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ESMO Open 2019New therapeutic options for refractory metastatic colorectal cancer (mCRC) include trifluridine/tipiracil (TAS-102) and regorafenib. However, the optimal... (Review)
Review
New therapeutic options for refractory metastatic colorectal cancer (mCRC) include trifluridine/tipiracil (TAS-102) and regorafenib. However, the optimal chemotherapeutic regimen for use of each agent beyond the second line for patients with mCRC remains unclear and various factors may influence treatment decision. Available efficacy data suggest treatment with either trifluridine/tipiracil or regorafenib may be appropriate as both can extend patient survival. Thus, the safety profiles of each agent, along with patient performance status, are likely to determine treatment choice. The safety profiles of trifluridine/tipiracil and regorafenib are markedly different: higher levels of non-haematological adverse events such as fatigue, diarrhoea, hypertension and hand-foot skin reaction are reported with regorafenib, while haematological events such as neutropaenia are more common with trifluridine/tipiracil. In general, neutropaenia is a manageable treatment-related toxicity, while hand-foot skin reaction can be troublesome for patients, affecting their ability to carry out everyday activities and get on with their lives, while also affecting treatment adherence. Thus, the occurrence of any potential adverse effects and patient adherence should be closely monitored at each clinic visit. As quality of life is an important issue for patients with mCRC, it is important to balance extended survival and the likely quality of this extended life. Likewise, discussing possible side effects along with treatment expectations with patients can greatly facilitate adherence to therapy, and ultimately improve patients' quality of life and eventual clinical outcomes.
PubMed: 31231561
DOI: 10.1136/esmoopen-2019-000495 -
Therapeutic Advances in Medical Oncology 2021The C-TASK-FORCE phase I/II and Danish randomized phase II trials reported the promising efficacy of trifluridine/tipiracil (TAS102) plus bevacizumab (BEV) in patients...
Efficacy and safety of trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil or regorafenib monotherapy for chemorefractory metastatic colorectal cancer: a retrospective study.
BACKGROUND
The C-TASK-FORCE phase I/II and Danish randomized phase II trials reported the promising efficacy of trifluridine/tipiracil (TAS102) plus bevacizumab (BEV) in patients with chemorefractory metastatic colorectal cancer (mCRC). However, there had been no direct comparative phase III trial to compare the efficacy between TAS102 plus BEV and standard therapy with either TAS102 or regorafenib monotherapy.
METHODS
We retrospectively reviewed the medical records of patients with mCRC who received TAS102 plus BEV, TAS102 monotherapy, or regorafenib monotherapy after standard chemotherapies during 2013-2019.
RESULTS
Patients received TAS102 plus BEV ( = 139), TAS102 monotherapy ( = 153), or regorafenib monotherapy ( = 133). With a median follow-up of 25.3 months, median overall survival (OS) was 11.5 months [95% confidence interval (CI), 9.9-13.9] for TAS102 plus BEV, 8.1 months (95% CI, 6.8-9.2) for TAS102 monotherapy, and 6.8 months (95% CI, 5.7-8.5) for regorafenib monotherapy. The hazard ratios were 0.67 (95% CI, 0.51-0.88) for TAS102 plus BEV TAS102 monotherapy and 0.71 (95% CI, 0.54-0.94) for TAS102 plus BEV regorafenib monotherapy. Median progression-free survival (PFS) was 4.4 months (95% CI, 3.7-5.4) for TAS102 plus BEV, 2.5 months (95% CI, 1.6-2.3) for TAS102 monotherapy, and 2.1 months (95% CI, 1.6-2.3) for regorafenib monotherapy. The hazard ratios were 0.57 (95% CI, 0.45-0.73) for TAS102 plus BEV TAS102 monotherapy and 0.44 (95% CI, 0.34-0.58) for TAS102 plus BEV regorafenib monotherapy. On multivariate analysis, TAS102 plus BEV was independently correlated with better OS and PFS. No unexpected adverse events were observed in any group.
CONCLUSION
Our study shows that OS and PFS are longer in patients treated with TAS102 plus BEV than in those treated with TAS102 or regorafenib monotherapy.
PubMed: 33959196
DOI: 10.1177/17588359211009143 -
Journal of Cancer Research and Clinical... Sep 2023In the phase III TAGS trial, trifluridine/tipiracil showed survival benefit versus placebo in patients with metastatic gastric/gastroesophageal junction cancer... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of prior therapies on outcomes with trifluridine/tipiracil in patients with metastatic gastric/gastroesophageal junction cancer in a randomized phase III trial (TAGS).
