TAS-102 for Treatment of Advanced Colorectal Cancers That Are No Longer Responding to Other Therapies

Author Manuscript Published OnlineFirst on April 28, 2016; DOI: 10.1158/1078-0432.CCR-15-2783 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

TAS-102 for Treatment of Advanced Colorectal Cancers that Are No Longer Responding to Other Therapies

Daphne L. van der Velden1, Frans L. Opdam2, and Emile E. Voest1

1 The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Molecular Oncology, Amsterdam, the Netherlands 2 The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Clinical Pharmacology, Amsterdam, the Netherlands

Corresponding Author: Frans L. Opdam, Division of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Postbus 90203, 1006 BE Amsterdam, the Netherlands. E-mail: [email protected]

Running Title: TAS-102 for Treatment of Advanced Colorectal Cancer

Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.

Abstract

TAS-102 is a novel oral formulation of trifluridine (TFT) and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TFT was originally synthesized in the 1960s and is a nucleoside analog that impedes DNA synthesis by inhibition of thymidylate synthase. TFT’s main mechanism of action however seems to be its incorporation into DNA, which distinguishes TFT from current well-known antimetabolites like 5-fluorouracil (5-FU). The rapid degradation of TFT brought initial clinical development to a halt, but TFT re-entered clinical trials when addition of a TPI was found to improve the bio-availability of TFT. The combined TFT-TPI formulation was tested in patients with treatment- refractory metastatic colorectal cancer in the randomized phase III RECOURSE study. Compared to placebo, TAS-102 was associated with an overall and progression free survival benefit and a 32% reduction in risk of death (median OS 7.1 (95% CI 6.5-7.8) vs. 5.3 months (95% CI 4.6-6.0), median PFS 2.0 (95% CI 1.9-2.1) vs 1.7 months (95% CI 1.7-1.8), HR for death 0.68 (95% CI 0.58-0.81, p<0.001)). Based on the results of this pivotal trial and supported by results from an earlier phase II study, TAS-102 recently gained FDA approval. This article reviews the development of TAS-102 and its therapeutic value for the proposed indication.

Introduction

Worldwide, colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women, with over 1.4 million new cases diagnosed in 2012. Approximately 25% of patients have metastatic disease at the time of presentation and almost 50% will develop metastases eventually (1, 2). A minority of patients with metastatic disease can be treated by surgery, which is the preferred treatment if feasible. In most cases of metastatic CRC (mCRC) though, resection is not feasible and chemotherapy is the mainstay of palliative treatment for the majority of patients.

Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 28, 2016; DOI: 10.1158/1078-0432.CCR-15-2783 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Until the beginning of this century, 5-fluorouracil (5-FU) was the only anticancer drug available for systemic treatment of mCRC. Fortunately the number of available therapies has expanded, and median survival of mCRC patients has improved markedly since oxaliplatin, irinotecan, bevacizumab (an VEGF- inhibitor), cetuximab and panitumumab (EGFR-inhibitors) have been introduced. For mCRC patients who have progressed on these therapies, the National Comprehensive Cancer Network (NCCN) guideline currently lists three options: best supportive care, participation in a clinical trial, or treatment with regorafenib. Regorafenib, a multi-kinase inhibitor, is the only systemic treatment option that has demonstrated statistically significant survival benefit in a randomized, placebo-controlled trial. The overall survival benefit of regorafenib was 1.4 months and 50% of patients developed progressive disease within two treatment cycles, often accompanied by severe toxicity (3). Altogether, this emphasizes the need for additional treatment options for patients who have exhausted all initial therapies.

TAS-102 (Lonsurf ®) is a novel oral formulation of the combination of trifluorothymidine (trifluridine or TFT) and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor (Figure 1). TFT was originally synthesized in 1964 (4). Despite promising anti-tumor activity in breast and colon cancer (5), clinical development was discontinued due to unacceptable toxicity and a poor pharmacokinetic profile. The rapid degradation of TFT by thymidine phosphorylase (TP) led to a mean plasma half-life of TFT of less than 15 minutes (6). Only after a potent TP inhibitor (TPI) became available, clinically meaningful plasma TFT concentrations could be reached (7, 8). Optimal TFT concentrations were obtained with TFT and TPI in a 1:0.5 molar ratio (9). Interestingly, the formulation (named TAS-102) showed anti-tumor activity against both 5-FU sensitive and resistant models in pre-clinical studies (10, 11). Its activity in 5-FU resistant tumors was confirmed in clinical studies, where TAS-102 showed anti-tumor activity in mCRC patients who had exhausted all above-mentioned therapies. TAS-102 might hereby represent an important new therapeutic option for treatment-refractory mCRC patients.

