The new combination agent TAS-102 is able to improve overall survival compared to placebo in patients whose metastatic colorectal cancer is refractory to standard therapies, researchers said at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona.
"Around 50% of patients with colorectal cancer develop metastases but eventually many of them do not respond to standard therapies," said Takayuki Yoshino of the National Cancer Centre Hospital East in Chiba, Japan, lead author of the phase III RECOURSE trial. "The RECOURSE study shows that TAS-102 improves overall survival in these patients compared to placebo. 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 novel nucleoside anti-tumour agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). FTD is the active component of TAS-102 and is directly incorporated into cancer DNA, leading to DNA dysfunction. However, when FTD is taken orally it is largely degraded to an inactive form. TPI prevents the degradation of FTD. This mechanism of action is different to that of fluoropyrimidine, oxaliplatin and irinotecan.
The phase II trial of TAS-102 had found an overall survival benefit in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidine 5-fluorouracil (5-FU), irinotecan and oxaliplatin.
The current RECOURSE study was a global phase III trial conducted in 13 countries at 114 centres. Patients had metastatic colorectal cancer refractory to all standard therapies including fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab for patients with wild-type KRAS tumours. Patients were randomised 2:1 to TAS-102 (534 patients) or placebo (266 patients). The primary endpoint was overall survival.
The researchers found that TAS-102 prolonged overall survival compared to placebo (hazard ratio 0.68): median overall survival was 7.1 months for TAS-102 and 5.3 months for placebo. TAS-102 also improved progression-free survival compared to placebo (hazard ratio 0.48), which was a secondary endpoint. Yoshino said: "We found a statistically significant difference in overall and progression-free survival, and a clinically meaningful improvement."
"TAS-102 has a mild safety profile and the most common side-effect is hematologic toxicity including neutropenia. Patients with metastatic colorectal cancer refractory to standard therapies now have a strong treatment option."
Commenting on the data, ESMO spokesperson Jean Yves Douillard, professor of medical oncology, Institut de Cancérologie de l'Ouest (ICO) René Gauducheau, Saint-Herblain, France, said: "The phase III trial of TAS-102 is a global study and confirms the results of the phase II study in Japanese patients, whose response to fluoropyrimidine is slightly different to patients in Europe and the US. It is good to know that the magnitude of benefit shown in the smaller phase II trial is confirmed in the larger phase III trial and that the results apply to Asians and Caucasians alike."
TAS-102 is a combination of two components. The tipiracil hydrochloride (TPI) prevents degradation of trifluridine (FTD) and also has angiogenic activity. "This is probably why TAS-102 is effective in classical fluoropyrimidine 5-fluorouracil (5-FU) resistant patients. The drug is very promising, tolerance is good and it is manageable with supportive care."
Douillard concluded: "In RECOURSE, TAS-102 was tested in patients who had received all types of chemotherapy available for colorectal cancer. I would probably move this drug into an earlier line of treatment and I would also combine it with either irinotecan or oxaliplatin."
Notes to Editors
Information contained in this press release was provided by the abstract's author and reflects the content of the study. It does not necessarily express ESMO's point of view
 Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012;13(10):993-1001.
 Abstracts from the 16th ESMO World Congress on Gastrointestinal Cancer are published in Annals of Oncology, Volume 25 suppl 2 June 2014 (Ann Oncol 2014 Jun; 25(Suppl 2): 1-117)
 Abstract presentation: Saturday, 28 June 2014, 12:00 hrs, Session XIX: Metastatic colorectal cancer
ABSTRACT O - 0022
Results of a multicenter, randomised, double-blind, phase III study of TAS-102 vs. placebo, with best supportive care (BSC), in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies (RECOURSE).
