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

Resources

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 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

Parameter	FTD/TPI pts (n = 138)	Pbo pts (n = 72)	FTD^high (>43.51 h•µg/mL, n = 69)	FTD^low (≤43.51 h•µg/mL, n = 69)	FTD^high/FTD^low HR or relative risk [95% CI]	FTD^high/pbo HR or relative risk [95% CI]	FTD^low/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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