PD-013 Final survival results of a multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer patients refractory to standard therapies (C-TASK FORCE)

Abstract

Introduction: TAS-102 is comprised of a trifluridine and a tipiracil hydrochloride. The concentration of phosphorylated trifluridine in tumors was higher in TAS-102 with bevacizumab than in TAS-102 monotherapy in preclinical model, resulting in enhanced activity of the combination against colorectal cancer (CRC) cells compared with either drug alone (Tsukihara H, Oncol Rep. 2015). Clinical efficacy was demonstrated by the phase I/II study (C-TASK FORCE) which showed centrally-assessed progression-free survival (PFS) rate at 16 weeks as primary endpoint was 42.9%, and median PFS by investigator assessment was 5.6 months in patients ( pts) with metastatic CRC (mCRC) (Kuboki Y et al. #3544, ASCO 2015). Neutropenia is the most common TAS-102-associated adverse event and it has been hypothesized to be associated with trifluridine concentration. Methods: Eligibility criteria were mCRC pts who were refractory or intolerant to all standard therapies and had no prior regorafenib. Data cutoff was 29 Jan 2016. Here, we report the final results of a prespecified analysis of survival outcomes by RAS status, 26 cancer-related actionable gene mutations using Next Generation Sequencing (NGS) and thymidine kinase 1 (TK1) immunohistochemical expression level, and a post hoc analysis of survival outcomes by chemotherapy-induced neutropenia (CIN) in the first cycle. Results: From February to July 2014, 25 pts were enrolled and received TAS-102 (35 mg/m2 BID on day 1-5 and 8-12 q4w) with bevacizumab (5 mg/kg q2w). Median overall survival (OS) was 11.4 months. There was no statistically significant difference in PFS and OS between pts with wild-type RAS and mutant (Table). Any mutation identified by NGS as well as TK-1 expression level was not associated with survival outcomes. Pts who developed ≥ grade 2 CIN in the first cycle had a longer PFS compared to pts who did not (median, 5.8 months versus 1.9 months; Log-rank P-value = 0.0006), as well as OS (median, 12.7 versus 5.2 months; Log-rank P-value < 0.0001) (Table). Conclusion: The combination of TAS-102 with bevacizumab showed a promising antitumor activity. Compared with previous reports, the combination therapy seemed more effective than TAS-102 monotherapy irrespective of RAS status, known actionable mutations and TK-1 expression. The CIN in the first cycle was statistically significantly associated with survival outcomes, suggesting increased phosphorylated trifluridine levels by combining TAS-102 with bevacizumab may contribute to the enhanced antitumor activity. Clinical trial information: UMIN000012883.