On September 13, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the clinical data of olverembatinib (HQP1351), the company’s novel drug candidate, in patients with succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST), in a Mini Oral at the 2024 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Ascentage Pharma, SEP 13, 2024, View Source;ascentage-pharma-releases-latest-data-showing-sustained-clinical-efficacy-of-olverembatinib-in-sdh-deficient-gist-during-a-mini-oral-presentation-302248193.html [SID1234646579]).

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These data of olverembatinib, presented in the Mini Oral at ESMO (Free ESMO Whitepaper) 2024, showed sustained clinical benefit in patients with SDH-deficient GIST. As of March 12, 2024, six of the 26 patients with SDH-deficient GIST enrolled in the study achieved partial responses (PRs). The objective response rate (ORR) was 23.1%, and the median progression-free survival (PFS) was 22 months. Furthermore, studies on mechanism of action (MOA) revealed that olverembatinib exerts its antitumor activity by modulating multiple signaling pathways involved in angiogenesis, apoptosis, proliferation, and survival.

Olverembatinib, a novel orally-administered tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma, is the first approved third-generation BCR-ABL inhibitor in China. To date, olverembatinib has been approved for two indications in China, including adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation; and adult patients with CML-CP resistant to and/or intolerant of first-and second-generation TKIs. Olverembatinib is jointly commercialized in China by Ascentage Pharma and Innovent Biologics. This is a study of an investigational drug not yet approved by the US Food and Drug Administration (FDA).

In addition to hematologic indications, olverembatinib is also being clinically evaluated for the treatment of GIST. To date, olverembatinib has already been granted a Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) for the treatment of patients with SDH-deficient GIST who had received first-line treatment. Recently, olverembatinib was cleared by the China CDE to enter a registrational Phase III study in patients with SDH-deficient GIST.

Prof. Haibo Qiu, of Sun Yat-Sen University Cancer Center, and the presenter of the report, commented, "SDH-deficient GIST is an extremely rare type of cancer. According to Chinese and International clinical guidelines, there are currently no standard treatment options for unresectable SDH-deficient GIST. In this Phase I study, we have observed encouraging clinical benefit data and further explored the MOA of olverembatinib. Supported by existing data, we will soon initiate a registrational Phase III study in efforts to bring a new treatment option to more patients with SDH-deficient GIST."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "Clinical data presented in the Mini Oral reaffirmed olverembatinib’s clinical benefit and favorable tolerability in patients with SDH-deficient GIST, thus indicated another potential breakthrough for an indication with a huge unmet medical need. We will actively advance this clinical development program which hopefully will soon offer patients a safe and effective new treatment option."

As one of the world’s leading and most influential oncology congresses, the ESMO (Free ESMO Whitepaper) Congress showcases the latest results in some of the most cutting-edge cancer research from around the world.

Highlights of the data on olverembatinib presented at this year’s ESMO (Free ESMO Whitepaper) Congress are as follows:

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

Format: Mini oral
Presentation#: 1722MO
Category: Sarcoma
Date & Time: Friday September 13, 2024, 16:30 – 16:35 CEST
Speaker: Haibo Qiu, MD, PhD, Sun Yat-sen University Cancer Center
Highlights:

Background: SDH-deficient GIST is a rare disease with limited treatment options. The oncogenic mechanism of SDH deficiency has not been elucidated. Olverembatinib, already approved in China for the treatment of adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP), with or without the T315I mutation, has shown promising clinical efficacy in SDH-deficient GIST. This report provides the most updated Phase I efficacy data and translational data of olverembatinib in SDH-deficient GIST.
Methods: This study (HQP1351-SJ0003; NCT03594422) was designed to evaluate the safety and efficacy of olverembatinib in patients (≥12 years of age) with GIST or other solid tumors. Olverembatinib was administered orally every other day (QOD). The study evaluated the clinical efficacy of olverembatinib and analyzed the drug’s MOA using multiple in vitro and in vivo assays including a SDHB knock-down rat pheochromocytoma PC12 (#5F7)-derived mouse xenograft model.
Enrolled Patients: As of March 12, 2024, a total of 26 patients with SDH-deficient GIST (confirmed by IHC) were treated with olverembatinib, including 25 (96.2%) who had received 1 to 4 TKIs and 13 (50.0%) who had received ≥3 TKIs.
Efficacy and Safety Results: Olverembatinib was well tolerated at doses of 30 to 50 mg. In all, 6 (23.1%) patients achieved partial responses (PRs) and the median PFS was 22.0 months (range: 12.9-38.6).
Preclinical Results: Olverembatinib had superior antiproliferative activity (vs. other approved TKIs) in SDHB-deficient cell lines (IC50, 0.129-5.132 μM). In PC12#5F7 (SDHB knock-down) 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 as well as providing a benchmark for future studies in this rare subtype of GIST. MOA studies revealed that olverembatinib exerts antitumor activity by modulating multiple signaling pathways involved in angiogenesis, apoptosis, proliferation, and survival.