TAS-102 Significantly Improves Overall Survival in Patients With Metastatic Colorectal Cancer
A large, phase III international study of the oral agent TAS-102 in patients with heavily pretreated metastatic colorectal cancer has found that the therapy improved overall survival by 1.8 months and also delayed disease progression. TAS-102 had few side effects and was also effective in patients whose disease was refractory to fluorouracil (5-FU). The study by Mayer et al is published in the The New England Journal of Medicine.
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.
Study Methodology
Researchers in the United States, Europe, Australia, and Japan enrolled 800 patients with biopsy-documented adenocarcinoma of the colon or rectum between June 17, 2012, and October 8, 2013. All the patients had received at least two prior regimens of standard chemotherapies and were required to have received chemotherapy with each of the following agents: a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab (Avastin), and, for patients with KRAS wild-type tumors, cetuximab (Erbitux) or panitumumab (Vectibix). Of the 800 randomized patients, 534 received TAS-102 and 266 received a placebo.
The primary endpoint of the study was overall survival; secondary endpoints included progression-free survival, response rate, rate of disease control, and safety.
Study Findings
The researchers found that median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio (HR) for death in the TAS-102 group vs the placebo group was 0.68 (95% confidence interval [CI] = 0.58–0.81; P < .001). 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.
The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status from 0 or 1 to ≥ 2) was 5.7 months with TAS-102 vs 4.0 months with placebo (HR = 0.66; 95% CI = 0.56–0.78; P < .001).
“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 [5-FU]. Such benefit was observed across essentially all prespecified patient subgroups and was validated by means of a multivariate analysis. TAS-102 was associated with few serious adverse events, with neutropenia being the most frequently observed adverse event,” concluded the study authors.
“Colorectal cancer is the second most common cause of cancer deaths in the United States and is an enormous health problem around the world,” said Robert J. Mayer, MD, Faculty Vice President for Academic Affairs, Medical Oncology at Dana-Farber Cancer Institute and first author of the study, said in a statement. “To have a well-tolerated, effective new drug in a cancer that is so prevalent is good news for patients.”
According to Dr. Mayer, TAS-102 will now be tested in combination with other drugs traditionally used in conjunction with 5-FU.
Dr. Mayer is the corresponding author for the New England Journal of Medicine article.
Funding for this study was provided by Taiho Oncology–Taiho Pharmaceutical. For full disclosures of the study authors, visit www.nejm.org.
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