Investigational New Drugs (2020) 38:1588–1597 https://doi.org/10.1007/s10637-020-00930-5 PHASE II STUDIES 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 1 & Hidetoshi Hayashi 2 & David Planchard 3 & Teresa Morán 4 & Vanesa Gregorc 5 & Jonathan Dowell 6 & Hiroshi Sakai 7 & Kiyotaka Yoh 8 & Makoto Nishio 9 & Alexis B. Cortot 10 & Karim A. Benhadji 11 & Nital Soni 11 & Jinhong Huang 12 & Lukas Makris 13 & Susana Cedres 14 Received: 26 February 2020 / Accepted: 20 March 2020 / Published online: 3 April 2020 # The Author(s) 2020 Summary 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 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00930-5) contains supplementary material, which is available to authorized users. * Nobuyuki Yamamoto Makoto Nishio nbyamamo@wakayama-med.ac.jp mnishio@jfcr.or.jp Hidetoshi Hayashi Alexis B. Cortot hidet31@med.kindai.ac.jp alexis.cortot@chru-lille.fr David Planchard Karim A. Benhadji david.planchard@gustaveroussy.fr KBenhadji@taihooncology.com Teresa Morán Nital Soni mmoran@iconcologia.net nsoni@taihooncology.com Vanesa Gregorc Jinhong Huang vanesa.gregorc@hsr.it j-huang@taiho.co.jp Jonathan Dowell Lukas Makris Jonathan.Dowell@UTSouthwestern.edu lmakris@taihooncology.com Hiroshi Sakai hiroshi_sakai@cancer-c.pref.saitama.jp Susana Cedres scedres@vhio.net Kiyotaka Yoh kyoh@east.ncc.go.jp Extended author information available on the last page of the article Invest New Drugs (2020) 38:1588–1597 1589 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 dUTPase . Non-small-cell lung cancer . 5-fluorouracil . Progression-free survival Introduction (Japan, France, Spain, Italy, and the United States). Eligible patients were enrolled by the investigators and randomly Non-small-cell lung cancer (NSCLC) is the leading cause of assigned to TAS-114 plus S-1 (TAS-114/S-1) or S-1 alone in cancer incidence and cancer-related mortality worldwide [1]. a 1:1 ratio. The random allocation sequence was generated, Recently, the development of immunotherapy and its combi- and treatment assignment performed centrally using a dynam- nation with cytotoxic chemotherapies has garnered new op- ic allocation method (biased coin) via an interactive voice/web tions for therapeutics in advanced NSCLC [2]. However, de- response system. Patients were stratified by histological sub- spite recent advances, most patients still progress after treat- type (squamous vs. non-squamous) and region (Europe/ ment, and cytotoxic chemotherapies remain essential in United States vs. Japan). NSCLC treatment algorithms [3, 4]. Thus, highly efficacious, The study was approved by independent ethics committees well-tolerated chemotherapies are still warranted. or institutional review boards at each site. The study conduct S-1 is an oral 5-fluorouracil (5-FU) derivative that is widely was in accordance with Good Clinical Practice Guidelines and used for the treatment of various solid tumors, including the Declaration of Helsinki. All patients provided written in- NSCLC [5]. Recently, a phase 3 study of S-1 monotherapy formed consent before enrollment (ClinicalTrials.gov identifi- demonstrated non-inferiority compared with docetaxel in pa- er NCT02855125). tients with NSCLC; thus, S-1 is considered a standard chemo- therapy option in East Asia [6]. Patients TAS-114 is a potent inhibitor of deoxyuridine triphosphatase (dUTPase), which is a gatekeeper protein that Key eligibility criteria were age ≥ 18 years (≥ 20 years in prevents uracil and 5-FU misincorporation into DNA. TAS- Japan), histologically confirmed advanced or metastatic 114 inhibits the conversion of deoxyuridine triphosphate NSCLC; prior treatment with at least two systemic therapies (dUTP) and 5-fluoro-dUTP (FdUTP) into