Olverembatinib Recommended for Breakthrough Therapy Designation in China for SDH-Deficient GIST

The China National Medical Products Adminstration’s Center for Drug Evaluation (CDE) has recommended that olverembatinib (HQP1351) receive breakthrough therapy designation for the treatment of patients with gastrointestinal stromal tumor (GIST) that is succinate dehydrogenase (SDH) deficient.¹

Olverembatinib is a third-generation TKI and a multikinase inhibitor that targets ABL1, KIT, PDGFR, FGFR, FLT3, VEGFR, and SRC.² In preclinical models, the agent was found to have strong antitumor activity against GIST, and data from early clinical studies showcased efficacy in patients with SDH-deficient GIST.

“We are highly appreciative of the regulator’s recognition of olverembatinib’s clinical potential,” Yifan Zhai, MD, PhD, chief medical officer of Ascentage Pharma, stated in a press release. “This breakthrough therapy designation indicates olverembatinib’s promising therapeutic utility in SDH-deficient GIST, marking a major milestone in its clinical development for nonhematologic indications. Moving forward, we will maintain close contact with the CDE to expedite the clinical development program in China and allow patients to benefit from this novel therapeutic as soon as possible.”

The agent is under evaluation in the ongoing open-label, multicenter phase 1b/2 trial (NCT03594422), which enrolled patients with metastatic GIST whose disease was resistant to or did not respond to imatinib (Gleevec) or other TKIs.² Patients needed to have an ECOG performance status ranging from 0 to 2, an estimated survival of 3 months or longer, and acceptable hematologic, bone marrow, renal, and liver function.³

They could not have received chemotherapy, a biological agent, immunotherapy, or radiotherapy with 28 days prior to their first dose of study drug, nor could they have received TKIs within 2 weeks of beginning olverembatinib. They must have recovered from all toxicities experienced with prior agents.

Study participants received oral olverembatinib every other day as part of 28-day cycles.² After 3 patients were treated at a dose of 20 mg, other patients were randomly assigned in a 1:1:1 ratio to receive the agent at 30 mg, 40 mg, and 50 mg.

A total of 39 patients received at least 1 dose of the study drug. They had a median age of 52 years (range, 19-72) and most (76.9%) were male. Regarding ECOG performance status, 30.8% had a status of 0, 64.1% had a status of 1, and 5.1% had a status of 2. Additionally, 20.5% of patients received 1 prior approved TKI, 38.5% received 2, and 41.0% received 3 or more.

Twenty-nine patients harbored KIT mutations, with 19 having KIT exon 11 positivity and 10 having other KITmutations. Two patients had PDGFRA mutations. Moreover, 8 patients had wild-type disease.

Of the 31 patients who had KIT/PDGFRA mutations, 13 had a best response of stable disease for at least 2 cycles. Eight patients withdrew early, and 10 patients experienced disease progression prior to cycle 3 of treatment.

Notably, 6 of the 8 patients with KIT wild-type disease had SDH deficiency. In this group, 2 patients achieved partial responses (PRs) to olverembatinib. One patient experienced a 35.9% reduction in tumor size, with the effect lasting for 16 cycles. Another patient achieved a 54.2% reduction in tumor size during the first evaluation. Four patients had stable disease following 2, 6, 14, and 36 cycles, respectively.

The investigators had concluded that the agent was well tolerated at doses up to 50 mg every other day and that the findings support further investigation of the agent.

Additional data on 20 patients with SDH-deficient GIST who received the agent are slated for poster presentation at the 2023 ASCO Annual Meeting.^4,5 With a data cutoff date of January 15, 2023, and a median treatment duration of 7.8 months (range, 1.81-42.3), 5 patients achieved PRs. In 16 evaluable patients who received olverembatinib for at least 16 weeks, the clinical benefit rate was 93.8%. Moreover, the longest treatment duration was 42 months.

Regarding safety, all participants experienced at least 1 treatment-emergent toxicity and most events were grade 1 or 2 in severity. Two patients reported grade 3 adverse effects. Notably, anemia was the only hematologic toxicity that had an incidence rate of at least 20%, and it was observed in 55% of patients.

Previously, olverembatinib was approved in China for the treatment of adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) with a T3151 mutation.¹ The agent was shown to have sustained efficacy and reduced toxicity in patients with TKI-resistant, T3151-mutant CML-CP and CML-AP, according to data from 2 phase 2 trials (NCT03383087; NCT03883100).⁶

References

1. Ascentage Pharma’s novel drug olverembatinib recommended for a breakthrough therapy designation in China for the treatment of SDH-deficient GIST, the second BTD for the drug. News release. Ascentage Pharma. May 31, 2023. Accessed June 1, 2023. https://www.ascentage.com/ascentage-pharmas-novel-drug-olverembatinib-recommended-for-a-breakthrough-therapy-designation-in-china-for-the-treatment-of-sdh-deficient-gist-the-second-btd-for-the-drug/
2. Qiu H, Zhou Z, Zhou Y, et al. Promising 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. 2022;40(suppl 16):11513. doi:10.1200/JCO.2022.40.16_suppl.11513
3. A study of HQP1351 in patients with GIST or other solid tumors. ClinicalTrials.gov. Updated February 13, 2023. Accessed June 1, 2023. https://clinicaltrials.gov/ct2/show/NCT03594422
4. Ascentage Pharma presents updated results from multiple clinical studies at American Society of Clinical Oncology annual conference. News release. Ascentage Pharma. May 27, 2023. Accessed June 1, 2023. https://www.ascentage.com/ascentage-pharma-presents-updated-results-from-multiple-clinical-studies-at-american-society-of-clinical-oncology-annual-conference/
5. Qiu H, Zhou Z-w, Zhou Y, et al. Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant succinate dehydrogenhase (SDH)–deficient gastrointestinal stromal tumor. J Clin Oncol. 2023;41(suppl 16):11540. doi:10.1200/JCO.2023.41.16_suppl.11540
6. Jiang Q, Li Z, Hou Y, et al. Updated results of pivotal phase 2 trials of olverembatinib (HQP1351) in patients (Pts) with tyrosine kinase inhibitor (TKI)-resistant chronic- and accelerated-phase chronic myeloid leukemia (CML-CP and CML-AP) with T315I mutation. Blood. 2022;140(suppl 1):203-204. doi:10.1182/blood-2022-170698