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

Correspondence

Virginia Martinez-Marin¹  Paolo Dei Tos²  David S. Moura³  Marta Martin-Ruiz³  Nadia Hindi⁴  Javier Martin-Broto⁴  Antonio Gutierrez⁵  Rocio Letón⁶  Maria Monteagudo⁶  Mercedes Robledo⁷  Javier Martinez-Trufero⁸  Giovanni Grignani⁹  Javier Lavernia^1,10  Antoine Italiano^1,11  Cesar Serrano^1,12  Claudia Valverde^1,12  Bruno Vincenzi^1,13  Jean-Yves Blay^1,14  Elena Fumagalli^1,15  Jose A. López-Guerrero^1,16  Antonio Fernandez-Serra^1,16  Julia Cruz^1,17  Ricardo Gonzalez-Campora^1,18  Ana Vallejo^1,19  Francois Le Loarer^2,20  Rafael Ramos^2,21  Diana Hernández-Jover^2,22 

[1] Department of Medical Oncology, Hospital Universitario La Paz-IdiPAZ, P. Castellana, 261, 28046, Madrid, Spain;Department of Medicine, School of Medicine, University of Padua, 35122, Padua, Italy;Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain;Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain;Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Av. de los Reyes Católicos, 2, 28040, Madrid, Spain;General de Villalba University Hospital, 28400, Madrid, Spain;Hematology department, University Hospital Son Espases, 07120, Mallorca, Spain;Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain;Medical Oncology Department, University Hospital Miguel Servet, 50009, Zaragoza, Spain;Medical Oncology Unit, Città della Salute e della Scienza Hospital, 10126, Turin, Italy;Medical Oncology department, Fundación Instituto Valenciano de Oncologia, 46009, Valencia, Spain;Medical Oncology department, Institute Bergonié, 33076, Bordeaux, France;Medical Oncology department, Vall d’Hebron University Hospital, 08035, Barcelona, Spain;Medical Oncology, University Campus Bio-Medico and Fondazione Policlinico Universitario Campus Bio-Medico, 00128, Rome, Italy;Medicine Department, Centre Léon Bérard, 69008, Lyon, France;Medicine Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133, Milan, Italy;Molecular Biology department, Fundación Instituto Valenciano de Oncologia, 46009, Valencia, Spain;Pathology department, Fundación Instituto Valenciano de Oncologia, 46009, Valencia, Spain;Pathology department, Hospital Quironsalud, 14004, Cordoba, Cordoba, Spain;Pathology department, Hospital Regional Universitario de Malaga, 29010, Malaga, Spain;Pathology department, Institute Bergonié, 33076, Bordeaux, France;Pathology department, University Hospital Son Espases, 07120, Mallorca, Spain;Radiology department, Sant Pau University Hospital, 08025, Barcelona, Spain;

关键词: Wild type GIST;    SDH: Regorafenib;    Biomarker;    Clinical trial;   

DOI  :  10.1186/s12943-023-01832-9

 received in 2023-06-08, accepted in 2023-07-26,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundApproximately 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.MethodsAdult 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.ResultsFrom 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.ConclusionsRegorafenib 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 registrationClinicalTrials.gov Identifier: NCT02638766.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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