their (one of which must be platinum doublet and either monophosphate forms. TAS-114 itself does not have antitu- pemetrexed, docetaxel, or immunotherapy) for advanced or mor activity; however, when it is combined with 5-FU deriv- metastatic NSCLC; Eastern Cooperative Oncology Group atives, it can increase the amount of FdUTP in the tumor for performance status (ECOG PS) of 0–1; adequate bone marrow selective incorporation into DNA, thus enhancing the antitu- function (absolute neutrophil count ≥ 1500/mm3, hemoglo- mor effect [7, 8]. bin ≥ 10.0 g/dL, platelets ≥ 100,000/mm3); adequate liver Two previous phase 1 studies of TAS-114 combined with function (total bilirubin ≤ 1.5 × upper limit of normal [ULN], S-1, conducted separately in Europe and Japan, concluded that aspartate aminotransferase/alanine aminotransferase ≤ 3 × the recommended dose was TAS-114 240 mg/m2 plus S-1 30 ULN [in patients with existent liver metastases, ≤ 5 × mg/m2. The combination of TAS-114 and S-1 demonstrated ULN]); and adequate renal function (calculated creatinine promising antitumor activity, with a manageable safety profile clearance ≥ 50 mL/min [Cockcroft-Gault]). All eligibility in heavily pretreated solid tumors. The overall response rate criteria are listed in Online Resource Text S1. (ORR), including unconfirmed partial response (PR), in NSCLC was approximately 30% [9, 10]. Based on these re- sults, we conducted a randomized phase 2 study to investigate Treatment the combination of TAS-114 with S-1 vs. S-1 monotherapy in patients with advanced NSCLC. TAS-114 400 mg and/or S-1 30 mg/m2 were concurrently administered orally twice daily under fasting conditions in a schedule consisting of 14 consecutive days of treatment followed by a 7-day rest. TAS-114 dosing was switched from Materials and methods body surface area (BSA)-based to a flat-fixed dose to avoid the risk of dosing errors. TAS-114 400 mg was equivalent to Study design 240 mg/m2, which is the recommended dose of TAS-114 for an overall mean BSA of 1.69 m2 based on the results of the This was an open-label, multicenter, international, random- two phase 1 studies [9, 10]. In these studies, there was no ized phase 2 study conducted at 28 sites across five countries correlation between the oral clearance of TAS-114 and BSA. 1590 Invest New Drugs (2020) 38:1588–1597 Treatment was repeated every 3 weeks until disease progres- baseline and with at least one tumor evaluation. We performed sion, intolerable toxicities, or withdrawal of consent. No a sensitivity analysis in which PFS, ORR, and DCR were also crossover was permitted. analyzed based on the investigator’s assessment. The safety analysis was conducted on an as-treated population, defined as Endpoints and study assessments all patients who received at least one dose of the study drug. PFS and OS were estimated using the Kaplan–Meier meth- The primary endpoint was progression-free survival (PFS) as od; HRs were estimated using a Cox proportional hazards determined by independent central review (ICR). Secondary model stratified by geographical region and histological sub- endpoints were ORR, disease control rate (DCR), overall sur- types. Medians (with 95% confidence intervals [CIs]) were vival (OS), and safety. PFS was defined as the time from calculated using the Brookmeyer-Crowley method. For randomization to the date of first radiologic disease progres- between-group comparisons, the stratified log-rank test with sion or death, whichever occurred first. ORR was defined as a one-sided significance level of 5% was used for PFS and OS, the proportion of patients with complete response (CR) or PR. and Fisher’s exact test for ORR and DCR. All statistical anal- DCR was defined as