TAS-102 Group Research Articles

Prognostic impact of codon-specific KRAS mutational status on survival in patients with metastatic colorectal cancer treated with TAS-102 or regorafenib.

75 Background: Previous study demonstrated KRAS (Kirsten rat sarcoma virus) codon G12 mutation as a potential biomarker of resistance in metastatic colorectal cancer (mCRC). Our study aimed to evaluate the prognostic impact of codon-specific KRAS mutational status on survival in patients with mCRC treated with TAS-102 or regorafenib. Methods: mCRC Patients treated with TAS-102 or regorafenib were retrospectively enrolled into our study. Patients were classified into KRAS G12 (KRASG12) mutation and no KRASG12 mutation according to extended RAS testing. Survival was estimated for comparison, stratified by KRAS mutational status and treatment. Kaplan-Meier curves were estimated for overall survival (OS). Results: A total of 183 patients were enrolled into our study, with 91 patients treated with TAS-102 and 92 patients treated with regorafenib. The median age was 63 years old in our cohort. Most patients were male (54%) with left side colon (85%). After extended RAS/RAF mutational testing, 28% patients had KRASG12 mutation, 50% had RAS/RAFWT, 9% had KRASG13 mutation, 8% had KRASother mutation, 3% had NRAS mutation and 2% had BRAF mutation. For patients treated with TAS-102 group, 20% patients had KRASG12 mutation, while for regorafenib group, 38% patients had KRASG12 mutation. The median OS of TAS-102 was 4.5 versus 11.3 months for KRASG12 mutation and no KRASG12 mutation, respectively (p= 0.013). The median OS of regorafenib was 10.5 versus 6.3 months for KRASG12 mutation and no KRASG12 mutation, respectively (p= 0.183). Furthermore, 34% patients with KRASG12 mutation received TAS-102, while 56% patients without KRASG12 mutation received TAS-102. For patients with KRASG12 mutation, the median OS was 4.5 m versus 10.5 months for TAS-102 and regorafenib group, respectively (p= 0.113). For patients without KRASG12 mutation, the median OS was 11.3m versus 6.3 months for TAS-102 and regorafenib group, respectively (p= 0.047). Conclusions: The prognostic impact of KRASG12 was divergent between mCRC patients treated with TAS-102 and regorafenib. Codon-specific KRAS mutational status should be taken into consideration before treatment.

Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data

IntroductionThere have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice. MethodsWe performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs. ResultsOne hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials. ConclusionThe present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice.

Risk-benefit Analysis of FOLFIRI Plus Ramucirumab/Aflibercept as a Third-line Treatment in Metastatic Colorectal Cancer.

The efficacy of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (F-RAM) or aflibercept (F-AFL) as a second-line treatment in metastatic colorectal cancer (mCRC) is established. In this study, the risks and benefits of F-RAM/AFL as a third-line treatment after first- and second-line bevacizumab for mCRC were evaluated. Overall survival (OS) and adverse events (AEs) were compared between groups treated with F-RAM/AFL (n=17) and trifluridine/tipiracil combination tablet (TAS-102) (n=26). Median OS was longer in the third-line F-RAM/AFL group (379 days; 95%CI=157-458 days) than in the TAS-102 group (183 days; 95%CI=80-204 days) (log-rank test, p=0.015). Discontinuation due to AEs was only observed in the F-RAM/AFL group (3 cases). As a third-line treatment for mCRC, F-RAM/AFL should be prioritized over TAS-102 in terms of efficacy; however, the risk of AEs should be considered.

Chemotherapy rechallenge or reintroduction (CTr/r), regofenib (REG) and TAS-102 for metastatic pretreated colorectal cancer (mCRC) patients (pts): A propensity score analysis of treatment beyond second-line (PROSERpINA Study).

