摘要
Succinate dehydrogenase(SDH)-deficient gastrointestinal stromal tumors(GISTs)are generally resistant to targeted therapy with tyrosine kinase inhibitors(TKIs),such as imatinib,and there are no standard therapeutic options for advanced SDH-deficient GISTs.The precise oncogenic mechanisms of SDH mutations in GIST have not been elucidated.Olverembatinib,a novel multikinase inhibitor,has shown promising activity in treating imatinib-resistant GIST.We conducted a phase 1 study(NCT03594422)to evaluate the safety and antitumor activity of olverembatinib in 66 patients with unresectable/metastatic GIST/other solid tumors,including 26 with TKI-failed SDH-deficient GISTs.To our knowledge,this is the largest prospective clinical trial for this rare GIST subtype.The median follow-up was 14.5(0.9–57.5)months.Olverembatinib was well tolerated;treatment-emergent adverse events(≥20%)included increases in hepatic transaminases,increases in leukocytes and neutrophils,anemia,and pyrexia.For SDH-deficient GISTs,confirmed partial responses were observed in 6 of the 26 evaluable patients(objective response rate,23.1%;95%CI,9–43.7);an additional 16(61.5%)did not progress during the first 6 months of treatment.This resulted in a clinical benefit rate of 84.6%(95%CI,65.1–95.6),and the median progression-free survival was 25.7 months(95%CI,12.9–NR).As a putative mechanism of action,translational research revealed significant lipid enrichment with the overexpression of lipid uptake-related genes and proteins,including CD36,fatty acid binding proteins,fatty acid transport proteins,and lipid metabolites,in SDH-deficient GIST patients,and olverembatinib suppressed lipid uptake and CD36 expression in GIST cells.Olverembatinib also exerts antitumor effects by inhibiting tumorigenic signaling pathways associated with hypoxia,angiogenesis,proliferation,and survival.
基金
supported by Ascentage Pharma Group Corp.Ltd.(Hong Kong)and the National Natural Science Foundation of China(82573567)。
