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Pyrimidine analogues and fluoropyrimidinesIn useRational designNeeds review

Trifluridine-tipiracil

Also known as TAS-102, Lonsurf, trifluorothymidine-tipiracil

An oral fixed-dose combination of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, which blocks its breakdown by thymidine phosphorylase. Its US label lists refractory metastatic colorectal and gastric cancer.

From discovery to approval

  1. 1964 · First described

    A 1964 paper by Heidelberger and colleagues is titled as describing syntheses of 5-trifluoromethyl-2'-deoxyuridine, which the current US label names trifluridine (title only). A 2000 paper describes tipiracil as a thymidine phosphorylase inhibitor that raised blood levels of this nucleoside in mice and monkeys.[2][3][4][5][6][1]

  2. 2015-09-22 · FDA regular · 51 years after first description

    Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy.[7]

  3. 2016-04-25 · EMA regular · 52 years after first description

    Marketing authorisation valid throughout the European Union (initial authorisation; the EPAR page lists a bevacizumab combination among the current indications).[8]

  4. 2023-08-02 · FDA regular · 59 years after first description

    As a single agent or in combination with bevacizumab, adults with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy; the letter names the SUNLIGHT study as the supporting protocol.[9]

How it works

Trifluridine is taken up by cancer cells and incorporated into DNA, interfering with DNA synthesis and inhibiting cell proliferation. Tipiracil inhibits thymidine phosphorylase, which breaks trifluridine down, so it increases trifluridine exposure. The two are combined in a 1:0.5 molar ratio.[1]

Where it came from and why

A 2016 review says early clinical development of trifluridine alone was discouraging because of its short half-life; it was found to be rapidly degraded by thymidine phosphorylase, and tipiracil, a specific inhibitor of that enzyme, raised its serum levels when combined.

Cancers

  • Metastatic colorectal cancer

    The US label lists metastatic colorectal cancer, alone or with bevacizumab, previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy and, if RAS wild-type, an anti-EGFR therapy; the global RECOURSE trial tested it against placebo in refractory disease.[1]

  • Metastatic gastric or gastro-oesophageal junction cancer

    The US label lists metastatic gastric or gastro-oesophageal junction adenocarcinoma previously treated with at least two prior lines of chemotherapy including a fluoropyrimidine, a platinum, a taxane or irinotecan, and HER2-targeted therapy where appropriate.[1]

Worth knowing

  • The 2015 RECOURSE trial assigned 800 patients 2:1 to TAS-102 or placebo; median overall survival was 7.1 months with TAS-102 and 5.3 months with placebo (hazard ratio 0.68, 95% CI 0.58 to 0.81; P<0.001).[10]
  • A 2015 review explains that sufficient thymidylate synthase inhibition by trifluridine needs continuous infusion, so with twice-daily oral dosing the main cytotoxic mechanism is incorporation into DNA.[11]
  • A 2004 preclinical study reports that orally given trifluridine retained antitumour activity against the fluorouracil-resistant NUGC-3 human cancer line, where fluorouracil, FdUrd and S-1 were less active than in the parental line.[5]
  • In the 2000 paper, oral trifluridine given to monkeys with tipiracil reached about 70-fold higher peak concentration and about 100-fold higher exposure than trifluridine alone.[3]
  • The Drugs@FDA history lists the original approval of NDA 207981 on 22 September 2015 as a new molecular entity and new combination with standard review and orphan status.[12]

On this site

References

  1. Taiho Pharmaceutical Co., Ltd. Lonsurf (trifluridine and tipiracil) tablets, film coated: prescribing information. DailyMed, set ID f5beed22-d71d-4c0d-8dca-2c7317d65d85, published 18 November 2025. Source
  2. HEIDELBERGER C, PARSONS DG, REMY DC. SYNTHESES OF 5-TRIFLUOROMETHYLURACIL AND 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE. J Med Chem. 1964;7:1-5. PubMedDOI
  3. Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y, et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. Biochem Pharmacol. 2000;59(10):1227-36. PubMedDOI
  4. Mota JM, Fonseca LG, Braghiroli MI, Hoff PM. Review on TAS-102 development and its use for metastatic colorectal cancer. Crit Rev Oncol Hematol. 2016;104:91-7. PubMedDOI
  5. Emura T, Suzuki N, Yamaguchi M, Ohshimo H, Fukushima M. A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA. Int J Oncol. 2004;25(3):571-8. PubMed
  6. Maehara Y, Oki E, Ota M, Harimoto N, Ando K, Nakanishi R, et al. Lineage of drug discovery research on fluorinated pyrimidines: chronicle of the achievements accomplished by Professor Setsuro Fujii. Int J Clin Oncol. 2023;28(5):613-624. PubMedDOI
  7. US Food and Drug Administration. NDA approval letter, Lonsurf (trifluridine and tipiracil) tablets, NDA 207981, Taiho Oncology, Inc.; electronically signed 22 September 2015. Source
  8. European Medicines Agency. Lonsurf (trifluridine/tipiracil): European public assessment report page; marketing authorisation issued 25 April 2016; page last updated 5 April 2024. Source
  9. US Food and Drug Administration. Supplement approval letter, Lonsurf (trifluridine/tipiracil), NDA 207981/S-012, Taiho Oncology, Inc.; electronically signed 2 August 2023. Source
  10. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-19. PubMedDOI
  11. Lenz HJ, Stintzing S, Loupakis F. TAS-102, a novel antitumor agent: a review of the mechanism of action. Cancer Treat Rev. 2015;41(9):777-83. PubMedDOI
  12. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 207981 (trifluridine and tipiracil; Lonsurf). Page read 2026-10-26. Source