Refractory Metastatic Colon Cancer

Posted by • May 15th, 2015

TAS-102, a combination of trifluridine and tipiracil in which tipiracil interferes with the deactivation of trifluridine, improved overall and progression-free survival in patients whose disease had progressed after treatment with fluorouracil-containing drug combinations. A new Original Article assesses the efficacy and safety of TAS-102 in a global population of such patients.

Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer.

Clinical Pearls

What is the current treatment for colorectal cancer?

Fluoropyrimidines have long represented the cornerstone of treatment for colorectal cancer. Such compounds act primarily as inhibitors of thymidylate synthase, the rate-limiting enzyme in the synthesis of pyrimidine nucleotides. Fluorouracil has been combined with folinic acid (also known as leucovorin) to enhance the capacity of fluorouracil to bind to thymidylate synthase. The addition of irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) to fluorouracil and folinic acid, in combination with either a vascular endothelial growth factor inhibitor (bevacizumab) or an epidermal growth factor inhibitor (e.g., cetuximab or panitumumab) if the tumor contains a wild-type RAS gene, represents contemporary standard therapy and has extended the median survival among patients with metastatic colorectal cancer to almost 30 months.

What is TAS-102?

TAS-102 is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluridine is the active cytotoxic component of TAS-102. Its triphosphate form is incorporated into DNA, and incorporation appears to result in its antitumor effects. Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase and, when combined with trifluridine to form TAS-102, prevents the rapid degradation of the trifluridine, allowing for the maintenance of adequate plasma levels of the active drug.

Morning Report Questions

Q: Does TAS-102 prolong overall survival and progression-free survival when compared to placebo in this population?

A: The results of this placebo-controlled, double-blind, phase 3 clinical trial conducted in Japan and in the United States, Europe, and Australia confirmed the results of previous assessments of oral TAS-102 in patients with metastatic colorectal cancer who had already undergone extensive treatment: TAS-102 was associated with a clinically relevant prolongation of overall survival in essentially all treatment subgroups. At the time that the target was reached (574 deaths), the median overall survival was 7.1 months (95% confidence interval [CI], 6.5 to 7.8) in the TAS-102 group and 5.3 months (95% CI, 4.6 to 6.0) in the placebo group. The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) in the TAS-102 group and 1.7 months (95% CI, 1.7 to 1.8) in the placebo group. The assessment of tumor status with regard to KRAS showed that 49% of the patients had wild-type tumors and 51% had mutant tumors. Benefit from treatment with TAS-102 was observed in both patient subgroups.

Figure 1. Kaplan-Meier Curves for Overall Survival and Forest Plot of Subgroup Analyses.

Figure 2. Kaplan-Meier Curves for Progression-free Survival and Forest Plot of Subgroup Analyses.

Q: What adverse events are associated with the use of TAS-102?

A: In the trial by Meyer et al., the most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. Grade 3 or 4 stomatitis, hand-foot syndrome, and coronary spasm, which are associated with the use of fluoropyrimidines, were encountered in less than 1% of the patients treated with TAS-102.

Table 2. Frequency of Adverse Events and Laboratory Abnormalities.

One Response to “Refractory Metastatic Colon Cancer”

  1. John Pothan says:

    is this available in New Zealand? I have stage 4 have had 3 types of chem with not much luck. Best results was with Xeloda for 11 months my CEA was 3400 came down to 70. But now up to 3200. Can you help please?