Background: Treatment of pts with GIST has been transformed by TKIs. However, treatment resistance is a challenge in managing locally advanced or metastatic disease. Pts with SDH-deficient GIST typically present with multifocal and multinodular disease that is insensitive to most TKIs. Olverembatinib is an investigational novel, potent, orally active third-generation TKI with promising activity against GIST in multiple preclinical models. Methods: The aim of this study was to evaluate the safety and efficacy (per RECIST v1.1) of olverembatinib in pts with TKI-resistant metastatic SDH-deficient GISTs (confirmed by immunohistochemistry). Olverembatinib was administered orally once every other day (QOD) in 28-day cycles. Results: As of January 15, 2023, 20 pts with SDH-deficient GIST had received ≥ 1 dose of olverembatinib (median age, 30 [14-56] years), and 19 had received 1 to TKIs (50% of pts ≥ 3; Table). The dose range of olverembatinib was 20 to 50 mg (50 mg cohort [n = 6]; 40 mg [n = 8]; 30 mg [n = 6]). The median (range) treatment duration was 7.8 (1.81-42.3) months. A total of 5 of 20 pts experienced partial response (PR) as the best response. Of 16 evaluable pts treated with > 4 cycles of olverembatinib, the clinical benefit rate (CBR; complete response + PR + stable disease > 4 cycles) was 93.8% (15/16); the longest treatment duration was 42 months. All pts experienced treatment-emergent adverse events (AEs; most, grade 1 or 2); 2 pts experienced grade 3 AEs; the only hematologic AE with an incidence rate ≥ 20% was anemia (55%). A total of 15 (75%) pts experienced treatment-related AEs (grade 3 neutropenia [n = 1]). No treatment-related serious AEs were reported. Conclusions: Olverembatinib was well tolerated up to 50 mg QOD and showed antitumor activity in pts with TKI-resistant, SDH-deficient GIST. A total of 5 PRs were reported among 20 evaluable pts and 15 SDs among 16 pts treated for ≥ 4 cycles (98.3% CBR). These promising findings warrant further investigation. Internal study identifier: HQP1351SJ003. Clinical trial registration: NCT03594422.