A novel antimetabolite: TAS-102 for metastatic colorectal cancer

Abstract

TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, with an estimated 1.4 million cases and 693,900 deaths occurring in the year 2012 [1]. Unfortunately, 20–30% of newly diagnosed patients present with metastatic CRC (mCRC) [2]. In addition, CRC recurs in 20–50% of patients who have undergone primary colon cancer resections with curative intent [3–5]. For most patients with mCRC, treatment is palliative and not curative, and treatment goals are to prolong overall survival (OS) and maintain quality of life as long as possible.

The past 10 years have seen unprecedented advances in mCRC treatment. For more than 50 years, 5-fluorouracil (5-FU) has been the backbone of all chemotherapy schedules, both alone and in combinations with other drugs [6–10]. The combination therapies – irinotecan with 5-FU/folinic acid (FOLFIRI) [11] or oxaliplatin with 5-FU/folinic acid (FOLFOX) [12] – have become the most effective cytotoxic regimens and resulted in significantly increased response rates and improved OS. Biological agents have further increased the effect of cytotoxic therapy, including bevacizumab [13–15], ziv-aflibercept [16], cetuximab [17,18], panitumumab [19,20] and ramucirumab [21]. We can also use regorafenib, a small-molecule inhibitor of multikinases, in salvage-line settings [22]. OS in patients with mCRC has reached a median of approximately 30 months [23–27], mainly driven by the availability of new active agents which have shown efficacy in refractory mCRC. However, there is an unmet clinical need for patients who present with disease progression after exhausting all standard therapies.

Introduction to the drug

TAS-102 is a new oral drug for patient with refractory mCRC, or who are intolerant to standard chemotherapy. TAS-102 is a combination of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase (TP) inhibitor (tipiracil hydrochloride: TPI), at a molar ratio of 1 : 0.5 (weight ratio, 1 : 0.471). In this review, we summarize its new mechanism of action, pharmacokinetics and pharmacodynamics, and discuss the role of TAS-102 in future clinical practice.

Introduction to the compound

Chemistry

TAS-102 is a new oral anti-cancer drug, consisting of 2′-deoxy-5-(trifluoromethyl) uridine (FTD) as the antitumor component and 5-chloro-6-[(2-iminopyrrolidin-1-yl) methyl] pyrimidine-2,4(1H,3H)-dione monohydrochloride (TPI) which prevents the degradation of FTD at a molar ratio of 1 : 0.5 (weight ratio, 1 : 0.471). FTD has a molecular weight of 296.20 and its chemical formula is C₁₀H₁₁F₃N₂O₅. TPI has a molecular weight of 279.12 and its chemical formula is C₉H₁₁C_lN₄O₂ ·HCl. Box 1 shows the chemical structures of FTD and TPI.

Box 1. Drug summary.

Drug name	TAS-102
Phase	Launched
Indication	Colorectal cancer
Pharmacology description	TAS-102 is an oral combination of a thymidine-based nucleoside analog (trifluridine) and a TP inhibitor (tipiracil hydrochloride) in a molar ratio of 1.0 : 0.5.
Route of administration	Oral
Chemical structure	Trifluridine	tipiracil hydrochloride
Pivotal trial(s)	RECOURSE study

Pharmacodynamics

FTD is a thymidine-based nucleoside analog with a methyl group substituted to the trifluoromethyl group at the 5′ position of thymidine (Figure 1). The thymidine analog trifluorothymidine was synthesized originally by Heidelberger et al. in 1964 [28,29], who had already shown that FTD can be phosphorylated by thymidine kinase-1 (TK1) to its active monophosphate form in uninfected tissues, to mediate cytotoxicity [30].

Figure 1. Mechanism of action of TAS-102.

Thymidine analog trifluorothymidine (FTD) is converted by thymidine kinase-1 (TK1) to its monophosphate form, F₃dTMP, which is further phosphorylated to its triphosphate form, F₃dTTP, which is readily incorporated into DNA. TAS-102 exerts antitumor activity primarily via FTD incorporation into DNA. Thymidine phosphorylase inhibitor (TPI) inhibits the degradation of FTD.