Clinical development

Multiple phase I trials of TAS-102 monotherapy were conducted to determine the maximum tolerated dose (MTD) and optimal dosing schedule (Table 1). The first phase I study enrolled 14 patients with therapy-refractory mCRC. Based on a preclinical monkey model, treatment was administered once daily during 14 days in a 21 day schedule. 50 mg/m2/day was declared the MTD, with neutropenia being the DLT. No objective tumor responses were observed, but stable disease (SD) was observed in 29% of patients (12).

Even though no DLTs occurred at 50 mg/m2/day, myelotoxicity appeared more pronounced in later treatment cycles. This seemed to be explained by progressive drug accumulation as observed at the end of every treatment cycle. Two additional phase I studies were therefore initiated to define a dosing interval that would minimize hematologic toxicity. TAS-102 was administered once daily for five days per week in both studies, either on a 2-weeks-on, 2-weeks-off schedule (n = 24), or on a 1-week-on, 2- weeks-off schedule (n = 39). The recommended phase II dose for these schedules was 100 and 160 mg/m2/day, respectively. Since the 2-week rest between doses did not decrease blood concentration of FTD, and because of the higher administered dose, the 2-weeks-on, 2-weeks-off schedule was

recommended. Consistent with the data from the study by Hong et al, neutropenia was the DLT for both dosing schedules. No objective responses were seen, but SD was observed in almost 30% of patients (13).

Because of the limited anti-tumor activity of TAS-102 in these studies, and because earlier studies suggested improved antitumor activity of FTD when administered in multiple daily-doses (5, 14, 15), another phase I study was initiated in which TAS-102 treatment was divided over three daily doses (16). In this study 60 mg/m2/day was declared the recommended phase II dose. Although no objective responses according to RECIST criteria were seen, five patients did demonstrate radiographic reductions in tumor burden and 60% of patients had SD.

Based on these results an additional phase I study was initiated in Japan to establish the MTD and optimal phase II dose in Japanese patients (17). Patients were treated with two daily doses for five days per week on the 2-weeks-on, 2-weeks-off schedule. Although the MTD was not reached, 35 mg/m2 twice daily already caused grade 3 neutropenia in three out of six patients and was therefore declared the recommended dose for subsequent studies. No objective tumor responses were observed, but 52% of patients showed SD with a mean duration of 2.5 months.

This study was followed by a double-blind phase II trial of 169 Japanese patients with unresectable chemo-refractory mCRC (18). Patients were randomized between placebo or TAS-102 35 mg/m2 twice daily for five days per week on a 2-weeks-on, 2-weeks-off schedule, based on the study by Doi et al (17). One patient in the TAS-102 group (1%) achieved a partial response, whilst no objective responses were observed in the placebo group. Median overall survival (OS) was 9.0 months (95% CI 7.3-11.3) in the TAS-102 treated patients (n = 112) and 6.6 months (95% CI 4.9-8.0) in the placebo group (n = 57; hazard ratio for death 0.56, p = 0.001) (18).

One more phase I study was initiated to confirm the safety of the 35 mg/m2 twice daily in Western mCRC patients (19). Based on treatment of 27 patients with chemo-refractory mCRC, 35 mg/m2 twice daily was indeed declared the recommended dose for Western mCRC patients. SD was reached in 65% of patients with a median PFS and OS of 4.1 and 8.9 months, similar to the results of the Japanese phase II trial.

A double-blind, randomized, placebo-controlled phase III study (RECOURSE trial) was then conducted to assess the efficacy and safety of TAS-102 in a global population of mCRC patients who were refractory or intolerant to standard of care therapy (20). Patients were stratified according to KRAS-status of their tumor, time between first diagnosis of metastases and randomization (<18 vs. ≥18 months), and ethnicity. OS was the primary endpoint; secondary endpoints included PFS, response rate, disease control rate and safety. A total of 800 patients were randomized (2:1) to receive TAS-102 plus best supportive care or placebo plus best supportive care. Both treatment groups were comparable with respect to prior systemic therapies and were heavily pretreated, with ≥4 prior treatment lines in 61% of patients. At the time of primary analysis, median OS was 7.1 months (95% CI 6.5-7.8) in the TAS-102 group versus 5.3 months (95% CI 4.6-6.0) in the placebo group, leading to a hazard ratio for death of 0.68 (95% CI 0.58-0.81, p<0.001). Median PFS was 2.0 months (95% CI 1.9-2.1) in the TAS-102 group and 1.7 months (95% CI 1.7-1.8) in the placebo group, with a hazard ratio for progression of 0.48 (95% CI

