Clinical and Proteomic Biomarkers of Trifluridine/Tipiracil in Fluoropyrimidine-Refractory Advanced Pancreatic Adenocarcinoma: A Single-Arm Phase II Trial

PURPOSE: Patients with refractory pancreatic cancer have limited therapeutic option and dismal prognoses. This study aimed to evaluate the efficacy and safety of trifluridine/tipiracil (FTD/TPI) in patients with fluoropyrimidine-refractory pancreatic cancer and their predictive biomarkers. METHODS: In this single-arm phase II clinical trial, patients of refractory pancreatic cancer were enrolled and administered with FTD/TPI on days 1-5 and 8-12 of a 28-day cycle. The primary end point was the 16-week progression-free survival (PFS) rate. Secondary end points included median PFS, median overall survival (OS), disease control rate (DCR), and toxicities. Clinical and proteomic biomarkers were assessed before treatment and correlated with PFS and OS. RESULTS: Between March 2021 and June 2023, a total of 28 patients were enrolled. The median age was 64 years (range, 49-80), and 16 (57.1%) patients were male. All patients (100%) received prior fluoropyrimidine. Twenty-three patients (82.1%) received two or more lines of chemotherapy. After a median follow-up of 4.8 months, the 16-week PFS rate was 35.7% (95% CI, 17.8 to 53.2). The median PFS was 3.3 months (95% CI, 1.8 to 4.8) and the median OS was 4.6 months (95% CI, 3.8 to 5.4). The DCR was 50% (14/28; 95% CI, 30.7 to 69.4). The most common grade 3 or worse adverse events were neutropenia (n = 9, 32.1%) and anemia (n = 4, 14.3%) without new safety signals. Neutrophil-to-lymphocyte ratio (NLR) > 5 and high IL1RL1 level were poor prognostic factors, while high APOA4, MSTN, and LUM levels were associated with better prognoses. CONCLUSION: To our knowledge, this is the first prospective study to suggest the potential efficacy and acceptable safety of FTD/TPI in patients with pancreatic cancer refractory to fluoropyrimidine. Further randomized trials are needed to validate these findings. NLR, IL1RL1, APOA4, MSTN, and LUM levels are promising biomarkers that warrant further investigation.