title: TAS-102 for Treatment of Advanced Colorectal Cancers That Are No Longer Responding to Other Therapies.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Daphne L
authors.initials: DL
authors.lastname: van der Velden
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. F.opdam@nki.nl.
authors.forename: Frans L
authors.initials: FL
authors.lastname: Opdam
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D011759:Pyrrolidines; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D013941:Thymine; D014271:Trifluridine / Q000009:adverse effects / Q000627:therapeutic use*; D014498:Uracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013940:Thymidylate Synthase; D013941:Thymine; D014271:Trifluridine