FTD inhibits thymidylate synthase

FTD is metabolized to monophosphorylated FTD, F₃dTMP through phosphorylation by intracellular thymidine kinase. F₃dTMP binds covalently to the active site of thymidylate synthase (TS) at tyrosine 146. The resulting inhibition of TS leads to intracellular depletion of dTTP and subsequent dUMP accumulation, resulting in uracil misincorporation into DNA, causing DNA damage [31]. However, F₃dTMP does not form a ternary complex with the TS enzyme and 5,10-CH2-THF [32] and FTD-dependent TS inhibition rapidly declines after FTD is removed [33,34]. Therefore, this TS inhibition is not same as that of 5-FU.

FTD itself is incorporated into DNA

F₃dTMP is also further phosphorylated to the triphosphate metabolite, trifluoromethyl deoxyuridine 5′-tri-phosphate (F₃dTTP). F₃dTTP is incorporated into DNA, primarily at sites opposite adenine [35,36]. The DNA glycosylase assay showed no detectable excision of FTD paired to adenine by any of the uracil DNA glycosylases (UDG), thymine DNA glycosylase (TDG), methyl-CpG binding domain 4 (MBD4), or fractions of HeLa cell extracts. Most FTD is incorporated at T-sites (T/A, not T/G base pairs) in cellular DNA. However, when misincorporated FTD forms an FTD:G mismatch, it becomes a target of TDG or MBD4 – eventually causing cell death because of DNA strand break formation [37]. In contrast, Matsuoka showed that FTD induced few DNA strand breaks with its massive misincorporation into DNA. FTD induced p53-dependent sustained arrest at the G₂ phase, which was associated with a proteasome-dependent decrease in the Cyclin-B1 protein level and the suppression of CCNB1 and CDK1 gene expression [38]. DNA damage by FTD requires further study.

Reportedly, the inhibitory activity of FTD on DNA synthesis is about 2000-fold higher than that of dThd [39]. In addition, much more FTD was incorporated into DNA than were FdUrd and other antitumor nucleosides, Ara-C and dFdC, in a HeLa cell model [40]. Furthermore, F₃dTTP incorporated into DNA was retained even at 24 h after a washing-out procedure. Although intracellular F₃dTTP is rapidly eliminated from tumor cells after removal of FTD from the culture medium, almost 80% of F₃dTTP, once incorporated into DNA, stays in the DNA for up to 24 h. FTD was incorporated in a time-dependent manner and not in a concentration-dependent manner [40].

The antitumor effect was examined in human tumor xenograft models. Inhibition of tumor growth continued long after the end of drug administration [41]. Furthermore, the amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated.

TAS-102 retains its effect on FU-related resistant cancer cells

FTD showed an anti-tumor effect against 5FU-sensitive tumor cells – and more importantly, against FU-resistant tumor cells – in a mouse xenograft model [36]. These results suggest that TAS-102 exerts its antitumor activity predominantly because of its prolonged DNA incorporation, rather than through TS inhibition. Therefore, most of its antitumor effect is thought to be induced by DNA dysfunction [33].

TPI increases bioavailability of FTD

FTD is degraded by TP in vivo, therefore the elimination half-life of FTD after intravenous administration to humans is very rapid – 12 min [42]. In monkeys, the plasma FTD level after oral administration alone was very low, suggesting extensive first-pass metabolism by the liver and intestine TP [43,44]. In addition, TP is reported to be highly expressed in human tumor tissues [45–48], therefore, inhibition of intratumoral TP is speculated to further augment the antitumor effect of FTD [43]. A variety of inhibitors have been developed for TP; TPI was found to both inhibit TP-mediated processes and to potentiate activity of various thymidine derivatives by combining with them [44]. Indeed, TPI inhibits FTD degradation in the liver and intestines after oral administration, thus improving its bioavailability [44]. The optimum ratio of FTD to TPI for oral administration was determined by measuring maximum FTD plasma levels after oral administration in mice and monkeys. The optimum ratio was 1 : 0.5 M. This ratio enabled high antitumor activity and low FTD toxicity in a mouse xenograft model [43].

