IS7-5 - New Drug Development for Refractory Metastatic Colorectal Cancer in Japan

Abstract

Cytotoxic agents, fluoropyrimidine, irinotecan and oxaliplatin, and monoclonal antibodies, bevacizumab, cetuximab and panitumumab have been shown to significantly improve overall survival (OS) for metastatic colorectal cancer (mCRC). Recently, two other agents targeting vascular endothelial growth factor (VEGF) have shown promise. Regorafenib is an orally active inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases, which showed statistically significant improvement in OS for mCRC who had progressed after standard therapies. Ziv-aflibercept is a fusion protein consisting of key domains of VEGF receptor 1 and 2, which showed statistically significant improvement in OS for previously treated mCRC. However, no standard salvage therapy available, although many patients retain good performance status.TAS-102 is a novel oral nucleoside antitumor agent consisting of 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor, tipiracil-hydrochloride (TPI). FTD is the active antitumor component of TAS-102 while TPI prevents degradation of FTD, thereby enabling sustained and effective cytotoxic levels of this novel anti-metabolite. TAS-102 is effective against human colorectal tumor cell lines with innate and acquired resistance to 5FU, both in-vitro as well as in-vivo models. A prior randomized phase 2 study demonstrated a significant survival improvement of TAS-102 over placebo in refractory mCRC (HR = 0.56 p = 0.0011, Yoshino T., et al., Lancet Oncology 2012). Based on these results, TAS-102 has been approved in Japan before the rest of the world. An international phase III trial, called the RECOURSE, was conducted to evaluate the efficacy and safety of TAS-102 in patients with mCRC refractory to standard therapies (ClinicalTrials.gov NCT01607957). We have started the phase 1/2 trial to investigate the efficacy and safety of TAS-102 plus bevacizumab in refractory mCRC (UMIN000012883). Update on promising new agents will be presented.