the proportion of patients with CR, PR, yses were performed using SAS software version 9.4 in the or stable disease. OS was defined as the time from randomi- UNIX environment (SAS Institute Inc., North Carolina, zation to death. Tumor shrinkage for each patient and its cor- USA). relation with PFS by ICR was assessed as an exploratory analysis. Tumor assessments were performed every 6 weeks from the first study drug administration until disease progression Results according to the RECIST version 1.1. Assessment results were evaluated by independent central radiologists Patients (Medpace Imaging Core Lab, Ohio, USA) and by the inves- tigators at each site. From August 2016 to July 2017, a total of 128 patients were Adverse events (AEs) were reported using the verbatim randomly assigned to treatment: 64 patients each were term, and the severity was graded based on the National assigned to the TAS-114/S-1 and S-1 groups (Fig. 1). A total Cancer Institute Common Terminology Criteria for Adverse of 127 patients received at least one study treatment; one pa- Events version 4.03. AEs were coded by preferred term ac- tient in the S-1 group was found ineligible, and thus, cording to the Medical Dictionary for Regulatory Activities discontinued before the initial study drug administration. (MedDRA®: trademark is registered by the International Twenty patients were receiving treatment by the cut-off date Federation of Pharmaceutical Manufacturers & Associations for primary analysis (30 September 2017). Baseline character- on behalf of the International Council for Harmonisation) ver- istics were generally balanced in the two groups, except for sion 19.0. sex, ECOG PS, and epidermal growth factor receptor (EGFR) mutation status (Table 1). More than half of the patients had Statistical analysis received a prior systemic regimen as fourth-line or further therapy. Over 70% of patients had received prior programmed The sample size was estimated based on PFS. A total sample death 1/programmed death-ligand 1 antibodies. size of 124 patients was required to provide 60 events (pro- gressive disease or death) by ICR for the primary analysis, which corresponds to 71 events based on investigator review Treatment under the assumption that the discrepancy in progressive dis- ease events between ICR and investigator review is 15%. In the TAS-114/S-1 and S-1 groups, patients received me- Based on the results of previous clinical trials [9–13], the dians of 4.0 (range, 1–14) and 3.0 (range, 1–12) treatment median PFS in the S-1 group was estimated to be 2.2 months, cycles, respectively. In the TAS-114/S-1 group, the me- and 4.2 months in the TAS-114/S-1 group, corresponding to a dians for relative dose intensity (RDI) of TAS-114 and hazard ratio (HR) of 0.524, with 80% statistical power and a S-1 were 85.9% and 84.8%, respectively. In the S-1 one-sided significance level of 0.05. group, the median RDI was 95.5%. By the data cut-off The PFS and OS analyses were conducted on an intent-to- date, 107 patients had discontinued study treatment. In treat (ITT) population, of all patients randomized in the study, both groups, the main reason for discontinuation was dis- regardless of whether they received any study treatment or ease progression. After study discontinuation, 54.5% and not. The ORR was analyzed based on the tumor response- 65.4% of patients in the TAS-114/S-1 and S-1 groups, evaluable population, defined as all patients in the ITT popu- respectively, received other anticancer treatments. The lation with measurable disease (at least one target lesion) at median duration for survival follow-up was 9.03 months. Invest New Drugs (2020) 38:1588–1597 1591 Fig. 1 CONSORT flow diagram Efficacy