TAS-102 is a novel oral formulation of trifluridine (TFT) and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TFT was originally synthesized in the 1960s and is a nucleoside analogue that impedes DNA synthesis by inhibition of thymidylate synthase. TFT's main mechanism of action, however, seems to be its incorporation into DNA, which distinguishes TFT from current well-known antimetabolites like 5-fluorouracil (5-FU). The rapid degradation of TFT brought initial clinical development to a halt, but TFT reentered clinical trials when addition of a TPI was found to improve the bioavailability of TFT. The combined TFT-TPI formulation was tested in patients with treatment-refractory metastatic colorectal cancer in the randomized phase III RECOURSE study. Compared with placebo, TAS-102 was associated with an overall survival (OS) and progression-free survival (PFS) benefit and a 32% reduction in risk of death [median OS, 7.1 (95% CI, 6.5-7.8) vs. 5.3 months (95% CI, 4.6-6.0); median PFS, 2.0 (95% CI, 1.9-2.1) vs. 1.7 months (95% CI, 1.7-1.8); HR for death, 0.68 (95% CI, 0.58-0.81, P < 0.001)]. Based on the results of this pivotal trial and supported by results from an earlier phase II study, TAS-102 recently gained FDA approval. This article reviews the development of TAS-102 and its therapeutic value for the proposed indication. Clin Cancer Res; 22(12); 2835-9. ©2016 AACR.
©2016 American Association for Cancer Research.