0.41-0.57, p<0.001). The survival benefit of TAS-102 was observed across all pre-specified subgroups, was irrespective of prior regorafenib use (which became available during the trial) and was validated by multivariate Cox regression analysis. Although objective response rate did not statistically significantly differ between the TAS-102 and placebo group (1.6% vs. 0.4%, p=0.29), disease control rate was higher in the TAS-102 group (44% vs. 16%, p<0.001). Despite the absence of extensive quality of life data, TAS- 102 treatment significantly delayed the worsening of ECOG performance status (5.7 months vs. 4.0 months in the placebo group, hazard ratio 0.66 (95% CI 0.56-0.78, p<0.001).

To summarize, overall survival benefit of TAS-102 in Western and Japanese patients with mCRC refractory or intolerant to standard therapies was demonstrated in the multinational, randomized, double-blind and placebo-controlled phase III RECOURSE study (20). Based on this study and supported by the almost identical results of the randomized, double-blind and placebo-controlled phase II study in Japanese patients (18), TAS-102 was approved for treatment of mCRC refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and VEGF and EGFR inhibitors. It should be noted however that objective tumor responses have rarely been observed. TAS-102 should therefore be more regarded as a tumor-growth stabilizing drug, than as a drug inducing objective tumor shrinkage.

Toxicity

TAS-102 is generally well tolerated. Neutropenia was the major DLT in all phase I studies, for Japanese and Western patients. Most grade 3 and 4 toxicities across all studies were of hematologic origin. Other common toxicities included grade 1-2 gastrointestinal complaints and fatigue (12, 13, 16-19).

In the pivotal phase III study, the overall incidence of adverse events (AEs) in the TAS-102-treated group was similar to that of the placebo-treated group (98% vs. 93%). Grade ≥3 adverse events occurred more frequently in the TAS-102 group than in the placebo group though (69% vs. 52%). TAS-102-treated patients were more likely to develop grade ≥3 neutropenia (38% vs. 0%), leukopenia (21% vs. 0%), anemia (18% vs. 3%) and thrombocytopenia (5% vs. <1%), as well as grade ≥3 diarrhea (3% vs. <1%), nausea (2% vs. 1%) and vomiting (2% vs. <1%). One TAS-102 treatment-related death due to sepsis was reported. The overall incidence of serious AEs however, was higher in the placebo group (34% vs. 30%) and incidence of grade ≥3 hepatic or renal dysfunction, anorexia, stomatitis, hand–foot syndrome and cardiac events (typical toxicities of fluoropyrimidine treatment) was similar between both groups. Altogether, TAS-102 was very well tolerated. This is further illustrated by the fact that only 4% of TAS- 102-treated patients discontinued treatment because of toxicity, and only 14% of patients required dose reductions. Due to neutropenia, start of new treatment cycles was delayed with ≥4 days in 53% of patients though (20).

Pharmacokinetics

Key pharmacokinetic parameters of TFT and TPI are shown in Table 2. Following TAS-102 administration,

TFT and TPI are rapidly absorbed with mean Tmax values of 1-2 hours for TFT and 2-3.5 hours for TPI (17). No absolute bioavailability study has been conducted with TAS-102 to evaluate the oral bioavailability of TFT and TPI. TFT is rapidly degraded by intestinal and liver thymidine phosphorylase. TPI is an inhibitor of thymidine phosphorylase. The TFT AUC was approximately 100-fold higher following administration

of TAS-102 than following administration of TFT alone. The TFT Cmax was 70-fold higher for TAS-102 compared to TFT alone (7).

In vitro studies showed that TFT and TPI are not metabolized by CYP enzymes. It was demonstrated that TFT is primarily metabolized by thymidine phosphorylase. 5-(trifluoromethyl) uracil (FTY) is the major inactive metabolite (12). TPI is a specific inhibitor of TPase and consequently an inhibitor of the metabolism of FTD in the intestinal tract and liver. Due to the low absorption of TPI, its activity might be focused in the intestinal tract.

