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Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas

Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are cha...

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Autores principales: Jimenez, Camilo, Subbiah, Vivek, Stephen, Bettzy, Ma, Junsheng, Milton, Denai, Xu, Mingxuan, Zarifa, Abdualrazzak, Akhmedzhanov, Fechukwu Omolara, Tsimberidou, Apostolia, Habra, Mouhammed Amir, Rodon Anhert, Jordi, Fu, Siqing, Naing, Aung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465458/
https://www.ncbi.nlm.nih.gov/pubmed/32824391
http://dx.doi.org/10.3390/cancers12082307
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author Jimenez, Camilo
Subbiah, Vivek
Stephen, Bettzy
Ma, Junsheng
Milton, Denai
Xu, Mingxuan
Zarifa, Abdualrazzak
Akhmedzhanov, Fechukwu Omolara
Tsimberidou, Apostolia
Habra, Mouhammed Amir
Rodon Anhert, Jordi
Fu, Siqing
Naing, Aung
author_facet Jimenez, Camilo
Subbiah, Vivek
Stephen, Bettzy
Ma, Junsheng
Milton, Denai
Xu, Mingxuan
Zarifa, Abdualrazzak
Akhmedzhanov, Fechukwu Omolara
Tsimberidou, Apostolia
Habra, Mouhammed Amir
Rodon Anhert, Jordi
Fu, Siqing
Naing, Aung
author_sort Jimenez, Camilo
collection PubMed
description Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12–74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0–41%). The clinical benefit rate was 73% (95% CI: 39–94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37—not reached). The median survival duration was 19 months (95% CI: 9.9—not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients’ hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor.
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spelling pubmed-74654582020-09-04 Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas Jimenez, Camilo Subbiah, Vivek Stephen, Bettzy Ma, Junsheng Milton, Denai Xu, Mingxuan Zarifa, Abdualrazzak Akhmedzhanov, Fechukwu Omolara Tsimberidou, Apostolia Habra, Mouhammed Amir Rodon Anhert, Jordi Fu, Siqing Naing, Aung Cancers (Basel) Article Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12–74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0–41%). The clinical benefit rate was 73% (95% CI: 39–94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37—not reached). The median survival duration was 19 months (95% CI: 9.9—not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients’ hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor. MDPI 2020-08-16 /pmc/articles/PMC7465458/ /pubmed/32824391 http://dx.doi.org/10.3390/cancers12082307 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 Article
Jimenez, Camilo
Subbiah, Vivek
Stephen, Bettzy
Ma, Junsheng
Milton, Denai
Xu, Mingxuan
Zarifa, Abdualrazzak
Akhmedzhanov, Fechukwu Omolara
Tsimberidou, Apostolia
Habra, Mouhammed Amir
Rodon Anhert, Jordi
Fu, Siqing
Naing, Aung
Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas
title Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas
title_full Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas
title_fullStr Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas
title_full_unstemmed Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas
title_short Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas
title_sort phase ii clinical trial of pembrolizumab in patients with progressive metastatic pheochromocytomas and paragangliomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465458/
https://www.ncbi.nlm.nih.gov/pubmed/32824391
http://dx.doi.org/10.3390/cancers12082307
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