Study protocol of an open-label, single arm phase II trial investigating the efficacy and safety of Trifluridine/Tipiracil combined with irinotecan as a second line therapy in patients with cholangiocarcinoma (TRITICC).

BACKGROUND: The prognosis of patients with advanced biliary tract cancer (BTC) who have progressed on gemcitabine plus cisplatin is dismal. Trifluridine/tipiracil (FTD/TPI) and irinotecan have proven efficacy in different gastrointestinal malignancies. We therefore hypothesized that this combination might improve the therapeutic outcome in patients with BTC after failure of first line treatment. METHODS: TRITICC is an interventional, prospective, open-label, non-randomised, exploratory, multicentre, single-arm phase IIA clinical trial done in 6 sites with expertise in managing biliary tract cancer across Germany. A total of 28 adult patients (aged ≥ 18 years) with histologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy will be included to receive a combination of FTD/TPI plus irinotecan according to previously published protocols. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment. DISCUSSION: The aim of TRITICC is to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with biliary tract cancer refractory to previous Gemcitabine based treatment. TRIAL REGISTRATION: EudraCT 2018-002936-26; NCT04059562.

A Phase I dose-escalation study of third-line regorafenib with trifluridine/tipiracil in metastatic colorectal cancer.

Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1-5 and 8-12 of a 28-day cycle, REG on days 2-22. Two dose levels were used: FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose is FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d. Median progression-free survival was 3.81 months (95% CI: 1.51-5.29), median OS 11.1 months (95% CI: 2.3-18.2). Conclusion: The combination of REG and FTD/TPI is feasible and safe. Efficacy signals exceed that of the single agents at acceptable toxicity levels and are clinically meaningful.

Lay abstract Many patients with metastatic colorectal cancer need a sequence of different treatments over time. Regorafenib and trifluridine/tipiracil (also called TAS-102) are two drugs which are both used late in this sequence of treatments, but there is no rule as to which should be used first. Both drugs have very different mechanisms of action, and it might be beneficial to patients to administer them both at the same time as a combination treatment, instead of sequential treatment. We therefore conducted a Phase Ib study with a small number of patients to investigate whether this combined treatment would be feasible and safe. The study was designed to test the drug combination at different doses, and we found that treatment with trifluridine/tipiracil at 25 mg/m² twice daily combined with regorafenib at 120 mg daily had acceptable side effects and is likely to be safe for use in future clinical trials. Efficacy results suggest that combined treatment with both drugs may extend patient's life span. However, these observations are preliminary and need testing in further clinical trials. Clinical trial registration: EudraCT 2016-001968-11; NCT03305913 (ClinicalTrials.gov).

Trifluridine/tipiracil plus bevacizumab for third-line management of metastatic colorectal cancer: SUNLIGHT study design.

Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Preliminary studies of FTD/TPI plus bevacizumab have produced encouraging results in the treatment of refractory metastatic colorectal cancer. Here, we describe the design of the multinational Phase III SUNLIGHT, an open-label study of FTD/TPI plus bevacizumab as third-line treatment for patients with unresectable metastatic colorectal cancer. A total of 490 patients will be randomized 1:1 to receive either FTD/TPI plus bevacizumab, or FTD/TPI monotherapy. The primary objective is to significantly improve overall survival with FTD/TPI plus bevacizumab compared with FTD/TPI monotherapy. The first patient was enrolled in November 2020.

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study.

Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 twice daily (bid) on days 1-5 and 15-19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m2 bid on days 1-5 and 15-19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.

Delphi consensus for the third-line treatment of metastatic colorectal cancer.

