Updated clinical and translational results of olverembatinib (HQP1351) in patients with succinate dehydrogenase (SDH)–deficient tumors.

Abstract

11539 Background: SDH deficiency causes succinate accumulation and metabolic defects in gastrointestinal stromal tumor (GIST) and paraganglioma. Olverembatinib downregulates lipid uptake protein CD36, restricting fatty acid supply required for SDH-deficient GIST cell growth. We report updated clinical and translational results from study HQP1351SJ0003 (NCT03594422) of olverembatinib in SDH-deficient GIST and paraganglioma. Methods: Patients (pts) (≥ 12 years) with GIST and other solid tumors received olverembatinib 30 to 50 mg PO QOD. Primary cells from tumor tissues of 9 pts with SDH-deficient GISTs were used for ex vivo analyses. All samples were collected at Sun Yat-sen University Cancer Center, with informed consent from pts. Cell migration/invasion was evaluated by wound healing, Transwell migration, and Matrigel invasion assays. Lipid levels were quantitated by LC-MS. Knockdown of CD36 and p38 was done by siRNA. Protein levels were assessed by western blot. Results: As of November 13, 2025, a total of 32 pts, including 26 pts with IHC-confirmed SDH-deficient GIST, had received olverembatinib. The median age of pts with SDH-deficient GIST was 30 (range 13-56) years; 19 (73.1%) were female. Twenty-five pts (96.2%) had received ≥ 1 TKI and 13 (50.0%) ≥ 3. Six (23.1%) pts experienced PR as best response, and the median PFS was 25.7 (range 12.9-NR) months. An additional six pts with paraganglioma had received olverembatinib (all were SDH-deficient as determined by either negative SDHB IHC or SDHB gene mutation). The median age was 47.5 (range 31-61) years; all were male. Best responses were observed in four pts, with SD lasting ≥ 4 cycles (CBR, 66.7%); SD represents meaningful clinical benefit in this slow-growing tumor type. The median PFS was 8.25 (range 1.87-NR) months. SDH-deficiency was associated with a higher risk of tumor metastasis. In SDH-deficient (vs. SDH-competent) GIST cells, significantly higher linoleic acid levels were observed. Supplementation of free fatty acids promoted SDH-deficient cell migration, which could be inhibited by olverembatinib at 30 nM. In addition, siRNA knockdown of p38, a kinase target of olverembatinib, and treatment with two p38 inhibitors significantly downregulated CD36 protein levels, suggesting that p38 regulates cellular CD36. Further, western blot analysis showed that olverembatinib dose-dependently inhibited CD36 protein and phosphorylated p38 protein levels in primary cells from SDH-deficient pts. These findings suggest olverembatinib suppresses fatty acid-promoted migration via the p38-CD36 pathway. Conclusions: Olverembatinib showed sustained clinical efficacy in SDH-deficient GIST and paraganglioma. Mechanistically, olverembatinib inhibits fatty acid–promoted invasion and migration of SDH-deficient GIST by targeting the p38-CD36 signaling pathway. Clinical trial information: NCT03594422 .