Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS study).

LESSONS LEARNED A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without CIN. The pre-specified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. BACKGROUND TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70mg/m2 /day on day 1-5 and 8-12, every 4 weeks) plus BEV (5mg/kg, day1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. METHODS Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily, on days 1-5, every 2 weeks) with BEV (5mg/kg, day1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). RESULTS From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70mg/m2 /day). Of the 44 eligible patients, 16-w PFS rate was 40.9% (95% confidence interval: 26.3% to 56.8%) and the null hypothesis was rejected (p < 0.0001). Median PFS and overall survival was 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%) and leucopenia (15.9%). CONCLUSION Biweekly TAS-102 plus BEV showed promising anti-tumor activity with safety.