RECOURSE Trial: TAS-102 versus Placebo plus Best Supportive Care in Patients with Metastatic Colorectal Cancer
TAS-102 is a novel cytotoxic agent with a unique mechanism of action that is being clinically tested for the treatment of patients with metastatic colorectal cancer (mCRC). It consists of the nucleoside trifluridine (FTD), which gets incorporated into DNA to dysregulate DNA function, combined with the thymidine phosphorylase inhibitor tipiracil hydrochloride (TPI), which prevents the degradation of FTD and increased accumulation of the functional molecule. The RECOURSE trial was a global, multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial that evaluated the efficacy and safety of TAS-102 in 800 patients with mCRC who have failed standard therapies, including fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab/panitumumab (in patients with wild-type KRAS). Patients were stratified based on KRAS mutation status, time from diagnosis of metastatic disease, and geographical region. The primary end point was overall survival (OS); secondary efficacy end points included progression-free survival (PFS), overall response rate (ORR), and safety (Van Cutsem, et al. RECOURSE trial. ESMO 2014: Abstract LBA13).
A total of 800 patients were randomized to TAS-102 therapy (N = 504) or to placebo (n = 266). TAS-102 therapy resulted in a significant improvement in OS compared with placebo (hazard ratio [HR], 0.68; P <.0001) and PFS (0.48; P <.0001), with a median OS of 7.1 months and 5.3 months, respectively, and a median PFS of 2.0 months and 1.7 months, respectively. This OS and PFS benefit from TAS-102 therapy extended to all prospectively defined subgroups analyzed, including by KRAS status, region, performance status, and previous use of regorafenib.
A multivariate analysis did not identify any predictive factors for OS; however, statistically significant prognostic factors included time since diagnosis of first metastasis, ECOG performance status, and number of metastatic sites. There was a significant delay in time to worsening of ECOG PS status to ?2 with TAS-102 compared with placebo (5.7 vs 4.0 months; HR = 0.66; P <.0001). In terms of safety, there was a higher incidence of nausea, decreased appetite, fatigue, diarrhea, and vomiting, the majority of which were grade 1 or 2 in severity.
Serious adverse events were reported in 29.6% of patients treated with TAS-102 and in 33.6% of patients receiving placebo; however, treatment discontinuation because of adverse events was 3.6% in the TAS-102 group and 1.5% in the placebo group.
The investigators concluded that TAS-102 demonstrated a clinically relevant improvement in survival outcomes compared with placebo in patients with relapsed or refractory mCRC, with the survival benefit extending across all subgroups tested, including previous regorafenib use.