Evaluation of a Novel Combination Therapy, Based on Trifluridine/Tipiracil and Fruquintinib, against Colorectal Cancer

Abstract

Introduction: Trifluridine/tipiracil hydrochloride (FTD/TPI, Lonsurf®) is an oral antineoplastic agent that has been approved as a late-stage chemotherapy for colorectal cancer. Its major mechanism of action is the dysfunction of tumoral DNA including DNA strand breaks and decreased replication. Fruquintinib (ELUNATE®) is a novel kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-1, -2, and -3. In this study, we evaluated the antitumor activity of combination therapy with FTD/TPI and fruquintinib in vivo. Methods: The enhancement of the antitumor effects with FTD/TPI and fruquintinib combination, compared to the single drugs given alone was evaluated using two human colorectal cancer xenografts in nude mouse models. FTD/TPI (200 mg/kg) was orally administered for 5 consecutive days followed by 2 days of rest in a 7-day period. Fruquintinib (10 mg/kg) was orally administered consecutively for 2 and 3 weeks in SW48 and HCT 116 tumor-bearing models, respectively. After treatment with these agents, the microvessel density was evaluated by CD31 immunohistochemical analyses. Results: In both models, FTD/TPI and fruquintinib significantly inhibited tumor growth, and the activity of the combined treatment was significantly superior to that of either monotherapy. Body weight loss of greater than 20% was not observed in any group. A histochemical analysis showed nuclei enlargement, abnormal mitosis and karyorrhexis in the FTD/TPI treatment group. The microvessel density in the HCT 116 tumors treated with FTD/TPI and fruquintinib was significantly lower than that in the control group. Conclusion: The combination of FTD/TPI and fruquintinib could be a promising treatment option for colorectal cancer.

Trifluridine/tipiracil (FTD/TPI) in metastatic colorectal cancer treatment

“…One possible option to increase the FTD/TPI activity is to combine it with anti-EGFR, antiangiogenic drugs, chemotherapy (e.g., oxaliplatin), or other drugs. In mouse models, a phase II study recently showed the promising activity of fruquintinib, a kinase inhibitor of vascular endothelial growth factor receptor 1-3 [40]. Trifluridine and tipiracil combined with Yttrium-90 ( 90 Y) radioembolization (NCT02602327) have an activity in liver-dominant mCRC [41].…”

A Retrospective Study of Trifluridine/Tipiracil with Fruquintinib in Patients with Chemorefractory Metastatic Colorectal Cancer

“…Regorafenib and fruquintinib are small-molecule inhibitors able to hinder multiple kinases, including VEGFR, FGFR, and PDGFR [ 26 , 27 ]. Studies using colorectal cancer xenograft models have found that fruquintinib combined with FTD/TPI can enhance antitumor effects [ 18 ]. In addition, compared with regorafenib, fruquintinib has a narrower spectrum of targets and a lower incidence of AEs, which might enhance therapeutic efficacy through increased drug exposure at the maximum tolerated dose [ 26 , 27 ].…”

“…A study involving colorectal cancer xenografts found that phosphorylated FTD levels were increased in tumors by combining TAS-102 and an angiogenesis inhibitor, resulting in increased antitumor activity [ 17 ]. In addition, preclinical models illustrated that FTD/TPI and fruquintinib led to a notable decrease in the microvessel area and exhibited remarkable superiority over each monotherapy studied in mice bearing subcutaneous colorectal tumor xenografts [ 18 ]. Hence, their unique mechanisms suggest that they may be complementary when received in combination.…”