1722MO - Updated efficacy results of olverembatinib (HQP1351) in patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST) and potential mechanisms of action (MOA)

Background

SDH-deficient GIST is a rare disease with limited treatment options. The oncogenic mechanisms of SDH deficiency have not been elucidated. Olverembatinib, approved in China for adults with TKI-resistant chronic- or accelerated-phase CML, with or without the T315I mutation, has shown promising clinical efficacy in SDH-deficient GIST. We report updated phase I efficacy data and translational results.

Methods

The aim of the study (HQP1351-SJ0003; NCT03594422) was to evaluate the safety and efficacy of olverembatinib in patients (≥12 years of age) with GIST and other solid tumors. Olverembatinib was administered orally at assigned dose ranging 20 to 40 mg every other day (QOD). Protein expression (MOA) analyses were performed using multiple in vitro and in vivo assays including an SDHB knock-down rat pheochromocytoma PC12 (#5F7)-derived mouse xenograft model.

Results

As of March 12, 2024, 26 patients with SDH-deficient GIST (confirmed by IHC) had received ≥1 dose of olverembatinib; 25 (96.2%) had received 1 to 4 tyrosine kinase inhibitors and 13 (50.0%), ≥3. Olverembatinib was well tolerated at doses of 30 to 50 mg. In all, 6 (23.1%) patients experienced partial response as best response, and the median progression-free survival was 22.0 (12.9-38.6) months. Olverembatinib had superior antiproliferative activity (vs. other approved TKIs) in SDH-deficient cell lines (IC₅₀, 0.129-5.132 μM). In PC12#5F7 cells, olverembatinib decreased HIF-2α, VEGFA, and FGFR1 protein levels and inhibited phosphorylation of FGFR1, IGF-1R, SRC, AKT, and ERK1/2. In PC12#5F7-derived xenograft models, olverembatinib demonstrated dose-dependent antitumor activity at 10 and 20 mg/kg (QOD).

Conclusions

Olverembatinib showed sustained clinical efficacy in SDH-deficient GIST, indicating potential benefit of this treatment and providing a benchmark for future studies in this rare subtype of GISTs. MOA studies revealed that olverembatinib exerts antitumor activity by modulating multiple signaling pathways involved in angiogenesis, apoptosis, proliferation, and survival.

Clinical trial identification

NCT03594422.

Editorial acknowledgement

Funding

Ascentage Pharma Group Corp Ltd. (Hong Kong).

Disclosure

C. Yang, Z. Chen, L. Men, Y. Xiong, E. Liang, C. Wang: Financial Interests, Personal, Full or part-time Employment: Ascentage Pharma (Suzhou) Co., Ltd.; Financial Interests, Personal, Stocks/Shares: Ascentage Pharma Group International. D. Yang: Financial Interests, Personal, Leadership Role: Ascentage Pharma Group Inc., Ascentage Pharma (Suzhou) Co., Ltd., Ascentage Pharma Co., Ltd., Ascentage Pharma Group International; Financial Interests, Personal, Stocks/Shares: Ascentage Pharma Group International. Y. Zhai: Financial Interests, Personal, Leadership Role: Ascentage Pharma Group Inc., Ascentage Pharma (Suzhou) Co., Ltd., Ascentage Pharma Co., Ltd., Ascentage Pharma Group International. All other authors have declared no conflicts of interest.