Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial

F Longo-Muñoz, G Argiles, J Tabernero, A Cervantes, C Gravalos, C Pericay, S Gil-Calle, H Mizuguchi, A Carrato-Mena, M L Limón, R Garcia-Carbonero, F Longo-Muñoz, G Argiles, J Tabernero, A Cervantes, C Gravalos, C Pericay, S Gil-Calle, H Mizuguchi, A Carrato-Mena, M L Limón, R Garcia-Carbonero

Abstract

Purpose: TAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.001]. The current analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup.

Methods: Primary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics.

Results: The RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28-0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30-0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group.

Conclusions: In the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified. CLINICALTRIALS.

Gov study number: NCT01607957.

Keywords: Fluoropyrimidine; Metastatic colorectal cancer; Spain; TAS-102; Tipiracil hydrochloride; Trifluridine.

Conflict of interest statement

Author A reports employment at Taiho Oncology Inc. Author B reports providing scientific advice to Bayer. Author C reports consulting/advisory fees from Amgen, Boehringer Ingelheim, Celgene, Chugai, Imclone Systems Inc., Eli Lilly and Company, Merck & Co., Merck Serono, Millennium, Novartis, F. Hoffmann-La Roche Ltd., Sanofi, Symphogen, and Taiho Oncology Inc. All other authors declare that they have no conflicts of interest. Informed consent Informed consent was obtained from all individual participants included in the study. Research involving human participants All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Figures

Fig. 1
Fig. 1
Comparison of the mechanisms of action of TAS-102 and 5-FU. 5-FU fluorouracil; dTMP and dTTP deoxythymidine mono- and triphosphate; dUMP deoxyuridine monophosphate; F3dTMP, F3dTDP, and F3dTTP trifluorodeoxythymidine mono-, di-, and triphosphate; FdUMP fluorodeoxyuridine monophosphate; TK1 thymidine kinase 1; TPase thymidine phosphorylase; TPI tipiracil hydrochloride; TS thymidylate synthase
Fig. 2
Fig. 2
a Kaplan–Meier curves for overall survival in the Spanish subgroup and overall RECOURSE populations; b overall survival estimates for the TAS-102 and placebo treatment groups at months 3, 6, 9, and 12
Fig. 3
Fig. 3
Kaplan–Meier curves for radiologic progression-free survival in the Spanish subgroup and overall RECOURSE populations

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