<p>Clinical Evaluation of the Safety and Efficacy of Trifluridine/Tipiracil in the Treatment of Advanced Gastric/Gastroesophageal Junction Adenocarcinoma: Evidence to Date</p>

Abstract

Trifluridine/tipiracil or TAS-102 (Taiho Oncology, Lonsurf ® , Princeton, NJ, USA) is a combination tablet of trifluridine, a thymidine-based nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor, in a 1:0.5 molar ratio. This drug was first approved for use in metastatic colorectal cancer patients. Recently, the U S Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted approval of trifluridine/tipiracil for treatment of metastatic gastric and gastroesophageal junction adenocarcinoma in patients following at least two lines of chemotherapy including fluoropyrimidine and platinum chemotherapy agents, as well as taxanes or irinotecan. This approval was granted after the findings from first a Phase II trial (EPOC1201) investigating trifluridine/tipiracil, and later a global Phase III trial (TAGS trial) that compared trifluridine/tipiracil vs placebo with best supportive care. Both trials primarily utilized trifluridine/tipiracil at a dose of 35 mg/m 2 twice daily. In the EPOC1201 trial, the primary end point of disease control rate was greater than 50% after eight weeks of therapy. The most common grade three or four adverse event was neutropenia; additional toxicities included leukopenia, anemia, and anorexia. In the TAGS trial, overall survival in patients treated with trifluridine/tipiracil (5.7 months) was significantly improved as compared to the placebo-controlled group (3.6 months). Treatment with trifluridine/tipiracil not only did not impair quality of life but also tended to reduce the risk of deterioration of quality of life. The results of these studies along with the subsequent FDA and EMA approval have generated an important breakthrough in regard to treatment options for patients with refractory metastatic gastric or gastroesophageal junction adenocarcinoma.

Biomarkers of Trifluridine-Tipiracil Efficacy

“…DNA incorporation appears to be the main cytotoxic mechanism in the currently used clinical formulation of oral intermittent dosing [15]. In contrast, a better inhibition of thymidylate synthase is obtained with continuous In addition, trifluridine/tipiracil has been approved for the treatment of another difficult-to-treat gastrointestinal cancer, gastric and gastroesophageal junction adenocarcinoma, in patients that had previously received two or more standard of care lines of treatment [10]. The approval in this case was based on the multinational TAGS trial (NCT02500043) that showed prolongation in OS, PFS and the time to deterioration of ECOG performance status with trifluridine/tipiracil compared to placebo [11].…”

“…After oral administration, trifluridine is catabolized on first pass in the liver by the enzyme thymidine phosphorylase (TP) to the inactive metabolite trifluorothymidine, which is then excreted by the kidneys [ 15 ]. Tipiracil is an inhibitor of TP that prevents first-pass catabolism of trifluridine, increasing its concentration and allowing for oral administration [ 10 ]. After reaching cancer cells, trifluridine is transported intracellularly by hENT1 to exert its antitumor effects [ 20 ].…”

“…A metaanalysis of published series of metastatic colorectal cancer patients treated with trifluridine/tipiracil showed a pooled median OS of 6.6 months (95% confidence interval: 6.1-7.1 months) and a pooled median PFS of 2.2 months (95% confidence interval: 2.1-2.3 months) [9]. In addition, trifluridine/tipiracil has been approved for the treatment of another difficult-to-treat gastrointestinal cancer, gastric and gastroesophageal junction adenocarcinoma, in patients that had previously received two or more standard of care lines of treatment [10]. The approval in this case was based on the multinational TAGS trial (NCT02500043) that showed prolongation in OS, PFS and the time to deterioration of ECOG performance status with trifluridine/tipiracil compared to placebo [11].…”