Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer

Abstract

Trifluridine/tipiracil (Lonsurf®) is a fixed-dose combination tablet comprising trifluridine, an antineoplastic nucleoside analogue, and tipiracil, a thymidine phosphorylase inhibitor. Trifluridine/tipiracil has recently been granted an additional indication in the USA for the treatment of metastatic gastric cancer, including gastroesophageal junction adenocarcinoma, in patients who have been previously treated with at least two systemic treatment regimens, and has received a positive opinion for this indication in the EU. In the large pivotal phase III TAGS trial, trifluridine/tipiracil plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) compared with placebo plus BSC in this patient group. Progression-free survival (PFS) and the disease control rate were also improved with trifluridine/tipiracil relative to placebo. Health-related quality of life was not adversely affected by the addition of trifluridine/tipiracil to BSC and time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status was significantly delayed. The most common adverse events were mainly haematological (neutropenia, leucopenia and anaemia) and gastrointestinal (nausea, vomiting and diarrhoea), and were generally manageable with dosage modifications and/or supportive care. Adverse events ≥ Grade 3 were most frequently haematological in nature. Thus, trifluridine/tipiracil provides a valuable and much needed treatment option for patients with metastatic gastric or gastroesophageal junction adenocarcinoma that has progressed on at least two prior therapies.

Equilibrative Nucleoside Transporter 2: Properties and Physiological Roles

“…Some of the frequently used drugs in antiviral therapy and translocated by ENT2 (and another NTs) are zidovudine, zalcitabine, didanosine, and rivabirine [45]. The nucleoside derivatives commonly used in cancer treatment such as cytarabine [55], gemcitabine [55], fludarabine [50], cladribine [5], clofarabine [5], trifluridine [56], 5fluorouracil [57], and 50-deoxy-5-fluorouridine (5 ′ dFUR) [58] are translocated by a variety of NTs including ENT2 [4,37]. For example, gemcitabine has activity in various solid tumors and some hematological malignant diseases [54].…”

The effect of trifluridine/tipiracil for patients with heavily pretreated metastatic gastric cancer

“…[ 19 ] However, resistance to chemotherapeutic agents often leads to treatment failure, [ 20 ] once resistance appears, treatment programs will become limited. [ 21 ] Therefore, more optimized chemotherapy agents and therapy methods will be required.…”

“…Clinical studies have shown that trifluridine/tipiracil has a positive efficacy on patients with advanced GC and its toxicity is acceptable, [ 10 ] moreover, trifluridine/tipiracil monotherapy was beneficial to the median PFS and OS values of patients with advanced GC, [ 10 , 19 , 21 ] and it has well tolerance. [ 18 ] Trifluridine has 2 antitumor mechanisms.…”

“…It not only inhibits thymidylate synthase, which is similar to fluorouracil, but also produce double-stranded DNA breaks by incorporating the triphosphate form into DNA. [ 21 ] Tipiracil can improve the pharmacokinetics of trifluridine when used in combination with trifluridine, thereby increasing the drug concentration and antitumor activity. [ 22 ] Although trifluridine is classified as fluoropyrimidine, its main mechanism of action is different from that of traditional fluoropyrimidines such as 5-FU, allowing for make trifluridine overcome 5-FU resistance.…”

Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics

“…Inhibits de novo purine synthesis Produces genotoxic thioguanine nucleotides that inhibit DNA and RNA synthesis and alter their subsequent metabolism [7,9] Thymidine phophorylase inhibitor Tipiracil Hydrochloride (TAS-102) Induces cell cycle arrest at G2 phase and DNA double-strand breaks with enhanced drug potency. [135,136] Antifolate Methotrexate, Pemetrexed…”