Multicenter phase II study of trifluridine/tipiracil for esophageal squamous carcinoma refractory/intolerant to 5-fluorouracil, platinum compounds, and taxanes: the ECTAS study

Abstract

BackgroundThe standard treatment for unresectable advanced/recurrent esophageal cancer in Japan is 5-Fluorouracil plus platinum-containing drugs as first-line chemotherapy and taxanes as second-line chemotherapy. However, the standard regimen after patients become refractory to these treatments remains to be established. Therefore, we investigated the efficacy of trifluridine/tipiracil (FTD/TPI) in patients with esophageal cancer who are refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. Methods This single-arm phase II trial was conducted in seven hospitals in Japan. Eligible patients were those with unresectable advanced/recurrent esophageal cancer that was refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. The primary endpoint was the three-month progression-free survival rate, and the secondary endpoints were the six-month progression-free survival rate, progression-free survival, overall survival, response rate, disease control rate, and toxicity. ResultsForty-two patients were enrolled between October 2015 and June 2016. All tumors were squamous cell carcinomas. The progression-free survival rates at three and six months were 15.4% (90% confidence interval: 7.4%-26.0%) and 7.7% (90% confidence interval: 2.6%-16.6%), respectively. The median progression-free survival and median overall survival were 1.3 (95% confidence interval: 1.0-1.8) months and 4.5 (95% confidence interval: 3.6-5.7) months, respectively. The response rate was 0%, and the disease control rate was 23.8% (95% confidence interval: 13.5%-38.5%). The major grade 3/4 toxicities were neutropenia (47.6%), leukocytopenia (35.7%), and anemia (21.4%). No treatment-related deaths occurred. Exploratory subgroup analyses showed better progression-free survival in the subgroup without distant metastasis at diagnosis. ConclusionsTrifluridine/tipiracil monotherapy is feasible and shows modest activity in patients with refractory esophageal squamous cell carcinoma.

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

“…However, given the modest response rate of immunotherapy, improving chemotherapy against ESCC using molecular‐targeted therapy such as our novel FTD/TPI and MK1775 combination is still fundamental. The FTD/TPI and MK1775 combination could be a good candidate strategy as the last line of treatment after taxanes, given the good tolerability of FTD/TPI shown in our previous phase II trial 12 . Several trials are already evaluating WEE1 inhibitors in non‐small cell lung, ovarian, colon, and squamous cells of head and neck cancer when using monotherapy or combined with other cytotoxic agents.…”

“…The FTD/TPI and MK1775 combination could be a good candidate strategy as the last line of treatment after taxanes, given the good tolerability of FTD/TPI shown in our previous phase II trial. 12 Several trials are already evaluating WEE1 inhibitors in non‐small cell lung, ovarian, colon, and squamous cells of head and neck cancer when using monotherapy or combined with other cytotoxic agents. In a phase II trial conducted in 718 patients with RAS/TP53 mutant metastatic colorectal cancer (FOCUS4‐C), monotherapy of MK1775 increased PFS with good tolerance but no improvement in OS.…”

“…However, overall, it failed to maintain progression-free survival (PFS), 12 indicating that FTD/TPI needs additional cotreatment. Therefore, we aimed to develop a combination therapy with FTD/TPI and another small molecule to achieve better efficacy against ESCC.…”

“…We reported that FTD/TPI had good tolerability for heavily pretreated patients with ESCC and efficacy in controlling the primary esophageal lesion. However, overall, it failed to maintain progression‐free survival (PFS), 12 indicating that FTD/TPI needs additional cotreatment. Therefore, we aimed to develop a combination therapy with FTD/TPI and another small molecule to achieve better efficacy against ESCC.…”

Folate Receptor 4-Expressing T cell Is Associated with Disease-Free Survival in Patients with Esophageal Squamous Cell Carcinoma

“…Although radical esophagectomy improves the survival rate of ESCC patients, the recurrence rate is still as high as 27%-52%, limiting its clinical efficacy [ 2 , 3 ]. Chemotherapeutic drugs such as cisplatin, 5-fluorouracil (5-FU), and paclitaxel for ESCC exhibit obvious limitations in clinical outcomes [ 4 ]. Currently, immunotherapeutic monoclonal antibodies offer hope for the treatment of ESCC.…”