Abstract 3600: The prominent safety profile of TAS-115, a novel c-Met + VEGFR dual kinase inhibitor can lead to potentiate the efficacy via durable inhibition of angiogenesis
Authors: Ochiiwa Hiroaki , Fujita Hidenori , Ito Kimihiro , Takenaka Toru , Huang Jinhong , Ito Satoko , Suzuki Takamasa , Egami Kousuke , Suefuji Takashi , Sato Ayako , Sato Tsudoi , Fujioka Yayoi , Kato Masanori , Aoyagi Yoshimi , Hashimoto Akihiro , Kazuno Hideki , Miyadera Kazutaka , Suda Yoshimitsu , Yonekura Kazuhiko 
Published: June 2012

Abstract
c-Met is a receptor tyrosine kinase involved in various malignant phenotypes of diverse cancers. The inhibition of VEGF/VEGFR has been established as a standard therapy for several cancers. Therefore, their dual inhibition is considered to be one of most attractive strategy for cancer therapy. However, unexpectedly success of VEGFR inhibitors (VEGFRI) has been concurrently associated with emerging new type toxicities which result in occasional patient's death and requiring drug off period, frequent interruptions or dose reduction. Moreover, those interruptions resulted in a rapid tumor regrowth due to the aggressive angiogenic signaling which can confer the drug resistance to VEGFRI. These issues are considered to be main reason for the lack of success of their combination with other chemotherapeutics and the limitation of their usage. This sequence of events prompted us to develop a novel c-Met + VEGFRs dual inhibitor TAS-115, which has a high potency and prominent safety profile. A 4wks tolerability study in mice revealed no animal death even at more than 28 times higher drug exposure over the effective doses (ED50). Whereas, therapeutic index (MTD/ED50) of other VEGFRIs including foretinib, sunitinib and sorafenib were only 2-4. Similar safety profile was observed in the tox study in rats treated for 3wks, its therapeutic index was more than 10, while those of other VEGFRIs were only 0.6-2.5 due to severe toxicities. To confirm whether its better safety profile provide more benefit, longer term efficacy studies were conducted. There was no difference in efficacy within the first 2wks, however, over 2wks the animals in foretinib treatment group at MTD began to die and administration could not be continued. In contrast, TAS-115 dosing has continued for over 6wks without any toxic manifestation. The deference in their efficacies at MTD for over 4wks became greater (p&lt;0.001). Moreover, to evaluate how the drug off period of VEGFRIs affect angiogenesis, using sunitinib as a reference, the efficacy study was done with 2wks on / 1wk off dosing regimen, mimicking its clinical setting. Although tumor growth was inhibited with 2wks consecutive dosing of sunitinib via angiogenesis inhibition, the 1wk rest caused a regrowth with recovery of vascularity. And even though its next 2wks dosing re-inhibited tumor growth, repeating these cycles allowed progressive growth with aggressive angiogenic phenotype including higher gene expressions of various angiogenic factors. Meanwhile, TAS-115 could completely inhibit tumor growth for more than 6wks via durable inhibition of angiogenesis. In addition, TAS-115 prolonged the life span in the peritoneal dissemination mouse models of human gastric cancer cell line resistant to sunitinib. Taken together, the prominent safety profile of TAS-115 can lead to more therapeutic benefit via a durable inhibition of angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3600. doi:10.1158/1538-7445.AM2011-3600