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Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance

BACKGROUND: Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer. ME...

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Autores principales: Creelan, Ben C., Gray, Jhanelle E., Tanvetyanon, Tawee, Chiappori, Alberto A., Yoshida, Takeshi, Schell, Michael J., Antonia, Scott J., Haura, Eric B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474279/
https://www.ncbi.nlm.nih.gov/pubmed/30880334
http://dx.doi.org/10.1038/s41416-019-0428-3
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author Creelan, Ben C.
Gray, Jhanelle E.
Tanvetyanon, Tawee
Chiappori, Alberto A.
Yoshida, Takeshi
Schell, Michael J.
Antonia, Scott J.
Haura, Eric B.
author_facet Creelan, Ben C.
Gray, Jhanelle E.
Tanvetyanon, Tawee
Chiappori, Alberto A.
Yoshida, Takeshi
Schell, Michael J.
Antonia, Scott J.
Haura, Eric B.
author_sort Creelan, Ben C.
collection PubMed
description BACKGROUND: Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer. METHODS: An open-label, dose-escalation phase 1/2 trial (NCT01999985) with 2-stage expansion was conducted with 25 lung cancer patients. Dose expansion required activating EGFR mutations and progression following prior EGFR TKI. RESULTS: Patients were 72% Caucasian and received median of 2 prior lines of therapy. Maximum-tolerated dose was 30 mg afatinib with 100 mg dasatinib. New or increased pleural effusions were observed in 56% of patients. No radiologic responses were observed, although several EGFR-mutant TKI-resistant patients (26%) had prolonged stable disease over 6 months. The combination reduced the EGFR mutation and T790M variant allele frequency in cell-free DNA (p < .05). Nonetheless, the threshold for futility was met, based on 6-month progression-free survival. For EGFR TKI-resistant patients, median progression-free survival was 3.7 months (95% confidence interval (CI), 2.3–5.0) and overall survival was 14.7 months (95% CI, 8.5–20.9). CONCLUSIONS: The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed.
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spelling pubmed-64742792020-03-18 Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance Creelan, Ben C. Gray, Jhanelle E. Tanvetyanon, Tawee Chiappori, Alberto A. Yoshida, Takeshi Schell, Michael J. Antonia, Scott J. Haura, Eric B. Br J Cancer Article BACKGROUND: Bypass activation of Src family kinases can confer resistance to EGFR tyrosine kinase inhibitors (TKIs) based on preclinical models. We prospectively assessed the safety and clinical activity of dasatinib and afatinib in combination for patients with resistant EGFR-mutant lung cancer. METHODS: An open-label, dose-escalation phase 1/2 trial (NCT01999985) with 2-stage expansion was conducted with 25 lung cancer patients. Dose expansion required activating EGFR mutations and progression following prior EGFR TKI. RESULTS: Patients were 72% Caucasian and received median of 2 prior lines of therapy. Maximum-tolerated dose was 30 mg afatinib with 100 mg dasatinib. New or increased pleural effusions were observed in 56% of patients. No radiologic responses were observed, although several EGFR-mutant TKI-resistant patients (26%) had prolonged stable disease over 6 months. The combination reduced the EGFR mutation and T790M variant allele frequency in cell-free DNA (p < .05). Nonetheless, the threshold for futility was met, based on 6-month progression-free survival. For EGFR TKI-resistant patients, median progression-free survival was 3.7 months (95% confidence interval (CI), 2.3–5.0) and overall survival was 14.7 months (95% CI, 8.5–20.9). CONCLUSIONS: The combination had a manageable toxicity profile and in vivo T790M modulation, but no objective clinical responses were observed. Nature Publishing Group UK 2019-03-18 2019-04-16 /pmc/articles/PMC6474279/ /pubmed/30880334 http://dx.doi.org/10.1038/s41416-019-0428-3 Text en © Cancer Research UK 2019 https://creativecommons.org/licenses/by/4.0/This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Creelan, Ben C.
Gray, Jhanelle E.
Tanvetyanon, Tawee
Chiappori, Alberto A.
Yoshida, Takeshi
Schell, Michael J.
Antonia, Scott J.
Haura, Eric B.
Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance
title Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance
title_full Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance
title_fullStr Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance
title_full_unstemmed Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance
title_short Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance
title_sort phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (egfr-) mutated lung cancer with acquired tyrosine kinase inhibitor (tki) resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474279/
https://www.ncbi.nlm.nih.gov/pubmed/30880334
http://dx.doi.org/10.1038/s41416-019-0428-3
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