TPI inhibits tumor angiogenesis

TP is also identical to platelet-derived endothelial cell growth factor (PD-ECGF) and can promote tumor growth in vivo by mechanisms that include endothelial cell migration and angiogenesis [49–52]. Angiogenesis stimulates tumor growth and metastasis of many cancers. PD-ECGF/TP is known to catabolize thymidine to thymine and 2-deoxyribose 1-phosphate (2dDR1P), which may induce secretion of oxidative stress-induced angiogenic factors, such as IL-8, VEGF and MMP-1 [53]. PD-ECGF/TP is often overexpressed in many solid tumors [48] and its levels correlate well with microvessel density in colorectal cancer [54]. PD-ECGF/TP is also a potential chemotherapeutic target in the treatment of colorectal tumors, as with VEGF and its receptors (VEGF-R). TPI may exhibit an anti-angiogenic effect mediated through inhibition of TP. High PD-ECGF/TP expression is often associated with high vessel counts in colorectal tumors that express low VEGF, in contrast to tumors with high VEGF expression and high vessel density [55]. Therefore, PD-ECGF/TP expression by infiltrating cells in human colorectal tumors provides an additional alternate mechanism for tumor neovascularization. This result suggests that TPI can improve treatment efficacy even with other anti-angiogenic therapies, such as bevacizumab.

Pharmacokinetics and metabolism

When administering TAS-102 35 mg/m² twice daily, the mean elimination half-lives after a single dose were FTD: 1.4 h, and TPI: 2.1 h. The mean elimination half-lives at steady state were FTD: 2.0 h, and TPI: 2.4 h. FTD accumulation was 2.4-fold for area under curve (AUC) for plasma concentration over time and 1.4-fold for peak plasma concentration (C_max) after repeated administrations. In contrast, PK parameters of TPI and an inactive form of TAS-102 did not obviously change at steady state [56]. Systemic concentrations of FTD and TPI increased linearly with higher oral doses [56]. The intestinal absorption mechanism of FTD in humans was investigated using HIEC cells as an in vitro model of human intestinal epithelial cells, in which CNT1 was found to be a major transporter responsible for intestinal absorption of FTD in humans [57]. The C_max of FTD is decreased by 40% in fed condition compared with fasted state in humans. However, AUC of FTD was comparable between both conditions. Taking TAS-102 within 1 h after completing meals is recommended, based on the observed correlation between the increased FTD C_max and decrease in neutrophil counts.

FTD mainly binds to human serum albumin. In vitro protein binding of FTD in human plasma is >96%, independent of drug concentration and presence of TPI. Plasma protein binding of TPI is below 8%. As with normal nucleosides, FTD can easily cross the blood–brain barrier in low micromolar concentrations and is also predominantly metabolized to TF-Thy in the brain [58].

FTD and TPI are not metabolized by cytochrome P450 enzymes. FTD is mainly eliminated by metabolism through TP to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY) [30]. No other major metabolites were detected in plasma or urine. The enzyme activities of PD-ECGF/TP, TK and TS are the most important in FTD metabolism and cytotoxic activity in cancer cells. In vivo, PD-ECGF/TP mediates FTD catabolism and TK levels are often higher in human tumor tissues than normal tissues [59], which would lead to more rapid FTD activation.

Following a single dose of TAS-102 at 60 mg, mean 48-h cumulative urinary excretion was 1.5% for unchanged trifluridine, 19.2% for FTY and 29.3% for unchanged TPI. The cumulative percentages of the FTD and TPI doses excreted in the urine from 0–10 h after drug administration were 1–8% and 19–23%, respectively [56]. A population pharmacokinetic analysis revealed that renal function and body size were the primary determinants of the PK of TAS-102; renal function should be monitored closely during treating with TAS-102; dosing of TAS-102 by body surface area is adequate to reduce the variability of exposure to FTD and TPI; the PK parameters did not significantly vary with race, age, sex or hepatic function [60].

Clinical efficacy

Early clinical study

In the year 1971, an early clinical study on FTD was carried out to evaluate its efficacy with two dosage schedules of FTD in patients with breast, lung and colon carcinomas [61]. The first regimen consisted of five daily doses ranging from 1.5 to 30 m/kg/day given by single rapid injections of FTD in 9 patients. The second regimen consisted of a dose of 2.5 mg/kg/day given for 8–13 days, given by single rapid injection, of FTD every 3 h in 32 patients. FTD produced some response in colon and breast cancer patients. A reduction of >50% in tumor size occurred in 8 of 23 patients with breast cancer and an almost complete regression occurred in 1 of 6 patients with colon cancer. However, these clinical studies were discontinued, because of the short half-life of FTD because of its rapid clearance, extensive degradation by TP and severe side effects.

