The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer

Eric Van Cutsem, Robert J Mayer, Stéphanie Laurent, Robert Winkler, Cristina Grávalos, Manuel Benavides, Federico Longo-Munoz, Fabienne Portales, Fortunato Ciardiello, Salvatore Siena, Kensei Yamaguchi, Kei Muro, Tadamichi Denda, Yasushi Tsuji, Lukas Makris, Patrick Loehrer, Heinz-Josef Lenz, Atsushi Ohtsu, RECOURSE Study Group, Eric Van Cutsem, Robert J Mayer, Stéphanie Laurent, Robert Winkler, Cristina Grávalos, Manuel Benavides, Federico Longo-Munoz, Fabienne Portales, Fortunato Ciardiello, Salvatore Siena, Kensei Yamaguchi, Kei Muro, Tadamichi Denda, Yasushi Tsuji, Lukas Makris, Patrick Loehrer, Heinz-Josef Lenz, Atsushi Ohtsu, RECOURSE Study Group

Abstract

Background: In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups.

Methods: Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics.

Results: Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59-0.81; P = 0.0001). Median OS in the three regions was 6.5-7.8 months in the trifluridine/tipiracil arm and 4.3-6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34-0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48-0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57-1.00; P = 0.0470). Median PFS was 2.0-2.8 months for trifluridine/tipiracil and 1.7-1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability.

Conclusions: Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957.

Keywords: Fluoropyrimidine; Metastatic colorectal cancer; Randomised controlled trial; TAS-102; Tipiracil; Trifluridine.

Copyright © 2017. Published by Elsevier Ltd.

Figures

Fig. 1.. Kaplan–Meier curves and forest plots…
Fig. 1.. Kaplan–Meier curves and forest plots for overall survival (OS) and progression-free survival (PFS).
(A) Kaplan–Meier curve for OS by geographical subregion; (B) forest plot for OS by geographical subregion; (C) Kaplan–Meier curve for PFS by geographical subregion; (D) forest plot for PFS by geographical subregion. Abbreviations: CI, confidence interval; FTD/TPI, trifluridine/tipiracil; HR, hazard ratio; ITT, intention-to-treat.
Fig. 1.. Kaplan–Meier curves and forest plots…
Fig. 1.. Kaplan–Meier curves and forest plots for overall survival (OS) and progression-free survival (PFS).
(A) Kaplan–Meier curve for OS by geographical subregion; (B) forest plot for OS by geographical subregion; (C) Kaplan–Meier curve for PFS by geographical subregion; (D) forest plot for PFS by geographical subregion. Abbreviations: CI, confidence interval; FTD/TPI, trifluridine/tipiracil; HR, hazard ratio; ITT, intention-to-treat.
Fig. 2.. Overall survival as of 8th…
Fig. 2.. Overall survival as of 8th October 2014 (intention-to-treat population).
Abbreviations: CI, confidence interval; FTD/TPI, trifluridine/tipiracil; HR, hazard ratio; OS, overall survival.

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Source: PubMed

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