TAS-102 ‘Superior’ To Placebo For Metastatic Colorectal Cancer

Metastatic colorectal cancer survival and disease control is significantly improved by use of TAS-102 compared with placebo

medwireNews: Oral TAS-102 is superior to placebo in patients with metastatic colorectal cancer (CRC) for overall survival (OS), disease control and delay of performance status worsening, suggest phase III trial results published in The New England Journal of Medicine.

The agent is a combination of the thymidine-based nucleic acid analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, which prevents rapid degradation of the active agent, explain Robert Mayer, from the Dana–Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors.

“This superiority is particularly meaningful given that more than 90% 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% had disease that was refractory to treatment in which a fluoropyrimidine was a component of their most recent treatment regimen”, the researchers emphasise.

They add that the results give “clinical support” for previously reported preclinical findings suggesting that TAS-102 has a different mechanism of action than fluoropyrimidines.

In all, 534 patients were randomly assigned to receive cycles of oral TAS-102, consisting of 35 mg/m2 twice daily, 5 days a week for 2 weeks followed by a 2-week rest period, and 266 patients were given placebo, with treatment lasting an average of 12.7 and 6.8 weeks, respectively. Both groups received best supportive care but no other anti-cancer therapies.

Median OS was 7.1 months for the TAS-102 group versus 5.3 months for the control group, with a significant hazard ratio (HR) for death of 0.68. One-year survival was achieved by 27% and 18% of the groups, respectively.

Moreover, the OS benefit was significant for all prespecified patient subgroups, including those classified by age, gender, time to diagnoses of first metastases, number of metastatic sites, and Eastern Cooperative Oncology Group (ECOG) performance status.

TAS-102 also provided a significant gain in OS for Western patients and those in Japan, patients with and without wild-type KRAS, patients with primary colon and primary rectal tumours, and regardless of whether patients had used the multikinase inhibitor regorafenib.

Progression-free survival was also significantly longer in patients given TAS-102 than controls, at a median of 2.0 versus 1.7 months (HR=0.48), and again this was true for all prespecified subgroups.

The objective response rate was 1.6% for TAS-102 versus 0.4% with placebo, with disease control at 6 weeks achieved by 44% and 16% of patients, respectively.

Finally, TAS-102 plus best supportive care significantly delayed worsening of ECOG performance status from baseline of 0 or 1 compared with placebo plus best supportive care, the researchers report. The median time to an ECOG performance status of 2 or above was 5.7 versus 4.0 months, with a HR of 0.66.

Patients given TAS-102 were more likely to have grade 3 or more severe adverse events than controls (69 vs 52%), with 38% developing neutropenia and 4% febrile neutropenia. Grade 3 or above anaemia (18 vs 3%), thrombocytopenia (5 vs <1%) and gastroenterological side effects were also more common with the active drug.


Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372: 1909–1919. doi: 10.1056/NEJMoa1414325

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