FTD was also investigated as an antiviral agent and is registered as Virotic®, for use against herpes simplex virus (HSV) infections. In 1964, Kaufman et al. showed that FTD had a significant antiviral action against herpes simplex keratitis in rabbits, even in strains resistant to thymidine-based nucleoside analog (2′-deoxy-5-iododeoxyuridine) [62]. Because of its very rapid half-life, FTD was not administered systemically, but was provided as a 1% ophthalmic solution for the treatment of viral disease. FTD was approved by the Food and Drug Administration (FDA) in 1980 for the treatment of primary keratoconjunctivitis and epithelial keratitis [63].

Phase I studies (Table 1)

Table 1.

Summary of phase I studies.

Study	Tumor type	N (CRC)	Dose (mg/m2)	Schedule	RD (mg/m2)	Dose limiting Toxicity	DCR (%)	TTF (days)
9801	Metastatic solid tumor	14 (14)	50–100	Once daily, day 1–14, every 3 weeks	50	Granulocytopenia	29	57
9802	Metastatic solid tumor	24 (20)	50–110	Once daily, day 1–5 and 8–12, every 4 weeks	100	Granulocytopenia	29	63.5
9803	Metastatic solid tumor	39 (32)	100–180	Once daily, day 1–5, every 3 weeks	160	Granulocytopenia	30	50
9804	Metastatic breast cancer	19 (0)	50–80	Twice daily, day 1–5 and 8–12, every 4 weeks	50	Granulocytopenia	63	117
9805	Metastatic solid tumor	15 (9)	60–80	Three times daily, day 1–5 and 8–12, every 4 weeks	60	Granulocytopenia	60	123
J001	Metastatic solid tumor	21 (18)	30–70	Twice daily, day 1–5 and 8–12, every 4 weeks	70	Neutropenia	52	92.5
Bendell et al.	Metastatic colorectal cancer	27 (27)	60–70	Twice daily, day 1–5 and 8–12, every 4 weeks	70	Febrile neutropenia	65	PFS 4.1 (months)

CRC: colorectal cancer, RD: recommended dose, DCR: disease control rate, TTF: time to failure, PFS: progression free survival.

Phase I studies were conducted to establish the adequate dosage schedule of TAS-102 from 1998. The first phase I study (TAS102–9801) [64] treated 14 patients with advanced solid tumors once daily with TAS-102 on days 1–14 every 21 days. The recommended dose (RD) for this schedule was 50 mg/m²/day, and the dose-limiting toxicity (DLT) was granulocytopenia. In the second phase I study (TAS102–9802) [65], 24 patients with solid tumor were treated with once-daily TAS-102 on days 1–5 and 8–12 every 28 days. The RD was 100 mg/m²/day. The third phase I study (TAS102–9803) [65] evaluated once-daily TAS-102 on days 1–5 every 21 days. The DLT was granulocytopenia and RD was 160 mg/m²/day.

Other phase I studies were conducted to evaluate twice-daily or three-times-daily administration of TAS-102 because divided daily dosing of FTD resulted in higher antitumor activity in preclinical studies because of increased incorporation of FTD into DNA [40]. In the phase I study (TAS102–9804) [66], Green et al. administered to patients with metastatic breast cancer twice-daily TAS-102 on days 1–5 and 8–12 every 28 days. The DLT was granulocytopenia; the RD for heavily pretreated metastatic breast cancer was 50 mg/m²/day using this schedule. In next phase I study (TAS102–9805) [67], 15 patients with metastatic gastrointestinal cancer were treated with three times daily with TAS-102 on days 1–5 and 8–12 every 28 days. DLT was granulocytopenia and RD was 70 mg/m²/day. Based on the results derived from schedules with multiple daily doses, the phase I study (J001) was done in Japan with twice-daily TAS-102 on days 1–5 and 8–12 every 28 days [56]. The RD was 70 mg/m²/day and DLT was neutropenia. The disease control rate (DCR) was 50.0%, including 6 patients who were able to continue treatment over 12 weeks; the median progression-free survival (PFS) and OS in this cohort were 2.4 and 9.8 months, respectively. These results suggested that the efficacy of TAS-102 should be investigated using the J001 schedule in phase II trials (J003).

After the Japanese mCRC phase II trial (J003), a more recent phase I study was designed to evaluate safety and determine whether the phase II dosing and schedule was feasible in similar patients with refractory mCRC in the United States [68]. Patients were enrolled into two sequential doses (60 or 70 mg/m²/day) using a standard 3 + 3 design. No DLT was observed in the 60 mg/m² group; one DLT (grade 3 febrile neutropenia) was observed at 70 mg/m². Therefore, the RD was identified as 70 mg/m²/day. In conclusion, the 70 mg/m² daily dose is generally well tolerated by patients with refractory mCRC in a Western population.

