126IN - Colorectal cancer: A new oral cytotoxic agent reappears

Date 01 October 2012
Event ESMO Congress 2012
Session ESMO-JSMO Joint symposium: Recent advances in the treatment of GI tract and liver cancer in the EU and Japan
Topics Anticancer Agents
Colon and Rectal Cancer
Biological Therapy
Presenter Takayuki Yoshino
Authors T. Yoshino
  • Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, JP-277-8577 - Kashiwa/JP


Cytotoxic agents, such as fluoropyrimidine, irinotecan, and oxaliplatin and antibodies such as bevacizumab, and cetuximab and panitumumab have been shown to significantly improve the survival of patients with unresectable metastatic colorectal cancer (mCRC). Although many patients have a good long-term performance status, a standard therapy for patients refractory to or unable to tolerate these agents does not currently exist. TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride (TPI) at a molar ratio of 1 to 0.5. TAS-102 possesses a mechanism of action different from that of other antitumor agents, including fluoropyrimidine, irinotecan and oxaliplatin. Based on a phase I clinical trial in Japan, the recommended dose of TAS-102 (35 mg/m2/b.i.d) twice daily administered orally in days 1-5 and 8-12 of a 28-day cycle was determined. These results indicated that TAS-102 was expected to further improve the outcomes of patients with unresectable mCRC. We conducted randomized, double-blind phase II trial as a placebo-controlled study to evaluate the efficacy of TAS-102. A total of 172 colorectal cancer patients who were refractory or intolerable to 2 or more regimens of standard chemotherapy with a fluoropyrimidine, irinotecan, and oxaliplatin underwent either TAS-102 plus best supportive care (BSC) (114 patients) or placebo plus BSC (58 patients) with the primary endpoint of overall survival. TAS-102 significantly decreased death risk compared to placebo (hazard ratio, 0.56; 95% confidential interval [CI], 0.39-0.81; P = 0.0011). The median overall survival was 9.0 months in the TAS-102 group and 6.6 months in the placebo group. TAS-102 significantly improved progression-free survival (median, 2.0 months vs 1.0 month; hazard ratio, 0.41; 95% CI, 0.28-0.59; P < 0.0001). TAS-102 was effective regardless of KRAS mutational status. Grade 3 or higher adverse events observed in the TAS-102 group were neutropenia (50.4%), leucopenia (28.3%), and anemia (16.8%). There were no treatment-related deaths. An international phase III trial is ongoing to confirm the clinical benefits of TAS-102 worldwide.


T. Yoshino: I have honoraria with Chugai, Takeda, Bristol-Myers Squibb, Yakult and Merck Serono. I have research funding from Bayer, Taiho, Daiichi-sankyo and Quintiles. I have received consulting fee from Takeda.