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The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers
Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Dove Medical Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388194/ https://www.ncbi.nlm.nih.gov/pubmed/28435288 http://dx.doi.org/10.2147/OTT.S109295 |
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author | Sabari, Joshua K Santini, Fernando C Schram, Alison M Bergagnini, Isabella Chen, Ruqin Mrad, Chebli Lai, W Victoria Arbour, Kathryn C Drilon, Alexander |
author_facet | Sabari, Joshua K Santini, Fernando C Schram, Alison M Bergagnini, Isabella Chen, Ruqin Mrad, Chebli Lai, W Victoria Arbour, Kathryn C Drilon, Alexander |
author_sort | Sabari, Joshua K |
collection | PubMed |
description | Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK inhibitors in advanced ALK-rearranged lung cancers, the development of acquired resistance represents an ongoing challenge. Later generation ALK inhibitors such as brigatinib are important potential tools in the management of patients with acquired resistance characterized by continued dependency on ALK. Brigatinib is active in vitro against many ALK kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC(50) <50 nM) against ALK C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with ALK-rearranged lung cancers who receive brigatinib after crizotinib, substantial and durable responses and intracranial disease control can be achieved based on early-phase clinical trial data. The drug is also being explored in TKI-naïve patients. From a safety perspective, early pulmonary toxicity has been observed, prompting the decision to pursue lead-in dosing for the drug. Early data point to ALK G1202R and ALK E1210K as potential mechanisms of clinical resistance to brigatinib. |
format | Online Article Text |
id | pubmed-5388194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-53881942017-04-21 The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers Sabari, Joshua K Santini, Fernando C Schram, Alison M Bergagnini, Isabella Chen, Ruqin Mrad, Chebli Lai, W Victoria Arbour, Kathryn C Drilon, Alexander Onco Targets Ther Review Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK inhibitors in advanced ALK-rearranged lung cancers, the development of acquired resistance represents an ongoing challenge. Later generation ALK inhibitors such as brigatinib are important potential tools in the management of patients with acquired resistance characterized by continued dependency on ALK. Brigatinib is active in vitro against many ALK kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC(50) <50 nM) against ALK C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with ALK-rearranged lung cancers who receive brigatinib after crizotinib, substantial and durable responses and intracranial disease control can be achieved based on early-phase clinical trial data. The drug is also being explored in TKI-naïve patients. From a safety perspective, early pulmonary toxicity has been observed, prompting the decision to pursue lead-in dosing for the drug. Early data point to ALK G1202R and ALK E1210K as potential mechanisms of clinical resistance to brigatinib. Dove Medical Press 2017-04-06 /pmc/articles/PMC5388194/ /pubmed/28435288 http://dx.doi.org/10.2147/OTT.S109295 Text en © 2017 Sabari et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Review Sabari, Joshua K Santini, Fernando C Schram, Alison M Bergagnini, Isabella Chen, Ruqin Mrad, Chebli Lai, W Victoria Arbour, Kathryn C Drilon, Alexander The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers |
title | The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers |
title_full | The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers |
title_fullStr | The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers |
title_full_unstemmed | The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers |
title_short | The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers |
title_sort | activity, safety, and evolving role of brigatinib in patients with alk-rearranged non-small cell lung cancers |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388194/ https://www.ncbi.nlm.nih.gov/pubmed/28435288 http://dx.doi.org/10.2147/OTT.S109295 |
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