Phase II study

On the basis of the phase I data [56], TAS-102 was further evaluated in a double-blind, randomized, placebo-controlled, phase II study (J003) in 169 patients with refractory mCRC or who were intolerant of standard chemotherapy. Patients were randomly assigned in a 2 : 1 ratio to either TAS-102 (oral, 35 mg/m², twice daily on days 1–5 and 8–12 every 28 days) or placebo [69]. All patients received best supportive care. Median OS, the primary endpoint, was 9.0 months in the TAS-102 group and 6.6 months in the placebo group (HR: 0.56; 95% CI: 0.44–0.71; p = 0.001; Table 2). Median PFS (as assessed by the independent review committee) was 2.0 months in the TAS-102 group and 1.0 month in the placebo group (HR: 0.41; 95% CI: 0.28–0.59; p < 0.0001). TAS-102 offered a significant prolongation in median OS and PFS. In the assessment by the independent review committee, 49 (43%) patients given TAS-102 achieved disease control [1 patient (1%) had a partial response and 48 patients (43%) had stable disease], as did 6 (11%) given placebo (all 6 had stable disease). The proportion of patients who achieved disease control was significantly higher in the TAS-102 group (p < 0.0001). In prespecified subgroup analyses and interaction tests for OS, PFS and DCR, the effect of TAS-102 was similar in all categories, although not all improvements were significant.

Table 2.

Phase II and III efficacy results for TAS-102.

			OS				PFS				ORR		DCR
Trial	Arms	n	Time (m)	HR	95% CI	p-value	Time (m)	HR	95% CI	p-value	(%)	p-value	(%)	p-value
J003	Placebo	57	6.6	0.56	0.44–0.71	0.0011	1.0	0.41	0.28–0.59	<0.0001	0	1.00	11	<0.0001
Phase II	TAS-102	113	9.0				2.0				1		43
RECOURSE	Placebo	266	5.3	0.68	0.58–0.81	<0.001	1.7	0.48	0.41–0.57	<0.001	0.4	0.29	16	<0.001
Phase III	TAS-102	534	7.1				2.0				1.6		44

CI: confidence intercal; DCR: disease control rate; HR: hazard ratio; ORR: objective response rate.

In subgroup analysis, TAS-102 was likely to be more active in KRAS-mutated tumors compared with wild-type tumors; however, this subgroup analysis was limited by sample size. Therefore, the authors concluded that further investigation in future clinical studies with larger samples are warranted.

Phase III study

Based on these promising results, a multinational randomized phase III study (the RECOURSE study) was conducted to confirm the superiority of TAS-102 to placebo in the treatment of patients with refractory mCRC or who were intolerant to standard chemotherapy [70]. In this study, 800 patients were randomized to receive TAS-102 (n = 534) or placebo (n = 266) in the primary analysis. The primary endpoint, median OS, was 5.3 months in the placebo group and 7.1 months in the TAS-102 group (HR: 0.68; 95% CI: 0.58−0.81; p < 0.001; Table 2). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR: 0.48; 95% CI: 0.41– 0.57; p < 0.001). These results confirmed significant OS and PFS benefits with TAS-102. Furthermore, the OS and PFS benefit with TAS-102 was consistent across all subgroups. In particular, the HRs for OS in subgroups were 0.58 in patients with KRAS wild-type tumors and 0.80 in KRAS-mutated tumors; 0.64 in Western population and 0.75 in Asian patients; 0.73 in patients with PS 0 and 0.61 in patients with PS 1; and 0.69 for patients who had already received, or not received, regorafenib – OS benefit was maintained irrespective of regorafenib use.

In multivariate Cox regression analysis, none of the factors were identified as predictive. The ORR was 1.6% (8/502) in the TAS-102 group and 0.4% (1/258) in placebo group (p = 0.29). The DCR was 44% (221/502) in the TAS-102 group and 16% (42/258) in placebo group (p < 0.001). In addition, median time to an ECOG performance status of ≥2 was 5.7 months in the TAS-102 group versus 4.0 months in the placebo group (HR: 0.66; 95% CI: 0.56–0.78; p < 0.001). TAS-102 significantly delayed worsening of disease for patients with mCRC. The percentage of patients who received post-study treatment was similar between arms (41.2% in TAS-102, 42.5% in placebo).

