TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer: a randomised, open-label, phase 3 study (GRAPE trial)

Tatsuya Ioka, Makoto Ueno, Hideki Ueno, Joon Oh Park, Heung Moon Chang, Naoki Sasahira, Masashi Kanai, Ik Joo Chung, Masafumi Ikeda, Shoji Nakamori, Nobumasa Mizuno, Yasushi Omuro, Taketo Yamaguchi, Hiroki Hara, Kazuya Sugimori, Junji Furuse, Hiroyuki Maguchi, Masayuki Furukawa, Kengo Fukuzawa, Jun Suk KimSeigo Yukisawa, Masahiro Takeuchi, Takuji Okusaka, Narikazu Boku, Ichinosuke Hyodo

    Research output: Contribution to journalArticlepeer-review

    17 Citations (Scopus)


    Background: In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). Patients and methods: This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40–60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40–60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. Results: A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82–1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67–0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. Conclusion: TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.

    Original languageEnglish
    Pages (from-to)78-88
    Number of pages11
    JournalEuropean Journal of Cancer
    Publication statusPublished - 2019 Jan

    Bibliographical note

    Funding Information:
    This work was supported by Taiho Pharmaceutical Co. Ltd (no grant number).

    Funding Information:
    The authors thank all the patients, their families and the investigators who participated in the study; members of the independent data monitoring committee (Keisuke Aiba, Satoshi Morita and Yoshiharu Motoo); and medical adviser Yuh Sakata. Masahiro Takeuchi had a role in the statistical analysis plan as study statistician. Medical writing for the article was assisted by Taiho Pharmaceutical Co., Ltd. , and English editing was done by SunFlare Co., Ltd., funded by Taiho. The authors retained full control of the article content.

    Publisher Copyright:
    © 2018 The Authors


    • Fluorouracil
    • Leucovorin
    • Pancreatic cancer
    • S-1
    • Second-line chemotherapy
    • TAS-118

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research


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