The Role of Trifluridine/Tipiracil in Advanced CRC

Marwan G. Fakih, MD:TAS-102 is approved for the management of patients with metastatic colorectal cancer who have progressed on all standard chemotherapy. This is based on a randomized clinical trial that enrolled patients with metastatic colorectal cancer who progressed on fluoropyrimidines, progressed following oxaliplatin, and progressed following irinotecan. Those patients should have also received prior anti-EGFR therapy if they have a RAS wild-type tumor, specifically KRAS wild-type, at the time of the conduct of that clinical trial. On the RECOURSE clinical trial, there was an improvement in overall survival in patients who have received TAS-102 versus placebo.

Particularly, on the RECOURSE clinical trial, there has been an improvement in progression-free survival, as well as overall survival. The study shows an improvement by about 52% in prolongation in progression-free survival, and showed an improvement in 32% in prolongation and overall survival. In addition, this clinical trial has shown a significant improvement in the deterioration time in the ECOG performance status of patients. In other words, patients who have received TAS-102 were less likely to have a deterioration in performance status with time compared to those who have received placebo.

TAS-102 is a combination of two compounds: trifluridine, which is the active compound and tipiracil. Tipiracil is actually a thymidine phosphorylase inhibitor, and it works by inhibiting the degradation of trifluridine. That is very important because trifluridine has a short half-life. And, without tipiracil, we are not able to administer, effectively, trifluridine orally to patients.

TAS-102 is a nucleoside analog and it’s a thymidine nucleoside analog. The compound is phosphorylated. And, the phosphorylated compound, trifluridine, is incorporated into the DNA. The incorporation of trifluridine into the DNA results in cancer cell death. This compound is somewhat different than 5-FU or capecitabine. While 5-FU works predominantly through the inhibition of thymidylate synthase, trifluridine works predominantly through the incorporation into the DNA. Matter of fact, preclinical studies have shown that cancer cell lines that are resistant to 5-FU can actually be sensitive to trifluridine. This supports that the mechanism of activity is different.

How do we dose TAS-102 in patients with metastatic colorectal cancer? TAS-102 is an oral agent. It is administered twice daily, 5 days on, 2 days off on the first week and on the second week of treatment, followed by a 14-day break. In other words, it’s a 4-week cycle with an administration of 5 days continuously on the first and second week. Trifluridine is dosed at 35 mg/m2 per dose twice daily, day 1 through day 5 on week 1 and week 2, every 4 weeks.

Case Scenario 1:

• This is a 70-year old woman who 3 years ago presented with bloody stool.
• Medical history included type 2 diabetes; no other comorbidities.
• A colonoscopy revealed a 1.5 cm tumor in the sigmoid colon.
• A CT scan revealed multiple hepatic and pulmonary lesions.
• Biopsy of liver lesion and colon mass showed moderately differentiated adenocarcinoma, KRAS, NRAS, BRAF wild-type and MSS.
• Her ECOG performance status at the time was 0.
• FOLFIRI plus cetuximab was initiated.
• She later developed progressive disease.
• She was given FOLFOX plus bevacizumab.
• Her ECOG performance status is now 1.