Journal Article

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

Hernández-Jover, Diana, Vincenzi, Bruno, Tos, Paolo Dei, Moura, David S., Serrano, Cesar, Valverde, Claudia, Gutierrez, Antonio, Blay, Jean-Yves, López-Guerrero, Jose A., Monteagudo, Maria, Robledo, Mercedes, Cruz, Julia, Fumagalli, Elena, Lavernia, Javier, Letón, Rocio, Martin-Ruiz, Marta, Martinez-Marin, Virginia, Gonzalez-Campora, Ricardo, Martin-Broto, Javier, Vallejo, Ana, Le Loarer, Francois, Italiano, Antoine, Ramos, Rafael, Fernandez-Serra, Antonio, Hindi, Nadia, Grignani, Giovanni, Martinez-Trufero, Javier

2023

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adult / Antineoplastic Agents - therapeutic use / Biomarker / Biomedical and Life Sciences / Biomedicine / Cancer Research / Clinical trial / Consent / Correspondence / COVID-19 / Disease control / DNA methylation / Gastrointestinal Neoplasms - genetics / Gastrointestinal Stromal Tumors - drug therapy / Gastrointestinal Stromal Tumors - genetics / Genes / Genetic testing / Genomics / Humans / Imatinib / Inhibitor drugs / Kinases / MAP kinase / Medical imaging / Metastases / Metastasis / Mutation / Oncology / Pathology / Patients / Phase 2 and 3 studies / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase / Proto-Oncogene Proteins c-kit - genetics / Proto-Oncogene Proteins c-kit - therapeutic use / Response rates / Sarcoma / Sarcoma - drug therapy / SDH: Regorafenib / Signal transduction / Skin cancer / Targeted cancer therapy / Toxicity / Tumors / Wild type GIST