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

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 improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016. Electronic supplementary material The online version of this article (10.1007/s10637-020-00930-5) contains supplementary material, which is available to authorized users.


Supplementary
Oncology), or recurrent disease following radiation therapy or surgical resection. 4. Patients who had received at least two prior therapies for advanced or metastatic disease condition, including platinum doublet and pemetrexed, docetaxel, or immunotherapy, and were refractory to or unable to tolerate their last prior therapy. For patients with known epidermal growth factor receptor activating mutations or anaplastic lymphoma kinase translocations, and/or ROS proto-oncogene 1 rearrangements, appropriate targeted treatment should have been used. The following histological tumor types could also be included: adenocarcinoma with bronchioloalveolar differentiation and large cell carcinoma.
5. The tumor is locally advanced or metastatic and not suitable for surgery and radiotherapy is not indicated. 11. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to the first dose and for 6 months after the last dose) if conception is possible during this interval. Female patients are considered to not be of childbearing potential if they have a history of hysterectomy, or are post-menopausal defined as no menses for 12 months without an alternative medical cause.
12. Willing and able to comply with required scheduled visits and study procedures.

Exclusion criteria
1. Treatment with any of the following within the specified time frame prior to the study drug administration: major surgery within prior 4 weeks and minor surgery within 7 days; radiotherapy for an extended field within 4 weeks prior or limited field within 2 weeks prior; any anticancer therapy or investigational agent within 3 weeks prior.
2. A serious illness or medical condition including but not limited to the following: patients with brain or subdural metastases are not eligible unless they have completed local therapy and have discontinued the use of therapeutic corticosteroids and are stable for at least 1 month before study drug administration; known leptomeningeal metastatic disease; known acute or chronic active systemic infection; any cardiac disease, such as myocardial infarction, unstable angina, symptomatic congestive heart failure New York Heart Association class III or IV within the last 6 months. If >6 months, cardiac function must be within normal limits and the patient must be free of cardiac-related symptoms; chronic nausea, vomiting, or diarrhea considered to be clinically significant by investigator's discretion; current or past severe lung disease (e.g., interstitial pneumonia, pulmonary fibrosis, or severe emphysema); pleural, peritoneal, or pericardial effusion which will require surgical intervention in the near term; any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the trial drug (e.g., Crohn's disease, ulcerative colitis); known human immunodeficiency virus or acquired immune deficiency syndrome-related illness, or chronic or acute hepatitis B or C; any other clinically significant acute or chronic medical or psychiatric condition or any laboratory abnormality that may increase the risk associated with study drug administration, or may interfere with the interpretation of study results; poorly controlled (despite medication) or severe diabetes mellitus; continuous systemic steroid administration (oral or intravenous); other concurrent active cancer (synchronous double cancer or heterochronous double cancer with a disease-free interval of 3 years or shorter, excluding lesions consistent with intraepithelial cancer, i.e., carcinoma in situ, or intramucosal cancer) that is assessed as cured by local treatment.
3. Concomitant treatment with the following drugs that may interact with S-1: sorivudine,