3556 Background: The optimal treatment for mCRC beyond 2nd line is still questioned. Recently, REG and TAS-102 showed to improve survival compared to BSC. While in real-world practice CTr/r is often considered in this setting, supporting evidences are limited. In absence of studies comparing all these strategies, we aimed to compare the prognostic performance of CTr/r, REG and TAS-102 in mCRC treated beyond 2nd line. Methods: mCRC pts progressing after at least 2 lines of CT, treated with CTr/r, REG or TAS-102 between Jan-10 and Jan-19 were considered eligible. The primary endpoint was OS; secondary endpoints were PFS and RR. Cox’s proportional hazard models for survivals were estimated. A propensity score (PS) adjustment for baseline characteristics was further accomplished for survival analysis. Results: The clinical data of 341 pts (CTr/r 133, REG 150, TAS-102 58) were retrospectively collected. At multivariate analysis type of treatment, ECOG PS, number of metastatic sites and treatment line independently correlated with OS ( p < .001, p .001, p < .001 and p .029, respectively). The mOS was 18.5 (95% CI, 14.3–22.7), 6 (95% CI, 5.6–9.5) and 7.6 months (95%CI, 5.6–9.5), for CTr/r, REG and TAS-102 group, respectively (log-rank p < .0001). mOS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (15.8 vs 7.1 months; adjusted HR 1.96, 95% CI 1.44-2.66; p < .0001) at the PS analysis, adjusted for ECOG PS, number of metastatic sites and treatment line; 2-yrs OS was 34% and 11.6% for CTr/r and REG/TAS-102, respectively. PFS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (5.5 vs 3.9 months; HR 1.45, 95% CI 1.11-1.91; p .006) at the PS analysis. Accordingly, RR was higher in pts receiving CTr/r compared to REG/TAS-102 (29.0 vs 1.5%; Chi-square p < .00001). Conclusions: Our analysis, although underpowered, generates the hypothesis of a superiority of CTr/r in comparison to REG or TAS-102, in both efficacy and activity. Given the retrospective nature of our analysis, and the potential role of selection bias in treatment assignment, a prospective validation is mandatory.

Cost-effectiveness of trifluridine/tipiracil (TAS102) for heavily pretreated metastatic gastric cancer.

Trifluridine/tipiracil (TAS102), a novel oral cytotoxic chemotherapy, significantly improved overall survival compared with placebo in heavily pretreated advanced gastric cancer. This study aimed to evaluate the cost-effectiveness of TAS102 in the third-line or later treatment for this population from the US payer perspective. A Markov model was developed to simulate advanced gastric cancer, including three health states: progression-free survival (PFS), progressive disease (PD) and death. Model inputs were derived from a randomised, double-blind, placebo-controlled, phase 3 trial (TAGS trial, NCT02500043). Utilities were extracted from public resources. Costs were calculated from an American payer perspective. Sensitivity analyses were conducted to explore the impact of uncertainty. From the US payer perspective, treatment with TAS102 for patients with heavily pretreated advanced gastric cancer was estimated to increase costs by $59,180 compared with the placebo, with a gain of 0.06 quality-adjusted life years (QALYs) for an incremental cost-effectiveness ratio (ICER) of $986,333 per QALY. The costs for progression-free survival of TAS102 group had the greatest impact on the ICERs, as well as the cost of TAS102. Trifluridine/tipiracil (TAS102) is not a cost-effective choice for patients with heavily pretreated metastatic gastric cancer from an American payer perspective.

Usefulness of TAS-102 as Third-line Chemotherapy for Metastatic Colorectal Cancer.

The feasibility and oncological outcomes of treatment with TAS-102, that is recommended as third-line chemotherapy for patients with metastatic colorectal cancer (mCRC), remain unknown. Between 2013 and 2015, seven patients (five males, two females) with mCRC who were administered TAS-102 as third-line chemotherapy at our Institution were retrospectively studied. During the same period, seven patients with mCRC with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type primary lesions who were administered irinotecan with panitumumab comprised the control group. The duration of third-line chemotherapy in the TAS-102 group was 217.0 (range=136-337) days compared to 226.9 (range=122-335) days in the control group, with no significant difference in the duration of administration between the two groups. No significant difference in overall survival was identified between the two groups No serious adverse effects were encountered in either group. TAS-102 may be suitable as third-line chemotherapy for patients with mCRC.

