Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Kemper, Marcel, Evers, Georg, Schulze, Arik Bernard, Sperveslage, Jan, Schülke, Christoph, Lenz, Georg, Herold, Thomas, Hartmann, Wolfgang, Schildhaus, Hans-Ulrich, Bleckmann, Annalen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2021
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
_version_ 1784569253686411264
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
work_keys_str_mv AT kempermarcel polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT eversgeorg polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT schulzearikbernard polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT sperveslagejan polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT schulkechristoph polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT lenzgeorg polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT heroldthomas polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT hartmannwolfgang polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT schildhaushansulrich polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition
AT bleckmannannalen polyclonalonandofftargetresistancemutationsinaneml4alkpositivenonsmallcelllungcancerpatientunderalkinhibition