Abstract 3126
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 FTDhigh (n = 69) vs FTDlow (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 FTDhigh 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
| Parameter | FTD/TPI pts (n = 138) | Pbo pts (n = 72) | FTDhigh (>43.51 h•µg/mL, n = 69) | FTDlow (≤43.51 h•µg/mL, n = 69) | FTDhigh/FTDlow HR or relative risk [95% CI] | FTDhigh/pbo HR or relative risk [95% CI] | FTDlow/pbo HR or relative risk [95% CI] |
|---|---|---|---|---|---|---|---|
| Median OS, mo [95% CI] | 8.9 [7.2, 10.2] | 5.7 [4.0, 7.3] | 9.2 [7.8, 11.1] | 8.1 [5.3, 12.2] | 0.72 [0.46, 1.11] | 0.49 [0.32, 0.76] | 0.60 [0.39, 0.92] |
| Median PFS, mo [95% CI] | 3.3 [1.9, 3.8] | 1.8 [1.6, 1.8] | 3.7 [2.1, 3.9] | 2.0 [1.9, 3.9] | 0.82 [0.57, 1.18] | 0.26 [0.17, 0.40] | 0.44 [0.29, 0.66] |
| Grade ≥3 neutropenia, n (%) | 54 (39) | 0 | 33 (48) | 21 (30) | 1.57 [1.02, 2.42] | NA | NA |
| Any Grade ≥3 AE, n (%) | 98 (71) | 38 (53) | 49 (71) | 49 (71) | 1.00 [0.81, 1.24] | 1.35 [1.03, 1.75] | 1.35 [1.03, 1.75] |
| Any Tx-related Grade ≥3 AE, n (%) | 70 (51) | 8 (11) | 39 (57) | 31 (45) | 1.26 [0.90, 1.76] | 5.09 [2.56, 10.09] | 4.04 [2.00, 8.17] |
| Febrile neutropenia, n (%) | 3 (2) | 0 | 2 (3) | 1 (1) | 2.00 [0.19, 21.55] | NA | NA |
| Any dose reduction, n (%) | 22 (16) | 0 | 16 (23) | 6 (9) | 2.67 [1.11, 6.41] | NA | NA |
| Pts with ≥1 cycle initiation delay of ≥4 days, n (%)* | 69/130 (53) | 4/56 (7) | 41/67 (61) | 28/63 (44) | 1.38 [0.98, 1.93] | 8.57 [3.27, 22.45] | 6.22 [2.33, 16.64] |
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.