Abstract 2259
Background
TAS-102 is an oral nucleoside antitumor agent, consisting of trifluridine (FTD) and tipiracil hydrochloride. FTD is incorporated into DNA after phosphorylation by thymidine kinase 1 (TK1). In the RECOURSE Phase III, an overall survival (OS) benefit for TAS-102 over placebo was observed in the overall population and was consistent with that in 266 Japanese patients (pts) (TAS-102 vs. placebo; 7.8M vs 6.7M, HR = 0.77). Correlations between TK1 expression and OS, progression-free survival (PFS) and disease control rate (DCR), were investigated.
Methods
Immunohistochemical analysis of TK1 expression in cytoplasm was blindly assessed. TK1 expression was divided into high or low according to the cut-off points at each 5% increment of occupancy of positive cells previously reported (#2365, ESMO 2013).
Results
179 FFPE archival tumor tissues from 183 additional consenting Japanese pts were evaluable for TK1 expression. The median OS with a high TK1 expression tends to shorter than that with a low TK1 in the placebo group, whereas TAS-102 tended to reduce the risk of death at each cut-off point in pts with a high TK1 without a statistical significance (Table). In addition, OS benefit was more pronounced in pts with a high TK1 at cut-off point of 10% or 15%.
Conclusions
TK1 could be a negative prognostic factor of mCRC and some OS benefit for TAS-102 was observed in pts with a high TK1. Further investigation is needed to clarify the clinical significance of TK1 expression on TAS-102 treatment since this study included a small number of pts. The PFS and DCR are presented in this meeting.
| OS at each cut-off point | TAS-102 N/Event | TAS-102 Median | PBO N/Event | PBO Median | HR (95% CI) | HR p-value |
|---|---|---|---|---|---|---|
| Cut-off value of 5% | ||||||
| H | 103/94 | 9.3 | 37/32 | 6.9 | 0.82 (0.55, 1.24) | 0.35 |
| L | 22/19 | 9.0 | 17/17 | 9.5 | 1.05 (0.50, 2.20) | 0.90 |
| 10% | ||||||
| H | 70/63 | 9.9 | 25/21 | 6.9 | 0.71 (0.43, 1.18) | 0.19 |
| L | 55/50 | 8.1 | 29/28 | 7.9 | 1.08 (0.66, 1.75) | 0.76 |
| 15% | ||||||
| H | 45/41 | 8.8 | 18/16 | 7.0 | 0.69 (0.38, 1.25) | 0.22 |
| L | 80/72 | 9.2 | 36/33 | 7.7 | 0.97 (0.64, 1.49) | 0.91 |
| 20% | ||||||
| H | 28/27 | 7.1 | 12/11 | 6.8 | 0.91 (0.44, 1.90) | 0.81 |
| L | 97/86 | 9.8 | 42/38 | 7.9 | 0.88 (0.59, 1.29) | 0.51 |
| 25% | ||||||
| H | 14/14 | 6.6 | 9/9 | 6.8 | 0.92 (0.36, 2.31) | 0.85 |
| L | 111/99 | 9.5 | 45/40 | 7.9 | 0.92 (0.63, 1.33) | 0.64 |
H = High TK1; L = Low TK1; HR = Hazard Ratio; PBO = placebo; CI = Confidence Interval
Clinical trial identification
JapicCTI-121918. As reference, the protocol number of parental clinical study is EudraCT No: 2012-000109-66
Legal entity responsible for the study
Taiho Pharmaceutical Co., Ltd.
Funding
Taiho Pharmaceutical Co., Ltd.
Disclosure
K. Yamazaki, Y. Komatsu, K. Yamaguchi: Honoraria (lecture fee) from Taiho Pharmaceutical Co., Ltd. T. Yoshino: Corporate-sponsored Research: Research funding from GlaxoSmithKline K.K., Boehringer Ingelheim GmbH. T. Tanase: Employee of Taiho Pharmaceutical Co., Ltd. Stocks of Otsuka Holdings Co., Ltd. All other authors have declared no conflicts of interest.