• Yasutoshi Kuboki, Tomohiro Nishina, Eiji Shinozaki, Kentaro Yamazaki, Kohei Shitara, Wataru Okamoto, Takeshi Kajiwara, Toshihiko Matsumoto, Takahiro Tsushima, Nobuo Mochizuki, Shogo Nomura, Toshihiko Doi, Akihiro Sato, Atsushi Ohtsu, and Takayuki Yoshino.
• National Cancer Center Hospital East, Kashiwa, Japan.
• Lancet Oncol. 2017 Sep 1; 18 (9): 1172-1181.

BackgroundIn patients with heavily treated metastatic colorectal cancer, TAS-102-a combination of trifluridine and tipiracil-has shown a significant overall survival benefit compared with placebo. In preclinical models, TAS-102 plus bevacizumab has shown enhanced activity against colorectal cancer xenografts compared with that for either drug alone. In this phase 1/2 study, we assessed the activity and safety of TAS-102 plus bevacizumab.MethodsWe did this investigator-initiated, open-label, single-arm, multicentre, phase 1/2 trial of TAS-102 plus bevacizumab in four cancer centres in Japan. Eligible patients were aged 20 years or older; had histologically confirmed unresectable, metastatic colorectal adenocarcinoma; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumours with wild-type KRAS); and had no previous treatment with regorafenib. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Using a dose de-escalation design in phase 1, the recommended phase 2 dose (RP2D) was determined for TAS-102 (35 mg/m2 given orally twice daily on days 1-5 and 8-12 in a 28-day cycle for level 1) plus bevacizumab (5 mg/kg, administered by intravenous infusion for 30 min every 2 weeks). In phase 2, patients received the RP2D. The primary endpoint was centrally assessed progression-free survival at 16 weeks, analysed in the first 21 patients to be enrolled and treated with the RP2D who had at least one imaging assessment. This study is completed and registered with the University Hospital Medical Information Network, number UMIN000012883.FindingsBetween Feb 25, 2014, and July 23, 2014, we enrolled 25 patients with metastatic colorectal cancer: six patients in phase 1 and 19 patients in phase 2. The six patients who received TAS-102 at level 1 experienced no dose-limiting toxicities and this was deemed the RP2D. Nine of 21 patients who received the RP2D did not have a centrally assessed progression event; 16-week progression-free survival was 42·9% (80% CI 27·8-59·0). The most common grade 3 or worse adverse events as assessed in all 25 patients were neutropenia (18 [72%] patients), leucopenia (11 [44%]), anaemia (four [16%]), febrile neutropenia (four [16%]), and thrombocytopenia (three [12%]). Treatment-related serious adverse events were reported in three (12%) patients. No treatment-related deaths occurred.InterpretationTAS-102 plus bevacizumab has promising activity with manageable safety, suggesting that this combination might become a potential treatment option for patients with metastatic colorectal cancer in a refractory setting.FundingTaiho Pharmaceutical.Copyright © 2017 Elsevier Ltd. All rights reserved.

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