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The American Journal of Managed Care Jan 2019Pancreatic cancer remains a disease that is difficult to treat due to a typically late presentation, relatively high resistance to chemotherapy, and lack of effective... (Review)
Review
Pancreatic cancer remains a disease that is difficult to treat due to a typically late presentation, relatively high resistance to chemotherapy, and lack of effective targeted therapies. The standard of care relies on cytotoxic chemotherapy, primarily FOLFIRINOX and gemcitabine-based regimens. Dose modifications and/or the use of alternative combinations can reduce adverse effects, but these regimens remain highly toxic. As a result, long-term survival is low for patients with advanced or metastatic disease. There is a great need for novel anticancer agents that provide efficacy with minimal toxicity. Currently, inhibitors of immune tolerance and immune checkpoint inhibitors; PARP inhibitors; novel cytotoxic chemotherapies, such as trifluridine/tipiracil; and modifiers of the tumor microenvironment, such as pegylated hyaluronidase, are in clinical trials for the treatment of pancreatic cancer. This activity will review the current treatment landscape and preview emerging therapies for the treatment of advanced pancreatic cancer.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Hyaluronoglucosaminidase; Immune Tolerance; Microsatellite Instability; Neoplasm Staging; Palliative Care; Pancreatic Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Quality of Life; Risk Factors; Terminal Care; Tumor Microenvironment
PubMed: 30681819
DOI: No ID Found -
Current Oncology (Toronto, Ont.) May 2023Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials.
METHODS
A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected.
RESULTS
Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11-4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06-67.21%). Summary PFS was 4.56 months (95% CI: 3.57-5.55 months), and summary OS was 11.17 months (95% CI: 10.15-12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination.
CONCLUSION
The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit.
Topics: Humans; Bevacizumab; Uracil; Colorectal Neoplasms; Trifluridine; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37366880
DOI: 10.3390/curroncol30060397 -
Targeted Oncology Nov 2022The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in... (Observational Study)
Observational Study
BACKGROUND
The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in a statistically significant and clinically relevant improvement in progression-free survival (PFS), with tolerable toxicity in patients with refractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in a real-world setting is limited.
OBJECTIVE
The aim of our work was to provide further evidence on the activity and safety of this combination in a real-world series of Western mCRC patients refractory or intolerant to previous therapies.
PATIENT AND METHODS
We conducted a retrospective, observational study of patients with mCRC refractory or intolerant to standard therapies. Patients were treated with trifluridine-tipiracil and bevacizumab. Previous therapy with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, aflibercept, regorafenib, and cetuximab or panitumumab (only RAS wild-type) was allowed, as was previous participation in clinical trials. Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS), PFS, and safety data were retrospectively collected and analyzed.
RESULTS
We recorded 31 patients treated between 1 December 2017 and 30 June 2022. Median age was 69 years (range 38-82 years), 39% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, tumor location was left-sided in 77% of cases, 54% had synchronous presentation, 35% were RAS mutant, 3% were BRAF mutant, and 71% underwent primary tumor resection; 64% of patients had liver metastases, 55% had lung metastases, and 23% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range 0-5), and 84% of patients received at least one previous anti-angiogenic agent. The ORR and DCR were 3% and 71%, respectively. With a median follow-up of 8 months (range 2-39), median PFS was 6 months (95% confidence interval [CI] 3.1-8.9 months) and median OS was 14 months (95% CI 10.1-17.8 months). Adverse events of any grade were reported in 58% of patients. The most common grade 3-4 toxicities were neutropenia (19%) and anemia (6%); 35% of patients required either dose delays or dose reductions due to toxicity. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was administered either on first or subsequent cycles of treatment in 35% of patients. No treatment-related deaths occurred. Sixty percent of the patients who discontinued treatment eventually received one or more lines of subsequent therapy.
CONCLUSIONS
Our series provides further evidence on the activity and safety of the combination of trifluridine-tipiracil and bevacizumab in a real-world series of Western refractory mCRC patients.
