Olverembatinib Demonstrates Promising Outcomes in SDH-Deficient GIST

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The investigational tyrosine kinase inhibitor (TKI), olverembatinib (HQP1351), demonstrated antitumor activity and was well-tolerated in patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST), according to results from a phase 1 study (NCT03594422).¹

"Olverembatinib may offer a new treatment option to patients with SDH-deficient GIST, a highly rare subtype of GIST that currently lacks standard of care treatment," said Ruihua Xu, MD, PhD, the principal investigator of this study, president of the Chinese Society of Clinical Oncology and director of Sun Yat-Sen University Cancer Center, in a press release. "The drug's impressive efficacy and manageable safety signal a potential breakthrough in the treatment of SDH-deficient GIST."

Olverembatinib is novel, potent, orally active third-generation TKI being developed for the treatment of GIST based on positive preclinical data and the need for new therapies to address TKI resistance in patients with locally advanced or metastatic disease. Moreover, the SDH-deficient subset of GIST makes these patients more likely to present with multifocal or multinodular disease and therefore, be insensitive to most TKIs.

The agent was granted breakthrough therapy designation in China for the treatment of patients with SDH-deficient GIST who have received first-line therapy based on prior results from the phase 1 study. In the United States, the developer of olverembatinib was given clearance from the FDA to launch a phase 1b study.²

When administered at 50 mg every other day for up to 28 cycles, olverembatinib achieved a partial response (PR) in 5 of 20 patients in the study. In addition, 19 patients had stable disease (SD), and 7 patients had progressive disease (PD). The clinical benefit rate, which was based on PR, SD, and PD data from 16 evaluable patients, was 93.8%. Forty-two months was the longest treatment duration observed in the study.

Treatment-emergent adverse events (TEAEs) occurred in all patients treated with olverembatinib in the study. The AEs observed were predominantly grade 1 or 2 in severity. Grade 3 TEAEs occurred in 2 patients, and there was 1 hematologic AE of anemia, which effected 55% of patients. The treatment-related AE observed was grade 3 neutropenia, which occurred in 75% of patients. There were no treatment-related serious AEs observed during the study.

In the study, 20 patients with SDH-deficient GIST were administered at least 1 dose of olverembatinib. The study population, of which 30% were male, had a median age of 30 years (range, 14-56 years). The primary site of disease for the majority of patients was the stomach. The cohort had received 1 to 4 prior lines of therapy, and most received at least 3 prior lines.

Pharmacokinetics data from the study showed that the plasma concentration was highest when olverembatinib was dosed at 50 mg. However, the 40-mg dose also induced a high level of plasma concertation.

"This year, we presented updated clinical results that further validated olverembatinib's clinical potential in SDH-deficient GIST, a rare subtype representing an urgent treatment gap in GIST," said Yifan Zhai, MD, PhD, chief medical officer of Ascentage Pharma, in the press release.¹ "We are truly excited by the prospect of a novel therapeutic that could potentially address an urgent clinical need and bring renewed hope to patients. Remaining committed to the mission of addressing unmet clinical needs in China and around the world, we will press forward with this clinical development program in order to bring a safe and effective new treatment option to patients as soon as possible."

According to Xu et al, the phase 1 study results were promising and warrant further investigation of olverembatinib in SDH-deficient GIST.²

_REFERENCES:

_{1. Qiu H, Zhou Z, Ahou Y, et al. Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)–resistant succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST). J Clin Oncol. 2023;41(suppl 16): 11540-11540. doi:10.1200/JCO.2023.41.16_suppl.11540}

_{2. Innovent announces the second breakthrough therapy designation by NMPA for olverembatinib for the treatment of patients with SDH-deficient GIST. News release. Innovent Biologics. June 2, 2023. Accessed June 7, 2023. https://tinyurl.com/32htp2ve}