Takayuki Yoshino1, Robert Mayer2, Alfredo Falcone3, Atsushi Ohtsu1, Rocio Garcia-Carbonero4, Nobuyuki Mizunuma5, Kentaro Yamazaki6, Yasuhiro Shimada7, Josep Tabernero8, Yoshito Komatsu9, Alberto Sobrero10, Eveline Boucher11, Marc Peeters12, Ben Tran13, Heinz-Josef Lenz14, Alberto Zaniboni15, Howard Hochster16, Fabio Benedetti17, Manuel Aivado17, Lukas Makris18, Masanobu Ito19, Eric Van Cutsem20, on behalf of the RECOURSE Study Group
1National Cancer Center Hospital East, Chiba, Japan, 2Dana-Farber Cancer Institute, Boston, MA, 3University of Pisa, Pisa, Italy, 4Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBIS), Spain, 5The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan, 6Shizuoka Cancer Center, Shizuoka, Japan, 7National Cancer Center Hospital, Tokyo, Japan, 8Vall d'Hebron University Hospital, Barcelona, Spain, 9Hokkaido University Hospital, Hokkaido, Japan, 10Ospedale San Martino, Genova, Italy, 11Centre Eugene Marquis, Rennes cedex, France, 12Antwerp University Hospital, Edegem, Belgium, 13The Royal Melbourne Hospital, Victoria, Australia, 14USC Norris Comprehensive Cancer Center, Los Angeles, CA, 15Fondazione Poliambulanza, Brescia, Italy, 16Yale Cancer Center, New Haven, CT, 17Taiho Pharma USA Inc., Princeton, NJ, 18Stathmi Inc, New Hope, PA, 19Taiho Pharmaceutical Co., Ltd., Tokyo, Japan, 20Digestive Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium
TAS-102 is a combination agent consisting of a novel oral nucleoside, trifluridine (FTD) and a thymidine phosphorylase inhibitor, tipiracil hydrochloride (TPI), which prevents the degradation of FTD, thereby enabling sustained and effective cytotoxic levels. TAS-102 is effective against human colorectal tumour cell lines with innate and acquired resistance to 5FU, both in-vitro as well as in-vivo models. Previously, a randomised phase 2 study demonstrated a significant survival improvement for TAS-102 over placebo in refractory mCRC (HR=0.56 p=0.0011, Yoshino T. et al., Lancet Oncology 2012). RECOURSE was conducted to evaluate the efficacy and safety of TAS-102 in pts with mCRC refractory to standard therapies.
Enrollment criteria included documented mCRC and at least 2 prior lines of standard chemotherapy, including fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab; and cetuximab or panitumumab for pts with KRAS wild-type tumours. Among other criteria, pts had to either be intolerant to or have experienced radiologic progression within 3 months of the last administration of each of all standard chemotherapies. Pts were stratified by KRAS status (wild-type, mutant-type), time since diagnosis of metastasis (<18 months, >18 months), and geographic region (Japan, US/EU/Australia). Pts were randomised 2:1 to receive TAS-102 (35 mg/m2 BID on Days 1- 5 and 8-12 of each 28-day cycle) plus BSC, or placebo plus BSC. Pts continued study treatment until disease progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR: CR, PR or SD), and safety. The study was designed to detect with 90% power an OS hazard ratio of 0.75 (25% risk reduction) for TAS-102 compared to placebo with a 1-sided type I error of 0.025.
800 pts were randomised to TAS-102 (534 pts) or placebo (266 pts). Baseline characteristics were well balanced between both arms. The hazard ratios for OS and PFS were 0.68 (95% CI: 0.58 -0.81; 1-sided p < 0.0001) and 0.48 (95% CI: 0.41 -0.57; 1-sided p < 0.0001), respectively, both favoring TAS-102. Median OS was 7.1 months (95% CI: 6.5-7.8) and 5.3 months (95% CI: 4.6-6.0) for TAS-102 and placebo, respectively. Median PFS, ORR, and DCR for TAS-102 and placebo were 2.0 months vs. 1.7 months, 1.6% vs. 0.4% (NS), and 44.0% vs. 16.3% (2-sided p < 0.0001), respectively. The most frequent grade>3 AEs in TAS-102 or placebo (observed in at least 5% of pts for TAS-102) were neutropenia (34.9% in TAS-102, 0% in placebo), leukopenia (12.8%, 0%), and anemia (16.5%, 2.6%). Febrile neutropenia was observed 3.8% in TAS-102 and 0% in placebo.
In mCRC pts refractory to standard therapies, TAS-102 demonstrated a significant improvement in OS and PFS compared with placebo, with a favorable safety profile.