This phase III trial provided convincing evidence that TAS-102 is efficacious in heavily treated patients regardless of previous exposure to regorafenib and Kras status.

Safety and tolerability

Table 3 summarizes the common adverse effects of TAS-102. TAS-102 has a good safety profile. The most commonly reported adverse events of TAS-102 related to myelosuppression. During the phase I clinical trials [56,64–68], dose-limiting toxicities were grade 4 leukopenia, neutropenia and thrombocytopenia. A significant association was observed between the decrease in neutrophil count and FTD PK parameters, C_max and AUC [56]. In the phase II study, grade 3/4 adverse events included neutropenia, leukopenia, anemia, fatigue and diarrhea. Although half of patients experienced neutropenia, the rate of febrile neutropenia was only 4%.

Table 3.

Adverse events between TAS-102 and regorafenib.

	TAS-102								Regorafenib
	J003 (phase II)				RECOURSE (phase III)				CORRECT
	TAS-102 (n = 113)		Placebo (n = 57)		TAS-102 (n = 533)		Placebo (n = 265)		Regorafenib (n = 533)		Placebo (n = 265)
Adverse event, n (%)	All grade	Grade3/4	All grade	Grade3/4	All grade	Grade3/4	All grade	Grade3/4	All grade	Grade3/4	All grade	Grade3/4
Overall adverse events	97	65	70	5	98	69	93	52	98	69	93	52
Serious adverse events	21		9		30		34		30		34
Neutropenia	72	50	2	0	67	38	<1	0	67	38	<1	0
Thrombocytopenia	39	4	2	0	42	5	8	<1	42	5	8	<1
Anemia	73	17	16	5	77	18	33	3	77	18	33	3
Hyperbilirubinemia	–	–	–	–	36	9	26	12	36	9	26	12
Increased ALT level	–	–	–	–	24	2	27	4	24	2	27	4
Increased AST level	–	–	–	–	30	4	35	6	30	4	35	6
Hand-foot syndrome	–	0	–	–	2	0	2	0	2	0	2	0
Fatigue	58	6	42	4	35	4	23	6	35	4	23	6
Diarrhea	38	6	21	0	32	3	12	<1	32	3	12	<1
Anorexia	62	4	33	4	39	4	29	5	39	4	29	5
Nausea	65	4	28	0	48	2	24	1	48	2	24	1
Vomiting	34	4	25	0	28	2	14	<1	28	2	14	<1
Stomatitis	–	–	–	–	8	<1	6	0	8	<1	6	0
Fever	–	–	–	–	19	1	14	<1	19	1	14	<1
Asthenia	–	–	–	–	18	3	11	3	18	3	11	3
Febrile neutropenia	4	4	0	0	4	4	0	0	4	4	0	0

ALT: alanine aminotransferase; AST: aspartate aminotransferase elevation.

A phase III study further reinforced the general tolerability of TAS-102 [70]. About 69% of patients experienced some type of grade 3/4 adverse event, which included neutropenia, leukopenia, anemia, hyperbilirubinemia and thrombocytopenia. Neutropenia was the most frequently observed clinically meaningful adverse event (grade 3/4). However, the frequency of grade 3/4 neutropenia decreased from 50% in the phase II study to 38% in the phase III study. In addition, febrile neutropenia occurred in only 4% of patients in TAS-102 group and incidence of treatment-related mortality was 0.19%. The grade 3/4 stomatitis, hand-foot syndrome, and coronary spasm, which are associated with the use of fluoropyrimidines, were seen in <1% of the patients treated with TAS-102. The adverse events were manageable and reversible. Patients were treated with symptomatic therapy and dose interruptions or reductions.

Regulatory affairs

Based on the results of the phase III clinical trial, TAS-102 was approved in Japan in March 2014, as a monotherapy to treat patients with unresectable mCRC that was refractory to standard chemotherapy. The FDA approved TAS-102 for its use in the United States in September 2015.

Conclusion

TAS-102 is an effective and well-tolerated oral anti-metabolite drug and has expanded the treatment options of patients with treatment-refractory mCRC. TAS-102 has also great potential in future clinical drug combination studies, both with cytotoxic agents (oxaliplatin and irinotecan) or targeted therapies (bevacizumab, cetuximab or panitumumab).

