TERRA: a randomized, double-blind, placebo-controlled phase 3 study of TAS-102 in Asian patients with metastatic colorectal cancer

Abstract

Background: The RECOURSE study demonstrated that trifluridine/tipiracil hydrochloride (TAS-102) significantly improved overall survival (OS) and progression-free survival (PFS) in patients ( pts) with metastatic colorectal cancer (mCRC) who had failed standard therapies. In the TERRA study, the efficacy and safety of TAS-102 were evaluated in similar Asian population with mCRC who had failed conventional cytotoxic therapies. Methods: This was a multicenter, randomized, double-blind, placebo-controlled phase 3 study. Pts must have had received at least 2 prior standard regimens for mCRC, including fluoropyrimidines, oxaliplatin, and irinotecan. Prior anti-VEGF or anti-EGFR targeted therapy was not mandatory therapy. Between 16 Oct, 2013 and 15 Jun, 2015, 516 pts were screened and 406 pts were enrolled. Pts were stratified by KRAS status and geographic region and were randomized in a 2:1 ratio to receive TAS-102 (35 mg/m2 BID on days 1-5 and 8-12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary endpoint was OS. Key secondary endpoints included PFS and safety. Results: In the primary analysis, TAS-102 demonstrated an improvement in OS versus placebo, hazard ratio ([HR] 0.79; 95% confidence interval [CI] 0.62-0.99; P = 0.035) (the median OS were 7.8 versus 7.1 months, respectively). Improvement in PFS was also observed (HR: 0.43; 95% CI 0.34-0.54, P < 0.001) for the TAS-102 group vs placebo (median PFS were 2.0 versus 1.8 months, respectively). In particular, the HRs for OS in the subgroups were 0.77 in pts with KRAS wild-type tumors and 0.83 in pts with KRAS mutated tumors. The disease control rate (DCR) was higher in the TAS-102 group (44.1% versus 14.6 %). Most frequent Grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (20.3% in TAS-102, 0% in placebo), anemia (15.9%, 5.9 %) and leukopenia (4.8%, 0%). Conclusions: The TERRA study demonstrated an improvement in OS and PFS in Asian pts with mCRC who had failed conventional cytotoxic therapies. The safety profile of TAS-102 was similar to that in previous studies. A data according to the pre and post-study treatments, especially targeted therapies, will be presented.