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

Abstract

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.

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

“…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.…”

Oral drugs in the treatment of metastatic colorectal cancer

“…Preclinical studies have recognized several effective combinations in vitro and in vivo, including combinations with oxaliplatin, irinotecan, cetuximab, and bevacizumab. [93][94][95] The first phase 1 study assessing the recommended dose and safety of TAS-102 in combination with irinotecan has been completed, but due to a limited sample size, no conclusions could be drawn. [96] A Japanese phase 1/2 study investigating TAS-102 in combination with bevacizumab showed a PFS rate of 42.9% at 16 weeks and an acceptable toxicity profile, with a recommended TAS-102 dose of 35 mg/m 2 twice daily on days 1-5 during weeks 1 and 2, followed by 2 weeks of rest with bevacizumab 5 mg/kg every 2 weeks.…”

Effect of a novel oral chemotherapeutic agent containing a combination of trifluridine, tipiracil and the novel triple angiokinase inhibitor nintedanib, on human colorectal cancer xenografts

“…TFTD in combination with irinotecan hydrochloride (18), oxaliplatin (19), bevacizumab, cetuximab, or panitumumab (20) exhibited superior in vivo activity against human colorectal cancer, including 5-FU-resistant tumors, compared with any of these drugs alone, as demonstrated by previous studies. In the present study, the effects of TFTD in combination with nintedanib against human colorectal tumor xenografts in a nude mouse model were evaluated.…”