Clinical significance of thymidine kinase 1 expression on TAS-102 treatment in RECOURSE phase III trial of TAS-102 versus placebo for metastatic colorectal cancer

Date

08 Oct 2016

Session

Poster Display

Presenters

Kentaro Yamazaki

Citation

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

Authors

K. Yamazaki¹, T. Yoshino², E. Shinozaki³, Y. Komatsu⁴, Y. Tsuji⁵, T. Nishina⁶, H. Baba⁷, T. Denda⁸, N. Sugimoto⁹, A. Tsuji¹⁰, K. Yamaguchi¹¹, T. Takayama¹², Y. Shimada¹³, Y. Hamamoto¹⁴, K. Muro¹⁵, M. Gotoh¹⁶, T. Tanase¹⁷, A. Ohtsu²

Author affiliations

¹ Gastrointestinal Oncology And Endoscop, Shizuoka Cancer Center, 411-8777 - Shizuoka/JP
² Department Of Gastroenterology And Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
³ Department Of Gastroenterology, Cancer Institute Hospital of JFCR, 135-8550 - Tokyo/JP
⁴ Cancer Center, Hokkaido University Hospital, 060-8638 - Sapporo/JP
⁵ Medical Oncology Dept., KKR Tonan Hospital, 060-0001 - Sapporo/JP
⁶ Dept. Of Gastroenterology, Shikoku Cancer Center, 791-0280 - Matsuyama/JP
⁷ Gastroenterological Surgery, Kumamoto University, 860-8556 - Kumamoto/JP
⁸ Gastroenterology, Chiba Cancer Center Hospital, 260-8717 - Chiba/JP
⁹ Dept. Of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Dideases, 537-8511 - Osaka/JP
¹⁰ Department Of Medical Oncology, Kobe City Medical Center General Hospital, 650-0047 - Kobe/JP
¹¹ Department Of Gastronerology, Saitama Cancer Center, 330-9301 - Saitama/JP
¹² Department Of Gastroenterology And Oncology, Tokushima University Hospital, 770-8503 - Tokushima/JP
¹³ Department Of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
¹⁴ Department Of Gastroenterology, Keio University School of Medicine, 160-0016 - Tokyo/JP
¹⁵ Department Of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya/JP
¹⁶ Internal Medicine Ii, Osaka Medical College, 569-8686 - Takatsuki/JP
¹⁷ Data Science Dept., Taiho Pharmaceutical Co., Ltd., 101-0047 - Tokyo/JP

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.

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