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)

Yoshino, Takayuki; Mayer, Roland; Falcone, Alfredo; Ohtsu, Atsushi; García‐Carbonero, Rocío; Mizunuma, Nobuyuki; Yamazaki, K.; Shimada, Yasuyuki; Tabernero, Josep; Sobrero, A.; Boucher, E.; Peeters, M.; Tran, Brian; Zaniboni, Alberto; Hochster, Howard S.; Benedetti, Fabio; Aivado, Manuel; Makris, Lukas; Ito, Miki; Cutsem, E. Van

doi:10.1093/annonc/mdu193.22

Cited by 12 publications

(8 citation statements)

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“…In a randomized phase II trial, the overall survival period of patients receiving TAS-102 with the best supportive care (9 months) was significantly longer than that of a placebo with the best supportive care group (6.6 months, P=0.0011) in patients with metastatic colorectal cancer, who were refractory to or intolerant of standard chemotherapies ( 16 ). TAS-102 showed a significant improvement in overall and progression free survival and a favorable safety profile in comparison to placebo in patients with metastatic colorectal cancer refractory to standard chemotherapies in an international multicenter randomized double-blind phase III study (RECOURSE), patients received in both arms the best supportive care ( 17 ). TAS-102 was approved for clinical use in Japan in March 2014.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts

et al. 2015

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TAS-102 is a novel oral nucleoside antitumor agent that consists of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5, and was approved in Japan in March 2014 for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. In the present study, we used colorectal cancer xenografts to assess whether the efficacy of TAS-102 could be improved by combining it with bevacizumab, cetuximab or panitumumab. TAS-102 was orally administered twice a day from day 1 to 14, and bevacizumab, cetuximab and panitumumab were administered intraperitoneally twice a week for 2 weeks. Growth inhibitory activity was evaluated based on the relative tumor volume (RTV) after 2 weeks of drug administration and time taken for the relative tumor volume to increase five-fold (RTV5). Tumor growth inhibition and RTV5 with TAS-102 and bevacizumab combination treatment were significantly better than those with TAS-102 or bevacizumab alone in the SW48 and HCT116 tumor models, and the concentration of phosphorylated FTD in tumors determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was higher in the TAS-102 and bevacizumab combination group than in the TAS-102 monotherapy group. The combination of TAS-102 and cetuximab or panitumumab was also significantly more effective than either monotherapy in the SW48 tumor model. There was no significant difference in the body weight between the mice treated with TAS-102 monotherapy and any of the combination therapies on day 29. Our preclinical findings indicate that the combination therapy of TAS-102, bevacizumab and cetuximab or panitumumab is a promising treatment option for colorectal cancer.

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Section: Introductionmentioning

confidence: 99%

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts

et al. 2015

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“…In those studies, the extent of hematological toxicity indicated a negative correlation with the TFT exposure [4,10], suggesting that the concentrations of TFT incorporated into the DNA of neutrophils would increase, accompanied by the increases in the TFT exposure, which resulted in a negative correlation between the TFT exposure and the neutrophil count. Actually, only one dose (the highest tolerable dose) was applied as the recommended dose in the phase 2 and subsequent phase 3 studies [17,18], which demonstrates a significant improvement in the overall survival in comparison with the placebo group in patients with colorectal adenocarcinoma; thus, the median overall survival was 7.1 months (95 % CI 6.5-7.8) in the TAS-102 group and 5.3 months (95 % CI 4.6-6.0) in the placebo group in the phase 3 study. Although the other dose was not evaluated in the phase 2 and 3 studies, the highest tolerable dose is likely to provide the highest TFT concentration in DNA of tumors, leading to the promising efficacy in patients with colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse

Yamashita

Komoto

Oka

et al. 2015

Cancer Chemother Pharmacol

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A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.

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“…TAS-102 is a new oral antitumor agent combining trifluridine (FTD, active component) and tipiracil hydrochloride (TPI, thymidine phosphorylase inhibitor), which prevents the degradation of FTD [Van Cutsem et al 2014]. This drug has been evaluated in the RECOURSE phase III study against placebo in patients with heavily pretreated mCRC, in which TAS-102 prolonged OS (primary endpoint) from 5.3 to 7.1 months (HR = 0.68) and PFS (HR = 0.48) [Yoshino et al 2014]. The survival benefit was observed whatever prior use of regorafenib (17%) and was consistent in all prespecified subgroups, except for patients who received only two lines of therapy prior to study entry.…”

Section: Subsequent Lines Of Therapymentioning

confidence: 99%

Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review

et al. 2015

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Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity, followed by reintroduction of prior full therapy when required, before switching to other drugs. Consequently, randomized strategy trials are needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy.

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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)

Cited by 12 publications

References 0 publications

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts

Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts

Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse

Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review

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