An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE).

Kuboki, Yasutoshi; Nishina, Tomohiro; Shinozaki, Eiji; Yamazaki, Kentaro; Shitara, Kohei; Okamoto, Wataru; Kajiwara, Takeshi; Matsumoto, Toshihiko; Tsushima, Takahiro; Mochizuki, Nobuo; Fukutani, Miki; Nakamoto, Masako; Hasegawa, Hiromi; Sugama, Ayako; Nomura, Shosaku; Sato, Akihiro; Ohtsu, Atsushi; Yoshino, Takayuki

doi:10.1200/jco.2015.33.15_suppl.3544

Cited by 8 publications

(3 citation statements)

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“…Specifically TAS-102 has great potential to improve the treatment of gastrointestinal malignancies when combined with other agents, such as with the VEGF inhibitor bevacizumab or the DNA synthesis inhibitors oxaliplatin or irinotecan. Recently the first promising results of the combination of TAS-102 (70 mg/m 2 /day) and bevacizumab were reported [Kuboki et al 2015], showing a DCR of 64% by central assessment and 72% by investigator assessment, a median OS of 11 months, no drug–drug interaction, and acceptable toxicity. Other possibilities are combining TAS-102 with the anti-EGFR antibodies cetuximab or panitumumab or with the small-molecule inhibitors of the EGFR tyrosine kinase domain gefitinib or erlotinib, or one of the new second- or third-generation EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

Peters

2015

Ther Adv Med Oncol

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Fluoropyrimidines form the mainstay in treatment of gastrointestinal malignancies. For decades 5-fluorouracil (5FU), was the major fluoropyrimidine. Currently it is usually given in a combination with leucovorin and oxaliplatin, i.e. FOLFOX, or irinotecan, i.e. FOLFIRI, or all three, i.e. FOLFIRINOX, but gradually it has been replaced by oral fluoropyrimidine prodrug formulations, such as tegafur-uracil and S-1 (both contain ftorafur), and capecitabine (Xeloda®). Novel drugs such as the antivascular endothelial growth factor antibody, bevacizumab, and the anti-epidermal growth factor receptor antibody, cetuximab, are often combined with one of these treatment options. However, when resistance emerged, no alternatives were available. TAS-102, a combination of trifluorothymidine and the thymidine phosphorylase inhibitor TPI in a 1:0.5 ratio, is a novel oral formulation, which is active in 5FU-resistant models, both in vitro and in xenograft models. In addition to inhibition of thymidylate synthase, the major mechanism of action of classical fluoropyrimidines, TAS-102's major mechanism of action is incorporation into DNA, thereby causing DNA damage. TAS-102 also follows an alternative activation pathway via thymidine kinase, and is not a substrate for dihydropyrimidine dehydrogenase. All together this explains the efficacy in 5FU-resistant models. In early clinical studies, the twice-daily schedule (5 days on, 2 days rest) for 2 weeks every 4 weeks, led to a significant disease control rate in various malignancies. This schedule showed consistent activity in two randomized trials on fluoropyrimidine refractory colorectal cancer patients, reflected by an increase of 2-3 months in overall survival in the TAS-102 group compared with placebo. Considering the impressive preclinical potential of various combinations TAS-102 has the promise to become an alternative for 5FU-resistant cancer.

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Section: Discussionmentioning

confidence: 99%

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

Peters

2015

Ther Adv Med Oncol

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“… 16 , 17 In a Phase I/II trial of TAS-102 combined with bevacizumab, Kuboki et al confirmed that standard dosing of TAS-102 (35 mg/m 2 twice daily on days 1–5 and 8–12 of a 28-day cycle) and bevacizumab (5 mg/kg every 14 days) were the RP2Ds, and the study met its primary endpoint; thus, the PFS rate at 16 weeks was 42.9% (95% CI 27.8%–59.0%) in 21 evaluable patients with refractory mCRC. 64 mPFS and mOS were relatively impressive at 5.6 and 11.2 months, respectively, although these findings should be validated in a randomized trial. One ongoing randomized Phase II trial is comparing TAS-102 plus bevacizumab therapy with capecitabine plus bevacizumab therapy in patients with untreated mCRC deemed unsuitable for intensive therapy (defined as combination 5-FU with oxaliplatin or irinotecan, TASCO1, NCT02743221, Table 2 ).…”