PURPOSE: The optimal drug regimen and sequence are still unknown for patients with metastatic colorectal cancer (mCRC) who are candidates for third-line (3L) or subsequent treatment. The aim of this study is to know the opinion of experts on the most appropriate treatment options for mCRC in 3L and to clarify certain clinical decisions in Spain. METHODS: Using a modified Delphi method, a group of experts discussed the treatment in 3L of patients with mCRC and developed a questionnaire with 21 items divided into 5 sections. RESULTS: After 2 rounds, the 67 panelists consulted agreed on 17 items (81%). They considered that the main objective of 3L is to equally increase survival and improve patients' quality of life (QoL), but preferably the QoL. It was agreed that patients with mCRC in 3L prefer to receive active versus symptomatic treatment. Panelists considered trifluridine/tipiracil (FTD/TPI) to be the best oral treatment available to them in 3L. In patients with MSI-H or dMMR and BRAF V600E, the panelists mostly prefer targeted treatments. Panelists agreed the use of a therapeutic sequence that not only increases outcomes but also allows patients to be treated later. Finally, it was agreed that FTD/TPI has a mechanism of action that allows it to be used in patients refractory to previous treatment with 5-fluorouracil. CONCLUSION: The experts agreed with most of the proposed items on 3L treatment of mCRC, prioritizing therapeutic options that increase survival and preserve QoL, while facilitating the possibility that patients can continue to be treated later.

Phase II study of trifluridine/tipiracil in metastatic breast cancers with or without prior exposure to fluoropyrimidines.

BACKGROUND: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study. METHODS: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability. RESULTS: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications. CONCLUSION: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC.

Trifluridine/tipiracil (FTD/TPI) and regorafenib in older patients with metastatic colorectal cancer.

Colorectal cancer is a disease of older patients, but few guidelines directly address age in their recommendations. Older patients may present comorbidities that affect the choice of chemotherapy, and care must be taken when choosing the best approach. This narrative review aimed to describe the literature regarding approved oral agents for third-line treatment in older patients with refractory metastatic colorectal cancer, regorafenib, and trifluridine/tipiracil (FTD/TPI).

Real-world evidence of trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer using an administrative claims database in Japan.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard therapies for refractory metastatic colorectal cancer (mCRC). No results of large real-world data directly comparing FTD/TPI + bevacizumab (BEV) with FTD/TPI or REG monotherapy have been reported. We evaluated the efficacy and safety of FTD/TPI + BEV in a real-world setting. MATERIALS AND METHODS: This retrospective study used a Japanese claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Eligible patients were aged 20 years and over with a diagnosis of mCRC, and received their first dose of FTD/TPI or REG from 2014 to 2021. The primary endpoint was overall survival (OS) in a propensity score matching (PSM) population in which PSM was carried out by matching using a 1 : 1 ratio for the FTD/TPI + BEV group and the control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were carried out using the inverse probability treatment weighted (IPTW) approach and the analysis in the all eligible population. Secondary endpoints included time to treatment discontinuation (TTD), incidence of adverse events, and post-treatment. RESULTS: Eligible population was 2369 for the FTD/TPI + BEV group and 9318 for the control group. The PSM population was 1787 for each group. Median OS (mOS) was longer in the FTD/TPI + BEV group compared to the control group [17.0 versus 11.6 months, hazard ratio (HR) = 0.70, P < 0.001] in the PSM population. Similarly, mOS was longer for the FTD/TPI + BEV group compared to that for the control group in IPTW analyses and in the all eligible population (both HRs = 0.68). Median TTD was 3.3 months for the FTD/TPI + BEV group and 1.8 months for the control group in the PSM population (P < 0.001). CONCLUSIONS: Real-world data showed that FTD/TPI + BEV was significantly associated with OS and TTD compared to FTD/TPI or REG. In clinical practice, FTD/TPI + BEV can be a favorable regimen for refractory mCRC.

Bevacizumab mitigates codon-specific effects of trifluridine/tipiracil on efficacy outcome parameters in metastatic colorectal cancer.