TAS-102 compared to current systemic treatment options for mCRC

Clinical comparative studies in which patients are randomized between TAS-102 and standard therapies have not yet been performed. Cetuximab and panitumumab have demonstrated single-agent activity in chemo-refractory mCRC (21, 22), but only regorafenib has been tested in a similar setting as TAS-102, in a global, multicenter, randomized, double-blind and placebo-controlled phase III study (the CORRECT trial) (3).

As in the RECOURSE trial, all patients in the CORRECT trial were heavily pretreated and refractory to their last line of standard treatment. Refractory-criteria In the RECOURSE trial were even more stringent though, requiring that patients were refractory to their last administration of all standard therapies. In addition, 18% of patients in the RECOURSE trial had previously received and progressed on regorafenib, and survival benefit was maintained regardless of prior regorafenib use. Median PFS and OS in the CORRECT study were 1.9 and 6.4 months in the regorafenib group, vs. 1.7 and 5.0 months in the placebo group. This is comparable to the PFS (2.0 months for TAS-102 versus 1.7 months for placebo) and OS benefit of TAS-102 (7.1 months for TAS-102 versus 5.3 months for placebo) as observed in the RECOURSE study. Both studies reported similar disease control rates (41% for regorafenib, vs. 44% for TAS-102).

Regorafenib has a very different safety profile though, with skin toxicity, fatigue, diarrhea, anorexia, oral mucositis, hypertension and elevated transaminases being the most common toxicities. From the CORRECT and RECOURSE trials, regorafenib seemed to be less well tolerated than TAS-102, with AEs occurring in almost 100% of patients (vs. 93% for TAS-102), dose modifications in 67% (vs. 14%), treatment discontinuation due to toxicity in 10% (vs. 4%) of patients, and eight deaths that could not be attributed to disease progression in 500 regorafenib-treated patients (vs. one in 533 TAS-102-treated patients). Altogether, the efficacy of TAS-102 for patients with mCRC who have exhausted all treatment options seems to be comparable to that of regorafenib, the only approved drug in this setting. The safety profile is different and seems to be in favor of TAS-102. However, since no comparative studies of regorafenib and TAS-102 have been performed, no direct comparison can be made.

Conclusion and future directions

In summary, TAS-102 has clinically meaningful anti-tumor activity and a manageable safety profile, as demonstrated in a global population of patients with heavily pretreated and treatment-refractory mCRC. Based on the results of the RECOURSE trial (20) and supported by the results of the phase II study

by Yoshino and colleagues (18), TAS-102 has been approved in Japan by the FDA and recently by the EMA for treatment of mCRC refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and VEGF and EGFR inhibitors.

Some questions remain to be elucidated. Several studies are currently conducted to further explore the mechanism of action of TAS-102, and to gain insight into the effects of TAS-102 treatment in patients with renal insufficiency and hepatic impairment (Table 3). Another ongoing topic of investigation is combination treatment. Combined treatment approaches could enhance the anti-tumor activity of TAS- 102 or might help to prevent recurrent disease due to drug resistance. Optimal treatment combinations as well as optimal treatment sequences remain to be established, but results from pre-clinical and even a few clinical studies are promising (23-29). In addition to exploring combination treatment (e.g with panitimumab (Clinicaltrials.gov NCT02613221) or bevacizumab (Clinicaltrials.gov NCT02654639), future studies should try to identify predictive biomarkers regarding benefit or resistance to TAS-102. [18F]fluorothymidine Positron Emission Tomography (PET) imaging for example has been suggested as a means to assess pharmacodynamics of TAS-102 in individual patients (30). The role of TAS-102 in earlier lines of CRC treatment, as well as its role in treatment of other tumor types, may be evaluated to decide whether the benefits derived from TAS-102 can be expanded. For example, a study of TAS-102 plus best supportive care versus placebo plus best supportive care in patients with metastatic gastric cancer is ongoing (Clinicaltrials.gov NCT02500043). While awaiting these answers, TAS-102 already offers a new opportunity for treatment-refractory mCRC patients. Although TAS-102 is well tolerated, its tumoristatic rather than tumoricidal effect and small OS benefit should be considered before prescribing the drug.

