Standard-Dose Trifluridine/Tipiracil as Safe Treatment Alternative in Metastatic Colorectal Cancer Patients With DPD Deficiency

Clinical Practice Points

• Severe toxicity of the fluoropyrimidine drugs 5-fluorouracil (5-FU) and its oral prodrug capecitabine is associated with deficiency of the primary inactivating enzyme dihydropyrimidine dehydrogenase (DPD).

• Pretreatment screening for DPD deficiency is applied followed by initial dose reduction in DPD-deficient patients in order to prevent severe toxicity Nonetheless, severe toxicity may still occur and therefore, new treatment options are highly warranted.

• Trifluridine/tipiracil is a new anticancer drug that is registered for the treatment of metastatic colorectal cancer in patients who have been previously treated with, or have contraindications for 5-FU-based chemotherapy. Importantly, its metabolism is completely independent of DPD.

• Thereby, trifluridine/tipiracil may offer a new treatment paradigm for the safe treatment of DPD-deficient metastatic colorectal cancer patients.

Introduction

The fluoropyrimidine drugs 5-fluorouracil (5-FU) and its oral prodrug capecitabine are the cornerstone treatment of most gastrointestinal cancers since decades. Still an estimated 15% to 30% of patients develop severe toxicity, which is lethal in up to one percent of the treated population.¹ The main cause of toxicity of 5-FU-based chemotherapy is deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD). This enzyme inactivates up to 85% to 90% of the administered amount of 5-FU. Pretreatment screening for DPD deficiency in order to prevent 5-FU-induced severe and potentially lethal toxicity is increasingly applied and has recently become formally recommended by the European Medicines Agency.² DPD deficiency can be identified by either genotyping for the known risk alleles DPYD*2A, DPYD c.1679T>G, c.1236G>A/HapB3 and c.2846A>T, or otherwise by phenotyping through measurement of DPD enzyme activity in peripheral blood mononuclear cells.¹ In addition, concentration measurement of its endogenous substrate uracil with or without its DPD-mediated metabolite dihydrouracil is also increasingly described in studies.¹ In clinical practice, mostly pre-therapeutic genotype testing is performed, because clear guidelines exist with regard to genotype-guided dosing of fluoropyrimidines. In contrast, phenotype testing is generally more costly and more time-consuming, and evidence of safe and effective dosing of 5-FU in patients with a phenotypically determined DPD deficiency is lacking, and is thereby less frequently applied when compared to genotyping.^1,3,4 Another complication of treatment of DPD-deficient patients is that, even after initial 5-FU dose adjustment, patients may still develop severe toxicity requiring further dose reduction. In addition, patients may be reluctant to restart 5-FU-based therapy after severe toxicity. Therefore, alternative treatment options could be useful for the treating oncologist.

Trifluridine/tipiracil (Lonsurf; TAS-102) is a new, orally administered anticancer drug that is approved for the treatment of patients with metastatic colorectal cancer who have been previously treated with, or have contraindications for 5-FU-based chemotherapy.⁵ Trifluridine is a thymidine-based nucleoside analogue that is incorporated into DNA via phosphorylation, thereby inhibiting cell proliferation. However, it has a very short half-life in human of only several minutes, and therefore, it is given as combination drug with tipiracil, which is a strong thymidine phosphorylase inhibitor. The combined administration prevents early breakdown of trifluridine, thereby strongly increasing systemic exposure of trifluridine.⁶ Similarly to 5-FU, trifluridine belongs to the group of antimetabolite anticancer drugs. Interestingly, in contrast to 5-FU, trifluridine has a complete different pharmacokinetic pathway that is fully independent of DPD (Figure 1). Thereby, trifluridine/tipiracil may offer a new treatment paradigm for the safe treatment of DPD-deficient patients, without the additional risk for severe toxicity due to DPD deficiency. In addition, this eliminates the search for the right dose as from a pharmacological point of view, trifluridine/tipiracil does not require a priori dose reductions in DPD-deficient patients. The potential use of standard-dose trifluridine/tipiracil as new treatment option in DPD-deficient patients has recently also been proposed by others, however, the safety of trifluridine/tipiracil in this patient group remains thus far uninvestigated, or at least undescribed.^7,8 Therefore, the aim of this study was to investigate the safety of trifluridine/tipiracil in metastatic colorectal cancer patients with DPD deficiency.