22 Novel combination therapy, TAS-102 combined with the anti-EGFR antibody or the anti-VEGF antibody showed therapeutic benefit toward colorectal cancer xenografts

Ishida, Keiji; Sakamoto, Katsumi; Tanaka, Naoki; Oguchi, Katsuji; Yamamura, Kouzen; Fujioka, Akira; Nakagawa, Fumio; Matsuo, Kai; Utsugi, Teruhiro

doi:10.1016/s0959-8049(14)70148-0

Cited by 2 publications

(7 citation statements)

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“…In two preclinical trials, the antitumor efficacy was significantly enhanced. The concentrations of FTD and FTD phosphates were obviously higher in combination treatment of bevacizumab and TAS-102 than either monotherapy on human CRC xenografts 28,29. Soon after, in order to assess effectiveness and security, an open-label, single-arm, multicenter Phase I/II study (C-TASK FORCE) was performed 30.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: a meta-analysis

Chen¹,

Wu²,

Lin³

et al. 2018

CMAR

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BackgroundTAS-102 has been applied to metastatic colorectal cancer (mCRC) patients who had received at least two prior regimens of standard chemotherapy. This meta-analysis is designed to assess the efficacy and safety of TAS-102 in patients with mCRC.MethodsWe searched randomized controlled trials (RCTs) through PubMed, Embase, Web of Science and Cochrane clinical trial databases and clinicaltrial.gov from database initiation to March 2018. The overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and incidence of adverse events were summarized with the use of hazard ratio (HR) or risk ratio (RR).ResultsThree RCTs with 1318 patients were included. Results showed that TAS-102 significantly improved OS (HR 0.70, 95% confidence interval [CI] 0.62–0.79) and PFS (HR 0.46, 95% CI 0.40–0.52) in patients who were intolerant or refractory to fluoropyrimidine, irinotecan and oxaliplatin. The pooled odds ratio of DCR was 4.15 (95% CI 3.18–5.43). Notably, there were significant OS benefits both in patients with KRAS mutation (HR 0.76, 95% CI 0.63–0.92) and those with wild-type KRAS (HR 0.66, 95% CI 0.55–0.79). These benefits were also observed in patients with different numbers of metastatic sites. However, patients with >18 months since the diagnosis of first metastases seemed to have better OS (HR 0.65, 95% CI 0.55–0.77). The most common toxicities associated with TAS-102 were neutropenia (RR 116.51, 95% CI 23.51–577.33), leucopenia (RR 67.70, 95% CI 13.63–336.29), anemia (RR 4.28, 95% CI 2.70–6.79) and diarrhea (RR 5.10, 95% CI 1.40–18.61).ConclusionTAS-102 significantly improves OS, PFS and DCR in refractory mCRC patients with tolerable toxicity. Meanwhile, the OS benefits have nothing to do with KRAS status and the number of metastatic sites.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: a meta-analysis

Chen¹,

Wu²,

Lin³

et al. 2018

CMAR

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“…A number of preclinical studies have been performed to investigate the combination of TAS-102 with other drugs commonly used for the treatment of mCRC [68-70]. In studies using human CRC cell lines, FTD combined with oxaliplatin or SN-38, the active metabolite of irinotecan, demonstrated synergistic effects on growth inhibition [68,69,71].…”

Section: Preclinical Studies Of Tas-102 In Combination With Other Antmentioning

confidence: 99%

“…The tumor growth-inhibitory activity of TAS-102 in combination with irinotecan was significantly greater than that of either agent as monotherapy for mice with KM12C, KM12C/5-FU, DLD-1/5-FU, and SC-2 GI cancer xenografts [73]. Increased antitumor activity was also observed when TAS-102 was combined with the monoclonal antibodies cetuximab, panitumumab, or bevacizumab in CRC xenograft mouse models [70]. In a KRAS wild-type CRC xenograft, oral administration of TAS-102 in combination with the anti– epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab was associated with increased antitumor effects compared with monotherapy [70].…”

Section: Preclinical Studies Of Tas-102 In Combination With Other Antmentioning

confidence: 99%

“…Increased antitumor activity was also observed when TAS-102 was combined with the monoclonal antibodies cetuximab, panitumumab, or bevacizumab in CRC xenograft mouse models [70]. In a KRAS wild-type CRC xenograft, oral administration of TAS-102 in combination with the anti– epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab was associated with increased antitumor effects compared with monotherapy [70]. TAS-102 in combination with the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab also showed increased antitumor effects compared with monotherapy in CRC xenografts; this was not affected by either KRAS mutation status or BRAF mutation status [70].…”

Section: Preclinical Studies Of Tas-102 In Combination With Other Antmentioning

confidence: 99%

“…In a KRAS wild-type CRC xenograft, oral administration of TAS-102 in combination with the anti– epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab was associated with increased antitumor effects compared with monotherapy [70]. TAS-102 in combination with the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab also showed increased antitumor effects compared with monotherapy in CRC xenografts; this was not affected by either KRAS mutation status or BRAF mutation status [70]. Moreover, coadministration of TAS-102 with bevacizumab resulted in the detection of higher levels of FTD and its phosphorylated metabolites in the tumor compared with TAS-102 administered alone [70].…”

Section: Preclinical Studies Of Tas-102 In Combination With Other Antmentioning

confidence: 99%

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TAS-102, a novel antitumor agent: A review of the mechanism of action

Lenz

Stintzing²,

Loupakis

2015

Cancer Treatment Reviews

129

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Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5-FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.

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22 Novel combination therapy, TAS-102 combined with the anti-EGFR antibody or the anti-VEGF antibody showed therapeutic benefit toward colorectal cancer xenografts

Cited by 2 publications

References 0 publications

Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: a meta-analysis

Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: a meta-analysis

TAS-102, a novel antitumor agent: A review of the mechanism of action

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