Background: GIST is a rare mesenchymal tumor whose management has been transformed by approvals of TKIs. However, treatment resistance is a formidable challenge in managing locally advanced or metastatic GIST. Pts with SDH-deficient GIST are not sensitive to imatinib and other TKIs, are frequently multifocal, and typically have a multinodular architecture. Olverembatinib is a novel, potent, orally active third-generation TKI with promising activity against GIST in multiple preclinical GIST models. Methods: The aim of this phase Ib/II study was to evaluate the safety/tolerability, pharmacokinetics (PK), and efficacy (assessed per RECIST v1.1) of olverembatinib (NCT03594422) in pts with metastatic GIST whose disease was resistant or failed to respond to imatinib or other TKIs. Olverembatinib was administered orally once every other day (QOD) in 28-day repeated cycles. After 3 pts were treated at 20 mg, other pts were randomly allocated in a 1:1:1 ratio to 30, 40, and 50 mg regimens. Results: On the cutoff date of January 30, 2022, 39 pts (median age 52 [range 19-72] years) had received at least 1 dose of olverembatinib. The average (range) treatment period was 5.0 (0.2-35) months. PK analyses indicated an approximately dose-proportional increase in systemic exposure over the dose range of 20 to 50 mg. Thirty-one pts had KIT or PDGFRA mutations, 13 had stable disease for at least 2 cycles as the best response, 8 withdrew early, and 10 had progressive disease before Cycle 3. Very interestingly, 6 of 8 pts with KIT wild-type GIST were confirmed as SDH deficient: 2 pts had partial responses (PRs), 1 patient’s tumor had shrunk by 35.9% and lasted for 16 cycles, and another patient’s tumor had shrunk by 54.2% in the first evaluation. Four pts had stable disease as best response for 2, 6, 14, and 36 cycles. A total of 36 (92.3%) pts experienced treatment-emergent adverse events, most of which were mild or moderate. Ten (25.6%) pts experienced serious adverse events, of which intestinal obstruction attributed to GIST was the most reported. Common treatment-related adverse events (≥ 20%) included increased leukocyte (59.0%) and neutrophil (46.2%) counts, anemia (20.5%), constipation or asthenia (35.9% each), hyperuricemia (25.6%), hypoalbuminemia (23.1%), and elevated AST or ALT (20.5% each). Conclusions: Olverembatinib was well tolerated at doses of up to 50 mg QOD and showed antitumor activity in pts with TKI-resistant SDH-deficient GIST, with 2 PRs in 6 evaluable pts with SDH-deficient GIST and 1 with stable disease for 36 cycles. These promising findings warrant further investigation. Clinical trial information: NCT03594422.