Regorafenib (REG) versus trifluridine/tipiracil (TAS-102) as salvage-line in patients with metastatic colorectal cancer refractory to standard chemotherapies (REGOTAS): A propensity score analysis from a JSCCR multicenter observational study.

3540 Background: It is unclear which drug of REG or TAS-102 should be used earlier for the patients with metastatic colorectal cancer (mCRC) who have access to both drugs. This study investigated the comparison of the efficacy between REG and TAS-102 in patients with refractory to standard chemotherapies. Methods: The clinical data of patients who were treated with REG or TAS-102 among these drugs naive mCRC patients between Jun 2014 and Sep 2015 were retrospectively delivered from 24 institutions of Japanese Society for Cancer of the Colon and Rectum (JSCCR). The primary endpoint was overall survival (OS). Propensity score (PS) was calculated with a logistic regression, in which using baseline parameters were included. Two methods, adjusted and matched analysis, to take propensity score were used. The clinical outcomes were evaluated with Kaplan-Meier method and Cox models based on PS adjustment and matching. Results: Total of 589 patients were enrolled and 550 patients (223 patients in the REG group and 327 patients in the TAS-102 group) met criteria for inclusion in the analysis. The results from PS adjusted analyses showed that OS was similar between the two groups (HR of TAS-102 to REG, 0.96; 95% confidence interval, 0.78–1.18). There were also no statistically significant differences between two groups for progression-free survival (HR 0.94) and time to ECOG Performance status≥2 (HR 1.00), expect for time to treatment failure (HR 0.81; P = 0.025). In the subgroup analysis, REG showed favorable survival compared with TAS-102 in the age of < 65 years patients and unfavorable survival in ≥65 years patients (P for interaction = 0.012). In the PS matched sample (174 patients in each group), the clinical outcomes were similar to the results of the PS adjusted analysis. Conclusions: Although REG and TAS-102 showed a similar efficacy in mCRC patients with refractory to standard chemotherapies, the choice of the drug by age might affect the survival. Supported by JSCCR. Clinical trial information: UMIN000020416

Prognostic impact of primary tumor location in patients with metastatic colorectal cancer (mCRC) at the salvage lines.

741 Background: Recently it has been suggested that primary tumor location may have a clinical impact on the front line chemotherapies; namely, right-sided tumor benefit less from cytotoxic and targeted agents compared with left-sided tumor. Regorafenib and TAS 102 have recently emerged and the prognostic impacts of tumor location on these agents are unknown. Methods: Clinical information of patients who were administrated Regorafenib and/or TAS 102 was retrospectively collected. Patients’ demographics by tumor location were compared using Fisher’s exact test. Time to treatment failure (TTF), and overall survival (OS) by tumor location were calculated using Kaplan-Meyer Methods and compared using Log-rank test. In addition, subgroup analyses were performed to see the interactions between tumor location and covariates in each agent. All tests were performed at the two-sided .05 significance level. Results: The median TTF (mTTF) and OS (mOS) were 2.0 and 8.0 months in the regorafenib group (n = 98) and were 2.4 and 7.9 months in the TAS102 group (n = 95), respectively. In the regorafenib group, 71 patients had a left-sided tumor and 27 patients had a right-sided tumor. In the TAS102 group, 64 patients had a left-sided and 31 patients had a right-sided tumor. There was no significant difference between right and left sides in both groups with the exception that a greater number of older patients was seen in right-sided in the TAS102 group. No significant difference of TTF and OS by primary site were observed in regorafenib (HR 0.92, 95% CI 0.68-1.70, P = 0.71 for TTF, HR 1.09, 95% CI 0.68-1.81, P = 0.74 for OS) and in TAS 102 (HR 0.84, 95%CI 0.53-1.36, P = 0.48 for TTF, HR 1.26, 95% CI 0.72-2.33 P = 0.43 for OS). Significant interactions were shown between presence of liver metastasis and tumor location both in TTF and OS in regorafenib (p < 0.05). On the other hand, in TAS102, significant interactions were shown between period from 1st line chemotherapy and tumor location in TTF and between time to metastasis and tumor location in OS (p < 0.05). Conclusions: In contrast to front line chemotherapy, no clinical impact of tumor location was demonstrated at the salvage lines in mCRC.

Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial

PurposeTAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.001]. The current analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup.MethodsPrimary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics.ResultsThe RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28–0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30–0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group.ConclusionsIn the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified.ClinicalTrials.gov study numberNCT01607957

Effect of regorafenib and TAS-102 in metastatic colorectal cancer (mCRC) patients on survival in salvage line with different toxicity profile.

763 Background: In the CORRECT study, regorafenib has survival benefits in patients with metastatic colorectal cancer (mCRC) in salvage line. In the J-003 and RECOURSE study, TAS-102 has also survival benefit in them, too. But no randomized study is existed about the comparison between regorafenib and TAS-102. So we retrospectively compared the efficacy and toxicity of regorafenib and TAS-102 in patients with mCRC for salvage line in our hospital. Methods: The selection criteria were pathologically proven mCRC; 20 years or older; had a previous treatment history of two or more regimens of standard chemotherapy; no prior regorafenib and TAS-102 therapy; performance status 0-1; able to oral intake; and adequate organ functions. The patients in regorafenib group, regorafenib 160mg/body was given orally once daily for 21days followed by a 7-day rest. In TAS-102 group, TAS-102 35mg/m2 was given orally twice daily 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period. Results: The analysis covered 51 patients over the period from October 2009 to June 2015.The median age was 67 years (range 33-79); 29 males and 22 females; PS 0/1 score 19/32; 23 patients were treated regorafenib and 28 patients were treated TAS-102.Progression-free survival and overall survival were 2.6 and 10.6 months with regorafenib and 3.2 and 9.7 months with TAS-102 (no significant difference). The rate of grade 3-4 toxicity were hypertension (35%), hand-foot syndrome(35%), AST/ALT increased(12%) in regorafenib group, and leucopenia (15%), neutropenia (35%), anemia(10%) in TAS-102 group. There was no treatment death in both groups. Conclusions: Both regorafenib and TAS-102 give mCRC patients survival benefit in salvage line with different toxicity profile.

An open-label, randomized, parallel-group study of the pharmacokinetics of trifluridine as a component of TAS-102 versus FTD alone.

751 Background: TAS-102 is a novel oral combination therapy of FTD plus tipiracil hydrochloride (TPI) with FTD:TPI molar and weight ratios of 1:0.5 and 1:0.471, respectively. FTD is a thymidine-based nucleoside analog that has shown antitumor effects in preclinical and clinical studies. TPI stabilizes orally administered FTD by inhibiting thymidine phosphorylase and TAS-102 has shown efficacy in refractory metastatic colorectal cancer. The objective of this study was to show that TPI, administered with FTD as TAS-102, increases exposure to FTD in patients with advanced solid tumors. Methods: This is a Phase 1, randomized, open-label, pharmacokinetic study of TAS-102 in patients with advanced solid tumors. On the morning of Day 1, one group received TAS-102 35 mg/m2 and the other group received FTD 35 mg/m2. Both groups received TAS-102 35 mg/m2 on the evening of Day 1, then twice daily on Days 2-5 and 8-12 in a 28-day cycle. Blood samples were collected to evaluate FTD AUC0-last and Cmax (primary endpoints). Results: Overall, 44 patients (50% male, mean age 57 years) were treated. After a single dose, the ratio of the geometric mean of FTD AUC0-last and Cmax were 38- and 22-fold higher, respectively (Table) following TAS-102 vs FTD alone. After multiple doses (Day 12 in Cycles 1, 2, or 3), FTD AUC and Cmax were ~3- and 2-fold higher, respectively, than after a single dose of TAS-102 (Day 1). For TPI, AUC and Cmax were similar after single and multiple doses of TAS-102. After Cycle 1, FTD did not accumulate with successive cycles of TAS-102 treatment. The most commonly reported treatment-related adverse events were nausea (47.7%), fatigue (31.8%), and anemia (27.3%), with Grade 3-4 events at 4.5%, 2.3%, and 18.2%, respectively. Grade ≥ 3 decreases in neutrophil counts were observed in 42.9% of the TAS-102 group. Conclusions: TPI, in combination with FTD, substantially increased exposure to FTD vs FTD alone. Clinical trial information: NCT01867866. [Table: see text]