BACKGROUND: Molecular informed therapy changed treatment patterns of metastatic colorectal cancer (mCRC). Recently KRAS G12, the most prevalent RAS mutation in mCRC, was investigated to be a negative predictive marker for the efficacy of trifluridine/tipiracil (FTD/TPI). Whether this proposed selectivity remains when FTD/TPI is combined with bevacizumab remains elusive. We aimed to describe the efficacy of FTD/TPI + bevacizumab depending on the RAS mutational status in a real-world population. PATIENTS AND METHODS: Patients from five different cancer centers in Austria who received FTD/TPI + bevacizumab in any treatment line having available information on their molecular profile were eligible. Data were retrospectively collected by chart review. Survival data were compared using log-rank test. Multivariate Cox regression models included several established covariates. RESULTS: One hundred and twenty-three patients with mCRC were included in this study. Median overall survival (OS) was highly similar in the RAS wild type (WT) [9.63 months (95% confidence interval [CI] 8.055-13.775 months)] and the RAS mutant cohorts [8.78 months (95% CI 8.055-11.014 months)], which was confirmed in a multivariable model adjusting for potential confounders; hazard ratio (HR): 1.05 (95% CI 0.618-1.785; P = 0.857). In addition, no effect of KRAS G12 status on patient outcome was observed. In detail, OS was 8.88 months (95% CI 7.332-12.921 months) in patients with KRAS G12 mutation, compared to 9.47 months (95% CI 8.088-11.375 months) in patients with RAS WT/no-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; P = 0.387)]. CONCLUSION: This real-world study indicates that the efficacy of FTD/TPI + bevacizumab is independent of RAS mutational status and that bevacizumab may therefore mitigate the potentially limited efficacy of FTD/TPI monotherapy in the KRAS G12-mutated population.

HTA and Gastric Cancer: Evaluating Alternatives in Third- and Fourth-Line Patients.

Metastatic gastric cancer (mGC) represents an economic and societal burden worldwide. The present study has two aims. Firstly, it evaluates the benefits and the added value of the introduction of trifluridine/tipiracil (FTD/TPI) in the Italian clinical practice, defining the comparative efficacy and safety profiles with respect to the other available treatment options (represented by the best supportive care (BSC) and FOLFIRI (5-FU, irinotecan, and leucovorin) regimens). Secondly, it assesses the potential economic and organizational advantages for hospitals and patients, focusing on third- and fourth-line treatments. For the achievement of the above objective, a health technology assessment study was conducted in 2021, assuming the NHS perspective within a 3-month time horizon. The literature reported a better efficacy of FTD/TPI with respect to both BSC and FOLFIRI regimens. From an economic perspective, despite the additional economic resources that would be required, the investment could positively impact the overall survival rate for the patients treated with the FTD/TPI strategy. However, the innovative molecule would lead to a decrease in hospital accesses devoted to chemotherapy infusion, ranging from a minimum of 34% to a maximum of 44%, strictly dependent on FTD/TPI penetration rate, with a consequent opportunity to take on a greater number of oncological patients requiring drug administration for the treatment of any other cancer diseases. According to experts' opinions, lower perceptions of FTD/TPI emerged concerning equity aspects, whereas it would improve both individuals' and caregivers' quality of life. In conclusion, the results have demonstrated the strategic relevance related to the introduction of FTD/TPI regarding the coverage of an important unmet medical need of patients with metastatic gastric cancer who were refractory to at least two prior therapies, with important advantages for patients and hospitals, thus optimizing the clinical pathway of such frail patients.

Clinical Phase I Study of TAS102/Irinotecan/Bevacizumab Combination Therapy in Japanese Patients With Unresectable Metastatic Colorectal Cancer (mCRC).

BACKGROUND: In this phase I study, we aimed to examine the safety of a triple combination (TAS-102/irinotecan/bevacizumab) therapy in patients with previously treated metastatic colorectal cancer (mCRC). METHODS: In the TAS-102 dose-escalation phase, we determined dose-limiting toxicity (DLT), estimated the maximum tolerated dose (MTD), and determined the recommended dose (RD); in the expansion phase, we evaluated safety. The RD was administered in advance for 10 patients. The TAS-102 dose was increased to 25-35 mg/m2 and administered orally twice on days 1-5 and 8-12. Irinotecan (100 mg/m2) and bevacizumab (5 mg/m2) were administered on days 1 and 15 of the treatment, respectively. RESULTS: Fifteen patients were enrolled in dose-escalation Levels 1-3, and ten in the expansion phase. A 30 mg/m2 TAS-102 dose at Level 2 was administered to three patients, with one presenting grade 4 neutropenia. A 35 mg/m2 TAS-102 dose at Level 3 was administered to five patients, with three patients presenting grade 4 neutropenia and grade 3 DLTs. We added three patients at Level 2 and set the MTD at 30 mg/m2, with no DLTs. The RD was fixed at 25 mg/m2, with no DLTs (N = 10) or treatment-related deaths. One patient showed complete response at Level 2, four presented partial response, and eleven individuals maintained stable disease for over four months. The median progression-free survival duration was 7.6 months, while the median overall survival period was 16.9 months. CONCLUSION: The TAS-102/irinotecan/bevacizumab combination therapy was safe, effective, and well-tolerated in patients previously treated with mCRC.

