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. 1 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 2 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. 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).