Topics: Humans; Male; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Trifluridine; Bevacizumab; Retrospective Studies; Uracil; Colorectal Neoplasms; Colonic Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36239883
DOI: 10.1007/s11523-022-00916-8 -
OncoTargets and Therapy 2020Trifluridine/tipiracil or TAS-102 (Taiho Oncology, Lonsurf, Princeton, NJ, USA) is a combination tablet of trifluridine, a thymidine-based nucleoside analog, and... (Review)
Review
Trifluridine/tipiracil or TAS-102 (Taiho Oncology, Lonsurf, Princeton, NJ, USA) is a combination tablet of trifluridine, a thymidine-based nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor, in a 1:0.5 molar ratio. This drug was first approved for use in metastatic colorectal cancer patients. Recently, the U S Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted approval of trifluridine/tipiracil for treatment of metastatic gastric and gastroesophageal junction adenocarcinoma in patients following at least two lines of chemotherapy including fluoropyrimidine and platinum chemotherapy agents, as well as taxanes or irinotecan. This approval was granted after the findings from first a Phase II trial (EPOC1201) investigating trifluridine/tipiracil, and later a global Phase III trial (TAGS trial) that compared trifluridine/tipiracil vs placebo with best supportive care. Both trials primarily utilized trifluridine/tipiracil at a dose of 35 mg/m twice daily. In the EPOC1201 trial, the primary end point of disease control rate was greater than 50% after eight weeks of therapy. The most common grade three or four adverse event was neutropenia; additional toxicities included leukopenia, anemia, and anorexia. In the TAGS trial, overall survival in patients treated with trifluridine/tipiracil (5.7 months) was significantly improved as compared to the placebo-controlled group (3.6 months). Treatment with trifluridine/tipiracil not only did not impair quality of life but also tended to reduce the risk of deterioration of quality of life. The results of these studies along with the subsequent FDA and EMA approval have generated an important breakthrough in regard to treatment options for patients with refractory metastatic gastric or gastroesophageal junction adenocarcinoma.
PubMed: 32801768
DOI: 10.2147/OTT.S216598 -
P & T : a Peer-reviewed Journal For... Nov 2015Evolocumab (Repatha) for patients with hypercholesterolemia whose condition has not been controlled by statins and other therapies; trifluridine/tipiracil (Lonsurf) for...
Evolocumab (Repatha) for patients with hypercholesterolemia whose condition has not been controlled by statins and other therapies; trifluridine/tipiracil (Lonsurf) for metastatic colorectal cancer; and blood coagulation factor VIII (Nuwiq) for adults and children with hemophilia A.
PubMed: 26609205
DOI: No ID Found -
Therapeutic Advances in Medical Oncology 2021Colorectal cancer (CRC) is one of the most common forms of cancer, with an estimated 1.36 million new cases and almost 700,000 deaths annually. Approximately 21% of... (Review)
Review
Colorectal cancer (CRC) is one of the most common forms of cancer, with an estimated 1.36 million new cases and almost 700,000 deaths annually. Approximately 21% of patients with CRC have metastatic disease at diagnosis. The objective of this article is to review the literature on the efficacy and safety of oral drugs available for the treatment of metastatic colorectal cancer (mCRC). Several such drugs have been developed, and fluoropyrimidines are the backbone of chemotherapy in this indication. They exert their antitumour activity by disrupting the synthesis and function of DNA and RNA. Oral fluoropyrimidines include prodrugs capecitabine, tegafur, eniluracil/5-fluorouracil, tegafur/uracil, tegafur/gimeracil/oteracil and trifluridine/tipiracil (FTD/TPI). Oral drugs offer several advantages over injectable formulations, including convenience, flexibility, avoidance of injection-related adverse events (AEs) and, in some circumstances, lower costs. However, oral drugs may not be suitable for patients with gastrointestinal obstruction or malabsorption, they may result in reduced treatment adherence and should not be co-administered with drugs that interfere with absorption or hepatic metabolism. Oral fluoropyrimidines such as capecitabine, as monotherapy or in combination with oxaliplatin, irinotecan or bevacizumab, are as effective as intravenous 5-fluorouracil (5-FU) in first-line treatment of mCRC. Other oral fluoropyrimidines, such as FTD/TPI, are effective in patients with mCRC who are refractory, intolerant or ineligible for 5-FU. In addition, oral fluoropyrimidines are used in adjuvant treatment of mCRC. Regorafenib is an oral multikinase inhibitor used in patients in whom several previous lines of therapy have failed. Frequent AEs associated with oral drugs used in the treatment of CRC include hand-foot syndrome and gastrointestinal and haematological toxicities.
