Trifluridine–Tipiracil Improves Metastatic Gastric Cancer OS

A cytotoxic agent that combines trifluridine and tipiracil could be an option for the third- or later-line treatment of patients with advanced gastric or gastro-oesophageal junction adenocarcinoma

medwireNews: Heavily pretreated patients with metastatic adenocarcinoma of the stomach or gastro-oesophageal junction derive a significant overall survival (OS) benefit from treatment with trifluridine–tipiracil, phase III trial findings indicate. 

Compared with placebo, the risk of death was reduced by a significant 31% among participants who received the cytotoxic chemotherapy comprising the thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil. 

The median OS times were 5.7 and 3.6 months for the trifluridine–tipiracil and placebo groups, respectively, while the 12-month OS rates were 21% and 13%, according to the data presented at the ESMO 2018 Congress, in Munich, Germany, and simultaneously published in The Lancet Oncology. 

The authors of an accompanying commentary note that “no therapies were available for this group of patients” when the TAGS trial was initiated, but since then “the introduction of immunotherapies has provided new treatment options.” 

Although Henrik Nienhüser and Thomas Schmidt, both from the University of Heidelberg in Germany, concede that trifluridine–tipiracil “represents a new treatment option”, they do not believe that it is superior to immunotherapies. 

“Head-to-head studies will be needed to establish the best treatment regimen for heavily pretreated patients with gastric cancer”, they write. 

The double-blind trial included 507 patients who had received at least two prior lines of therapy for metastatic disease; they were randomly assigned to receive either trifluridine–tipiracil 35 mg/m2 twice daily or placebo alongside best supportive care. 

The secondary endpoint of progression-free survival (PFS) was also significantly improved with trifluridine–tipiracil relative to placebo, at a median of 2.0 versus 1.8 months and 6-month rates of 15% versus 6%, report the researchers. They point out, however, that “[t]he median estimates were confounded by the timing of the first on-treatment tumour assessment, which took place approximately 8 weeks (1.9 months) after treatment initiation.” 

And the commentators note that while the between-group difference “might be statistically significant, it is of little clinical relevance”, and the benefit with regard to PFS remains unclear. 

The objective response rate was comparable between patients given trifluridine–tipiracil and those given placebo (4 vs 2%), but the disease control rate was significantly higher in the trifluridine–tipiracil group (44 vs 14%). 

Treatment-related adverse events of grade 3 or worse occurred in 53% and 13% of the trifluridine–tipiracil and placebo groups, respectively, and adverse events of any grade led to discontinuation in a respective 13% and 17%. There was one treatment-related death in each study arm, due to cardiopulmonary arrest in the trifluridine–tipiracil group and toxic hepatitis in the placebo group. 

Kohei Shitara, from the National Cancer Center Hospital East in Kashiwa, Japan, and co-investigators write that “[a]dverse events were generally manageable through dosing modifications, which did not seem to affect the overall ability of the patients to receive treatment (as shown by the modest proportion of patients who discontinued treatment because of adverse events).” 

And they conclude: “In view of trifluridine/tipiracil’s efficacy and tolerability, future research exploring the treatment in novel combination regimens could be warranted.” 



Arkenau H-T, Tabernero J, Shitara K, et al. TAGS: a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer . ESMO 2018 Congress, 19-23 October, Munich, Germany (LBA25_PR).  

Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet Oncol; Advance online publication 21 October 2018.

Nienhüser H, Schmidt T. 9 weeks that matter for patients with gastric cancer . Lancet Oncol; Advance online publication 21 October 2018.