Recent Advances in Succinate Dehydrogenase Deficient Gastrointestinal Stromal Tumor Systemic Therapies.

opinion statementGastrointestinal stromal tumors (GIST) are the most common gastrointestinal soft tissue sarcomas, with an incidence of about 15 cases per million person-years. Approximately 15% of GIST develop due to succinate dehydrogenase deficiency (SDH-Def), and such tumors do not respond well to the tyrosine kinase inhibitors (TKIs) used to treat other GIST. Due to its indolent nature SDH-Def GIST can often be surveilled if asymptomatic. In our current practice we typically treat advanced symptomatic SDH-Def GIST with the anti-angiogenic TKIs, sequentially treating with sunitinib, regorafenib and pazopanib. This practice is based on limited data. This systematic review provides an update on new data (12/21/2021 to 9/26/2024) for systemic treatment of SDH-Def GIST, both with agents generally used to treat other GIST subtypes and with agents approved in other malignancies. Olverembatinib and rogaratinib have shown promising activity in pre-clinical models and small SDH-Def GIST cohorts. Other agents whose benefits are explored here include the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab and temozolomide, whether as monotherapy or in combination with INBRX-109 (a pro-apoptotic antibody) or olaparib. Additional research into TKI agents with anti-vascular endothelial growth factor receptor (VEGFR) and anti-fibroblast growth factor receptor (FGFR) activity in this clinical setting is needed. Patients with SDH-Def will benefit more broadly from ongoing explorations of treatments with alternative mechanisms of action, especially those that exploit cellular pathways involved in SDH-Def GIST tumorigenesis.