Kura Oncology Presents Preclinical Data on Ziftomenib for Gastrointestinal Stromal Tumors

Kura Oncology, Inc., a clinical-stage biopharmaceutical company focusing on precision medicines for cancer treatment, has unveiled preclinical data indicating the potential of its menin inhibitor, ziftomenib, in treating advanced gastrointestinal stromal tumors (GIST). These findings were presented at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona.

The study showed that combining ziftomenib with imatinib exhibited strong and lasting antitumor activity in both imatinib-sensitive and imatinib-resistant GIST models. This combination was significantly more effective than imatinib alone. The data suggest that ziftomenib targets an epigenetic vulnerability in GIST tumors, creating a potent synergy with imatinib. This synergy was observed regardless of the KIT mutational status, implying that the combination could be explored for all GIST patients, even as an initial treatment.

Mechanistically, the combination of ziftomenib and imatinib works through a KIT-dependent process, significantly reducing KIT expression and activity. This reduction effectively silences the ERK and AKT/mTOR signaling pathways, leading to robust cell cycle arrest and apoptosis. Imatinib, already established as the frontline standard of care for GIST, could serve as a promising partner for ziftomenib due to its widespread use and availability in generic forms.

In August 2024, Kura received clearance from the U.S. Food and Drug Administration (FDA) for its Investigational New Drug (IND) application for ziftomenib in advanced GIST treatment. The company is planning a proof-of-concept study in the first half of 2025 to evaluate the combination of ziftomenib and imatinib in patients with advanced GIST who have not responded to imatinib alone.

Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma, characterized by their dependence on the KIT protein. Although imatinib has been successful in controlling advanced GIST initially, patients often develop resistance due to secondary KIT mutations. Other tyrosine kinase inhibitors (TKIs), such as sunitinib, target these resistant genotypes but offer limited response rates and long-term outcomes, highlighting the need for new therapeutic options. Studies have shown that the menin-MLL complex regulates KIT expression in GIST cells, and menin inhibitors like ziftomenib demonstrate additive effects when combined with imatinib in imatinib-sensitive models.

Ziftomenib is a potent, selective, and oral menin inhibitor currently under development for treating genetically defined acute myeloid leukemia (AML) patients with high unmet needs. In April 2024, ziftomenib received Breakthrough Therapy Designation (BTD) from the FDA for treating relapsed/refractory (R/R) NPM1-mutant AML, based on data from Kura’s ongoing KOMET-001 clinical trial.

Kura Oncology is dedicated to advancing precision medicines for cancer treatment. Their pipeline includes small molecule drug candidates targeting cancer signaling pathways. Ziftomenib, an oral drug targeting the menin-KMT2A interaction, has shown promise in treating R/R NPM1-mutant AML. The company has completed enrollment in a Phase 2 registration-directed trial of ziftomenib in this patient population. Additionally, Kura is conducting multiple clinical trials to evaluate ziftomenib in combination with current standards of care in newly diagnosed and R/R NPM1-mutant and KMT2A-rearranged AML.

Kura is also testing KO-2806, a next-generation farnesyl transferase inhibitor (FTI), in a Phase 1 dose-escalation trial, both as a monotherapy and in combination with targeted therapies. Another FTI, tipifarnib, is in a Phase 1/2 trial combined with alpelisib for patients with PIK3CA-dependent head and neck squamous cell carcinoma.
 

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