Results from the phase 3 RECOURSE trial indicate that the novel combination agent TAS-102 extends overall survival compared with placebo in patients with metastatic colorectal cancer (CRC) who are unresponsive to standard therapies. The trial was presented in June at the European Society for Medical Oncology (ESMO) 16th World Congress held in Barcelona, Spain.1

“Around 50% of patients with colorectal cancer develop metastases but eventually many of them do not respond to standard therapies,” said lead author Takayuki Yoshino, MD, of the National Cancer Centre Hospital East in Chiba, Japan. “I believe that this agent will become one of the standards of care in the refractory setting of metastatic colorectal cancer in Japan and worldwide.”

TAS-102 is a combination of the antimetabolite trifluridine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride (TPI). FTD is incorporated into DNA, causing DNA damage; however, when given orally, it is largely degraded by thymidine phosphorylase to an inactive form during its first pass through the liver. TPI prevents degradation of FTD and also has an antiangiogenic effect.

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The multicenter RECOURSE trial recruited 800 patients with metastatic CRC who had been treated previously with at least two standard therapies including fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, or, for patients with KRAS wild-type tumors, cetuximab or panitumumab. All patients either were unable to tolerate standard therapy or had experienced radiologic progression within 3 months of the last course of therapy.

Patients were randomly assigned 2:1 to receive TAS-102 (534 patients) or placebo (266 patients). TAS-102 was given in a dose of 35 mg/m2 two times a day on days 1 to 5 and days 8 to 12 of a 28-day cycle and continued until disease progression, death, or unacceptable toxicity. The primary endpoint was overall survival.

“We found a statistically significant difference in overall and progression-free survival, and a clinically meaningful improvement,” Dr. Yoshino said. Median overall survival was 7.1 months in patients treated with TAS-102 and 5.3 months in patients treated with placebo (hazard ratio 0.68; 95% CI, 0.58-0.81, 1-sided P<0.0001). Median progression-free survival was 2.0 months in the TAS-102 group in 1.7 months in the placebo group.

In the group treated with TAS-102, grade 3 or higher neutropenia, leukopenia, and anemia occurred in 34.9%, 12.8%, and 16.5% of patients, respectively. Febrile neutropenia was observed in 3.8% of patients treated with TAS-102.

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Commenting on the data, ESMO spokesperson Jean-Yves Douillard, MD, PhD, said, “The phase 3 trial of TAS-102 is a global study and confirms the results of the phase 2 study in Japanese patients, whose response to fluoropyrimidine is slightly different to patients in Europe and the United States. It is good to know that the magnitude of benefit shown in the smaller phase 2 trial is confirmed in the larger phase 3 trial and that the results apply to Asians and Caucasians alike.”

Dr. Douillard concluded, “The drug is very promising, tolerance is good and it is manageable with supportive care. I would probably move this drug into an earlier line of treatment and I would also combine it with either irinotecan or oxaliplatin.”


  1. Yoshino T, Mayer R, Falcone A, et al. Results of a multicenter, randomized, double-blind, phase III study of TAS-102 vs. placebo, with best supportive care (BSC), in patients (pts) with metastatic colorectal cancer (MCRC) refractory to standard therapies (RECOURSE). Ann Oncol. 2014;25(suppl 2):ii114.