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TAS-102 Improves Overall Survival in Patients with Metastatic Colorectal Cancer


Patients in an international randomized phase III trial who received the drug TAS-102 to treat metastatic colorectal cancer that had progressed following standard therapies lived longer than patients who received a placebo.


New England Journal of Medicine, May 14, 2015. (See the journal abstract.)


TAS-102 (tipiracil hydrochloride) is an oral drug that combines two agents, trifluridine and tipiracil hydrochloride. Trifluridine incorporates into DNA, and this process may result in the drug’s antitumor effects. Tipiracil hydrochloride helps to maintain blood concentrations of trifluridine by inhibiting an enzyme that degrades trifluridine.

In preclinical studies, TAS-102 showed antitumor activity against cancer cell lines that were resistant to fluorouracil, a standard therapy for colorectal cancer. Fluorouracil belongs to a class of drugs called fluoropyrimidines that has long been used to treat colorectal cancer.

TAS-102 was then evaluated in a randomized phase II clinical trial involving 169 Japanese patients with metastatic colorectal cancer. In that trial, the median overall survival was 9.0 months in the TAS-102 group and 6.6 months in the placebo group.

Based on these results, researchers developed the current study. The goal of the phase III trial was to compare the efficacy and safety of TAS-102 versus placebo in patients with metastatic colorectal cancer that had progressed following standard therapies.  

The Study

The study enrolled 800 patients with metastatic colorectal cancer from Japan, the United States, Europe, and Australia. The patients were randomly assigned in a 2:1 ratio to receive TAS-102 or placebo.

Most of the patients in the study had disease that no longer responded to fluoropyrimidines. To be eligible for the study, the patients had to undergo tumor testing to determine whether their cancers harbored a mutant KRAS gene. Patients were also required to have received chemotherapy with each of the following agents: a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with non-mutant KRAS tumors—cetuximab or panitumumab.

The primary endpoint was overall survival. Secondary end points included progression-free survival, response rate (the proportion of patients whose best response was a complete or partial response), and safety.

Robert J. Mayer, M.D., of the Dana-Farber Cancer Institute led the study, which was sponsored by the maker of TAS-102, Taiho Pharma U.S.A., Inc.


The median overall survival was 7.1 months in the TAS-102 group and 5.3 months in the placebo group, a statistically significant difference. The 1-year overall survival rates were 27 percent and 18 percent, respectively. Additional analyses showed that the survival benefit of TAS-102 was seen in essentially all prespecified subgroups, including subgroups defined according to factors such as KRAS status, time between the first diagnosis of metastases and randomization, and geographic region.

The median progression-free survival was 2.0 months in the TAS-102 group and 1.7 months in the placebo group. When the researchers assessed disease control (complete response, partial response, or stable disease) at least 6 weeks after the patients were randomly assigned to treatment groups, 221 patients (44 percent) in the TAS-102 group and 42 patients (16 percent) in the placebo group had achieved disease control.

In addition, the time to worsening of performance status (a measure of how well a patient is able to perform ordinary tasks and carry out daily activities) was significantly longer in the TAS-102 group than in the placebo group (5.7 versus 4.0 months).

Patients in the TAS-102 group experienced few serious adverse events. Overall, adverse events of grade 3 or higher occurred more frequently in the TAS-102 group than in the placebo group (69 percent versus 52 percent). The most common adverse events associated with TAS-102 included neutropenia, which occurred in 38 percent of those treated, and leukopenia, which occurred in 21percent. Four percent of the patients in the TAS-102 group developed febrile neutropenia, and there was one death related to TAS-102.


“In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival," the study authors concluded.

The effect of the drug, they continued, “is particularly meaningful given that more than 90 percent of the study patients had disease that had been refractory to treatment with fluoropyrimidines when they were last exposed to such drugs and that more than 50 percent had disease that was refractory to treatment in which a fluoropyrimidine was a component of their most recent treatment regimen.” 

The clinical results are consistent with preclinical studies indicating that the mechanism of action of TAS-102 differs from that of fluoropyrimidines, the authors observed.

“This is a unique drug that is active in patients with a hard-to-treat form of colorectal cancer," said Jo Anne Zujewski, M.D., of NCI’s Cancer Therapy Evaluation Program, who was not involved in the study. “The improvement in overall survival combined with the acceptable toxicity profile of this drug is impressive."

The Food and Drug Administration (FDA) has accepted a new drug application (NDA) for TAS-102 as a treatment for patients with refractory metastatic colorectal cancer and is expected to make a final approval decision on TAS-102 by December 19, 2015.

“If it is approved, this drug should make a difference for patients with colorectal cancer that has recurred after standard therapy," Dr. Zujewski continued. The maker of TAS-102 has an expanded access program so that patients may be able to obtain this drug during its review by the FDA, she noted.

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