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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...

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Autores principales: 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
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
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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.
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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
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