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N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325.

Randomized trial of TAS-102 for refractory metastatic colorectal cancer.

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From the Dana-Farber Cancer Institute, Boston (R.J.M, J.M.C.); University Hospitals, Leuven and KU Leuven, Leuven (E.V.C., H.P.), and Universitaire Ziekenhuizen Antwerp, Edegem (M.P.) - all in Belgium; University of Pisa, Pisa (A.F.), IRCCS Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca Sul Cancro, Genoa (A.S.), and the Fondazione Poliambulanza Istituto Ospedaliero, Brescia (A.Z.) - all in Italy; National Cancer Center Hospital East, Chiba (T.Y., A.O.), Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo (N.M.), Shizuoka Cancer Center, Shizuoka (K.Y.), National Cancer Center Hospital, Tokyo (Y.S.), Hokkaido University Hospital, Hokkaido (Y.K.), and Taiho Pharmaceutical, Tokyo (M.I.) - all in Japan; Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, Seville (R.G.-C.), and Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (J.T.) - all in Spain; Centre Eugène Marquis, Rennes, France (E.B.); Royal Melbourne Hospital, Melbourne, VIC, Australia (B.T.); University of Southern California Norris Comprehensive Cancer Center, Los Angeles (H.-J.L.); Yale Cancer Center, New Haven, CT (H.H.); Taiho Oncology, Princeton, NJ (F.B., H.M.); and Stathmi, New Hope, PA (L.M.).



Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients.


In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival.


The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). 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 [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001).


In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE number, NCT01607957.).

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