Trifluridine/Tipiracil: A Review in Metastatic Colorectal Cancer

Abstract

Trifluridine/tipiracil (Lonsurf(®)) is a novel, orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Trifluridine is incorporated into DNA via phosphorylation, ultimately inhibiting cell proliferation. Tipiracil increases systemic exposure of trifluridine when coadministered. Trifluridine/tipiracil has recently been approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who are refractory to or are not considered candidates for, current standard chemotherapy and biological therapy in the EU and USA and in unresectable advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily trifluridine/tipiracil (35 mg/m(2) twice daily on days 1-5 and 8-12 of each 28-day cycle) significantly improved overall survival and progression-free survival and was associated with a significantly higher disease control rate than placebo when added to best supportive care in the multinational, pivotal phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil was associated with an acceptable tolerability profile, with adverse events generally being managed with dose reductions, temporary interruptions in treatment or administration of granulocyte-colony stimulating factor. The most common grade 3-4 adverse events (≥10 %) were anaemia, neutropenia, thrombocytopenia and leukopenia. In conclusion, trifluridine/tipiracil is a useful additional treatment option for the management of mCRC in patients who are refractory to, or are not considered candidates for, currently available therapies.

Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

“…After further phosphorylation, the corresponding triphosphate competitively inhibits DNA polymerases with respect to thymidine triphosphate (Aoki, 2015). Trifluridine in combination with tipiracil (Lonsurf) has been approved in Japan, the United States, and the European Union for the treatment of adult patients with metastatic colorectal cancer who were previously subjected to chemotherapy involving fluoropyrimidine, oxaliplatin and irinotecan (Burness and Duggan, 2016;Matsuoka et al, 2018). Phase 3 clinical trials are also underway to collect additional data about the safety and efficacy of trifluridine-tipiracil during the treatment of patients with metastatic colorectal cancer (NCT03306394).…”

Precision treatment in colorectal cancer: Now and the future

“…More recently, a new cytotoxic drug, lonsurf, was approved by the U.S. FDA, National Institute of Health and Care Excellence (NICE) in England, and the European Medicines Agency (EMA) for refractory mCRC patients. Lonsurf is a combination of trifluridine (thymidine‐based nucleoside analogue) and tipiracil (a potent thymidine phosphorylase inhibitor) that suppresses cancer cell proliferation by interfering with DNA synthesis . Based on the RECOURSE group’s phase III randomized trial, which included nearly 800 participants from three different geographical areas, lonsurf results in a 1.8‐month improvement in median OS compared with the placebo group .…”

Trifluridine/Tipiracil: An Emerging Strategy for the Management of Gastrointestinal Cancers

“…Trifluridine, an analog of thymidine, is the active cytotoxic component of trifluridine/tipiracil, with antitumor activity based primarily on its incorporation into DNA [12] as evidenced by the positive correlation between activity and the amount of trifluridine incorporated into DNA [17]. Following entry into cancerous cells via nucleoside transporters, trifluridine is phosphorylated by thymidine kinase to form trifluridine triphosphate, which is readily incorporated into DNA in place of thymidine bases [18].…”

“…of action of 5-FU is primarily via the inhibition of thymidylate synthase (TS) by one of its metabolites, fluorodeoxyuridine monophosphate with N 5 , N 10 -methylenetetrahydrofolate, which impedes DNA synthesis [12]. Antitumor activity is also achieved through the misincorporation of 5-FU metabolites (fluoronucleotides) into DNA and RNA [13].…”