1973P Antitumor activity of olverembatinib (HQP1351) in patients (pts) with TKI-resistant succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST)

GIST treatment has been transformed by TKIs but resistance is a challenge in managing advanced disease. Pts with SDH-deficient GIST typically present with TKI-insensitive, multifocal/multinodular disease. Olverembatinib is a novel, potent, multitargeted TKI with promising preclinical activity against GIST. Antitumor activity of olverembatinib was evaluated via a panel of SDH-deficient cell lines. SDH knockdown was performed in PC12 cells to assess potential mechanisms of action. The aim of the phase 1 study was to assess safety and efficacy (RECIST v1.1) of olverembatinib, orally once every other day (QOD) in 28-day cycles, in pts with TKI-resistant, metastatic, SDH-deficient, IHC-confirmed GIST. Olverembatinib had superior antiproliferative effects on SDH-deficient cancer cell lines, and the increased sensitivity could be ascribed to FGFR pathway upregulation. As of January 15, 2023, 20 pts had received ≥ 1 dose of olverembatinib and 19, 1-4 TKIs (Table). The dose range of olverembatinib was 20-50 mg and median (range) treatment duration 7.8 (1.81-42.3) mo. 5/20 pts experienced PR as best response. Of 16 evaluable pts receiving > 4 cycles, the clinical benefit rate (CBR; CR + PR + stable disease [SD] > 4 cycles) was 93.8% (15/16); the longest treatment duration was 42 mo. All pts experienced TEAEs (mostly grade 1 or 2 [G1-2]); 2 had G3 AEs; the only hematologic AE with incidence rate ≥ 20% was anemia (55%). 15 (75%) pts had TRAEs (G3 neutropenia [n = 1]). No treatment-related SAEs were reported. Olverembatinib was effective in SDH-deficient tumors preclinically. In the phase 1 study, it was well tolerated up to 50 mg QOD and showed antitumor activity in pts with TKI-resistant, SDH-deficient GIST. 5 PRs were reported in 20 evaluable pts, and 15 SDs among 16 pts treated ≥ 4 cycles (93.8% CBR). These promising data warrant further investigation. Study: HQP1351SJ003.