TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial.

Background: Treatments that confer survival benefit are needed in patients with heavily pretreated metastatic colorectal cancer. The aim of this trial was to investigate the efficacy and safety of TAS-102-a novel oral nucleoside antitumour agent.

Methods: Between August 25, 2009, and April 12, 2010, we undertook a multicentre, double-blind, randomised, placebo-controlled phase 2 trial in Japan. Eligible patients were 20 years or older; had confirmed colorectal adenocarcinoma; had a treatment history of two or more regimens of standard chemotherapy; and were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin. Patients had to be able to take oral drugs; have measurable lesions; have an Eastern Cooperative Oncology Group performance status of between 0 and 2; and have adequate bone-marrow, hepatic, and renal functions within 7 days of enrolment. Patients were randomly assigned (2:1) to either TAS-102 (35 mg/m(2) given orally twice a day in a 28-day cycle [2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period]) or placebo; all patients received best supportive care. Randomisation was done with minimisation methods, with performance status as the allocation factor. The randomisation sequence was generated with a validated computer system by an independent team from the trial sponsor. Investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety analyses were done in the per-protocol population. The study is in progress and is registered with Japan Pharmaceutical Information Center, number JapicCTI-090880.

Findings: 112 patients allocated to TAS-102 and 57 allocated to placebo made up the intention-to-treat population. Median follow-up was 11·3 months (IQR 10·7-14·0). Median overall survival was 9·0 months (95% CI 7·3-11·3) in the TAS-102 group and 6·6 months (4·9-8·0) in the placebo group (hazard ratio for death 0·56, 80% CI 0·44-0·71, 95% CI 0·39-0·81; p=0·0011). 57 (50%) of 113 patients given TAS-102 in the safety population had neutropenia of grade 3 or 4, 32 (28%) leucopenia, and 19 (17%) anaemia. No patient given placebo had grade 3 or worse neutropenia or leucopenia; three (5%) of 57 had grade 3 or worse anaemia. Serious adverse events occurred in 21 (19%) patients in the TAS-102 group and in five (9%) in the placebo group. No treatment-related deaths occurred.

Interpretation: TAS-102 has promising efficacy and a manageable safety profile in patients with metastatic colorectal cancer who are refractory or intolerant to standard chemotherapies.