Abstract 2557: Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with oxaliplatin on human colorectal or gastric cancers and 5-FU-resistant gastric cancer xenografts

Abstract

Abstract Background: TAS-102 is a novel oral nucleoside antitumor agent composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molar ratio 1:0.5. FTD is the active antitumor component of TAS-102 and its triphosphate form is incorporated into DNA in tumor cells. TPI is a potent inhibitor of thymidine phosphorylase, an enzyme that degrades FTD, allowing adequate plasma concentrations of orally administered FTD to be maintained and potentiating the antitumor activity of FTD. In a recent international multicenter randomized double blind Phase III study (RECOURSE), use of TAS-102 was shown to significantly improve overall survival, progression-free survival and had a favorable safety profile in comparison to the placebo in patients with metastatic colorectal cancer refractory to standard chemotherapies. In this study, we evaluated the antitumor effects of TAS-102 in combination with oxaliplatin on gastrointestinal tumor xenografts, including a 5-FU-resistant subline, in a nude mouse model. Method: The human colorectal cell lines HCT-116 and SW48 and gastric cancer cell lines SC-2, MKN74 and MKN74/5-FU, a 5-FU-resistant cell line derived from MKN74, were implanted into nude mice subcutaneously. TAS-102 (150 mg/kg/day) was orally administered twice daily from days 1 to 14 and oxaliplatin (7 or 13 mg/kg/day) was administered intravenously on days 1 and 8. Growth inhibitory activity was evaluated by assessing tumor volume and the growth delay period, estimated based on the period required to reach a tumor volume five times greater than the initial volume (RTV5). Results: TAS-102 and oxaliplatin monotherapy were effective on all the evaluated colorectal and gastric cancers, even for a 5-FU-resistant gastric cancer cell line. The tumor growth inhibitory activity and RTV5 of the group receiving TAS-102 with oxaliplatin were significantly superior to those receiving either monotherapy for all evaluated cancers (P<0.05). Tumor growth inhibition in the combination treatment group was more than 70%. Furthermore, the RTV values on day 29 were less than 5 for SC-2, MKN74 and MKN74/5FU xenografts. These results demonstrate that combination therapy with TAS-102 and oxaliplatin is significantly more effective than either monotherapy in colorectal and gastric cancer xenografts, including a 5-FU-resistant xenograft, when evaluated by tumor growth inhibition and growth delay period. This combination appeared to be well-tolerated, as drug-related death or a reduction in body weight of more than 20% was not observed. Conclusion: The present preclinical findings indicate that combination therapy of TAS-102 and oxaliplatin is a promising treatment option for colorectal or gastric cancer, not only for chemo-naïve tumors, but also for recurrent tumors after 5-FU-based chemotherapy. Citation Format: Mamoru Nukatsuka, Fumio Nakagawa, Kazuaki Matsuoka, Hiroshi Tsukihara, Teiji Takechi. Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, with oxaliplatin on human colorectal or gastric cancers and 5-FU-resistant gastric cancer xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2557. doi:10.1158/1538-7445.AM2015-2557