Cargando…
Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab
Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051335/ https://www.ncbi.nlm.nih.gov/pubmed/36983691 http://dx.doi.org/10.3390/jpm13030508 |
_version_ | 1785014860951584768 |
---|---|
author | Zecchetto, Camilla Quinzii, Alberto Casalino, Simona Gaule, Marina Pesoni, Camilla Merz, Valeria Pietrobono, Silvia Mangiameli, Domenico Pasquato, Martina Milleri, Stefano Giacopuzzi, Simone Bencivenga, Maria Tomezzoli, Anna de Manzoni, Giovanni Melisi, Davide |
author_facet | Zecchetto, Camilla Quinzii, Alberto Casalino, Simona Gaule, Marina Pesoni, Camilla Merz, Valeria Pietrobono, Silvia Mangiameli, Domenico Pasquato, Martina Milleri, Stefano Giacopuzzi, Simone Bencivenga, Maria Tomezzoli, Anna de Manzoni, Giovanni Melisi, Davide |
author_sort | Zecchetto, Camilla |
collection | PubMed |
description | Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon’s two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies. |
format | Online Article Text |
id | pubmed-10051335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100513352023-03-30 Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab Zecchetto, Camilla Quinzii, Alberto Casalino, Simona Gaule, Marina Pesoni, Camilla Merz, Valeria Pietrobono, Silvia Mangiameli, Domenico Pasquato, Martina Milleri, Stefano Giacopuzzi, Simone Bencivenga, Maria Tomezzoli, Anna de Manzoni, Giovanni Melisi, Davide J Pers Med Protocol Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon’s two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies. MDPI 2023-03-11 /pmc/articles/PMC10051335/ /pubmed/36983691 http://dx.doi.org/10.3390/jpm13030508 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Protocol Zecchetto, Camilla Quinzii, Alberto Casalino, Simona Gaule, Marina Pesoni, Camilla Merz, Valeria Pietrobono, Silvia Mangiameli, Domenico Pasquato, Martina Milleri, Stefano Giacopuzzi, Simone Bencivenga, Maria Tomezzoli, Anna de Manzoni, Giovanni Melisi, Davide Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab |
title | Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab |
title_full | Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab |
title_fullStr | Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab |
title_full_unstemmed | Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab |
title_short | Targeting FGFR Pathway Is Not an Effective Therapeutic Strategy in Patients with Unselected Metastatic Esophagogastric Cancer Resistant to Trastuzumab |
title_sort | targeting fgfr pathway is not an effective therapeutic strategy in patients with unselected metastatic esophagogastric cancer resistant to trastuzumab |
topic | Protocol |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10051335/ https://www.ncbi.nlm.nih.gov/pubmed/36983691 http://dx.doi.org/10.3390/jpm13030508 |
work_keys_str_mv | AT zecchettocamilla targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT quinziialberto targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT casalinosimona targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT gaulemarina targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT pesonicamilla targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT merzvaleria targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT pietrobonosilvia targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT mangiamelidomenico targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT pasquatomartina targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT milleristefano targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT giacopuzzisimone targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT bencivengamaria targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT tomezzolianna targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT demanzonigiovanni targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab AT melisidavide targetingfgfrpathwayisnotaneffectivetherapeuticstrategyinpatientswithunselectedmetastaticesophagogastriccancerresistanttotrastuzumab |