BACKGROUND
In the phase III TAGS trial, trifluridine/tipiracil showed survival benefit versus placebo in patients with metastatic gastric/gastroesophageal junction cancer and ≥ 2 prior chemotherapies. This post hoc exploratory analysis assessed the impact of prior therapy type on outcomes.
METHODS
Based on prior treatment, patients in TAGS (N = 507) were categorized into overlapping subgroups: ramucirumab ± other agents (n = 169), no ramucirumab (n = 338), paclitaxel but no ramucirumab (n = 136), ramucirumab + paclitaxel sequentially or in combination (n = 154), neither paclitaxel nor ramucirumab (n = 202), irinotecan (n = 281), and no irinotecan (n = 226). Overall and progression-free survival, time to Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, and safety were assessed.
RESULTS
Baseline characteristics and prior therapy patterns were generally well balanced between trifluridine/tipiracil and placebo arms across subgroups. Trifluridine/tipiracil was associated with survival benefits versus placebo regardless of prior treatment: across subgroups, median overall survival was 4.6-6.1 versus 3.0-3.8 months (hazard ratios, 0.47-0.88), median progression-free survival was 1.9-2.3 versus 1.7-1.8 months (hazard ratios, 0.49-0.67), and median time to ECOG PS ≥ 2 was 4.0-4.7 versus 1.9-2.5 months (hazard ratios, 0.56-0.88). Among trifluridine/tipiracil-randomized patients, median overall and progression-free survival trended longer in those who had not received ramucirumab, paclitaxel and ramucirumab, or irinotecan (6.0-6.1 and 2.1-2.3 months, respectively) than in those who previously received these agents (4.6-5.7 and 1.9 months). The trifluridine/tipiracil safety profile was consistent across subgroups, with similar overall incidences of grade ≥ 3 adverse events. Minor variations in hematologic toxicities were noted.
CONCLUSIONS
In TAGS, third- or later-line trifluridine/tipiracil treatment demonstrated overall and progression-free survival and functioning benefits versus placebo and a consistent safety profile in patients with metastatic gastric/gastroesophageal junction cancer, regardless of prior treatment type.
CLINICAL TRIALS REGISTRATION
clinicaltrials.gov NCT02500043.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Esophagogastric Junction; Irinotecan; Paclitaxel; Pyrrolidines; Stomach Neoplasms; Trifluridine
PubMed: 37213030
DOI: 10.1007/s00432-023-04813-z -
Antiviral Research Aug 2023Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox (formerly monkeypox). Identifying novel and potent antiviral...
Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox (formerly monkeypox). Identifying novel and potent antiviral compounds is critical to successful drug development targeting poxviruses. Here we tested two compounds, nucleoside trifluridine, and nucleotide adefovir dipivoxil, for antiviral activities against vaccinia virus (VACV), mpox virus (MPXV), and cowpox virus (CPXV) in physiologically relevant primary human fibroblasts. Both compounds potently inhibited the replication of VACV, CPXV, and MPXV (MA001 2022 isolate) in plaque assays. In our recently developed assay based on a recombinant VACV expressing secreted Gaussia luciferase, they both exhibited high potency in inhibiting VACV replication with ECs in the low nanomolar range. In addition, both trifluridine and adefovir dipivoxil inhibited VACV DNA replication and downstream viral gene expression. Our results characterized trifluridine and adefovir dipivoxil as strong poxvirus antiviral compounds and further validate the VACV Gaussia luciferase assay as a highly efficient and reliable reporter tool for identifying poxvirus inhibitors. Given that both compounds are FDA-approved drugs, and trifluridine is already used to treat ocular vaccinia, further development of trifluridine and adefovir dipivoxil holds great promise in treating poxvirus infections, including mpox.