TAS-114/S-1 group, two patients each reported treatment- related serious anemia (3.1%), diarrhea (3.1%), and maculo- At the data cut-off date, 73 PFS events were observed by ICR. papular rash (3.1%) of any grade. More patients in the TAS- The median PFS was 3.65 months in the TAS-114/S-1 group 114/S-1 group had dose reductions/interruptions (mainly due and 4.17 months in the S-1 group (HR 1.16, 95% CI 0.71– to skin toxicities) than patients in the S-1 group (reductions: 1.88; P = 0.2744) (Fig. 2a). In the subgroup analyses, the data 31.3% vs. 11.1%; interruptions: 45.3% vs. 14.3%) (Online were generally similar to that of the overall population (Fig. Resource Table S1). No treatment-related death was reported. 2b). The DCR was similar between TAS-114/S-1 and S-1 groups (80.3% vs. 75.9%), whereas patients in the TAS-114/ S-1 group showed higher ORR than those in the S-1 group (19.7% vs. 10.3%) (Table 2). Additionally, Fig. 3a and b Discussion shows the relationship between tumor shrinkage and PFS by The present randomized study is the first to evaluate the effect RECIST for each patient. Investigator-assessed results were of a dUTPase inhibitor in combination with a 5-FU derivative. 3.48 months vs. 2.66 months for PFS (HR 0.79, 95% CI 0.52– Favorable tumor response and shrinkage trends were observed 1.21; P = 0.1352), 78.7% vs. 59.3% for DCR, and 19.7% vs. in the TAS-114/S-1 group; however, they did not translate into 10.2% for ORR (Table 2; Online Resource Figures S1 and an improved PFS. No difference in duration of response was S2). observed, and the early progressive disease (< 3 months) rate The data cut-off for OS was 30 November 2017, at which was similar across groups. A possible reason is that more time 65 events were observed. The median OS was 7.92 in the patients in the TAS-114/S-1 group experienced dose TAS-114/S-1 group and 9.82 months in the S-1 group (HR reductions/interruptions due to AEs, and these results may 1.31, 95% CI 0.80–2.14; P = 0.1431) (Online Resource have affected the primary endpoint result. Figures S3 and S4). According to the investigator review, the median PFS was 3.48 months for the TAS-114/S-1 group and 2.66 months for Safety the S-1 group (95 PFS events). In the S-1 group, a significant difference in the median PFS (1.51-month difference) was Treatment-related AEs (TRAEs) occurring in ≥ 10% of pa- observed between the ICR and investigator review, in contrast tients are shown in Table 3. The incidence rates of anemia, with the TAS-114/S-1 group (0.17-month difference). This skin toxicities, and Grade ≥ 3 TRAEs were higher in the TAS- may be a result of treatment bias owing to lack of blinding. 114/S-1 group compared with the monotherapy group. In fact, the number of censored cases was higher in the S-1 Serious TRAEs were reported in 17.2% of patients in the group by ICR; therefore, the PFS in the S-1 group was pre- TAS-114/S-1 group, and in 6.7% in the S-1 group. In the sumably influenced by informative censoring [14]. 1592 Invest New Drugs (2020) 38:1588–1597 Table 1 Baseline demographic characteristics (intent-to-treat Characteristic TAS-114/S-1 S-1 population) (n = 64) (n = 64) Age (years), median 65.5 64.0 Age group, n (%) < 65 years 28 (43.8) 33 (51.6) ≥ 65 years 36 (56.3) 31 (48.4) Sex, n (%) Male 41 (64.1) 48 (75.0) Female 23 (35.9) 16 (25.0) Region, n (%) Western 34 (53.1) 34 (53.1) Asian 30 (46.9) 30 (46.9) ECOG PS, n (%) 0 12 (18.8) 17 (26.6) 1 52 (81.3) 47 (73.4) Histology subtype, n (%) Squamous cell carcinoma 14 (21.9) 14 (21.9) Adenocarcinoma 48 (75.0) 48 (75.0) Large cell carcinoma 0 1 (1.6) Carcinoid tumor 1 (1.6) 0 Other 1 (1.6) 1 (1.6) EGFR mutation status, n (%) Positive 7 (10.9) 12 (18.8) Negative 46 (71.9) 38 (59.4) Unknown 