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...
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| Veröffentlicht in: | OncoTargets and therapy 2017-01, Vol.10, p.1983-1992 |
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| container_end_page | 1992 |
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| container_title | OncoTargets and therapy |
| container_volume | 10 |
| creator | Sabari, Joshua K Santini, Fernando C Schram, Alison M Bergagnini, Isabella Chen, Ruqin Mrad, Chebli Lai, W Victoria Arbour, Kathryn C Drilon, Alexander |
| 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
-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
kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC |
| doi_str_mv | 10.2147/OTT.S109295 |
| format | Article |
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-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
kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC
<50 nM) against
C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with
-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
G1202R and
E1210K as potential mechanisms of clinical resistance to brigatinib.</description><identifier>ISSN: 1178-6930</identifier><identifier>EISSN: 1178-6930</identifier><identifier>DOI: 10.2147/OTT.S109295</identifier><identifier>PMID: 28435288</identifier><language>eng</language><publisher>New Zealand: Dove Medical Press Limited</publisher><subject>Adenosine triphosphate ; Binding sites ; Brigatinib ; Cancer therapies ; Chlorine ; Development and progression ; Drug dosages ; Drug therapy ; Growth factors ; Health aspects ; Hydrogen bonds ; Insulin ; Kinases ; Lung cancer ; Lymphoma ; Mutation ; Non-small cell lung cancer ; Oncology ; Review ; Targeted cancer therapy</subject><ispartof>OncoTargets and therapy, 2017-01, Vol.10, p.1983-1992</ispartof><rights>COPYRIGHT 2017 Dove Medical Press Limited</rights><rights>2017. This work is licensed under https://creativecommons.org/licenses/by-nc/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Sabari et al. This work is published and licensed by Dove Medical Press Limited 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c591t-882f921da2c1ec93d1da1aff7f91c0cf0de22f07932b449709099ae9c3be45703</citedby><orcidid>0000-0002-6541-8374</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388194/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388194/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3862,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28435288$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sabari, Joshua K</creatorcontrib><creatorcontrib>Santini, Fernando C</creatorcontrib><creatorcontrib>Schram, Alison M</creatorcontrib><creatorcontrib>Bergagnini, Isabella</creatorcontrib><creatorcontrib>Chen, Ruqin</creatorcontrib><creatorcontrib>Mrad, Chebli</creatorcontrib><creatorcontrib>Lai, W Victoria</creatorcontrib><creatorcontrib>Arbour, Kathryn C</creatorcontrib><creatorcontrib>Drilon, Alexander</creatorcontrib><title>The activity, safety, and evolving role of brigatinib in patients with ALK -rearranged non-small cell lung cancers</title><title>OncoTargets and therapy</title><addtitle>Onco Targets Ther</addtitle><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
-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
kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC
<50 nM) against
C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with
-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
G1202R and
E1210K as potential mechanisms of clinical resistance to brigatinib.</description><subject>Adenosine triphosphate</subject><subject>Binding sites</subject><subject>Brigatinib</subject><subject>Cancer therapies</subject><subject>Chlorine</subject><subject>Development and progression</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>Hydrogen bonds</subject><subject>Insulin</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Lymphoma</subject><subject>Mutation</subject><subject>Non-small cell lung cancer</subject><subject>Oncology</subject><subject>Review</subject><subject>Targeted cancer therapy</subject><issn>1178-6930</issn><issn>1178-6930</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkl2L3CAUhkNp6X60V70vQqEU2kzVmIneLAzL9oMO7EWn12LMMXExOtVkyv77Oux0O1OK4Dnoc171-BbFK4IXlLDm4-1ms_hOsKCiflKcE9Lwcikq_PQoPysuUrrDeLnklD0vzihnVU05Py_iZgCk9GR3drr_gJIysI_Kdwh2we2s71EMDlAwqI22V5P1tkXWo21OwU8J_bLTgFbrb6iMoGJUvocO-eDLNCrnkIY8uTnraOU1xPSieGaUS_DyEC-LH59uNtdfyvXt56_Xq3Wpa0GmknNqBCWdopqAFlWXU6KMaYwgGmuDO6DU4EZUtGVMNFhgIRQIXbXA6gZXl8XVg-52bkfodL5sVE5uox1VvJdBWXm64-0g-7CTdcU5ESwLvDsIxPBzhjTJ0ab9c5SHMCdJuCCsXnIuMvrmH_QuzNHn50lKGeG0YQz_pXrlQFpvQj5X70Xlqq4Yzf9T00wt_kPl0cFodfBgbF4_KXh7VDCActOQgpsnG3w6Bd8_gDqGlCKYx2YQLPdektlL8uClTL8-7t8j-8c81W-y1sMX</recordid><startdate>20170101</startdate><enddate>20170101</enddate><creator>Sabari, Joshua K</creator><creator>Santini, Fernando C</creator><creator>Schram, Alison M</creator><creator>Bergagnini, Isabella</creator><creator>Chen, Ruqin</creator><creator>Mrad, Chebli</creator><creator>Lai, W Victoria</creator><creator>Arbour, Kathryn C</creator><creator>Drilon, Alexander</creator><general>Dove Medical Press Limited</general><general>Taylor & Francis Ltd</general><general>Dove Medical Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6541-8374</orcidid></search><sort><creationdate>20170101</creationdate><title>The activity, safety, and evolving role of brigatinib in patients with ALK -rearranged non-small cell lung cancers</title><author>Sabari, Joshua K ; 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Despite the activity of first- and second-generation ALK inhibitors in advanced
-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
kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC
<50 nM) against
C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with
-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
G1202R and
E1210K as potential mechanisms of clinical resistance to brigatinib.</abstract><cop>New Zealand</cop><pub>Dove Medical Press Limited</pub><pmid>28435288</pmid><doi>10.2147/OTT.S109295</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-6541-8374</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1178-6930 |
| ispartof | OncoTargets and therapy, 2017-01, Vol.10, p.1983-1992 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5388194 |
| source | Taylor & Francis Open Access; DOVE Medical Press Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; PubMed Central |
| subjects | Adenosine triphosphate Binding sites Brigatinib Cancer therapies Chlorine Development and progression Drug dosages Drug therapy Growth factors Health aspects Hydrogen bonds Insulin Kinases Lung cancer Lymphoma Mutation Non-small cell lung cancer Oncology Review Targeted cancer therapy |
| title | The activity, safety, and evolving role of brigatinib in patients with ALK -rearranged non-small cell lung cancers |
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