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Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy
INTRODUCTION: Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, wi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9465386/ https://www.ncbi.nlm.nih.gov/pubmed/36106113 http://dx.doi.org/10.3389/fonc.2022.976837 |
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author | Khan, Shaheer Lutzky, Jose Shoushtari, Alexander N. Jeter, Joanne Marr, Brian Olencki, Thomas E. Cebulla, Colleen M. Abdel-Rahman, Mohamed Harbour, J. William Sender, Naomi Nesson, Alexandra Singh-Kandah, Shahnaz Hernandez, Susana King, Jeanelle Katari, Manpreet S. Dimapanat, Lyssa Izard, Stephanie Ambrosini, Grazia Surriga, Oliver Rai, Alex J. Chiuzan, Codruta Schwartz, Gary K. Carvajal, Richard D. |
author_facet | Khan, Shaheer Lutzky, Jose Shoushtari, Alexander N. Jeter, Joanne Marr, Brian Olencki, Thomas E. Cebulla, Colleen M. Abdel-Rahman, Mohamed Harbour, J. William Sender, Naomi Nesson, Alexandra Singh-Kandah, Shahnaz Hernandez, Susana King, Jeanelle Katari, Manpreet S. Dimapanat, Lyssa Izard, Stephanie Ambrosini, Grazia Surriga, Oliver Rai, Alex J. Chiuzan, Codruta Schwartz, Gary K. Carvajal, Richard D. |
author_sort | Khan, Shaheer |
collection | PubMed |
description | INTRODUCTION: Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk. MATERIALS AND METHODS: This was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib. RESULTS: 34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome. CONCLUSIONS: The use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease. |
format | Online Article Text |
id | pubmed-9465386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94653862022-09-13 Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy Khan, Shaheer Lutzky, Jose Shoushtari, Alexander N. Jeter, Joanne Marr, Brian Olencki, Thomas E. Cebulla, Colleen M. Abdel-Rahman, Mohamed Harbour, J. William Sender, Naomi Nesson, Alexandra Singh-Kandah, Shahnaz Hernandez, Susana King, Jeanelle Katari, Manpreet S. Dimapanat, Lyssa Izard, Stephanie Ambrosini, Grazia Surriga, Oliver Rai, Alex J. Chiuzan, Codruta Schwartz, Gary K. Carvajal, Richard D. Front Oncol Oncology INTRODUCTION: Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk. MATERIALS AND METHODS: This was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib. RESULTS: 34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome. CONCLUSIONS: The use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease. Frontiers Media S.A. 2022-08-29 /pmc/articles/PMC9465386/ /pubmed/36106113 http://dx.doi.org/10.3389/fonc.2022.976837 Text en Copyright © 2022 Khan, Lutzky, Shoushtari, Jeter, Marr, Olencki, Cebulla, Abdel-Rahman, Harbour, Sender, Nesson, Singh-Kandah, Hernandez, King, Katari, Dimapanat, Izard, Ambrosini, Surriga, Rai, Chiuzan, Schwartz and Carvajal https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Khan, Shaheer Lutzky, Jose Shoushtari, Alexander N. Jeter, Joanne Marr, Brian Olencki, Thomas E. Cebulla, Colleen M. Abdel-Rahman, Mohamed Harbour, J. William Sender, Naomi Nesson, Alexandra Singh-Kandah, Shahnaz Hernandez, Susana King, Jeanelle Katari, Manpreet S. Dimapanat, Lyssa Izard, Stephanie Ambrosini, Grazia Surriga, Oliver Rai, Alex J. Chiuzan, Codruta Schwartz, Gary K. Carvajal, Richard D. Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy |
title | Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy |
title_full | Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy |
title_fullStr | Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy |
title_full_unstemmed | Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy |
title_short | Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy |
title_sort | adjuvant crizotinib in high-risk uveal melanoma following definitive therapy |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9465386/ https://www.ncbi.nlm.nih.gov/pubmed/36106113 http://dx.doi.org/10.3389/fonc.2022.976837 |
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