{"id":124592,"date":"2024-11-05T11:37:56","date_gmt":"2024-11-05T11:37:56","guid":{"rendered":"https:\/\/touchoncology.com\/?p=124592"},"modified":"2024-11-12T16:11:21","modified_gmt":"2024-11-12T16:11:21","slug":"trifluridine-tipiracil-and-bevacizumab-in-adults-with-refractory-metastatic-colorectal-cancer","status":"publish","type":"post","link":"https:\/\/touchoncology.com\/colorectal-cancer\/journal-articles\/trifluridine-tipiracil-and-bevacizumab-in-adults-with-refractory-metastatic-colorectal-cancer\/","title":{"rendered":"Trifluridine\/Tipiracil and Bevacizumab in Adults with Refractory Metastatic Colorectal Cancer"},"content":{"rendered":"
Trifluridine\/tipiracil (FTD\/TPI) is a novel oral formulation of two drugs with promising results in the treatment of metastatic colorectal cancer (mCRC).1<\/sup><\/span>\u00a0Trifluridine is a thymidine-based nucleoside analogue that, after intracellular phosphorylation, gets incorporated into DNA, causing DNA dysfunction.2<\/sup><\/span>\u00a0It was first identified by Callahan et al. in 1996 as an active impurity in the herbicide trifluralin, which has anti-parasitic properties.3<\/sup><\/span>\u00a0On the other hand, tipiracil, a thymidine phosphorylase inhibitor, was developed by K. Richardson in 1990 as part of a research programme aimed at creating a broad-spectrum anti-fungal agent.4<\/sup><\/span><\/p>\n The rationale for combining trifluridine and tipiracil lies in their synergistic pharmacological effect: tipiracil enhances the bioavailability of trifluridine by inhibiting its breakdown.5<\/sup><\/span>\u00a0Studies have shown that combining trifluridine\/tipiracil with an anti-angiogenic agent that targets\u00a0vascular endothelial growth factor<\/span>\u00a0(VEGF) (bevacizumab [BEV]) can lead to augmented intracellular concentrations of active trifluridine, as demonstrated in preclinical studies.6<\/sup><\/span>\u00a0This combination has been extensively studied, with clinical trials reporting promising results regarding the efficacy and safety in patients with refractory mCRC.7<\/sup><\/span><\/p>\n F<\/sup><\/sup>TD\/TPI was developed by Taiho Pharmaceutical (Tokyo, Japan<\/span>) and was first approved as a novel oral nucleoside anti-tumour combination agent in Japan in March 2014.8<\/sup><\/span>\u00a0It has shown significant survival benefits in patients with refractory mCRC in a randomized phase III trial involving both Asian and non-Asian patients.1<\/sup><\/span>\u00a0In September 2015, it was approved by the US Food and Drug Administration following a phase III clinical trial indicating an overall survival (OS) benefit in patients with refractory mCRC.9<\/sup><\/span>\u00a0The addition of BEV, an established anti-cancer agent that inhibits angiogenesis, was first studied in the\u00a0<\/em>C-TASK FORCE trial (ClinicalTrials.gov identifier<\/span>: NCT02743221) in Japan, followed by another study in Denmark in 2017\/2018.10,11<\/sup><\/span> These studies demonstrated that the combination therapy with BEV was associated with significantly longer median progression-free survival (PFS) and OS compared with FTD\/TPI monotherapy.12<\/sup><\/span>\u00a0More recently, the multinational phase III SUNLIGHT<\/sup>\u00a0(ClinicalTrials.gov identifier<\/span>: NCT04737187), TAS-CC3 (UMIN000022438) and BiTS (ClinicalTrials.gov identifier<\/span>: NCT03447490) studies demonstrated that the combination of FTD\/TPI and BEV has clinically meaningful activity in previously pre-treated patients with mCRC, establishing it as a potential new treatment option.12\u201318<\/sup><\/span>\u00a0These studies also highlighted that ongoing clinical trials are investigating this combination in earlier treatment lines for patients with mCRC.<\/p>\n In this review, we will summarize this treatment trajectory and discuss potential approaches to be explored in the future.<\/p>\n In vitro<\/em>\u00a0experiments with TAS-102 (FTD\/TPI), a synergistic combination of trifluorothymidine and the thymidine phosphorylase inhibitor TPI, have shown promising results in preclinical studies, particularly in overcoming resistance to standard chemotherapies such as 5-fluorouracil (5-FU). Initially, the compound was recognized for its dual mechanism of action: the inhibition of thymidylate synthase (TS) and the incorporation of FTD into DNA. The latter mechanism, in particular, was found to be significantly more effective in TAS-102 compared with other anti-tumour nucleosides, correlating positively with its anti-tumour activity in xenograft models.19<\/sup><\/span>\u00a0While the drug\u2019s pharmacokinetics in\u00a0in<\/em>\u00a0<\/em>vitro<\/em> settings remain a subject for further exploration, its non-cross-resistance with 5-FU and possible anti-angiogenic effects through thymidine phosphorylase inhibition make it a compelling candidate for both research and future clinical investigations. However, the dual synergistic action of both components improves cytotoxicity by activating different pathways, leading to cell death.<\/p>\n Subsequent studies expanded on these findings, demonstrating TAS-102\u2019s efficacy against a range of 5-FU-resistant cancer types, including colorectal, pancreatic and oesophageal cancers. These studies highlighted the compound\u2019s ability to induce marked DNA fragmentation in tumour cells, a key indicator of its cytotoxic effects, as illustrated in\u00a0Figure 1<\/em><\/span>.20<\/sup><\/span>\u00a0This cytotoxicity was attributed to the high dosage and short exposure times of TAS-102, which were effective in both\u00a0in vitro<\/em>\u00a0and xenograft models. TAS-102\u2019s unique mechanism and metabolism position it as a promising treatment alternative for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.21,22<\/sup><\/span>\u00a0This has the potential to reduce the toxicity of each component, ensuring safety in the use of both entities in improving cytotoxicity while minimizing potential toxicity in each of the entities used alone.<\/p>\nPreclinical studies<\/h1>\n