Effectiveness, safety, and prognostic factors of trifluridine/tipiracil for the treatment of patients with metastatic colorectal cancer in routine clinical practice.

Background: The combination of trifluridine and tipiracil is indicated in patients with metastatic colorectal cancer previously treated or non-candidates to chemotherapy and biological therapies. This study in routine clinical practice aimed to describe the effectiveness and safety of trifluridine and tipiracil and identify prognostic factors in patients with metastatic colorectal cancer in Spain. Methods: This analysis was a retrospective, observational, multicenter study that included patients aged ≥18 years who had received treatment with trifluridine/tipiracil for metastatic colorectal cancer in third- or subsequent lines. Results: Overall, 294 were evaluated. Trifluridine/tipiracilmedian (minimum, maximum) treatment duration was 3.5 (1.0-29.0) months, and 128 (43.5%) patients received subsequent treatments. One hundred (34%) patients showed disease control rate, and the median progression-free survival and overall survival from trifluridine/tipiracil treatment onset were 3.7 and 7.5 months, respectively. The most frequently reported adverse events were asthenia (all grades, 57.9%) and neutropenia (all grades, 51.3%). A 39.1% and 4.4% of the participants had a dose reduction and a treatment interruption due to toxicity. Patients with age ≥65 years, low tumor burden, ≤2 metastasis sites, treatment dose reduction, neutropenia, and ≥6 cycles, had significantly higher overall survival, progression-free survival, and response rate. Conclusions: This real-life study indicates that trifluridine/tipiracil shows effectiveness and safety in treating patients with metastatic colorectal cancer. The results show a profile of metastatic colorectal cancer patients with previously unknown prognostic factors who have a more significant benefit from treatment with trifluridine/tipiracil in routine clinical practice.

Severe pancytopenia caused by trifluridine/tipiracil in patients with metastatic colorectal cancer and an impaired renal function: A case report.

Although the incidence of hematological toxicity due to Trifluridine/tipiracil (FTD/TPI) treatment is high, the incidence of severe adverse events has been reported to be relatively low. However, it should be noted that patients with renal impairment are prone to severe hematological adverse events.

Combining Bevacizumab With Trifluridine/Thymidine Phosphorylase Inhibitor Improves the Survival Outcomes Regardless of the Usage History of Bevacizumab in Front-line Treatment of Patients With Metastatic Colorectal Cancer.

BACKGROUND/AIM: The efficacy of trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) plus bevacizumab as later-line treatment for metastatic colorectal cancer (mCRC) has been demonstrated. However, little is known about the impact of a usage history of bevacizumab in front-line treatment on the clinical benefit of combining bevacizumab with FTD/TPI. PATIENTS AND METHODS: A total of 62 patients with mCRC treated with FTD/TPI±bevacizumab was enrolled and assessed for chemotherapeutic efficacy and adverse events. RESULTS: Regardless of the usage history of bevacizumab in front-line treatment, the FTD/TPI plus bevacizumab group had a significantly better progression-free survival rate than the FTD/TPI monotherapy group, and no significant differences in the safety profile were observed between the two groups. CONCLUSION: Combining bevacizumab with FTD/TPI improves the survival outcomes with manageable toxicity, regardless of the usage history of bevacizumab in front-line treatment, in patients with mCRC.

Neutropenia is an indicator of outcomes in metastatic colorectal cancer patients treated with FTD/TPI plus bevacizumab: a retrospective study.