Expert commentary

TAS-102 has shown activity in 5-FU-resistant cells, both in in vitro and in vivo studies [36,71]. In the phase III trial, TAS-102 improved survival in patients who were refractory to 5-FU [70], which suggests that the antitumor activities of TAS-102 and 5-FU have different mechanisms [72]. DPD [73] and TS [74] are the most important biomarkers of 5-FU resistance. Increased TS levels are often associated with resistance to 5-FU [75]. FTD has another mechanism of cytotoxicity induced by TS inhibition. The antitumor activity of FTD is predominantly because of its prolonged DNA incorporation, which is an important factor in overcoming FU-resistant cancer. Although TP expression in tumors varies widely, TP expression level will not affect TAS-102 because TPI acts against colon cancer cells with both undetectable and high TP expression. In contrast, the oral 5-FU pro-drug capecitabine needs cellular TP to exert significant activity. TPI inhibits TP, which has a function in angiogenesis but also enhances the bioavailability of FTD [32,50,52]. The antitumor activity of TAS-102 in 5-FU resistant tumors might be explained by the differences in mechanism of action of FTD and 5-FU, as well as by the antiangiogenic effects of TPI.

TAS-102 and regorafenib are available for refractory mCRC and have similar efficacies. In the RECOURSE and the CORRECT [22] studies of refractory mCRC treated with standard chemotherapy, both drugs achieved more 6 month median OS time (7.1 and 6.4 months for TAS-102 and regorafenib, respectively) and DCR of 40% (44 and 41% for TAS-102 and regorafenib, respectively). Interestingly, the efficacy of TAS-102 was maintained irrespective of prior treatment with regorafenib and of Kras status. Table 2 shows the outcome of phase II/III study in TAS-102 [69,70]. The profile of adverse events differs between TAS-102 and regorafenib (Table 3). The most common adverse events are neutropenia, anemia, nausea and febrile neutropenia in patients with TAS-102, and Hand-foot syndrome, fatigue, diarrhea, hypertension, rash and liver dysfunction in patients with regorafenib. The side effect profiles of these two agents may be an important factor in the decision in what sequences these agents are used.

Five-year view

Current studies are testing combinations of TAS-102 with chemotherapy regimens such as oxaliplatin [76,77], irinotecan [78,79] docetaxel [80] bevacizumab [81] cetuximab/panitumumab [81] or erotinib [82], in CRC cell lines. Although synergic effects are seen in preclinical studies, clinical trials of combination therapy are necessary. A recent phase I/II study evaluated the efficacy of TAS-102 with bevacizumab and assessed the RD of TAS-102. It found the RD to be 70 mg/m²/day. Median PFS and OS were 5.6 months and 11.6 months, respectively, in patients with mCRC refractory to standard chemotherapy [83]. This clinical efficacy may reflect a preclinical study that showed phosphorylated FTD to increase by combining TAS-102 and bevacizumab in a CRC xenograft model [81]. Bevacizumab both inhibits angiogenesis and increases FTD accumulation and its subsequent phosphorylation in tumors. These combination therapies may be promising options.

Recent studies to identify predictive biomarker for TAS-102 showed that protein expression of two key enzymes, TK1 and TP, were not correlated with OS and PFS in patients treated with TAS-102 [84]. In contrast, Sakamoto et al. evaluated the association between the levels of FTD incorporation into DNA and the substrate specificities of hENT family members, TK1, deoxyUTPase (DUT) and DNA polymerase-α. The results indicated that FTD and FdUrd are incorporated into DNA with different efficiencies because of differences in the substrate specificities of TK1 and DUT [85]. Therefore, TK1 and DUT are potential bio-markers. Furthermore, Yamashita et al. reported that hematological toxicity may be a surrogate indicator of TAS-102 efficacy [86]. Better understanding of the TAS-102 toxicity profile and identifying the best candidates for its use, will be critical to translational development of this drug.

Key issues.

• TAS-102 is an oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI), at a molar ratio of 1 : 0.5.

• TAS-102 demonstrated significant improvement in OS and PFS for patients with refractory mCRC in placebo-controlled randomized phase II and III trials.

• The most commonly reported adverse events of TAS-102 related to myelosuppression.

• TAS-102 is US FDA-approved for treatment of colorectal cancers that had previously been treated with fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and/or EGF-receptor targeted therapy; and do not harbor KRAS mutations.