TY - JOUR
T1 - TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer
T2 - a randomised, open-label, phase 3 study (GRAPE trial)
AU - Ioka, Tatsuya
AU - Ueno, Makoto
AU - Ueno, Hideki
AU - Park, Joon Oh
AU - Chang, Heung Moon
AU - Sasahira, Naoki
AU - Kanai, Masashi
AU - Chung, Ik Joo
AU - Ikeda, Masafumi
AU - Nakamori, Shoji
AU - Mizuno, Nobumasa
AU - Omuro, Yasushi
AU - Yamaguchi, Taketo
AU - Hara, Hiroki
AU - Sugimori, Kazuya
AU - Furuse, Junji
AU - Maguchi, Hiroyuki
AU - Furukawa, Masayuki
AU - Fukuzawa, Kengo
AU - Kim, Jun Suk
AU - Yukisawa, Seigo
AU - Takeuchi, Masahiro
AU - Okusaka, Takuji
AU - Boku, Narikazu
AU - Hyodo, Ichinosuke
N1 - Funding Information:
This work was supported by Taiho Pharmaceutical Co. Ltd (no grant number).
Funding Information:
T.I. reports honoraria from Shire, Daiichi-Sankyo, Taiho, AstraZeneca, Otsuka, Chugai, Yakult and Mochida; and research funding from AstraZeneca, Sumitomo Dainippon, Baxalta/Shire, Eisai, Taiho and Incyte. M.U. reports honoraria from Taiho, Eli Lilly, Yakult, Teijin, Shire, Novartis, AstraZeneca, Ono and Eisai and research funding from Taiho, Shire, Daiichi-Sankyo, Eisai, AstraZeneca, Ono, MSD, Merck Serono, NanoCarrier, Sumitomo Dainippon and Incyte. H.U. reports honoraria from Taiho, Chugai and Yakult and research funding from Taiho, Eli Lilly, NanoCarrier and Baxalta. J.O.P. reports honoraria from Celgene and research funding from Celgene and AstraZeneca. H.M.C. reports honoraria and travel fee from Taiho and research funding from Celgene, Pharmacyclics, Taiho and Novartis. N.S. reports honoraria from Toshiba, Cook Medical and Boston Scientific and research funding from Zeria, Eisai, Kyowa Hakko Kirin, Baxalta and Taiho. M.K. reports stock ownership and patents from TheraBioPharma and honoraria and research funding from Taiho. M.I. reports honoraria and research funding from Bayer, Eisai, Bristol-Myers Squibb, Eli Lilly, Novartis, Yakult, Taiho, NanoCarrier and Chugai, honoraria from Kyowa Hakko Kirin, Shire, MSD, Abbott, Daiichi-Sankyo, Otsuka, Nobelpharma, Sumitomo Dainippon and Teijin and research funding from Kyowa Hakko Kirin, Ono, AstraZeneca, Zeria, Merck Serono, Kowa, ASLAN, Takara Bio and Baxalta/Shire. S.N. reports research funding from Eisai and Taiho. N.M. reports research funding from Taiho, Merck Serono, AstraZeneca, NanoCarrier, Eisai, MSD, Sumitomo Dainippon, Zeria and Novartis; honoraria from Novartis, Taiho, Ono and Teijin and travel fee from Taiho, Novartis and Eisai. H.H. reports research funding from AstraZeneca, Daiichi-Sankyo, Sumitomo Dainippon, Eli Lilly, Merck Serono, MSD, Ono, Taiho, Chugai, Boehringer Ingelheim, Eisai, LSK BioPharma, Incyte, Takeda and Pfizer and honoraria from MSD, Chugai, Taiho, Merck Serono, Yakult, Eli Lilly, Ono and Takeda. J.F. reports research funding and honoraria from Yakult, Eli Lilly, Chugai, Eisai, Ono, Daiichi-Sankyo, Merck Serono, Bayer, Novartis, Sumitomo Dainippon, MSD, Mochida, Takeda, Taiho and Astellas, research funding from Shionogi, Kyowa Hakko Kirin, Zeria, J-Pharma, Janssen, NanoCarrier, Onco Therapy Science, Baxalta/Shire and Bristol-Myers Squibb and honoraria from EA Pharma, Sawai, Pfizer, Nippon Kayaku, Kyowa Hakko Kirin, Sanofi, Shionogi, Sandoz, Otsuka, Zeria, Fujifilm, AstraZeneca, Asahi Kasei, J-Pharma, and Shire. M.T. reports honoraria from Shionogi, Hisamitsu, Astellas, Taiho and Abbvie. T.O. reports honoraria and research funding from Novartis, Taiho, Boehringer Ingelheim, Sumitomo Dainippon, Pfizer, Bayer, Chugai, Eli Lilly, Yakult, Ono, Eisai, AstraZeneca, Merck Serono and Baxter, research funding from NanoCarrier, Kowa and Kyowa Hakko Kirin and honoraria from Nobelpharma, Bristol-Myers Squibb, Nippon Chemiphar, EA Pharma, FUJIFILM RI Pharma, Nippon Kayaku, Daiichi-Sankyo, Celgene, Zeria and Teijin. N.B. reports research funding from Bristol-Myers Squibb, Taiho and Ono and honoraria from Taiho, Merck Serono, Ono, Shionogi, Chugai, Yakult and Eli Lilly. I.H. reports honoraria from Chugai, Taiho, Daiichi-Sankyo, Eli Lilly and Ono and research funding from Bristol-Myers Squibb, Chugai, Kyowa Hakko Kirin, Takeda, Merck Serono and Yakult. I.J.C., K.F. and J.S.K. report research funding from Taiho. M.F., Y.O. and H.M. report honoraria and research funding from Taiho. S.Y., K.S. and T.Y. report no conflicts of interest.
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
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Fluorouracil
KW - Leucovorin
KW - Pancreatic cancer
KW - S-1
KW - Second-line chemotherapy
KW - TAS-118
UR - http://www.scopus.com/inward/record.url?scp=85056895259&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2018.10.004
DO - 10.1016/j.ejca.2018.10.004
M3 - Article
C2 - 30471651
AN - SCOPUS:85056895259
VL - 106
SP - 78
EP - 88
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
ER -