REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial
Abstract Background Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexp...
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-023-01832-9 |
| _version_ | 1797577705747644416 |
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| author | Javier Martin-Broto Claudia Valverde Nadia Hindi Bruno Vincenzi Javier Martinez-Trufero Giovanni Grignani Antoine Italiano Javier Lavernia Ana Vallejo Paolo Dei Tos Francois Le Loarer Ricardo Gonzalez-Campora Rafael Ramos Diana Hernández-Jover Antonio Gutierrez Cesar Serrano Maria Monteagudo Rocio Letón Mercedes Robledo David S. Moura Marta Martin-Ruiz Jose A. López-Guerrero Julia Cruz Antonio Fernandez-Serra Jean-Yves Blay Elena Fumagalli Virginia Martinez-Marin |
| author_facet | Javier Martin-Broto Claudia Valverde Nadia Hindi Bruno Vincenzi Javier Martinez-Trufero Giovanni Grignani Antoine Italiano Javier Lavernia Ana Vallejo Paolo Dei Tos Francois Le Loarer Ricardo Gonzalez-Campora Rafael Ramos Diana Hernández-Jover Antonio Gutierrez Cesar Serrano Maria Monteagudo Rocio Letón Mercedes Robledo David S. Moura Marta Martin-Ruiz Jose A. López-Guerrero Julia Cruz Antonio Fernandez-Serra Jean-Yves Blay Elena Fumagalli Virginia Martinez-Marin |
| author_sort | Javier Martin-Broto |
| collection | DOAJ |
| description | Abstract Background Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. Methods Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. Results From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. Conclusions Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. Trial registration ClinicalTrials.gov Identifier: NCT02638766. |
| first_indexed | 2024-03-10T22:12:49Z |
| format | Article |
| id | doaj.art-da2ebd0056004ea28583248f6fd4476c |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-10T22:12:49Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-da2ebd0056004ea28583248f6fd4476c2023-11-19T12:34:25ZengBMCMolecular Cancer1476-45982023-08-012211810.1186/s12943-023-01832-9REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trialJavier Martin-Broto0Claudia Valverde1Nadia Hindi2Bruno Vincenzi3Javier Martinez-Trufero4Giovanni Grignani5Antoine Italiano6Javier Lavernia7Ana Vallejo8Paolo Dei Tos9Francois Le Loarer10Ricardo Gonzalez-Campora11Rafael Ramos12Diana Hernández-Jover13Antonio Gutierrez14Cesar Serrano15Maria Monteagudo16Rocio Letón17Mercedes Robledo18David S. Moura19Marta Martin-Ruiz20Jose A. López-Guerrero21Julia Cruz22Antonio Fernandez-Serra23Jean-Yves Blay24Elena Fumagalli25Virginia Martinez-Marin26Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM)Medical Oncology department, Vall d’Hebron University HospitalHealth Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM)Medical Oncology, University Campus Bio-Medico and Fondazione Policlinico Universitario Campus Bio-MedicoMedical Oncology Department, University Hospital Miguel ServetMedical Oncology Unit, Città della Salute e della Scienza HospitalMedical Oncology department, Institute BergoniéMedical Oncology department, Fundación Instituto Valenciano de OncologiaPathology department, Hospital Regional Universitario de MalagaDepartment of Medicine, School of Medicine, University of PaduaPathology department, Institute BergoniéPathology department, Hospital QuironsaludPathology department, University Hospital Son EspasesRadiology department, Sant Pau University HospitalHematology department, University Hospital Son EspasesMedical Oncology department, Vall d’Hebron University HospitalHereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM)Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM)Molecular Biology department, Fundación Instituto Valenciano de OncologiaPathology department, Fundación Instituto Valenciano de OncologiaMolecular Biology department, Fundación Instituto Valenciano de OncologiaMedicine Department, Centre Léon BérardMedicine Department, Fondazione IRCCS - Istituto Nazionale dei TumoriDepartment of Medical Oncology, Hospital Universitario La Paz-IdiPAZAbstract Background Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. Methods Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. Results From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. Conclusions Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. Trial registration ClinicalTrials.gov Identifier: NCT02638766.https://doi.org/10.1186/s12943-023-01832-9Wild type GISTSDH: RegorafenibBiomarkerClinical trial |
| spellingShingle | Javier Martin-Broto Claudia Valverde Nadia Hindi Bruno Vincenzi Javier Martinez-Trufero Giovanni Grignani Antoine Italiano Javier Lavernia Ana Vallejo Paolo Dei Tos Francois Le Loarer Ricardo Gonzalez-Campora Rafael Ramos Diana Hernández-Jover Antonio Gutierrez Cesar Serrano Maria Monteagudo Rocio Letón Mercedes Robledo David S. Moura Marta Martin-Ruiz Jose A. López-Guerrero Julia Cruz Antonio Fernandez-Serra Jean-Yves Blay Elena Fumagalli Virginia Martinez-Marin REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial Molecular Cancer Wild type GIST SDH: Regorafenib Biomarker Clinical trial |
| title | REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial |
| title_full | REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial |
| title_fullStr | REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial |
| title_full_unstemmed | REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial |
| title_short | REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial |
| title_sort | registri regorafenib in first line of kit pdgfra wild type metastatic gist a collaborative spanish geis italian isg and french sarcoma group fsg phase ii trial |
| topic | Wild type GIST SDH: Regorafenib Biomarker Clinical trial |
| url | https://doi.org/10.1186/s12943-023-01832-9 |
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