A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer

Abstract

Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m 2) or S-1 (30 mg/m 2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination Electronic supplementary material The online version of this article (

Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer

“…To date, there is limited clinical data in BC patients, with 23 BC patients enrolled onto a phase I study of TAS-114 in combination with capecitabine. Phase II trials in patients with advanced non-small-cell lung cancer (NSCLC) demonstrated that the combination of TAS-114 and S-1, an oral 5-FU derivative, resulted in an improved response rate without benefit in progression-free survival compared to S-1 alone 27 . However, this limited improvement was in heavily pre-treated patients that had been previously treated with ≥2 previous chemotherapy regimens.…”

“…These observations provide the rationale for the evaluation of this triple combination as a promising therapeutic strategy in TNBC. The importance of this discovery is pertinent as inhibitors of dUTPase are currently in early phase clinical evaluation and thus identifying the most effective clinical application for these new agents is of utmost importance 24 , 27 , 30 .…”

A multicenter phase II study of TAS-114 in combination with S-1 in patients with pretreated advanced gastric cancer (EPOC1604)

“…However, only one out of the 20 patients achieved an objective response, which was considered to be difficult to meet predefined criteria of efficacy. Also, the phase 2 trial of TAS-114 plus S-1 in patients with NSCLC failed to show antitumor activity Proportion surviving Months after registration A with increased incidence of toxicities [17]. We decided to discontinue the trial in the middle of the second stage based on these results.…”

“…None of the first 10 patients enrolled in the second stage achieved objective response. At the same time, it was reported that a randomized, international phase 2 trial of TAS-114 plus S-1 vs. S-1 monotherapy in 5-FU-naïve patients with NSCLC failed to show antitumor activity and presented increased incidences of adverse events [17]. Accrual was terminated in June 2018 based on these results.…”

Real-World Therapeutic Outcomes of S-1 Adjuvant Chemotherapy for pStage II/III Gastric Cancer in the Elderly

“…The efficacy of treatments using S-1 for several cancers has been reported all over the world. The promising effects of S-1 were shown by the following trials: a phase 3 trial including S-1 for gastric cancer [9], immune checkpoint inhibitor combination with S-1 for gastric cancer [10], and doublet treatments according to histological type for gastric cancer [11]; newly developed TAS-114 with combination with S-1 for non-small-cell lung cancer [12]; and oxaliplatin plus S-1 combination chemotherapy for older vulnerable patients with colorectal cancer [13]. It is likely that the clinical usefulness of S-1 will be demonstrated more and more in various cancers all over the world.…”