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Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition
Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor trea...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448518/ https://www.ncbi.nlm.nih.gov/pubmed/34548910 http://dx.doi.org/10.18632/oncotarget.28062 |
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author | Kemper, Marcel Evers, Georg Schulze, Arik Bernard Sperveslage, Jan Schülke, Christoph Lenz, Georg Herold, Thomas Hartmann, Wolfgang Schildhaus, Hans-Ulrich Bleckmann, Annalen |
author_facet | Kemper, Marcel Evers, Georg Schulze, Arik Bernard Sperveslage, Jan Schülke, Christoph Lenz, Georg Herold, Thomas Hartmann, Wolfgang Schildhaus, Hans-Ulrich Bleckmann, Annalen |
author_sort | Kemper, Marcel |
collection | PubMed |
description | Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK-fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off-target KRAS-mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS mutant clone and clinical tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive tumor disease also for ALK-positive NSCLC to personalize treatment in a subgroup of ALK-positive patients. |
format | Online Article Text |
id | pubmed-8448518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-84485182021-09-20 Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition Kemper, Marcel Evers, Georg Schulze, Arik Bernard Sperveslage, Jan Schülke, Christoph Lenz, Georg Herold, Thomas Hartmann, Wolfgang Schildhaus, Hans-Ulrich Bleckmann, Annalen Oncotarget Case Report Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK-fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated with the second-generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off-target KRAS-mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS mutant clone and clinical tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive tumor disease also for ALK-positive NSCLC to personalize treatment in a subgroup of ALK-positive patients. Impact Journals LLC 2021-09-14 /pmc/articles/PMC8448518/ /pubmed/34548910 http://dx.doi.org/10.18632/oncotarget.28062 Text en Copyright: © 2021 Kemper et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Case Report Kemper, Marcel Evers, Georg Schulze, Arik Bernard Sperveslage, Jan Schülke, Christoph Lenz, Georg Herold, Thomas Hartmann, Wolfgang Schildhaus, Hans-Ulrich Bleckmann, Annalen Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition |
title | Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition |
title_full | Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition |
title_fullStr | Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition |
title_full_unstemmed | Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition |
title_short | Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition |
title_sort | polyclonal on- and off-target resistance mutations in an eml4-alk positive non-small cell lung cancer patient under alk inhibition |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448518/ https://www.ncbi.nlm.nih.gov/pubmed/34548910 http://dx.doi.org/10.18632/oncotarget.28062 |
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