11 (17.2) 14 (21.9) ALK translocation status, n (%) Positive 2 (3.1) 0 Negative 44 (68.8) 43 (67.2) Unknown 18 (28.1) 21 (32.8) Brain metastases, n (%) 6 (9.4) 7 (11.0) Number of prior systemic regimens, n (%) 1 0 0 2 24 (37.5) 19 (29.7) 3 19 (29.7) 17 (26.6) 4 14 (21.9) 15 (23.4) ≥5 7 (10.9) 13 (20.3) Main prior systemic anti-cancer agent, n (%) Platinum 64 (100) 64 (100) PD-1/PD-L1 antibodies 46 (71.9) 49 (76.6) Pemetrexed 48 (75.0) 47 (73.4) Docetaxel 33 (51.6) 38 (59.4) EGFR-TKI 7 (11.0) 11 (17.2) ALK-TKI 2 (3.1) 0 ALK, anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TKI, tyrosine kinase inhibitor The OS result was immature at the data cut-off, but resulted from the percentage and timing of patients receiv- was lower in the TAS-114/S-1 group (not statistically sig- ing anticancer treatment after discontinuation, and some nificant). This difference between groups might have imbalances in patient background characteristics that are Invest New Drugs (2020) 38:1588–1597 1593 Fig. 2 (a) Progression-free survival by ICR (intent-to-treat population), interval; ECOG, Eastern Cooperative Oncology Group; EGFR, (b) forest plot of hazard ratios for treatment effect on progression-free epidermal growth factor receptor; HR, hazard ratio; ICR, independent survival (ICR). ALK, anaplastic lymphoma kinase; CI, confidence central review; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase known to be prognostic factors, such as EGFR mutation combination, and all five patients remaining in TAS-114 [15, 16]. Based on the efficacy and safety results, the treatment were switched to S-1 alone after the primary s p o n s o r d e c i d e d t o t e r m i n a t e t h e TA S - 11 4 / S - 1 analysis. 1594 Invest New Drugs (2020) 38:1588–1597 Table 2 Overall response rate and disease control rate by ICR ICR INV and INV (tumor response evaluable population) TAS-114/S-1 S-1 TAS-114/S-1 S-1 (n = 61) (n = 58) (n = 61) (n = 59) Overall response rate, 19.7 10.3 19.7 10.2 % (95% CI) (10.6–31.8) (4.0–21.5) (10.6–31.8) (3.9–21.2) CR 1 (1.6) 0 0 0 PR 11 (18.0) 6 (10.3) 12 (19.7) 6 (10.2) SD 37 (60.7) 38 (65.5) 36 (59.0) 29 (49.2) PD 12 (19.7) 13 (22.4) 13 (21.3) 23 (39.0) Disease control rate 80.3 75.9 78.7 59.3 (CR + PR + SD), % (95% CI) (68.2–89.4) (64.2–87.3) (66.3–88.1) (46.6–73.0) CI, confidence interval; CR, complete response; ICR, independent central review; INV, Investigator review; PR, partial response; PD, progressive disease; SD, stable disease Although the patient numbers were very limited (7 vs. 12 The overall safety profile in the TAS-114/S-1 group was patients), the subgroup analysis showed that EGFR-mutant consistent with previous phase 1 studies; anemia and skin patients tended to achieve longer PFS (11.6 months vs. 2.6 toxicities were more commonly observed in this group [9, months; HR 0.18; 95% CI 0.02–1.63) and OS (not reached vs. 10]. These toxicities were considered manageable by dose 10.6 months; HR 0.12; 95% CI 0.01–0.99) in the TAS-114/S- modification and standard symptomatic treatment and were 1 group vs. the S-1 group. It has been reported that advanced presumed to result from the combination of TAS-114 and NSCLC EGFR-mutant patients present defective DNA-repair S-1. In exploratory analysis, patients with anemia and/or skin functions [17, 18]. In a preclinical model, suppression of DNA toxicities in the TAS-114/S-1 group showed a tendency to- repair proteins increased its sensitivity to TAS-114 combined ward longer PFS compared with patients without these toxic- with the 5-FU metabolite 5-fluoro-2’-deoxyuridine [19]. ities (Online Resource Text S2). Moreover, anemia was also Thus, it is possible that the present favorable effect in patients commonly reported with DNA-damaging agents; it is possible with EGFR mutations in the TAS-114/S-1 group resulted from that the frequent anemia reported with TAS-114/S-1 was at- increased uracil and 5-FU incorporation into DNA. tributed to increased DNA damage [20, 21]. 