PubMed: 33995592
DOI: 10.1177/17588359211009001 -
Hospital Pharmacy Jan 2016Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to... (Review)
Review
Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with . Through the cooperation of publishes selected reviews in this column. For more information about , contact Wolters Kluwer customer service at 866-397-3433. The January 2016 monograph topics are idarucizumab, patiromer, coagulation factor VIII/antihemophilic factor (recombinant), cariprazine, and trifluridine and tipiracil. The Safety MUE is on idarucizumab.
PubMed: 38745711
DOI: 10.1310/hpj5101-71 -
The Oncologist May 2024We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil...
We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation.
Topics: Humans; Colorectal Neoplasms; Trifluridine; Thymine; Pyrrolidines; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Bevacizumab
PubMed: 38366864
DOI: 10.1093/oncolo/oyae007 -
Future Oncology (London, England) Jul 2018Fluoropyrimidines are currently the backbone of treatment for gastrointestinal (GI) cancers but development of resistance to these agents remains a major problem.... (Review)
Review
Fluoropyrimidines are currently the backbone of treatment for gastrointestinal (GI) cancers but development of resistance to these agents remains a major problem. Trifluridine/tipiracil is an oral chemotherapeutic agent recently approved for third-line treatment of chemorefractory metastatic colorectal cancer. This article reviews the clinical value of trifluridine/tipiracil as a monotherapy, including recent trials in GI cancers, and the potential benefit of combining it with other agents in patients with GI cancers, including the preclinical rationale for combination therapy and recently completed and ongoing clinical trials. Data gathered so far suggest that trifluridine/tipiracil has the potential to form the chemotherapeutic backbone in the continuum of care for GI cancers in the future.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Clinical Trials as Topic; Colonic Neoplasms; Docetaxel; Drug Combinations; Fluorouracil; Gastrointestinal Neoplasms; Humans; Immunotherapy; Indoles; Irinotecan; Organoplatinum Compounds; Oxaliplatin; Pyrrolidines; Quality of Life; Taxoids; Thymine; Trifluridine; Uracil
PubMed: 29701076
DOI: 10.2217/fon-2018-0147 -
Microbiology Spectrum Aug 2023Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the...
Mpox virus (formerly monkeypox virus [MPXV]) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.026 to 0.89 μM) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the postentry step to reduce the intracellular production of virions. Knockdown of IMP dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. This evidence shows that IMPDH is a potential target for the development of anti-MPXV agents. Mpox is a zoonotic disease caused by infection with the mpox virus, and a worldwide outbreak occurred in May 2022. The smallpox vaccine has recently been approved for clinical use against mpox in the United States. Although brincidofovir and tecovirimat are drugs approved for the treatment of smallpox by the U.S. Food and Drug Administration, their efficacy against mpox has not been established. Moreover, these drugs may present negative side effects. Therefore, new anti-mpox virus agents are needed. This study revealed that gemcitabine, trifluridine, and mycophenolic acid inhibited mpox virus propagation and exhibited broad-spectrum anti-orthopoxvirus activities. We also suggested IMP dehydrogenase as a potential target for the development of anti-mpox virus agents. By targeting this molecule, we identified a series of compounds with stronger anti-mpox virus activity than mycophenolic acid.
Topics: Guanosine; IMP Dehydrogenase; Mycophenolic Acid; Trifluridine; Monkeypox virus
PubMed: 37409948
DOI: 10.1128/spectrum.00566-23