR  1.67  95% CI  0.88–3.16  P-value  0.110  TTF, mo  Median  1.7  1.5  95% CI  1.5–2.2  1.4–1.6  HR  0.70  95% CI  0.44–1.12  P-value  0.134  CA19-9 response rate,n/evaluable population (%)  5/28 (17.9)  1/28 (3.6)  P-value  0.193  Methods This study assessed nal-IRI+5-FU/LV tolerability as per the NAPOLI-1 dosing regimen (Part 1), and safety and efficacy (Part 2). Part 2 outcomes are reported. Pts were randomised 1:1 and stratified by KPS (70 and 80 vs ≥ 90) and baseline albumin (≥4.0 g/dL vs < 4.0 g/dL). Primary endpoint was PFS; secondary endpoints were ORR, DCR, OS, TTF, CA199 response and QoL. The ITT population comprised all pts randomised. Results Differences in pt baseline characteristics were noted in the nal-IRI+5-FU/LV (n = 40/79) vs 5FU/LV (n = 39/79) arms, e.g. hepatic lesions (63% vs 51%), stage IV disease at diagnosis (78% vs 51%), and post-study anticancer therapy (55% vs 72%). Efficacy results are shown in the table. Investigator-assessed mPFS increase with nal-IRI+5-FU/LV was clinically meaningful and statistically significant vs 5-FU/LV (2.7 vs 1.5 mo, P = 0.039). Independently-assessed mPFS showed a similar trend (1.7 vs 1.6 mo, P = 0.376). mOS was 6.3 mo with nal-IRI+5-FU/LV and not reached with 5-FU/LV. DCR, TTF, CA19-9 and ORR response increased, ORR significantly, with nalIRI+5-FU/LV vs 5-FU/LV. The most commonly reported grade ≥3 TEAEs with nal-IRI+5-FU/LV vs 5-FU/LV were decreased neutrophil count (37% vs 3%), decreased white blood cell count (20% vs 0) and diarrhoea (17% vs 3%). Conclusions Treatment with nal-IRI+5-FU/LV was associated with clinically meaningful and statistically significant gains in investigator-assessed mPFS and ORR vs 5-FU/LV in Japanese patients, with no new or unexpected safety signals in this population. Clinical trial identification NCT02697058. Editorial acknowledgement Medical writing support was provided by Christopher Lamb of Physicians World Europe GmbH, Mannheim, Germany and was funded by Servier Global Medical Affairs (Suresnes, France). Legal entity responsible for the study Servier and the authors. Funding Servier. Disclosure T. Ioka: Advisory / Consultancy: Shire. M. Kanai: Advisory / Consultancy, Shareholder / Stockholder / Stock options: TheraBioPharma Inc. M. Ikeda: Advisory / Consultancy: Shire; Advisory / Consultancy, Research grant / Funding (self): Bayer Yakuhin; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy: Novartis Pharma; Advisory / Consultancy: MSD; Research grant / Funding (self): Kyowa Hakko Kirin; Research grant / Funding (self): Yakult; Research grant / Funding (self): Eli Lilly Japan; Research grant / Funding (self): Ono pharmaceutical; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Baxalta Japan Limited; Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Nano Carrier; Research grant / Funding (self): ASLAN Pharmaceuticals; Research grant / Funding (self): Novartis Pharma; Research grant / Funding (self): Takar Bio. T. Okusaka: Honoraria (self): Meiji Seika Pharma ; Honoraria (self): MSD; Honoraria (self): AbbVie Inc.; Honoraria (self), Research grant / Funding (self): Eisai Co. Ltd.; Honoraria (self): Yakult Honsha Co. Ltd.; Honoraria (self): Shire; Honoraria (self): ; Honoraria (self): Daiichi Sankyo Co. Ltd.; Honoraria (self): Taiho Pharmaceutical Co. Ltd; Honoraria (self): Takeda Pharmaceutical Co. Ltd.; Honoraria (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self): Teijin Pharma Ltd.; Honoraria (self): Eli Lilly Japan K.K.; Honoraria (self): Novartis Pharma K.K.; Honoraria (self): Nobelpharma Co. Ltd.; Honoraria (self): Bayer Yakuhin, Ltd.; Honoraria (self): Pfizer Japan Inc.; Honoraria (self): FUJIFILM RI Pharma Co. Ltd ; Honoraria (self), Research grant / Funding (self): Bristol-Myers K.K.; Research grant / Funding (self): AstraZeneca K.K.; Research grant / Funding (self): Baxter. J. Furuse: Advisory / Consultancy: Shire. Y. Komatsu: Advisory / Consultancy: Yakult; Advisory / Consultancy: Taiho; Advisory / Consultancy: Lilly. S. Shimizu: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Baxalta Japan; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Yakult; Research grant / Funding (institution): IQVIA Services Japan. P. Chugh: Full / Part-time employment: Servier. R. Tang: Full / Part-time employment: Servier. M. Ueno: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): 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. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]