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 Invest New Drugs (2020) 38:1588–1597 1595 Table 3 Treatment-related adverse events (as-treated TAS-114/S-1 S-1 population) (n = 64) (n = 63) All Grades ≥Grade 3 All Grades ≥Grade 3 Event n (%) n (%) n (%) n (%) All 60 (93.8) 35 (54.7) 57 (90.5) 10 (15.9) Hematology Anemia 37 (57.8) 14 (21.9) 10 (15.9) 0 White blood cell count decreased 10 (15.6) 2 (3.1) 5 (7.9) 0 Platelet count decreased 8 (12.5) 1 (1.6) 6 (9.5) 0 Neutrophil count decreased 6 (9.4) 2 (3.1) 7 (11.1) 1 (1.6) Non-hematology Decreased appetite 25 (39.1) 3 (4.7) 22 (34.9) 1 (1.6) Nausea 20 (31.3) 0 20 (31.7) 1 (1.6) Diarrhea 18 (28.1) 2 (3.1) 12 (19.0) 1 (1.6) Skin hyperpigmentation 18 (28.1) 0 11 (17.5) 0 Maculo-papular rash 18 (28.1) 4 (6.3) 2 (3.2) 0 Asthenia 17 (26.6) 4 (6.3) 9 (14.3) 2 (3.2) Rash 15 (23.4) 5 (7.8) 3 (4.8) 0 Vomiting 10 (15.6) 0 11 (17.5) 2 (3.2) Pruritus 10 (15.6) 0 7 (11.1) 0 Stomatitis 9 (14.1) 1 (1.6) 4 (6.3) 0 Malaise 8 (12.5) 0 5 (7.9) 0 Fatigue 6 (9.4) 1 (1.6) 9 (14.3) 1 (1.6) Dry skin 9 (14.1) 0 5 (7.9) 0 The present study had several limitations. These include Lukas Makris; Statistical analysis: Lukas Makris; Manuscript prepara- tion: Nobuyuki Yamamoto, Hidetoshi Hayashi, David Planchard, the relatively small sample size that may have prevented the Teresa Morán, Vanesa Gregorc, Jonathan Dowell, Hiroshi Sakai, identification of some group differences, the open-label de- Kiyotaka Yoh, Makoto Nishio, Alexis B. Cortot, Susana Cedres, Karim sign that may have introduced bias from the investigators, A. Benhadji, Nital Soni, Jinhong Huang, Lukas Makris; Manuscript and the background characteristic imbalances that may have editing: Nobuyuki Yamamoto, Hidetoshi Hayashi, David Planchard, Teresa Morán, Vanesa Gregorc, Jonathan Dowell, Hiroshi Sakai, affected the primary endpoint results. Kiyotaka Yoh, Makoto Nishio, Alexis B. Cortot, Susana Cedres, Karim A. Benhadji, Nital Soni, Jinhong Huang, Lukas Makris; Manuscript re- view: Nobuyuki Yamamoto, Hidetoshi Hayashi, David Planchard, Teresa Morán, Vanesa Gregorc, Jonathan Dowell, Hiroshi Sakai, Kiyotaka Yoh, Conclusions Makoto Nishio, Alexis B. Cortot, Susana Cedres, Karim A. Benhadji, Nital Soni, Jinhong Huang, Lukas Makris. Although the TAS-114/S-1 combination did result in a higher response rate and tumor shrinkage in this advanced NSCLC Funding information This work was supported by Taiho Oncology, Inc. and Taiho Pharmaceutical Co., Ltd. The funding sources played a role in population, it did not improve PFS or OS. the study design; collection, analysis, and interpretation of data; writing of the report; and in the decision to submit the article for publication. Acknowledgements We thank the patients, their families, the investiga- tors (Online Resource Table S2), and sites that participated in this study. Availability of data and material Anonymized, patient-level, analyzable The authors would like to thank Keyra Martinez Dunn, MD and Sarah datasets will not be shared according to the Sponsor policy on data shar- Bubeck, PhD, of Edanz Medical Writing, for providing medical writing ing (https://www.taiho.co.jp/en/science/policy/clinical_trial_ support which was funded by Taiho Pharmaceutical Co., Ltd. information_disclosure_policy/index.html). Author Contribution Study concepts: Karim A. Benhadji, Nital Soni, Jinhong Huang, Lukas Makris; Study design: Karim A. Benhadji, Nital Soni, Jinhong Huang, Lukas Makris; Data acquisition: Nobuyuki Compliance