Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer

BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progre...

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Autores principales: Johnson, Faye M, Janku, Filip, Gouda, Mohamed A, Tran, Hai T, Kawedia, Jitesh D, Schmitz, Debora, Streefkerk, Hendrik, Lee, J Jack, Andersen, Clark R, Deng, Defeng, Rawal, Seema, Shah, Pooja A, El-Naggar, Adel K, Johnson, Jason M, Frederick, Mitchell J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9732253/
https://www.ncbi.nlm.nih.gov/pubmed/36124629
http://dx.doi.org/10.1093/oncolo/oyac185
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author Johnson, Faye M
Janku, Filip
Gouda, Mohamed A
Tran, Hai T
Kawedia, Jitesh D
Schmitz, Debora
Streefkerk, Hendrik
Lee, J Jack
Andersen, Clark R
Deng, Defeng
Rawal, Seema
Shah, Pooja A
El-Naggar, Adel K
Johnson, Jason M
Frederick, Mitchell J
author_facet Johnson, Faye M
Janku, Filip
Gouda, Mohamed A
Tran, Hai T
Kawedia, Jitesh D
Schmitz, Debora
Streefkerk, Hendrik
Lee, J Jack
Andersen, Clark R
Deng, Defeng
Rawal, Seema
Shah, Pooja A
El-Naggar, Adel K
Johnson, Jason M
Frederick, Mitchell J
author_sort Johnson, Faye M
collection PubMed
description BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry. RESULTS: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, median progression-free and overall survival was 5 and 7 months, respectively. Bimiralisib was well tolerated, with expected hyperglycemia. Pharmacokinetic values were consistent with published studies. NOTCH1 mutations were detected in 83.3% of ctDNA. Staining for tumor cl-NOTCH1 was negative. The trial closed early due to sponsor insolvency. CONCLUSION: Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100).
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spelling pubmed-97322532022-12-13 Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer Johnson, Faye M Janku, Filip Gouda, Mohamed A Tran, Hai T Kawedia, Jitesh D Schmitz, Debora Streefkerk, Hendrik Lee, J Jack Andersen, Clark R Deng, Defeng Rawal, Seema Shah, Pooja A El-Naggar, Adel K Johnson, Jason M Frederick, Mitchell J Oncologist Clinical Trial Results BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry. RESULTS: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, median progression-free and overall survival was 5 and 7 months, respectively. Bimiralisib was well tolerated, with expected hyperglycemia. Pharmacokinetic values were consistent with published studies. NOTCH1 mutations were detected in 83.3% of ctDNA. Staining for tumor cl-NOTCH1 was negative. The trial closed early due to sponsor insolvency. CONCLUSION: Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100). Oxford University Press 2022-09-16 /pmc/articles/PMC9732253/ /pubmed/36124629 http://dx.doi.org/10.1093/oncolo/oyac185 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Trial Results
Johnson, Faye M
Janku, Filip
Gouda, Mohamed A
Tran, Hai T
Kawedia, Jitesh D
Schmitz, Debora
Streefkerk, Hendrik
Lee, J Jack
Andersen, Clark R
Deng, Defeng
Rawal, Seema
Shah, Pooja A
El-Naggar, Adel K
Johnson, Jason M
Frederick, Mitchell J
Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer
title Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer
title_full Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer
title_fullStr Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer
title_full_unstemmed Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer
title_short Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer
title_sort inhibition of the phosphatidylinositol-3 kinase pathway using bimiralisib in loss-of-function notch1-mutant head and neck cancer
topic Clinical Trial Results
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9732253/
https://www.ncbi.nlm.nih.gov/pubmed/36124629
http://dx.doi.org/10.1093/oncolo/oyac185
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