There is no effective chemotherapy for patients with esophageal squamous cell carcinoma (ESCC) refractory or intolerant to 5-FU, platinum, and taxanes. TAS-102 is an oral combination drug of trifluridine and tipiracil hydrochloride. Our preclinical study showed that TAS-102 has antitumor activity against 5-FU resistant esophageal cancer cells. We conducted this study to evaluate the safety and efficacy of TAS-102 in ESCC patients who were refractory or intolerant to standard treatment (UMIN000019268).
Patients with histologically proven advanced or recurrent ESCC, which had been refractory or intolerable to 5-FU, platinum, and taxanes, were eligible. Patients also had to satisfy following criteria: >20 years of age; ECOG performance status 0 or 1; adequate organ functions. TAS-102, 35 mg/m2 bid, was administered on days 1-5 and 8-12 for the first 2 weeks followed by 2-week rest. The regimen was repeated every 4 weeks until disease progression, serious adverse event, or refusal. Primary endpoint was progression-free survival rate at 3 months (PFS3). With expected PFS3 of 25% to 30% and the null hypothesis of 10% under 80% power and a one-sided significance level of 5%, 35 patients was needed.
A total of 42 patients were enrolled. 90% of the patients were male, 95% had distant metastasis, and 98% had target lesion (s). As of data cutoff, 34 events were observed. PFS3 was 15.4% (90% CI: 7.4%, 26.0%), which did not reject the null hypothesis. Median PFS and OS were 1.3 months and 4.5 months, respectively. Response rate was 0%, although 24% (10/42) of patients achieved stable disease. There were 3 patients not evaluable for response. Major treatment related adverse events of grade ≧3 were: neutrophil count decreased (48%), febrile neutropenia (7%), and appetite decreased (5%). No treatment related death was observed.
TAS-102 was feasible and showed modest efficacy in patients with refractory ESCC.
Clinical trial identification
Legal entity responsible for the study
Kyoto University Hospital
Taiho Pharmaceutical Co. Ltd.
T. Kojima: Corporate-sponsored research (to institution): Onoyakuhin, Shionogiseiyaku, MSD, Taihouyakuhin, Merukuserono, AstraZeneca. T. Tsushima: Takeda, Chugai Pharma, Taiho Pharmaceutical. H. Hara: AstraZeneca, Chugai Pharma, Merck Serono, MSD, Ono Pharmaceutical, Taiho. Pharmaceutical, Takeda, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Daiichi-Sankyo. K. Kato: ONO Phaumaceticals, MSD, Sionogi, Merck Serono. M. Muto: Olympus, Mitsui Knowledge Industry, Taiho Pharmaceutical, Chugai Pharma, Theravalues Corporation, Pfizer. All other authors have declared no conflicts of interest.