TAS-102 for the treatment of metastatic colorectal cancer

The survival of patients with metastatic colorectal cancer has notably increased in the past 20 years, from 12 months to around 30 months. Nevertheless, the prognosis of patients pretreated with all available agents is poor and there is high unmet need for newer treatments. TAS-102 is an orally administered combination of the nucleoside analogue trifluridine and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. In a randomized trial of 800 patients who had received at least two other treatments previously (most patients had received more than four treatments). TAS-102 demonstrated a significant prolongation of overall survival compared with placebo (median survival 7.1 vs. 5.3 months; hazard ratio 0 · 68, 95%CI: 0 · 58–0 · 81; p < 0 · 001). The toxicity was manageable, grade 3 or higher events occurred in 69% of patients in the TAS-102 group versus 52% in the placebo group, with neutropenia the most common event.

Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies.

Fluoropyrimidines form the mainstay in treatment of gastrointestinal malignancies. For decades 5-fluorouracil (5FU), was the major fluoropyrimidine. Currently it is usually given in a combination with leucovorin and oxaliplatin, i.e. FOLFOX, or irinotecan, i.e. FOLFIRI, or all three, i.e. FOLFIRINOX, but gradually it has been replaced by oral fluoropyrimidine prodrug formulations, such as tegafur-uracil and S-1 (both contain ftorafur), and capecitabine (Xeloda®). Novel drugs such as the antivascular endothelial growth factor antibody, bevacizumab, and the anti-epidermal growth factor receptor antibody, cetuximab, are often combined with one of these treatment options. However, when resistance emerged, no alternatives were available. TAS-102, a combination of trifluorothymidine and the thymidine phosphorylase inhibitor TPI in a 1:0.5 ratio, is a novel oral formulation, which is active in 5FU-resistant models, both in vitro and in xenograft models. In addition to inhibition of thymidylate synthase, the major mechanism of action of classical fluoropyrimidines, TAS-102's major mechanism of action is incorporation into DNA, thereby causing DNA damage. TAS-102 also follows an alternative activation pathway via thymidine kinase, and is not a substrate for dihydropyrimidine dehydrogenase. All together this explains the efficacy in 5FU-resistant models. In early clinical studies, the twice-daily schedule (5 days on, 2 days rest) for 2 weeks every 4 weeks, led to a significant disease control rate in various malignancies. This schedule showed consistent activity in two randomized trials on fluoropyrimidine refractory colorectal cancer patients, reflected by an increase of 2-3 months in overall survival in the TAS-102 group compared with placebo. Considering the impressive preclinical potential of various combinations TAS-102 has the promise to become an alternative for 5FU-resistant cancer.

Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer

BackgroundEarly clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients.MethodsIn this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival.ResultsThe median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001).ConclusionsIn patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology–Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.)

