Anticancer therapy – TAS-102

Published: 10-Feb-2015

Trifluridine could make a return to the cancer field in combination with thymidine phosphorylase inhibitor tipiracil

The drug 5-fluorouracil (5-FU) is an important cornerstone in many cancer therapy regimens, but it is not ideal, not least because of the requirement for slow intravenous infusion, and the tendency for resistance to develop. One alternative is trifluridine, which was first synthesised 50 years ago, but its serum half-life was of the order of minutes. Some success in treating breast and colon cancers was achieved via intravenous administration every three hours, but tumours returned when therapy ceased, and studies were stopped. It is, however, used as an antiherpes virus medicine.

Trifluridine returned in the cancer field, however, when it was realised that on oral dosing it was broken down into metabolites with no anticancer activity by the enzyme thymidine phosphorylase during the first pass of the liver. Taiho Oncology is now investigating the combination of trifluridine with tipiracil, an inhibitor of thymidine phosphorylase, to prevent this degradation occurring. This combination, code-named TAS-102, retains its effect in vitro on 5-FU-resistant cancer cells.1 Its activity arises via the incorporation of trifluridine into tumour cell DNA.2

After several successful Phase I studies, the combination was investigated in a double-blind, randomised, placebo-controlled Phase II trial in 169 patients with pretreated, metastatic colorectal cancer.3 Subjects were given 35mg/m2 of TAS-102 orally twice a day in 28 day cycles of five days’ treatment followed by two rest days for two weeks and then 14 rest days, or placebo. All of the patients were also given best supportive care.

The median overall survival was nine months in the treated group, and 6.6 in those given placebo. The main major side-effects were neutropenia, leukopenia and anaemia; serious side-effects occurred in 19% of those given TAS-102 and 9% of the placebo group.

The results of a Phase III trial, again in patients with metastatic colorectal cancer, have also been reported.4,5 A total of 800 subjects had been pre-treated with at least two prior chemotherapy regimens, including fluoropyrimidines, bevacizumab, irinotecan, oxaliplatin and, if their tumours were KRAS-wild type, cetuximab or panitumumab.

Subjects were given the same dosing regimen as the Phase II trial, with study treatment continuing until disease progression, death or unacceptable toxicity occurred. The median overall survival was 7.1 months for the treated group, and 5.3 months for those given placebo, and the company is submitting the combination for regulatory approval.


1. T. Emura et al. Int. J. Mol. Med. 2004, 13, 545

2. T. Emura et al. Int. J. Mol. Med. 2004, 13, 571

3. T. Yoshino et al. Lancet Oncol. 2012, 13, 993

4. T. Yoshino et al. Eur. Soc. Med. Oncol. Ann. Meet. 2014 (Madrid, 27–30 September), Abst. O-0022

5. E. van Cutsem et al. Eur. Soc. Med. Oncol. Ann. Meet. 2014 (Madrid, 27–30 September), Abst. LBA13

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