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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Dabrafenib (TafinlarTM) (Figure 6.46) is a B-RAF kinase inhibitor which inhibits B-RAFV600 mutation–positive melanoma cell growth. Developed by GSK, it gained FDA approval in 2013 for the treatment of B-RAFV600E mutation–positive advanced melanoma. Structure of dabrafenib (TafinlarTM).
Melanoma-associated emergencies
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Vidya Kharkar, M. R. L. Sujata
Dabrafenib is the next-generation agent similar to vemurafenib. The FDA approved dabrafenib in 2013 for BRAFV600-positive unresectable or metastatic melanomas. The dose is 150 mg twice a day orally. Dabrafenib is contraindicated in melanoma harboring wild-type BRAF.
Methods for Analysis of Trials with Changes from Randomized Treatment
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Nicholas R. Latimer, Ian R. White
Treatment switching has most often been acknowledged as an issue in health technology assessment (HTA), where there is a clear need to compare a state of the world in which the new intervention exists to a state of the world where the new intervention does not exist, in order that efficient resource allocation decisions can be made. In fact, switching has been an issue in greater than 50% of cancer technology appraisals [5]. Making adjustments to account for switching can have a large impact. In National Institute for Health and Care Excellence (NICE) Technology Appraisal 321, which considered dabrafenib for melanoma, 57% of participants randomized to the control group of the pivotal trial switched onto dabrafenib at some point during the trial. A standard ITT analysis produced an overall survival hazard ratio (HR) of 0.76 and an incremental cost-effectiveness ratio of over £95,000 per quality-adjusted life year gained, which is much higher than the ratio acceptable to NICE, even taking into account the end-of-life nature of the disease [6]. In addition to the ITT analysis, the manufacturer of dabrafenib conducted an analysis to adjust for the switching observed, which resulted in an overall survival HR of 0.55 and an incremental cost-effectiveness ratio of under £50,000 per quality-adjusted life year gained. Dabrafenib was recommended by NICE.
A systematic review of economic evaluations of tyrosine kinase inhibitors for non-small cell lung cancer (NSCLC)
Published in Expert Opinion on Pharmacotherapy, 2022
Joo-Young Byun, Sun-Kyeong Park, Boon Peng Ng, Yi-Shao Liu, Chae-Rin Kim, Chanhyun Park
We systematically reviewed relevant published studies of cost-effectiveness analyses (CEAs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [21]. The PubMed/Medline and Cochrane Library databases were used to search the published literatures up to January 2022. The strategy terms involved keywords or medical subject headings (MeSHs) of TKIs for NSCLC (medications in alphabetical order by TKI type): EGFR-TKI (erlotinib, afatinib, gefitinib, dacomitinib, osimertinib, mobocertinib); ALK-TKI (alectinib, brigatinib, lorlatinib, crizotinib, ceritinib); ROS1-TKI (entrectinib, crizotinib, ceritinib); RET-TKI (selpercatinib, pralsetinib); MET-TKI (capmatinib, tepotinib); and MEK-TKI (dabrafenib, trametinib). We additionally considered the search strategies related to ‘cost-effectiveness’ or ‘cost-utility.’ The detailed search strategies are presented in Supplementary Table S1.
Treatment of hairy cell leukemia
Published in Expert Review of Hematology, 2020
Dai Chihara, Robert J. Kreitman
BRAF inhibition with or without MEK inhibition such as vemurafenib and dabrafenib-trametinib are great options for patients with BRAF V600E-mutated HCL, but rarely achieve MRD negative disease without rituximab. Vemurafenib and dabrafenib-trametinib both can achieve very high response rates of 84–100% although long-term data are not yet reported. Two phase 2 trials of vemurafenib in the US and Europe used a time-limited approach while the dabrafenib-trametinib trial used indefinite treatment. Dabrafenib causes frequent pyrexia, chills, myalgia, and fatigue. For the management of this side effect, holding treatment for 2–3 days and/or giving a small dose of dexamethasone is usually effective after ruling out infectious causes. Combination of vemurafenib with rituximab achieves a high MRD-free CR rate and results of phase 2 trial are eagerly awaited. The early results reported suggest the potential of combining other agents like Moxe with a CD20 Mab or BRAF inhibitor.
A patent review of RAF kinase inhibitors (2010–2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Ruo-Jun Man, Ya-Liang Zhang, Ai-Qin Jiang, Hai-Liang Zhu
Dabrafenib is a selective B-RAFV600E kinase inhibitor developed by GlaxoSmithKline for non-surgical or metastatic melanoma [75]. Compared with chemotherapy, the dabrafenib Phase III clinical study published by the American Society of Clinical Oncology (ASCO) showed that dabrafenib is a novel oral targeted drug that interferes with B-RAF signaling, which enables B-RAF has a mutation. Further, the risk of death for patients with advanced melanoma was found to be reduced by 70% [76]. Clinical data show that dabrafenib has a good effect on brain metastasis with malignant melanoma. It was also found to have significant inhibitory effects against other solid tumors of the B-RAF-mutant type, such as gastrointestinal solid tumors, non-small cell lung cancer, and ovarian cancer [66,77]. However, the main limitation of dabrafenib is that efficacy is maintained for only a short period of time, after which tumors exhibit drug resistance and re-grow rapidly.