Section: Combination Therapies With Tas-102 and Ongoing Clinical Triamentioning

confidence: 83%

Emerging combination therapies for metastatic colorectal cancer – impact of trifluridine/tipiracil

Puthiamadathil¹,

Weinberg²

2017

CMAR

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Patients with metastatic colorectal cancer (mCRC) are surviving longer now than ever before, but mortality rates are still high and more effective therapies are clearly needed. For patients with disease that is refractory to fluoropyrimidines, oxaliplatin, irinotecan, and biologic agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways, novel treatment options trifluridine/tipiracil (TAS-102) and regorafenib can be effective disease stabilizers. However, objective clinical responses are rare and toxicities are manageable but common. In order to tackle poor clinical responses to TAS-102, there is an ongoing effort to effectively combine this drug with other agents, particularly those targeting angiogenesis. Certain subpopulations appear to benefit more than others from TAS-102; those that benefit often have underlying genetic defects in DNA repair pathways and/or develop neutropenia. In this review, we focus on the role of TAS-102 in the treatment of mCRC, including its use in combination with other agents, potential predictive biomarkers of response to TAS-102, and possible future directions.

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“…It can also modulate the immune system of CRC patients by inhibiting the maturation of tumor microenvironment (TME) dendritic cells (31). The combination of bevacizumab with TAS-102 may enhance the accumulation and phosphorylation levels of trifluorothymidine in tumor DNA without increasing systemic exposure or toxicity, thereby improving treatment efficacy (32).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the efficacy and safety of third-line treatments for metastatic colorectal cancer: a systematic review and network meta-analysis

Gao,

Tang,

et al. 2023

Front. Oncol.

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BackgroundThe objective of this study is to evaluate the efficacy and safety of different third-line treatment regimens for metastatic colorectal cancer (mCRC) through a comprehensive analysis and network meta-analysis (NMA). Additionally, the study aims to provide guidance on selecting appropriate third-line systemic treatment regimens for patients with mCRC.MethodsWe conducted a search of the PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials databases from January 1, 2005, to May 20, 2023, to include phase II/III randomized clinical trials (RCTs) of third-line treatments for mCRC. The primary outcome assessed in the NMA was median overall survival (mOS), and other outcomes included median progression-free survival (mPFS), disease control rate (DCR), and grade 3 or higher adverse events (≥3AEs).ResultsUltimately, nine phase II/III RCTs involving five treatment regimens were included in this study. Trifluridine/tipiracil (TAS-102) plus bevacizumab (hazard ratio [HR] 0.41, 95% credible interval [CrI] 0.32-0.52) was found to be the most effective treatment for mOS compared to best supportive care (BSC). TAS-102 plus bevacizumab also significantly improved mPFS compared to BSC (HR 0.20, 95% CrI 0.16-0.25). In terms of adverse events (AEs), TAS-102 (RR 0.52, 95% CrI 0.35-0.74) had a lower incidence of ≥3AEs compared to fruquintinib, but fruquintinib (RR 1.79, 95% CrI 1.10-3.11) showed better improvement in DCR than TAS-102. Subgroup analysis using the Bayesian surface under the cumulative ranking curve (SUCRA) ranked the regimens based on the OS benefit. The results indicated that TAS-102 plus bevacizumab ranked first across age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), and time from initial diagnosis of metastatic disease to randomization.ConclusionTAS-102, fruquintinib, TAS-102 plus bevacizumab, the regorafenib standard dose regimen (regorafenib), and the regorafenib dose-escalation regimen (regorafenib 80+) all demonstrated improved OS and PFS compared to BSC in mCRC patients. However, TAS-102 plus bevacizumab may be the optimal choice for third-line treatment in mCRC patients.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php, CRD42023434929.

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An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE).

Cited by 8 publications

References 0 publications

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

Emerging combination therapies for metastatic colorectal cancer – impact of trifluridine/tipiracil

Comparison of the efficacy and safety of third-line treatments for metastatic colorectal cancer: a systematic review and network meta-analysis

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An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE).

Cited by 8 publications

References 0 publications

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies

Emerging combination therapies for metastatic colorectal cancer &ndash; impact of trifluridine/tipiracil

Comparison of the efficacy and safety of third-line treatments for metastatic colorectal cancer: a systematic review and network meta-analysis

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Emerging combination therapies for metastatic colorectal cancer – impact of trifluridine/tipiracil