2. Academic Validation
  3. Olverembatinib, a multikinase inhibitor that modulates lipid metabolism, in advanced succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 1b study and translational research

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.
Hai-Bo Qiu # 1,  Zhiyan Liang # 2,  Jing Yang # 3,  Ye Zhou # 4 5,  Zhi-Wei Zhou 1,  Xiang-Bin Wan 6,  Ning Li 7,  Kai-Xiong Tao 8,  Yong Li 9,  Xin Wu 10,  Chen Yang 11,  Zi Chen 11,  Hengbang Wang 11,  Lichuang Men 11,  Yan Xiong 11,  Lihui Liu 11,  Dajun Yang 12 13,  Yifan Zhai 14 15,  Rui-Hua Xu 16 17
Affiliations

Affiliations

  • 1 Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 2 Ascentage Pharma Group Inc., Rockville, MD, USA.
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 5 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 6 Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
  • 7 Department of Gastroenterology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
  • 8 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 10 Department of General Surgical Medicine, The First Medical Center of the People's Liberation Army, Beijing, China.
  • 11 Guangzhou Healthquest Pharma Co. Ltd., Guangzhou, China.
  • 12 Ascentage Pharma Group Inc., Rockville, MD, USA. [email protected].
  • 13 Department of Experimental Research, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 14 Ascentage Pharma Group Inc., Rockville, MD, USA. [email protected].
  • 15 Guangzhou Healthquest Pharma Co. Ltd., Guangzhou, China. [email protected].
  • 16 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 17 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41184234 DOI: 10.1038/s41392-025-02456-9
Abstract

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.

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