Topics: Animals; Humans; Vaccinia virus; Vaccinia; Cowpox virus; Antiviral Agents; Trifluridine; Mpox (monkeypox); Cell Line; Poxviridae
PubMed: 37270160
DOI: 10.1016/j.antiviral.2023.105651 -
PharmacoEconomics Mar 2018The National Institute for Health and Care Excellence (NICE) invited Servier, the company manufacturing trifluridine and tipiracil (T/T; trade name: Lonsurf), to submit... (Review)
Review
The National Institute for Health and Care Excellence (NICE) invited Servier, the company manufacturing trifluridine and tipiracil (T/T; trade name: Lonsurf), to submit evidence for the clinical and cost effectiveness of T/T compared with best supportive care (BSC) for metastatic colorectal cancer (third-line or later). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company's submission (CS), the ERG report and the development of the NICE guidance for the use of this drug in England and Wales by the appraisal committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of T/T based upon the CS. In the CS, pooled evidence of two trials (a phase II trial and RECOURSE) showed that T/T resulted in a significant increase in overall survival [OS; hazard ratio (HR) 0.67, 95% CI 0.58-0.78] and progression-free survival (PFS; HR 0.46, 95% CI 0.40-0.53). The AC considered the survival benefit of T/T clinically meaningful although relatively small. The ERG highlighted that none of the participants in the phase II trial and approximately half of the RECOURSE participants (394 of 800) were from Europe, which might limit the applicability of the study findings to the NHS. Moreover, the ERG's critical assessment of the company's economic evaluation highlighted a number of concerns that resulted in 11 adjustments to the company's base-case analysis. The ERG adjustments that had the largest impact were using the RECOURSE trial data only (instead of the pooled evidence), fixing errors and violations and using the utilities from the CORRECT trial (identified in the literature review) only. The ERG preferred to use the RECOURSE trial data only given the suboptimal methodology used by the company to pool the evidence. However, since there were no fundamental arguments to prevent the two trials from being pooled, the ERG also presented its base-case analysis based on the pooled effectiveness estimates. The company base-case resulted in an incremental cost effectiveness ratio (ICER) of £44,032 per QALY gained while the ERG base-case resulted in ICERs of £52,695 and £49,392 per QALY gained based on the RECOURSE trial only and pooled evidence, respectively. Since the AC concluded that the most plausible ICER was £49,392 per QALY gained, and that T/T meets end-of-life criteria, T/T was recommended as a cost effective use of NHS resources.
Topics: Antineoplastic Agents; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Combinations; Humans; Pyrrolidines; Technology Assessment, Biomedical; Thymine; Trifluridine; Uracil
PubMed: 29177842
DOI: 10.1007/s40273-017-0591-4 -
Scientific Reports Jul 2022Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and...
Understanding the immunological effects of chemotherapy is of great importance, especially now that we have entered an era where ever-increasing pre-clinical and clinical efforts are put into combining chemotherapy and immunotherapy to combat cancer. Single-cell RNA sequencing (scRNA-seq) has proved to be a powerful technique with a broad range of applications, studies evaluating drug effects in co-cultures of tumor and immune cells are however scarce. We treated a co-culture comprised of human colorectal cancer (CRC) cells and peripheral blood mononuclear cells (PBMCs) with the nucleoside analogue trifluridine (FTD) and used scRNA-seq to analyze posttreatment gene expression profiles in thousands of individual cancer and immune cells concurrently. ScRNA-seq recapitulated major mechanisms of action previously described for FTD and provided new insight into possible treatment-induced effects on T-cell mediated antitumor responses.
Topics: Colorectal Neoplasms; Frontotemporal Dementia; Humans; Leukocytes, Mononuclear; Pyrrolidines; Single-Cell Analysis; Thymine; Trifluridine
PubMed: 35831404
DOI: 10.1038/s41598-022-16077-7 -
Journal of Comparative Effectiveness... Feb 2019To evaluate the cost-effectiveness of trifluridine and tipiracil hydrochloride (FTD/TPI) compared with best supportive care (BSC) or regorafenib for the treatment of...
AIM
To evaluate the cost-effectiveness of trifluridine and tipiracil hydrochloride (FTD/TPI) compared with best supportive care (BSC) or regorafenib for the treatment of patients with metastatic colorectal cancer who have been previously treated with or are not considered candidates for available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents in Greece.
METHODS
A partitioned survival model was locally adapted from a third-party payer perspective over a 10 year time horizon. Efficacy data and utility values were extracted from published studies. Resource consumption data were obtained from local experts using a questionnaire developed for the purpose of the study and was combined with unit costs obtained from official sources. All costs reflect the year 2017 in euros. Primary outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs) per QALY and LYs gained.
RESULTS
Total life time cost per patient for FTD/TPI, BSC and regorafenib was estimated to be €10,087, €1,879 and €10,850, respectively. In terms of health outcomes, FTD/TPI was associated with 0.25 and 0.11 increment in LYs compared with BSC and regorafenib, respectively. Furthermore, FTD/TPI was associated with 0.17, and 0.07 increment in QALYs compared with BSC and regorafenib, resulting in ICERs of €32,759 per LY gained and €49,326 per QALY gained versus BSC. Moreover, FTD/TPI was a dominant alternative over regorafenib.
CONCLUSION
The results indicate that FTD/TPI may represent a cost-effective treatment option compared with other alternative therapies as a third-line treatment of metastatic colorectal cancer in Greece.
