Biomarkers of Trifluridine-Tipiracil Efficacy

Abstract

Trifluridine/tipiracil (TAS-102) is a newer generation chemotherapy that has been approved for the later-line treatment of metastatic colorectal and gastric/gastroesophageal adenocarcinomas. The oral drug provides a modest benefit of prolongation of survival over placebo in pretreated patients with these cancers with acceptable toxicity. Studies have shown rare objective responses (2-4%), and the disease control rates were 44% in both colorectal and gastric cancer randomized trials. Thus, the majority of patients progress through treatment and are burdened by toxicities. To better characterize the sub-group of patients with a higher probability of benefit from trifluridine/tipiracil, predictive biomarkers have been sought using data from randomized trials as well as from non-randomized trials and real-world series. Biomarkers examined include clinical characteristics of the patients, laboratory tests, and tumor derived biomarkers. These studies show that early neutropenia on treatment, and ratios of leukocyte subsets, are potential biomarkers able to predict trifluridine/tipiracil benefit. Combinations of laboratory values and clinical characteristics and proteins involved in trifluridine transport and activation have been examined with initial positive results.

Keywords: TAS-102; biomarkers; colorectal; gastrointestinal cancers; predictive.

Figure 1

Chemical structures of the components of TAS 102: trifluridine on the left and tipiracil on the right.

Figure 2

Pathways of trifluridine metabolism and action. DP: biphosphate, MP: monophosphate, TK1: thymidine kinase 1, TP: thymidine phosphorylase, TS: thymidine synthetase.