O-0022 - Results of a multicenter, randomized, double-blind, phase III study of TAS-102 vs. Placebo, with best supportive care (bsc), in patients (pts) with...

Date 28 June 2014
Event World GI 2014
Session Metastatic colorectal cancer
Topics Anti-Cancer Agents & Biologic Therapy
Supportive Care
Colon Cancer
Rectal Cancer
Presenter Takayuki Yoshino
Citation Annals of Oncology (2014) 25 (suppl_2): ii105-ii117. 10.1093/annonc/mdu193
Authors L. Makris1, M. Ito2, . on behalf of the RECOURSE Study Group3, N. Mizunuma4, B. Tran5, F. Benedetti6, M. Aivado6
  • 1Stathmi Inc., New Hope/US
  • 2Taiho Pharmaceutical Co., Ltd., Chiyoda-ku/JP
  • 3/
  • 4The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku/JP
  • 5The Royal Melbourne Hospital, Victoria/AU
  • 6Taiho Oncology Inc., Princeton/US

Abstract

Introduction

TAS-102 is a combination agent consisting of a novel oral nucleoside, trifluridine (FTD) and a thymidine phosphorylase inhibitor, tipiracil hydrochloride (TPI), which prevents the degradation of FTD, thereby enabling sustained and effective cytotoxic levels. 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. Previously, a randomized phase 2 study demonstrated a significant survival improvement for TAS-102 over placebo in refractory mCRC (HR = 0.56 p = 0.0011, Yoshino T. et al., Lancet Oncology 2012). RECOURSE was conducted to evaluate the efficacy and safety of TAS-102 in pts with mCRC refractory to standard therapies.

Methods

Enrollment criteria included documented mCRC and at least 2 prior lines of standard chemotherapy, including fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab; and cetuximab or panitumumab for pts with KRAS wild-type tumors. Among other criteria, pts had to either be intolerant to or have experienced radiologic progression within 3 months of the last administration of each of all standard chemotherapies. Pts were stratified by KRAS status (wild-type, mutant-type), time since diagnosis of metastasis (<18 months, >18 months), and geographic region (Japan, US/EU/Australia). Pts were randomized 2:1 to receive TAS-102 (35 mg/m2 BID on Days 1-5 and 8-12 of each 28-day cycle) plus BSC, or placebo plus BSC. Pts continued study treatment until disease progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR: CR, PR or SD), and safety. The study was designed to detect with 90% power an OS hazard ratio of 0.75 (25% risk reduction) for TAS-102 compared to placebo with a 1-sided type I error of 0.025.

Results

800 pts were randomized to TAS-102 (534 pts) or placebo (266 pts). Baseline characteristics were well balanced between both arms. The hazard ratios for OS and PFS were 0.68 (95% CI: 0.58-0.81; 1-sided p < 0.0001) and 0.48 (95% CI: 0.41-0.57; 1-sided p < 0.0001), respectively, both favoring TAS-102. Median OS was 7.1 months (95% CI: 6.5-7.8) and 5.3 months (95% CI: 4.6-6.0) for TAS-102 and placebo, respectively. Median PFS, ORR, and DCR for TAS-102 and placebo were 2.0 months vs. 1.7 months, 1.6% vs. 0.4% (NS), and 44.0% vs. 16.3% (2-sided p < 0.0001), respectively. The most frequent grade>3 AEs in TAS-102 or placebo (observed in at least 5% of pts for TAS-102) were neutropenia (34.9% in TAS-102, 0% in placebo), leukopenia (12.8%, 0%), and anemia (16.5%, 2.6%). Febrile neutropenia was observed 3.8% in TAS-102 and 0% in placebo.

Conclusion

In mCRC pts refractory to standard therapies, TAS-102 demonstrated a significant improvement in OS and PFS compared with placebo, with a favorable safety profile.