TAS-102: A resurrected novel Fluoropyrimidine with expanding role in the treatment of gastrointestinal malignancies

TAS-102 is an orally administered fixed-dose formulation consisting of trifluorothymidine (TFT), a fluoropyrimidine antimetabolite, and tipiracil (TPI), an inhibitor of thymidine phosphorylase (TP) that prevents rapid degradation of TFT and ensures its bioavailability. The novelty of TAS-102 lies in its antitumor activity against 5-fluorouracil (5-FU) resistant tumors, demonstrated both in the in vitro models and xenografts. The cytotoxic activity of TFT relies primarily on extensive incorporation of the TFT metabolite into the cellular DNA inducing DNA dysfunction and cell death. In contrast, 5-fluorouracil (5-FU) interferes with DNA biosynthesis by inhibiting thymidylate synthase(TS), which partly explains the absence of cross-resistance between TAS-102 and 5-FU. TAS-102 is currently approved in the third-line setting for patients with metastatic colorectal and gastric cancer based on phase III randomized clinical trial data confirming an overall survival benefit with TAS-102. The preliminary data from recently reported studies suggest a potential expanding role of TAS-102 in a variety of gastrointestinal (GI) cancers. The current article presents an overview of the pharmacology, clinical development of TAS-102, and its emerging role in the treatment of GI cancers. In addition, we discussed the rationale underlying the ongoing clinical trials investigating various combinations of TAS-102 with other anticancer agents, including targeted therapies, in a wide range of GI tumors.