TAS-102, an oral combination of trifluridine and tipiracil hydrochloride, improved median overall survival in patients with refractory colorectal cancer.
TAS-102, an oral agent combination of trifluridine and tipiracil hydrochloride, improved the median overall survival of a global population of patients with refractory colorectal cancer by about 2 months as compared with placebo, according to the results of study published in the New England Journal of Medicine.
“Trifluridine, the active component of TAS-102, was developed approximately 50 years ago, at about the same time that fluorouracil was introduced. Although early clinical trials showed that trifluridine had antitumor activity, the required dosing schedule had a toxicity profile that was not considered feasible for long-term administration, and further drug development was discontinued,” explained study author Robert J. Mayer, MD, of the Dana-Farber Cancer Institute, and colleagues from the RECOURSE Study Group. “The subsequent availability of the thymidine phosphorylase inhibitor, tipiracil hydrochloride, and its later combination with trifluridine to form TAS-102 approximately 15 years ago allowed for a more constant pharmacokinetic level of the drug to be maintained with an acceptable toxicity profile, a development that led to the preclinical and clinical studies that resulted in this trial.”
According to background information published with the study, earlier trials of TAS-102 were conducted mainly among Japanese patients. This phase III analysis was designed to evaluate the safety and efficacy of TAS-102 among a more globally representative group of patients taken from Japan, the United States, Europe, and Australia.
The double-blind study included 800 patients with metastatic colorectal cancer who were randomly assigned 2:1 to TAS-102 (n = 534) or placebo (n = 266). All patients had undergone chemotherapy regimens containing a fluoropyrimidine, oxaliplatin, and irinotecan. About half of patients had KRAS-mutant tumors.
“TAS-102 was shown to have clinical activity in a large population of Japanese and Western patients with heavily pretreated metastatic colorectal cancer, including those whose disease was refractory to fluorouracil,” the researchers wrote. “Such benefit was observed across essentially all prespecified patient subgroups and was validated by means of a multivariate analysis.”
The median overall survival for TAS-102 was 7.1 months compared with 5.3 months for placebo (hazard ratio [HR] = 0.68; 95 % CI, 0.58–0.81; P < .001). One-year overall survival was 27% for TAS-102 compared with 18% for placebo. The improved overall survival seen with TAS-102 was observed in all of the prespecified subgroups including groups defined by KRAS status, time between first diagnosis of metastases and randomization, and geographic region.
Overall, TAS-102 was well tolerated; 38% of patients assigned the study drug had neutropenia, the most commonly reported adverse effect. Other effects included leukopenia (21%) and febrile neutropenia (4%); one treatment-related death was reported.