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Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus

BACKGROUND: Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a r...

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Autores principales: Liu, Xiaochun, Kambrick, Susan, Fu, Siqing, Naing, Aung, Subbiah, Vivek, Blumenschein, George R., Glisson, Bonnie S., Kies, Merrill S., Tsimberidou, Apostolia M., Wheler, Jennifer J., Zinner, Ralph G., Hong, David S., Kurzrock, Razelle, Piha-Paul, Sarina A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029622/
https://www.ncbi.nlm.nih.gov/pubmed/26933802
http://dx.doi.org/10.18632/oncotarget.7594
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author Liu, Xiaochun
Kambrick, Susan
Fu, Siqing
Naing, Aung
Subbiah, Vivek
Blumenschein, George R.
Glisson, Bonnie S.
Kies, Merrill S.
Tsimberidou, Apostolia M.
Wheler, Jennifer J.
Zinner, Ralph G.
Hong, David S.
Kurzrock, Razelle
Piha-Paul, Sarina A.
author_facet Liu, Xiaochun
Kambrick, Susan
Fu, Siqing
Naing, Aung
Subbiah, Vivek
Blumenschein, George R.
Glisson, Bonnie S.
Kies, Merrill S.
Tsimberidou, Apostolia M.
Wheler, Jennifer J.
Zinner, Ralph G.
Hong, David S.
Kurzrock, Razelle
Piha-Paul, Sarina A.
author_sort Liu, Xiaochun
collection PubMed
description BACKGROUND: Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab. RESULTS: The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)). PATIENTS AND METHODS: We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. CONCLUSION: The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.
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spelling pubmed-50296222016-09-29 Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus Liu, Xiaochun Kambrick, Susan Fu, Siqing Naing, Aung Subbiah, Vivek Blumenschein, George R. Glisson, Bonnie S. Kies, Merrill S. Tsimberidou, Apostolia M. Wheler, Jennifer J. Zinner, Ralph G. Hong, David S. Kurzrock, Razelle Piha-Paul, Sarina A. Oncotarget Research Paper BACKGROUND: Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab. RESULTS: The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)). PATIENTS AND METHODS: We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. CONCLUSION: The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development. Impact Journals LLC 2016-02-24 /pmc/articles/PMC5029622/ /pubmed/26933802 http://dx.doi.org/10.18632/oncotarget.7594 Text en Copyright: © 2016 Liu et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Liu, Xiaochun
Kambrick, Susan
Fu, Siqing
Naing, Aung
Subbiah, Vivek
Blumenschein, George R.
Glisson, Bonnie S.
Kies, Merrill S.
Tsimberidou, Apostolia M.
Wheler, Jennifer J.
Zinner, Ralph G.
Hong, David S.
Kurzrock, Razelle
Piha-Paul, Sarina A.
Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
title Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
title_full Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
title_fullStr Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
title_full_unstemmed Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
title_short Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus
title_sort advanced malignancies treated with a combination of the vegf inhibitor bevacizumab, anti-egfr antibody cetuximab, and the mtor inhibitor temsirolimus
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029622/
https://www.ncbi.nlm.nih.gov/pubmed/26933802
http://dx.doi.org/10.18632/oncotarget.7594
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