with ethical standards Yamamoto, Hidetoshi Hayashi, David Planchard, Teresa Morán, Vanesa Gregorc, Jonathan Dowell, Hiroshi Sakai, Kiyotaka Yoh, Makoto Nishio, Conflicts of interest/Competing interests N. Yamamoto has received Alexis B. Cortot, Susana Cedres; Data analysis and interpretation: grants and/or personal fees from Taiho Pharmaceutical. H. Hayashi has Nobuyuki Yamamoto, Karim A. Benhadji, Nital Soni, Jinhong Huang, received grants and personal fees from AstraZeneca, Boehringer 1596 Invest New Drugs (2020) 38:1588–1597 Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly References Japan, MSD, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical. D. Planchard has participated in consulting, acted in an 1. 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Yoh has received grants and/or personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, 3. National Comprehensive Cancer Network Clinical Practice Chugai Pharmaceutical, Eli Lilly Japan, MSD, Novartis, Ono Guidelines in Oncology. Non-small cell lung cancer. Version Pharmaceutical, Pfizer, and Taiho Pharmaceutical. M. Nishio has re- 2.2018. https://www2.tri-kobe.org/nccn/guideline/lung/english/ ceived grants and/or non-financial support from F. Hoffmann-La Roche non_small.pdf. Accessed 1 Aug 2019 and grants and/or personal fees from Astellas, AstraZeneca, Boehringer 4. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Mok TS, Reck M, Van Schil PE, Hellmann MD, Peters S (2019) Merck Serono, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sankyo Correction to: “Metastatic non-small cell lung cancer: ESMO Healthcare, and Taiho Pharmaceutical. A. Cortot has received grants, Clinical Practice Guidelines for diagnosis, treatment and follow- personal fees, and/or non-financial support from Astra-Zeneca, Bristol up”. Ann Oncol 30(5):863–870. https://doi.org/10.1093/annonc/ Myers Squibb, Merck, MSD, Novartis, Pfizer, Roche, and Takeda. KA mdy474 Benhadji and N. Soni are employees of Taiho Oncology Inc. J. Huang is 5. Takeda K (2013) Clinical development of S-1 for non-small cell an employee of Taiho Pharmaceutical and owns Taiho Pharmaceutical lung cancer: a Japanese perspective. Ther Adv Med Oncol 5(5): stock. L. Makris has received personal fees from Taiho Oncology, Inc. S. 301–311. https://doi.org/10.1177/1758834013500702 Cedres has served in a consulting or an advisory role for Bristol-Myers 6. Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Squibb, F. Hoffmann-La Roche AG, Pfizer, Boehringer Ingelheim, MSD Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T, Oncology, and Amphera; and has received travel and accommodation Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, funding from F. Hoffmann-La Roche AG, Pfizer, and Boehringer Morita S, Tamura T (2017) Randomized controlled trial of S-1 Ingelheim. T. Morán, V. Gregorc, and J. Dowell have no conflicts of versus docetaxel in patients with non-small-cell lung cancer previ- interest to disclose. ously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol 28(11):2698–2706. https://doi. Ethics approval The study was approved by independent ethics com- org/10.1093/annonc/mdx419 mittees or institutional review boards at each site. 7. Saito K, Nagashima H, Noguchi K, Yoshisue K, Yokogawa T, Matsushima E, Tahara T, Takagi S (2014) First-in-human, phase I dose-escalation study of single and multiple doses of a first-in-class Consent to participate All patients provided written informed consent enhancer of fluoropyrimidines, a dUTPase inhibitor (TAS-114) in before enrollment. healthy male volunteers. Cancer Chemother Pharmacol 73(3):577– 583. https://doi.org/10.1007/s00280-014-2383-2 Consent for publication All patients provided written