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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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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. |
format | Online Article Text |
id | pubmed-6474279 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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