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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)

Date

08 Oct 2016

Session

Poster Display

Presenters

Takayuki Yoshino

Citation

Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370

Authors

T. Yoshino1, J. Cleary2, R. Mayer2, K. Yoshida3, L. Makris4, F. Yamashita5, A. Ohtsu6, H. Lenz7, E. Van Cutsem8

Author affiliations

  • 1 Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 2 Gastrointestinal Cancer, Dana-Farber Cancer Institute, Boston/US
  • 3 Clinical Pharmacology, Taiho Oncology, Inc., Princeton/US
  • 4 Biostatistics, Stathmi Inc., New Hope/US
  • 5 Bioanalytics And Dmpk, Taiho Oncology, Inc., Princeton/US
  • 6 Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa/JP
  • 7 Division Of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles/US
  • 8 Gastroenterology/digestive Oncology, Leuven Cancer Institute, University Hosptials Leuven, Leuven/BE
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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.

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