Pharmacokinetic and pharmacodynamic (PK/PD) analysis results from the phase 3 RECOURSE trial of trifluridine and tipiracil (TAS-102) versus placebo (pbo) in patients (pts) with refractory metastatic colorectal cancer (mCRC)

Background

The efficacy and safety of TAS-102, an oral agent that combines trifluridine and tipiracil (FTD/TPI), in pts with mCRC refractory/intolerant to standard therapies were examined in the RECOURSE trial, which showed that there was a significant improvement in overall survival (OS) and progression-free survival (PFS) for pts treated with FTD/TPI vs pbo (HR = 0.68 and 0.48 for OS and PFS, respectively; both P 

Methods

Three blood samples were collected at steady state in Cycle 1 at 1, 3, and 6 hours after pts received 35 mg/m² of FTD/TPI or placebo in the morning. Pts were categorized into high and low exposure groups based on median AUC values for FTD (43.51 h•µg/mL) and TPI (0.65 h•µg/mL) estimated from population PK analysis.

Results

138 pts were evaluable for PK and 72 pbo pts had samples collected at ≥1 time point for PK/PD analysis. There was a trend towards longer survival and median total weeks of exposure to FTD/TPI for the FTD^high (n = 69) vs FTD^low (n = 69) groups: 13.86 and 6.14 weeks, respectively. All FTD/TPI groups had better survival outcomes than the pbo group. There were significant differences in incidence of Grade ≥3 neutropenia and dose reductions between FTD groups (Table). Rates of Grade ≥3 Tx-related adverse events (AEs) and Tx delays tended to be higher in the FTD^high group. No significant differences were observed between the TPI AUC high and low groups.

Conclusions

FTD/TPI pts with higher FTD AUC values were more likely to experience Grade ≥3 neutropenia and dose reductions and showed trends towards longer survival, more Grade ≥3 Tx-related AEs, and more Tx delays. Notably, all AUC groups had better survival outcomes than the pbo group.

NA, not applicable. *Any delays that have occurred at Cycle 2 or later; denominators = number of pts who initiated Cycle 2 for each group

Clinical trial identification

ClinicalTrials.gov Number: NCT01607957

Legal entity responsible for the study

Taiho Pharmaceutial Co., Ltd.

Funding

Taiho Pharmaceutical Co., Ltd.

Disclosure

T. Yoshino: received research funding from Sumitomo Dainippon Pharma Co., Ltd. R. Mayer: was a consultant/advisor to CASI Pharmaceuticals and receieved honoraria from Taiho Oncology, Inc. K. Yoshida: is an employee of Taiho Oncology, Inc. L. Makris: is an employee of Stathmi, Inc., and was a consultant/advisor to Taiho Oncology. A. Ohtsu: reports employment with Celgene and received honoraria from Taiho, Eisai, Daiichi-Sankyo, Merck Serono, and Chugai. H-J. Lenz: received research funding from Taiho. All other authors have declared no conflicts of interest.