126IN - Colorectal Cancer: A New Oral Cytotoxic Agent Reappears

ABSTRACT Cytotoxic agents, such as fluoropyrimidine, irinotecan, and oxaliplatin and antibodies such as bevacizumab, and cetuximab and panitumumab have been shown to significantly improve the survival of patients with unresectable metastatic colorectal cancer (mCRC). Although many patients have a good long-term performance status, a standard therapy for patients refractory to or unable to tolerate these agents does not currently exist. TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride (TPI) at a molar ratio of 1 to 0.5. TAS-102 possesses a mechanism of action different from that of other antitumor agents, including fluoropyrimidine, irinotecan and oxaliplatin. Based on a phase I clinical trial in Japan, the recommended dose of TAS-102 (35 mg/m2/b.i.d) twice daily administered orally in days 1-5 and 8-12 of a 28-day cycle was determined. These results indicated that TAS-102 was expected to further improve the outcomes of patients with unresectable mCRC. We conducted randomized, double-blind phase II trial as a placebo-controlled study to evaluate the efficacy of TAS-102. A total of 172 colorectal cancer patients who were refractory or intolerable to 2 or more regimens of standard chemotherapy with a fluoropyrimidine, irinotecan, and oxaliplatin underwent either TAS-102 plus best supportive care (BSC) (114 patients) or placebo plus BSC (58 patients) with the primary endpoint of overall survival. TAS-102 significantly decreased death risk compared to placebo (hazard ratio, 0.56; 95% confidential interval [CI], 0.39-0.81; P = 0.0011). The median overall survival was 9.0 months in the TAS-102 group and 6.6 months in the placebo group. TAS-102 significantly improved progression-free survival (median, 2.0 months vs 1.0 month; hazard ratio, 0.41; 95% CI, 0.28-0.59; P Disclosure T. Yoshino: I have honoraria with Chugai, Takeda, Bristol-Myers Squibb, Yakult and Merck Serono. I have research funding from Bayer, Taiho, Daiichi-sankyo and Quintiles. I have received consulting fee from Takeda.

TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial

Treatments that confer survival benefit are needed in patients with heavily pretreated metastatic colorectal cancer. The aim of this trial was to investigate the efficacy and safety of TAS-102-a novel oral nucleoside antitumour agent. Between August 25, 2009, and April 12, 2010, we undertook a multicentre, double-blind, randomised, placebo-controlled phase 2 trial in Japan. Eligible patients were 20 years or older; had confirmed colorectal adenocarcinoma; had a treatment history of two or more regimens of standard chemotherapy; and were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin. Patients had to be able to take oral drugs; have measurable lesions; have an Eastern Cooperative Oncology Group performance status of between 0 and 2; and have adequate bone-marrow, hepatic, and renal functions within 7 days of enrolment. Patients were randomly assigned (2:1) to either TAS-102 (35 mg/m(2) given orally twice a day in a 28-day cycle [2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period]) or placebo; all patients received best supportive care. Randomisation was done with minimisation methods, with performance status as the allocation factor. The randomisation sequence was generated with a validated computer system by an independent team from the trial sponsor. Investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety analyses were done in the per-protocol population. The study is in progress and is registered with Japan Pharmaceutical Information Center, number JapicCTI-090880. 112 patients allocated to TAS-102 and 57 allocated to placebo made up the intention-to-treat population. Median follow-up was 11·3 months (IQR 10·7-14·0). Median overall survival was 9·0 months (95% CI 7·3-11·3) in the TAS-102 group and 6·6 months (4·9-8·0) in the placebo group (hazard ratio for death 0·56, 80% CI 0·44-0·71, 95% CI 0·39-0·81; p=0·0011). 57 (50%) of 113 patients given TAS-102 in the safety population had neutropenia of grade 3 or 4, 32 (28%) leucopenia, and 19 (17%) anaemia. No patient given placebo had grade 3 or worse neutropenia or leucopenia; three (5%) of 57 had grade 3 or worse anaemia. Serious adverse events occurred in 21 (19%) patients in the TAS-102 group and in five (9%) in the placebo group. No treatment-related deaths occurred. TAS-102 has promising efficacy and a manageable safety profile in patients with metastatic colorectal cancer who are refractory or intolerant to standard chemotherapies.