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)

• Published in: European journal of cancer (1990) 2019-01, Vol.106, p.78-88
• Main Authors: Ioka, Tatsuya, Ueno, Makoto, Ueno, Hideki, Park, Joon Oh, Chang, Heung-Moon, Sasahira, Naoki, Kanai, Masashi, Chung, Ik Joo, Ikeda, Masafumi, Nakamori, Shoji, Mizuno, Nobumasa, Omuro, Yasushi, Yamaguchi, Taketo, Hara, Hiroki, Sugimori, Kazuya, Furuse, Junji, Maguchi, Hiroyuki, Furukawa, Masayuki, Fukuzawa, Kengo, Kim, Jun-Suk, Yukisawa, Seigo, Takeuchi, Masahiro, Okusaka, Takuji, Boku, Narikazu, Hyodo, Ichinosuke
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adult; Aged; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer; Carcinoma, Adenosquamous - drug therapy; Carcinoma, Adenosquamous - mortality; Carcinoma, Adenosquamous - pathology; Chemotherapy; Clinical trials; Confidence intervals; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Disease Progression; Drug Combinations; Drug Resistance, Neoplasm; Drugs; Female; Fluorouracil; Gemcitabine; Humans; Japan; Leucovorin; Leucovorin - administration & dosage; Leucovorin - adverse effects; Male; Metastases; Middle Aged; Oxonic Acid - administration & dosage; Oxonic Acid - adverse effects; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Patients; Progression-Free Survival; Randomization; Republic of Korea; S-1; Second-line chemotherapy; Survival; TAS-118; Tegafur - administration & dosage; Tegafur - adverse effects; Time Factors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2018.10.004

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). 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. 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. 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. •TAS-118 did not improve overall survival for gemcitabine-refractory advanced pancreatic cancer.•TAS-118 improved progression-free survival compared with S-1 monotherapy.•TAS-118 might be more effective than S-1 in some populations of patients.