Review on TAS-102 development and its use for metastatic colorectal cancer.
TAS-102 is the combination of trifluridine (TFT) with tipiracil (TPI) in a 1:0.5 molar ratio. TFT is a fluoropyrimidine that retains cytotoxic activity in 5-fluorouracil resistant cell lines. Due to TFT short half-life, early clinical development was discouraging. Thereafter, TFT was shown to be promptly degraded by thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor, a pro-angiogenic protein and a poor prognosis marker in colorectal cancer. TPI is a specific antagonist of thymidine phosphorylase and led to an increase in TFT serum levels when both agents are combined. Moreover, TPI is a potential anti-angiogenic molecule and could exert antitumor actions per se. TAS-102 was tested in several Phase I studies published in the early 21st century. The best regimen was settled as 70mg/m(2)/day, q12h, orally given at days 1-5 and days 8-13, each 28days. Recently, the first Phase III trial evaluating TAS-102 in refractory colorectal cancer patients was published. The RECOURSE trial demonstrated a survival advantage of the agent over supportive care, and definitely established TAS-102 as a novel strategy in the current armamentarium against colorectal cancer. Here we review the preclinical data regarding TFT and TPI that led to the development of TAS-102, and the set of clinical data that ultimately proved that TAS-102 improved outcomes in colorectal cancer patients.
Division of Oncology, Instituto do Câncer do Estado de São Paulo, University of São Paulo, São Paulo, Brazil. Electronic address: mauricio@usp.br.
Jose Mauricio
JM
Mota
Division of Oncology, Instituto do Câncer do Estado de São Paulo, University of São Paulo, São Paulo, Brazil.
Leonardo G
LG
Fonseca
Division of Oncology, Instituto do Câncer do Estado de São Paulo, University of São Paulo, São Paulo, Brazil.
Maria Ignez
MI
Braghiroli
Division of Oncology, Instituto do Câncer do Estado de São Paulo, University of São Paulo, São Paulo, Brazil.
Paulo M
PM
Hoff
D000818:Animals; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004338:Drug Combinations; D006801:Humans; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000627:therapeutic use*; D014498:Uracil / Q000031:analogs & derivatives* / Q000627:therapeutic use
D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine
Colorectal cancer; Tas-102; Tipiracil; Treatment; Trifluridine