Introduction
Gastrointestinal stromal tumors (GISTs) represent a diverse group of rare mesenchymal tumors predominantly arising in the gastrointestinal tract. Among these, the succinate dehydrogenase (SDH)-deficient subtype accounts for approximately 5% to 7.5% of all GIST cases, primarily affecting adolescents and young adults. These tumors demonstrate inherent resistance to standard tyrosine kinase inhibitors (TKIs) like imatinib, historically resulting in a median progression-free survival (PFS) of just 6 to 10 months with conventional therapies. Recent advances led by Professor Ruihua Xu and colleagues at Sun Yat-sen University have unveiled promising therapeutic avenues with the novel multikinase inhibitor olverembatinib, offering new hope for these difficult-to-treat tumors.
Clinical Study Design and Patient Cohort
Published on November 4th, 2025, in the high-impact journal Signal Transduction and Targeted Therapy (Impact Factor 52.7), the first prospective Phase 1b clinical trial focused exclusively on SDH-deficient GISTs was reported. This study enrolled 26 patients who had failed prior TKI treatments (including at least two different TKIs in over 60% of cases), representing the largest global cohort of this rare tumor subtype studied to date.
The olverembatinib treatment arm demonstrated an objective response rate (ORR) of 23.1%, together with an impressive clinical benefit rate (CBR) of 84.6%. Remarkably, all patients maintained a 100% overall survival rate at one year. Most notably, median progression-free survival reached 25.7 months, which is a more than twofold increase compared to historical data, marking a significant breakthrough in managing this rare GIST subtype.
Mechanistic Insights: Unveiling the Role of Lipid Metabolism
One of the groundbreaking aspects of this research lies in elucidating the anti-tumor mechanisms of olverembatinib beyond classical kinase inhibition. Through comprehensive RNA sequencing and lipidomic profiling, the study revealed that SDH-deficient GISTs undergo profound lipid metabolic reprogramming. Compared with non-SDH-deficient tumors, these tumors showed notably increased expression of lipid uptake genes such as CD36 and FABP4, accompanied by substantial intracellular lipid droplet accumulation.
These findings suggest that SDH-deficient tumor cells are highly dependent on exogenous lipids for survival, essentially rendering them “lipid-addicted.” Olverembatinib was shown to specifically downregulate the lipid transporter CD36, effectively disrupting the tumor’s energy supply. Complementary in vitro experiments further validated that SDH-deficient tumor cells grown under lipid-depleted conditions were significantly more sensitive to olverembatinib treatment, highlighting the drug’s multi-dimensional impact on tumor metabolism.
Multitarget Synergistic Effects Against Tumor Signaling
Apart from lipid metabolism modulation, olverembatinib exhibits potent multitarget kinase inhibition. It effectively suppresses critical pathways including hypoxia-inducible factors HIF-1α and HIF-2α, vascular endothelial growth factor receptors (VEGFR 1-3), and fibroblast growth factor receptors (FGFR 1-4), with half-maximal inhibitory concentrations (IC50) below 0.6 nM for FGFR and VEGFR family members.
In cancer cells where the SDHB gene is knocked out—modeling the SDH deficiency—treatment with olverembatinib led to an increase in cleaved caspase-3, indicating enhanced tumor cell apoptosis. This multi-pronged approach underscores olverembatinib’s robust capacity to attack tumor cells through simultaneous disruption of survival, angiogenesis, and metabolic pathways.
Clinical Safety and Future Perspectives
Safety analysis revealed that olverembatinib was generally well tolerated, with adverse events predominantly limited to grades 1 and 2 (93.9% of cases), commonly manifesting as transient liver enzyme elevations and leukocytosis. Importantly, no patients discontinued treatment due to adverse effects, supporting its feasible safety profile.
This pioneering trial represents a new paradigm for precision therapy in SDH-deficient GISTs, substantially raising the bar for clinical outcomes in this challenging population. Additionally, the identification of lipid metabolism’s role opens innovative therapeutic pathways potentially applicable to other SDH-deficient tumors, including paragangliomas.
Ongoing studies are focused on deeper mechanistic exploration and combination strategies aimed at further improving efficacy and overcoming resistance, with the ultimate goal of delivering more effective, targeted therapies for patients with these rare and recalcitrant tumors.
Conclusion
The Phase 1b clinical study led by Sun Yat-sen University provides compelling evidence that olverembatinib, a multikinase inhibitor that modulates tumor lipid metabolism, achieves remarkable clinical benefits in patients with advanced SDH-deficient gastrointestinal stromal tumors. Extending progression-free survival to more than two years, this drug marks a substantial therapeutic advancement where few effective options previously existed.
By integrating cutting-edge clinical trials with molecular and metabolic research, this work not only offers immediate hope for patients but also expands the frontier for precision oncology targeting metabolic vulnerabilities. It exemplifies the potential for innovative therapies to transform the prognosis of rare, treatment-resistant cancers.
Reference:
Qiu HB, Liang Z, Yang J, Zhou Y, Zhou ZW, Wan XB, Li N, Tao KX, Li Y, Wu X, Yang C, Chen Z, Wang H, Men L, Xiong Y, Liu L, Yang D, Zhai Y, Xu RH. Olverembatinib, a multikinase inhibitor that modulates lipid metabolism, in advanced succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 1b study and translational research. Signal Transduct Target Ther. 2025 Nov 4;10(1):361. doi: 10.1038/s41392-025-02456-9. PMID: 41184234; PMCID: PMC12583704
