Ascentage Pharma's Olverembatinib Shows 23.1% Response Rate in Rare GIST Subtype with Novel Lipid Metabolism Mechanism
Key Insights
Ascentage Pharma (search) published Phase Ib data in Nature's Signal Transduction and Targeted Therapy showing olverembatinib achieved a 23.1% objective response rate and 25.7-month median progression-free survival in SDH-deficient GIST (search) patients.
The study represents the largest prospective clinical trial to date in this rare GIST subtype, enrolling 26 patients with SDH (search)-deficient tumors who had failed prior tyrosine kinase inhibitor treatment.
Translational research revealed a novel mechanism where olverembatinib modulates lipid metabolism by inhibiting CD36 (search) expression, blocking tumor cells from acquiring exogenous lipids essential for survival.
Ascentage Pharma (search) Group International announced the publication of promising Phase Ib clinical data for olverembatinib (HQP1351) in patients with succinate dehydrogenase (SDH (search)) deficient gastrointestinal stromal tumors (search) (GIST), published in the high-impact journal Signal Transduction and Targeted Therapy. The study demonstrated a 23.1% objective response rate and revealed a novel mechanism of action through lipid metabolism modulation in this rare cancer subtype that currently lacks effective treatment options.
Clinical Efficacy in Rare GIST Subtype
The Phase Ib study (NCT03594422), led by Prof. Ruihua Xu and Prof. Haibo Qiu at Sun Yat-sen University Cancer Center (search), evaluated 66 patients with unresectable/metastatic GIST and other solid tumors, including 26 patients with SDH-deficient GIST (search) who had failed prior tyrosine kinase inhibitor (TKI) treatment. This represents the largest prospective clinical trial conducted to date in this rare GIST subtype.
Among the 26 patients with SDH-deficient GIST (search), olverembatinib demonstrated an objective response rate (ORR) of 23.1% and a clinical benefit rate (CBR) of 84.6% (95% CI, 65.1-95.6). The median progression-free survival (mPFS) reached 25.7 months (95% CI, 12.9-not reached), with a median follow-up of 14.5 months. The drug was well tolerated across the patient population.
"It took us approximately 5 years to enroll 26 patients in this study, which is now the world's largest prospective clinical trial in SDH-deficient GIST (search)," said Prof. Haibo Qiu. "In the study, olverembatinib demonstrated impressive clinical benefits, including a median PFS of 25.7 months, as well as favorable safety and tolerability profiles."
Novel Lipid Metabolism Mechanism Discovered
The translational research component revealed a previously unknown mechanism by which olverembatinib exerts antitumor effects through modulation of lipid metabolism. RNA sequencing and lipidomic analysis identified significant lipid metabolism dysregulation in SDH (search)-deficient tumors, characterized by weakened endogenous lipid synthesis and markedly enhanced uptake of exogenous lipids.
The study established that SDH (search) functional deficiency drives abnormal overexpression of CD36 (search), a key cell membrane lipid transporter, thereby increasing cellular uptake of exogenous lipids. This discovery represents the first direct mechanistic link between SDH, a key mitochondrial enzyme regulating energy metabolism, and CD36, demonstrating that SDH-deficient GISTs exhibit high dependence on exogenous lipids for survival and proliferation.
Importantly, the research confirmed that olverembatinib can effectively inhibit CD36 (search) expression, thereby blocking tumor cells from acquiring exogenous lipids—an effect not observed with other TKIs clinically available to treat SDH (search)-deficient GISTs. Beyond targeting lipid metabolism, olverembatinib inhibits multiple tumorigenic signaling pathways, including HIF, FGFR (search), and VEGFR (search).
Addressing Critical Unmet Medical Need
SDH-deficient GIST (search) accounts for 5% to 7.5% of all GIST cases, predominantly affecting children, adolescents and young adults, and is prone to relapses and metastasis. Gastrointestinal stromal tumors (search) are rare overall, occurring in only 10-15 cases per million people annually, yet they represent the most common mesenchymal tumor of the digestive tract.
Traditional targeted therapies such as tyrosine kinase inhibitors have shown limited efficacy in SDH-deficient GIST (search). Currently, there are no standard of care treatments for this patient population, and the rarity of this condition makes conducting clinical trials challenging.
"SDH-deficient GIST (search) is an extremely rare tumor type that lacks high-quality, prospective clinical data; and in Chinese and international clinical guidelines, there are currently no recommended treatments for unresectable SDH-deficient GIST," said Prof. Ruihua Xu, Academician of the Chinese Academy of Engineering. "This Phase I study has yielded encouraging efficacy and safety results, suggesting that olverembatinib may offer a new treatment option for this indication."
Regulatory Progress and Future Development
Olverembatinib has been granted Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) for the treatment of patients with SDH-deficient GIST (search) who have received first-line treatment. An international multicenter, open, single-arm, pivotal registrational Phase III study (POLARIS-3; NCT06640361) is currently recruiting patients to evaluate the efficacy and safety of olverembatinib in patients with SDH-deficient GIST who have received prior therapy.
"We are very encouraged by these results, as they signal a potential breakthrough in addressing an indication with urgent unmet clinical need," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma (search). "Remaining committed to our mission of addressing unmet clinical needs in China and around the world, we will press forward with this clinical development program to bring a safe and effective new treatment option to patients as soon as possible."
Olverembatinib is an orally available third-generation BCR::ABL1 (search) inhibitor TKI that represents the first third-generation BCR::ABL1 inhibitor approved in China. The drug is currently approved for chronic myeloid leukemia (search) indications and is being jointly commercialized in China by Ascentage Pharma (search) and Innovent Biologics (search).