References

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Table 1. Clinical trials leading to approval of TAS-102 for metastatic CRC

Reference Context n Prior treatment OR rate DCR rate Median Median HR (study population) regimens (CR or PR) (OR or SD) PFS in OS in for months months death Hong et al, Phase I study (USA) 14 4 (range 2-8) 0% 29% 1.9 - - 2006 (12) 1x daily dosing (all CRC) (mean)

Overman et Phase I study (USA) 24 3.5 (range 2-10) 0% 29% 3.8 - - al, 2008 (13) 1x daily, 4 week cycle (20 CRC) 1x daily, 3 week cycle 39 4.3 (range 1-13) 0% 30% 4.4 - - (32 CRC) Overman et Phase I study (USA) 15 3 (range 2-7) 0% 60% 4.0 - - al, 2008 (16) 3x daily dosing (9 CRC)

Doi et al, 2012 Phase I study (Japan) 15 3 (range 2-6) 0% 52% 2.6 10.2 - (17) 2x daily dosing (12 CRC)

Bendell et al, Phase I study (USA) 27 ≥4 in 74% 0% 65% 4.1 8.9 - 2015 (19) 2x daily dosing (all CRC)

Yoshino et al, Phase II RCT (Japan) 2012 (18) Lonsurf 112 ≥2 1% 54% 2.7 9.0 0.56 Placebo 57 ≥2 0% 14% 1.0 6.6

Mayer et al, Phase III RCT (global) 2015 (20) Lonsurf 534 ≥2 1.6% 44% 2.0 7.1 0.68

Placebo 266 ≥2 0.4% 16% 1.7 5.3

Table 2. Key pharmacokinetic parameters of trifluridine (TFT) and tipiracil (TPI)

Trifluridine Tipiracil

Absorption Absolute bioavailability unknown Absolute bioavailability unknown

Absorption at least 20% Absorption at least 29%

tmax 1 hour tmax 2-3.5 hours

Distribution Vss/F 10 L Vss/F 432 L

Protein binding 97% Protein binding 8%

Metabolism Substrate of thymidine phosphorylase, thymidine kinase Elimination / Excretion Time dependent pharmacokinetics

t1/2 1-2 hours t1/2 2 hours

Cl/F = 0.178 L/h/kg Cl/F = 1.88 L/h/kg

1.5-3.7%% of dose excreted 29% of dose excreted in urine unchanged in urine following single unchanged dose Interactions Inhibitor thymidine phosphorylase Substrate OCT2 Vss = volume of distribution in steady state; Cl/F= apparent total clearance of the drug from plasma after oral administration

Table 3. Ongoing clinical trials with TAS-102

Drug(s) Study setting and population Phase Clinicaltrials.gov ID

TAS-102 Mass balance study of oral FTD and TPI as components of I NCT02031055 Lonsurf in Patients with advanced solid tumors. TAS-102 Pharmacokinetics after single and multiple dose in Chinese I NCT02261532 patients with advanced solid tumors. TAS-102 Safety and tolerability in advanced solid tumors with hepatic I NCT02301104 impairment. TAS-102 Safety and tolerability in advanced solid tumors with renal I NCT02301117 impairment. TAS-102 vs. placebo* Study evaluating the cardiac safety of TAS-102 in patients I NCT01867879 with advanced solid tumors. TAS-102 tablets vs. oral Study comparing the bio-availability of TAS-102 tablets to an I NCT01874522 solution oral solution, containing equivalent amounts of FTD and TPI. TAS-102 vs. FTD alone Study comparing the pharmacokinetics of FTD as a I NCT01867866 component of TAS-102, with FTD alone. TAS-102 + CPT-11 + Safety and tolerability in various advanced gastro-intestinal I NCT01916447 bevacizumab tumors. Topotecan, Amrubicin or TAS- Small cell lung cancer, following platinum-based II NCT01904253 102* chemotherapy. Panitumumab Chemo-refractory metastatic colorectal cancer. I / II NCT02613221 + TAS-102 SGI-110 plus Irinotecan, versus Chemo-refractory metastatic colorectal cancer. I + II NCT01896856 Regorafenib or TAS-102 TAS-102 vs. placebo RCT in Asian patients with chemo-refractory metastatic III NCT01955837 colorectal cancer. TAS-102 vs. placebo RCT in metastatic gastric cancer refractory to standard III NCT02500043 treatments. * Terminated, results not yet published

Figure 1. Chemical structure of trifluridine (TFT) and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor

Figure 1:

O O

CF3 CI HN HN

O N O N HO-CH 2 O H NH HCI

HOH TFT TPI

TAS-102 for Treatment of Advanced Colorectal Cancers that Are No Longer Responding to Other Therapies

Daphne L. van der Velden, Frans L. Opdam and Emile E. Voest

Clin Cancer Res Published OnlineFirst April 28, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-15-2783

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