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

Abstract

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 chemotherapy-induced neutropenia (CIN). The prespecified 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 (70 mg/m² /day on days 1-5 and 8-12, every 4 weeks) plus BEV (5 mg/kg on day 1, 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 on day 1, 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 (70 mg/m² /day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%-56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 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 antitumor activity with safety.

Figure 1

Progression‐free survival.

Figure 2

Overall survival.

Figure 3

Prespecified subgroup analysis for progression‐free survival (PFS). (A): PFS by age. Straight line, age < 65 years; dotted line, age ≥ 65 years. (B): PFS by Eastern Cooperative Oncology Group (ECOG) PS. Straight line, ECOG PS 0; dotted line, ECOG PS 1. (C): PFS by primary location. Straight line, right‐sided primary; dotted line, left‐sided primary. (D): PFS by RAS status. Straight line, RAS wild‐type; dotted line, RAS mutant‐type. (E): PFS by prior regorafenib administration. Straight line, without prior regorafenib; dotted line, with prior regorafenib. (F): PFS by chemotherapy‐induced neutropenia within the first two cycles. Straight line, without neutropenia within the first two cycles; dotted line, with neutropenia within the first two cycles. Abbreviations: mt, mutant; PS, performance status; REG, regorafenib; wt, wild type.

Figure 4

Prespecified subgroup analysis for overall survival (OS). (A): OS by age. Straight line, age < 65 years; dotted line, age ≥ 65 years. (B): OS by Eastern Cooperative Oncology Group (ECOG) PS. Straight line, ECOG PS 0; dotted line, ECOG PS 1. (C): OS by primary location. Straight line, right‐sided primary; dotted line, left‐sided primary. (D): OS by RAS status. Straight line, RAS wild‐type; dotted line, RAS mutant‐type. (E): OS by prior regorafenib administration. Straight line, without prior regorafenib; dotted line, with prior regorafenib. (F): OS by chemotherapy‐induced neutropenia within the first two cycles. Straight line, without neutropenia within the first two cycles; dotted line, with neutropenia within the first two cycles. Abbreviations: mt, mutant; PS, performance status; REG, regorafenib; wt, wild type.