informed consent 8. Yano W, Yokogawa T, Wakasa T, Yamamura K, Fujioka A, for publication before enrollment. Yoshisue K, Matsushima E, Miyahara S, Miyakoshi H, Taguchi J, Chong KT, Takao Y, Fukuoka M, Matsuo K (2018) TAS-114, a Code availability All statistical analyses were performed using SAS first-in-class dual dUTPase/DPD inhibitor, demonstrates potential software version 9.4 in the UNIX environment (SAS Institute Inc., to improve therapeutic efficacy of fluoropyrimidine-based chemo- North Carolina, USA). therapy. Mol Cancer Ther 17(8):1683–1693. https://doi.org/10. 1158/1535-7163.Mct-17-0911 Ethical approval All procedures performed in studies involving human 9. Doi T, Yoh K, Shitara K, Takahashi H, Ueno M, Kobayashi S, participants were in accordance with the ethical standards of the institu- Morimoto M, Okusaka T, Ueno H, Morizane C, Okano N, tional and/or national research committee and with the 1964 Helsinki Nagashima F, Furuse J (2019) First-in-human phase 1 study of declaration and its later amendments or comparable ethical standards. novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors. Invest New Drugs 37(3):507–518. https://doi.org/10.1007/s10637-018-0697-3 Informed consent Informed consent was obtained from all individual participants included in the study. 10. Fasolo A, Aoyama T, Stathis A et al. A large phase I study of TAS- 114 in combination with S-1 in patients with advanced solid tumors. 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Publisher’s note Springer Nature remains neutral with regard to jurisdic- https://doi.org/10.1097/JTO.0b013e3181fd418d tional claims in published maps and institutional affiliations. Affiliations Nobuyuki Yamamoto 1 & Hidetoshi Hayashi 2 & David Planchard 3 & Teresa Morán 4 & Vanesa Gregorc 5 & Jonathan Dowell 6 & Hiroshi Sakai 7 & Kiyotaka Yoh 8 & Makoto Nishio 9 & Alexis B. Cortot 10 & Karim A. Benhadji 11 & Nital Soni 11 & Jinhong Huang 12 & Lukas Makris 13 & Susana Cedres 14 1 8 Third Department of Internal Medicine, Wakayama Medical Department of Thoracic Oncology, National Cancer Center Hospital University, 811-1 Kimiidera, Wakayama, Wakayama Prefecture 641- East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan 8509, Japan 9 Department of Thoracic Medical Oncology, The Cancer Institute 2 Department of Medical Oncology, Kindai University Faculty of Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Ariake, Koto, Tokyo 135-8550, Japan Japan 10 Thoracic Oncology Department, Centre Hospitalier Universitaire de 3 Department of Medical Oncology, Thoracic Group, Institut Gustave Lille, 2 Avenue Oscar Lambret, Lille 59000, France Roussy, 114 rue Édouard- Vaillant, Villejuif Cedex 94805, France 11 Department of Clinical Development, Taiho Oncology, Inc, 101 4 Medical Oncology, Catalan Institute of Oncology, Hospital Germans Carnegie Center, Suite 101, Princeton, NJ 08540, USA Trias i Pujol, Universitat Autonoma de Barcelona (UAB), B-ARGO, 12 Department of Pharmacovigilance, Taiho Pharmaceutical Co., Ltd, Carretera de Canyet s/n, Badalona, Barcelona 08916, Spain 1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo 101-8444, Japan 5 Department of Oncology, Division of Experimental Medicine, 13 Stathmi, Inc, 125 Brownsburg Rd, New Hope, PA 18938, USA IRCCS Ospedale San Raffaele, Via Olgettina, 60, Milano 20132, 14 Italy Medical Oncology Department, Vall d´Hebron University Hospital/ 6 Vall d´Hebron Institute of Oncology, Passeig de la Vall d’Hebron Department of Internal Medicine, University of Texas Southwestern 119-129, Barcelona 08035, Spain Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA 7 Department of Thoracic Oncology, Saitama Cancer Center, 780 Komuro, Ina, Kita-Adachi, Saitama 362-0806, Japan