Olverembatinib (HQP1351) hits p38–CD36 lipid-scavenging axis, delivers 23% PR and 25.7-mo PFS in SDH-deficient GIST

Olverembatinib (HQP1351) is an oral multikinase TKI with p38 inhibition implicated here in downregulating CD36 (fatty-acid uptake), a metabolic vulnerability in SDH-deficient tumors. In the HQP1351SJ0003 Phase 1b study (NCT03594422), heavily pretreated SDH-deficient GIST patients (n=26; 96.2% had ≥1 prior TKI and 50.0% had ≥3) treated with 30–50mg PO QOD achieved 23.1% PR (6/26) and median PFS 25.7 months (range 12.9–NR); this is materially above the “TKI-refractory, largely non-responding” experience typically reported in SDH-deficient GIST on standard KIT/VEGFR TKIs, where objective responses are uncommon and PFS is often in the ~6–12-month range depending on agent/series. In SDH-deficient paraganglioma (n=6; all SDH-deficient by SDHB IHC loss and/or SDHB mutation), best response was SD in 4/6 (CBR 66.7%) with median PFS 8.25 months (1.87–NR)—roughly in the ballpark of alkylator-based temozolomide series in SDHB-mutant disease (often quoted ~9–10-month median PFS with occasional PRs), but hard to benchmark given tiny n and indolent biology; translationally, olverembatinib inhibited fatty-acid–driven migration/invasion in primary SDH-deficient GIST cells and dose-dependently reduced phospho-p38 and CD36, supporting a p38→CD36 mechanism.