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

Nobuyuki Yamamoto, Hidetoshi Hayashi, David Planchard, Teresa Morán, Vanesa Gregorc, Jonathan Dowell, Hiroshi Sakai, Kiyotaka Yoh, Makoto Nishio, Alexis B Cortot, Karim A Benhadji, Nital Soni, Jinhong Huang, Lukas Makris, Susana Cedres, Nobuyuki Yamamoto, Hidetoshi Hayashi, David Planchard, Teresa Morán, Vanesa Gregorc, Jonathan Dowell, Hiroshi Sakai, Kiyotaka Yoh, Makoto Nishio, Alexis B Cortot, Karim A Benhadji, Nital Soni, Jinhong Huang, Lukas Makris, Susana Cedres

Abstract

Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (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/m2) or S-1 (30 mg/m2). 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 improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.

Keywords: 5-fluorouracil; Non-small-cell lung cancer; Progression-free survival; dUTPase.

Conflict of interest statement

N. Yamamoto has received grants and/or personal fees from Taiho Pharmaceutical. H. Hayashi has received grants and personal fees from AstraZeneca, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical. D. Planchard has participated in consulting, acted in an advisory role, and received lecture fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck, Novartis, Pfizer, Roche, prIME Oncology, and Peer CME, and has worked as a principal or co-investigator for clinical trial research for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, MedImmune, Merck, Novartis, Novocure, Pfizer, Roche, Sanofi-Aventis, and Taiho Pharmaceutical. H. Sakai has received personal fees from Taiho Pharmaceutical. K. Yoh has received grants and/or personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical. M. Nishio has received grants and/or non-financial support from F. Hoffmann-La Roche and grants and/or personal fees from Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Serono, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sankyo Healthcare, and Taiho Pharmaceutical. A. Cortot has received grants, personal fees, and/or non-financial support from Astra-Zeneca, Bristol Myers Squibb, Merck, MSD, Novartis, Pfizer, Roche, and Takeda. KA Benhadji and N. Soni are employees of Taiho Oncology Inc. J. Huang is an employee of Taiho Pharmaceutical and owns Taiho Pharmaceutical stock. L. Makris has received personal fees from Taiho Oncology, Inc. S. Cedres has served in a consulting or an advisory role for Bristol-Myers Squibb, F. Hoffmann-La Roche AG, Pfizer, Boehringer Ingelheim, MSD Oncology, and Amphera; and has received travel and accommodation funding from F. Hoffmann-La Roche AG, Pfizer, and Boehringer Ingelheim. T. Morán, V. Gregorc, and J. Dowell have no conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
CONSORT flow diagram
Fig. 2
Fig. 2
(a) Progression-free survival by ICR (intent-to-treat population), (b) forest plot of hazard ratios for treatment effect on progression-free survival (ICR). ALK, anaplastic lymphoma kinase; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HR, hazard ratio; ICR, independent central review; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase
Fig. 3
Fig. 3
Individual tumor shrinkage and progression-free survival (independent central review) in the (a) TAS-114/S-1 group and (b) S-1 group

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