PURPOSE: Trifluridine/tipiracil (FTD/TPI) improves the overall survival (OS) of metastatic colorectal cancer (mCRC) patients. Additionally, FTD/TPI plus bevacizumab (BEV) has demonstrated promising efficacy for mCRC patients who are refractory to standard chemotherapy. Chemotherapy-induced neutropenia (CIN) has been reported to be an indicator of efficacy for FTD/TPI. This study investigated whether CIN was an indicator of efficacy for FTD/TPI plus BEV. METHODS: We reviewed chemo-refractory mCRC patients who were treated with FTD/TPI alone (monotherapy) or FTD/TPI plus BEV (combination) at our institution and compared the safety and efficacy of the two. Progression-free survival (PFS) and OS were analyzed using Kaplan-Meier curves. We also investigated correlations between CIN and outcomes. RESULTS: In total, 56 patients received FTD/TPI, among whom 24 and 32 were treated with monotherapy and combination therapy, respectively. The median PFS was 1.8 and 4.7 months for the monotherapy and combination arms, respectively (hazard ratio [HR]: 0.28; 95% confidence interval [CI]: 0.15-0.51; P < 0.001). The median OS was 6.3 and 11.7 months for the monotherapy and combination arms, respectively (HR 0.25; 95% CI 0.13-0.48; P < 0.001). CIN (Grade 3 or worse) developed in five (20.8%) and 17 (53.1%) patients from the monotherapy and combination arms, respectively (P = 0.030). Patients with CIN in the combination arm had improved PFS and OS compared with non-CIN patients (P = 0.033 and P = 0.045, respectively). CONCLUSIONS: FTD/TPI plus BEV prolonged PFS and OS and had tolerable toxicity compared with FTD/TPI alone. CIN is an indicator of patients who will benefit from FTD/TPI plus BEV.

Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil.

PURPOSE: Trifluridine (FTD) is the active component of the nucleoside chemotherapeutic drug trifluridine/tipiracil (FTD/TPI), which is approved worldwide for the treatment of patients with metastatic gastrointestinal cancer. FTD exerts cytotoxic effects via its incorporation into DNA, but FTD has not been detected in the tumor specimens of patients. The purpose of this study was to detect FTD in tumors resected from metastatic colorectal cancer (mCRC) patients who were administered FTD/TPI. Another purpose was to investigate the turnover rate of FTD in tumors and bone marrow in a mouse model. METHODS: Tumors and normal tissue specimens were obtained from mCRC patients who were administered FTD/TPI or placebo at Kyushu University Hospital. Tumors and bone marrow were resected from mice with peritoneal dissemination treated with FTD/TPI. To detect and quantitate FTD incorporated into DNA, immunohistochemical staining of paraffin-embedded specimens (IHC-p staining) and slot-blot analysis of DNA purified from these tissues were performed using an anti-BrdU antibody. IHC-p staining of proliferation and apoptosis markers was also performed. RESULTS: FTD was detected in metastatic tumors obtained from mCRC patients who were administered FTD/TPI, but who had discontinued the treatment several weeks before surgery. In a peritoneal dissemination mouse model, FTD was still detected in tumors 13 days after the cessation of FTD/TPI treatment, but had disappeared from bone marrow within 6 days. CONCLUSION: These results indicate that FTD persists longer in tumors than in bone marrow, which may cause a sustained antitumor effect with tolerable hematotoxicity.

Real-world use of trifluridine/tipiracil for patients with metastatic colorectal cancer in Canada.

