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Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC

Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lu...

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Autores principales: Urbán, László, Dóczi, Róbert, Vodicska, Barbara, Kormos, Dóra, Tóth, László, Takács, István, Várkondi, Edit, Tihanyi, Dóra, Lakatos, Dóra, Dirner, Anna, Vályi-Nagy, István, Peták, István
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563786/
https://www.ncbi.nlm.nih.gov/pubmed/32872120
http://dx.doi.org/10.3390/jpm10030107
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author Urbán, László
Dóczi, Róbert
Vodicska, Barbara
Kormos, Dóra
Tóth, László
Takács, István
Várkondi, Edit
Tihanyi, Dóra
Lakatos, Dóra
Dirner, Anna
Vályi-Nagy, István
Peták, István
author_facet Urbán, László
Dóczi, Róbert
Vodicska, Barbara
Kormos, Dóra
Tóth, László
Takács, István
Várkondi, Edit
Tihanyi, Dóra
Lakatos, Dóra
Dirner, Anna
Vályi-Nagy, István
Peták, István
author_sort Urbán, László
collection PubMed
description Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. Results: The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. Conclusion: TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms.
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spelling pubmed-75637862020-10-27 Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC Urbán, László Dóczi, Róbert Vodicska, Barbara Kormos, Dóra Tóth, László Takács, István Várkondi, Edit Tihanyi, Dóra Lakatos, Dóra Dirner, Anna Vályi-Nagy, István Peták, István J Pers Med Case Report Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. Results: The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. Conclusion: TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms. MDPI 2020-08-28 /pmc/articles/PMC7563786/ /pubmed/32872120 http://dx.doi.org/10.3390/jpm10030107 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Urbán, László
Dóczi, Róbert
Vodicska, Barbara
Kormos, Dóra
Tóth, László
Takács, István
Várkondi, Edit
Tihanyi, Dóra
Lakatos, Dóra
Dirner, Anna
Vályi-Nagy, István
Peták, István
Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
title Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
title_full Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
title_fullStr Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
title_full_unstemmed Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
title_short Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
title_sort efficacy of incremental next-generation alk inhibitor treatment in oncogene-addicted, alk-positive, tp53-mutant nsclc
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563786/
https://www.ncbi.nlm.nih.gov/pubmed/32872120
http://dx.doi.org/10.3390/jpm10030107
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