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Clinical Colorectal Cancer Jun 2017Trifluridine/tipiracil (TAS-102) is a new oral combination therapy approved by the US Food and Drug Administration for the treatment of patients with metastatic... (Review)
Review
Trifluridine/tipiracil (TAS-102) is a new oral combination therapy approved by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer who are refractory to or intolerant of standard chemotherapy. This agent consists of a thymidine-based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil), which is included to reduce the degradative breakdown of trifluridine. In the phase III Randomized, double-blind, phase III Study of TAS-102 plus best supportive care [BSC] versus placebo plus BSC in patients with metastatic colorectal cancer [CRC] refractory to standard chemotherapies (RECOURSE) trial, trifluridine/tipiracil showed significant improvement in overall survival compared with placebo. Trifluridine/tipiracil is administered at a 35 mg/m dose orally twice daily in a 28-day cycle consisting of 5 treatment days/2 rest days for 2 weeks followed by a rest period of 2 weeks. Because trifluridine/tipiracil is a completely oral chemotherapy regimen, patient adherence to treatment is an important consideration. It is also critical to have strategies in place for managing toxicities, because side effects might have a negative effect on patient adherence. The most frequent adverse events reported in patients with metastatic colorectal cancer receiving trifluridine/tipiracil in the phase III RECOURSE trial were myelosuppression, nausea/vomiting, diarrhea, decreased appetite, and fatigue. In this review we aim to provide clinicians with practical recommendations for facilitating patient adherence to oral chemotherapy, managing trifluridine/tipiracil dosing, and address the most common adverse events in patients who receive trifluridine/tipiracil therapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Humans; Medication Adherence; Neoplasm Metastasis; Pyrrolidines; Thymine; Trifluridine; Uracil
PubMed: 28242161
DOI: 10.1016/j.clcc.2017.01.003 -
The Oncologist Nov 2023In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients...
BACKGROUND
In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure.
METHODS
We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150-180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined.
RESULTS
Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively.
CONCLUSION
Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].
Topics: Humans; Bevacizumab; Irinotecan; Colorectal Neoplasms; Uracil; Trifluridine; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Rectal Neoplasms; Drug Combinations
PubMed: 37284901
DOI: 10.1093/oncolo/oyad143 -
Cancer Science Dec 2023Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on...
Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Trifluridine; Esophageal Neoplasms; Phosphorylation; Histones; Cell Cycle Proteins; Cell Line, Tumor; Protein-Tyrosine Kinases
PubMed: 37724648
DOI: 10.1111/cas.15966 -
Drugs Sep 2019Trifluridine/tipiracil (Lonsurf) is a fixed-dose combination tablet comprising trifluridine, an antineoplastic nucleoside analogue, and tipiracil, a thymidine... (Review)
Review
Trifluridine/tipiracil (Lonsurf) is a fixed-dose combination tablet comprising trifluridine, an antineoplastic nucleoside analogue, and tipiracil, a thymidine phosphorylase inhibitor. Trifluridine/tipiracil has recently been granted an additional indication in the USA for the treatment of metastatic gastric cancer, including gastroesophageal junction adenocarcinoma, in patients who have been previously treated with at least two systemic treatment regimens, and has received a positive opinion for this indication in the EU. In the large pivotal phase III TAGS trial, trifluridine/tipiracil plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) compared with placebo plus BSC in this patient group. Progression-free survival (PFS) and the disease control rate were also improved with trifluridine/tipiracil relative to placebo. Health-related quality of life was not adversely affected by the addition of trifluridine/tipiracil to BSC and time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status was significantly delayed. The most common adverse events were mainly haematological (neutropenia, leucopenia and anaemia) and gastrointestinal (nausea, vomiting and diarrhoea), and were generally manageable with dosage modifications and/or supportive care. Adverse events ≥ Grade 3 were most frequently haematological in nature. Thus, trifluridine/tipiracil provides a valuable and much needed treatment option for patients with metastatic gastric or gastroesophageal junction adenocarcinoma that has progressed on at least two prior therapies.
PubMed: 31489588
DOI: 10.1007/s40265-019-01195-w -
Targeted Oncology Jan 2024The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC).
Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer.
BACKGROUND
The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC).
OBJECTIVE
This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC.
PATIENTS AND METHODS
The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed.
RESULTS
Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS.
CONCLUSION
Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted.
CLINICAL TRIAL REGISTRATION NUMBER
jRCTs031180122.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Aged, 80 and over; Bevacizumab; Colorectal Neoplasms; Interleukin-8; Uracil; Trifluridine; Angiogenesis; Frontotemporal Dementia; Tissue Inhibitor of Metalloproteinase-1; Colonic Neoplasms; Cell-Free Nucleic Acids; Biomarkers; Antineoplastic Combined Chemotherapy Protocols; Pyrrolidines; Thymine
PubMed: 38194163
DOI: 10.1007/s11523-023-01027-8 -
Current Oncology (Toronto, Ont.) Jun 2023Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R)...
Treatment Settings and Outcomes with Regorafenib and Trifluridine/Tipiracil at Third-Line Treatment and beyond in Metastatic Colorectal Cancer: A Real-World Multicenter Retrospective Study.
BACKGROUND
Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice.
MATERIALS AND METHODS
In 2012-2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes.
RESULTS
The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) ( = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T ( = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) ( = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) ( = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies.
CONCLUSIONS
The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.
Topics: Humans; Retrospective Studies; Uracil; Colorectal Neoplasms; Trifluridine; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37366896
DOI: 10.3390/curroncol30060413 -
Expert Review of Clinical Pharmacology 2016TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil... (Review)
Review
TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.
Topics: Animals; Antineoplastic Agents; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Neoplasm Metastasis; Pyrrolidines; Randomized Controlled Trials as Topic; Survival Rate; Thymine; Trifluridine; Uracil
PubMed: 26677869
DOI: 10.1586/17512433.2016.1133285 -
Gastric Cancer : Official Journal of... May 2022Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of trifluridine/tipiracil in older and younger patients with metastatic gastric or gastroesophageal junction cancer: subgroup analysis of a randomized phase 3 study (TAGS).
BACKGROUND
Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age.
METHODS
In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years.
RESULTS
Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51-0.89), 0.73 (95% CI 0.52-1.02), and 0.67 (95% CI 0.33-1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)].
CONCLUSIONS
The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Esophageal Neoplasms; Esophagogastric Junction; Frontotemporal Dementia; Humans; Pyrrolidines; Stomach Neoplasms; Thymine; Trifluridine
PubMed: 34997449
DOI: 10.1007/s10120-021-01271-9 -
Antiviral Chemistry & Chemotherapy Jan 2013This review article focuses on the anti-herpesvirus agents effective against herpes simplex virus, varicella-zoster virus and cytomegalovirus, which have either been... (Review)
Review
This review article focuses on the anti-herpesvirus agents effective against herpes simplex virus, varicella-zoster virus and cytomegalovirus, which have either been licensed for clinical use (idoxuridine, trifluridine, brivudin, acyclovir, valaciclovir, valganciclovir, famciclovir and foscarnet) or are under clinical development (CMX001 [the hexadecyloxypropyl prodrug of cidofovir], the helicase-primase inhibitor BAY 57-1293 [now referred to as AIC316], FV-100 [the valine ester of Cf 1743] and the terminase inhibitor letermovir [AIC246]).
Topics: Animals; Antiviral Agents; Cytomegalovirus; Herpesviridae Infections; Herpesvirus 3, Human; Humans; Simplexvirus
PubMed: 23343513
DOI: 10.3851/IMP2533