Background: Outcomes for patients with metastatic colorectal cancer (mcrc) are improving with the introduction of new treatments. Treatment for patients who are still fit after failure of all available therapies represents a significant unmet need. In the present study, we analyzed real-world treatment patterns for patients enrolled in Health Canada's trifluridine/tipiracil (ftd/tpi) Special Access Program (sap) and Taiho Pharma Canada's Patient Support Program (psp). Methods: Demographic information and clinical treatment data were collected from adults with mcrc who were previously treated with, or were not candidates for, available therapies and who were enrolled in the sap and psp. For all patients, ftd/tpi treatment status, discontinuation reasons, and prior therapies were examined. Results: The analysis included 717 Canadian patients enrolled in the ftd/tpi sap and psp from September 2017 to October 2018. In that cohort, 59.7% were men, median age was 65 years, and median duration of therapy was 77 days (25%-75% interquartile range: 43-106 days). Of treated patients, 67.1% maintained the same dose for the duration of therapy; 28.0% had a dose reduction.On multivariable analysis, duration of therapy was not influenced by sex, age, province, RAS mutation status, or prior therapies. However, prior oxaliplatin-based chemotherapy (capox or folfox) appeared to be associated with higher rates of discontinuation because of death or disease progression. Conclusions: In advanced mcrc, ftd/tpi is a well-tolerated therapy. The large number of patients enrolled in the access programs within a short period of time is reflective of major clinical need in this area, with many patients being eligible and interested in pursuing treatment in the refractory setting.

Rationale and design of the TRUSTY study: a randomised, multicentre, open-label phase II/III study of trifluridine/tipiracil plus bevacizumab versus irinotecan, fluoropyrimidine plus bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy.

BACKGROUND: Trifluridine/tipiracil is an oral agent approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is an antineoplastic thymidine analogue, and tipiracil improves its bioavailability. A phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with refractory mCRC demonstrated promising efficacy results with mild toxicity profile. It is important that quality of life be preserved in patients with mCRC without compromising their prognosis. Here, we outline the TRiflUridine/tipiracil in Second-line sTudY phase II/III study (JapicCTI-173618), designed to demonstrate non-inferiority in overall survival of trifluridine/tipiracil plus bevacizumab compared with irinotecan, fluoropyrimidine and bevacizumab combination regimens as second-line treatment in patients with mCRC. PATIENTS AND METHODS: Eligible patients have confirmed unresectable advanced or recurrent colorectal adenocarcinoma and have failed to respond to first-line oxaliplatin-based chemotherapy. A total of 524 patients are to be randomly assigned (1:1 ratio) to trifluridine/tipiracil plus bevacizumab or irinotecan, fluoropyrimidine and bevacizumab and stratified according to RAS status (wild type vs mutant). The primary endpoint of the phase II part is disease control rate with trifluridine/tipiracil plus bevacizumab therapy. Secondary endpoints are response rate and safety with trifluridine/tipiracil plus bevacizumab therapy. In the phase III part, the primary endpoint is overall survival, and secondary endpoints include quality of life, progression-free survival, response rate, disease control rate, safety, time to treatment failure, time to post-study treatment failure and the proportion of patients receiving post-study treatment. The first patient was enrolled in October 2017 and the study is anticipated to be completed in 2022. CLINICAL TRIAL REGISTRATION: JapicCTI-173618 (JapicCTI).

Two Cases of Long-Term Control of Metastatic Colorectal Cancer via FTD/TPI plus Bevacizumab in Elderly Patients.

With advances in new cytotoxic drugs and molecular-targeted drugs, the prognosis of patients with metastatic colorectal cancer (mCRC) has improved. However, physicians often hesitate to administer intensive standard regimens to elderly patients with mCRC. Recently, first-line regimens that are effective in and well-tolerated by patients who are not eligible for intensive chemotherapy have been established. However, the therapeutic strategies to adopt after the failure of first-line treatment for patients who are not eligible for intensive chemotherapy remain unclear. We herein report two cases of long-term control of mCRC via FTD/TPI+bevacizumab (Bmab) as second- or third-line treatment in elderly patients without severe adverse events. In case 1, first-line treatment with Tegafur-Uracil, which is a prodrug of 5-FU, caused disease progression in a short period after the initiation of chemotherapy. In case 2, intensive first-line treatment caused severe adverse events, and treatment was discontinued. However, in both cases, disease control was obtained for a long time without severe adverse events by subsequent treatment with FTD/TPI+Bmab. The success in these present cases indicates that FTD/TPI+Bmab as a second- or third-line treatment is a therapeutic option for elderly patients with mCRC who are not eligible for intensive chemotherapy, even after failure of treatment with 5-FU.