Topics: Adult; Antimetabolites; Colorectal Neoplasms; Cost-Benefit Analysis; Greece; Humans; Pyrrolidines; Survival Analysis; Thymine; Trifluridine
PubMed: 30547679
DOI: 10.2217/cer-2018-0076 -
Oncology Research and Treatment 2020Metastatic colorectal carcinoma (mCRC) is one of the most prevalent types of cancer worldwide. After tumor progression with first- and second-line treatment,... (Review)
Review
BACKGROUND
Metastatic colorectal carcinoma (mCRC) is one of the most prevalent types of cancer worldwide. After tumor progression with first- and second-line treatment, trifluridine (FTD) and tipiracil (TPI) has been shown to be a treatment option.
SUMMARY
Data from a pivotal phase 3 trial (RECOURSE) and an ongoing phase 3b trial (PRECONNECT) have shown that, in mCRC patients who experienced disease progression after 2 lines of standard therapy, treatment with FTD/TPI is safe and efficacious. Other third-line options include regorafenib, rechallenge with previous treatment lines or personalized approaches based on comprehensive molecular profiling. Randomized trials or sequential studies aiming for the right treatment sequence or predefined subtypes for FTD/TPI or regorafenib as well for rechallenge are missing. However, FTD/TPI as well as regorafenib are recommended by the current ESMO, German S3, and National Comprehensive Cancer Network (NCCN) guidelines in the same situation, thus offering physicians a number of alternatives for the treatment of mCRC patients after the second progression. Key Message: This narrative review summarizes published data and their impact for FTD/TPI as well for regorafenib and rechallenge chemotherapy in clinical practice settings of refractory situations of colorectal cancer.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease Progression; Drug Combinations; Humans; Neoplasm Metastasis; Phenylurea Compounds; Pyridines; Pyrrolidines; Survival Rate; Switzerland; Thymine; Treatment Outcome; Trifluridine; Uracil
PubMed: 32146471
DOI: 10.1159/000506080 -
British Journal of Cancer May 2023This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC).
METHODS
Patients were randomised (1:1) to receive FTD/TPI (35 mg/m twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33.
RESULTS
Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; P = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%).
CONCLUSIONS
FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC.
CLINICAL TRIAL REGISTRATION
JapicCTI-173618, jRCTs031180122.
Topics: Humans; Bevacizumab; Colorectal Neoplasms; Irinotecan; Trifluridine; Frontotemporal Dementia; Thymine; Pyrrolidines; Colonic Neoplasms; Rectal Neoplasms; Drug Combinations; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36871043
DOI: 10.1038/s41416-023-02212-2 -
Journal of Clinical Medicine Dec 2023Trifluridine/tipiracil (TAS-102) and fruquintinib are novel antitumor agents for patients with refractory metastatic colorectal cancer (mCRC). We conducted a...
INTRODUCTION
Trifluridine/tipiracil (TAS-102) and fruquintinib are novel antitumor agents for patients with refractory metastatic colorectal cancer (mCRC). We conducted a retrospective study to explore the clinical efficacy and drug toxicities of combination therapy with TAS-102 and fruquintinib in real-life clinical practice.
METHODS
Between March 2021 and February 2023, patients at two different centers with mCRC who failed two or more lines of prior therapy and received TAS-102 in combination with fruquintinib were recruited.
RESULTS
In total, 32 mCRC patients were included in the analysis. The objective response rate (ORR) and the disease control rate (DCR) were 9.4% and 75%. The median progression-free survival (PFS) and overall survival (OS) were 6.3 (95% CI: 5.3-7.3) and 13.5 (95% CI: 9.5-17.5) months, respectively. Patients without liver metastasis or peritoneal metastasis obtained better median PFS (7.1 m vs. 5.6 m, = 0.03 and 6.3 m vs. 3.4 m, = 0.04), and OS (15.2 m vs. 10.4 m, = 0.01 and 13.6 m vs. 7.1 m, = 0.03), respectively. Other clinicopathological features, including age, tumor site, KRAS status, dosage of fruquintinib, and treatment line, did not affect the clinical efficacy of TAS-102 combined with fruquintinib. The most common grade three-four toxicities were neutropenia (46.9%), anemia (21.9%), diarrhea (15.6%), nausea (12.5%), and hand-foot syndrome rash (12.5%).
CONCLUSIONS
Our results suggest that TAS-102 combined with fruquintinib has promising clinical efficacy and manageable safety for refractory mCRC patients in a real-world clinical setting. Further prospective trials are warranted to confirm our results.
PubMed: 38202064
DOI: 10.3390/jcm13010057