On October 24, 2024 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported preclinical data supporting the development of the Company’s menin inhibitor, ziftomenib, for the treatment of advanced gastrointestinal stromal tumors (GIST) (Press release, Kura Oncology, OCT 24, 2024, View Source [SID1234647368]).
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The new findings are being presented at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona. A copy of the poster, entitled "Menin Inhibitor Ziftomenib Synergizes with Imatinib in Tyrosine Kinase Inhibitor (TKI)-Resistant Gastrointestinal Stromal Tumor Models," is available in the Posters and Presentations section on Kura’s website.
"Kura has generated a substantial body of preclinical data that support potential for ziftomenib in combination with KIT inhibitors for the treatment of patients with advanced GIST," said Francis Burrows, Ph.D., Senior Vice President, Translational Research. "Our results indicate that the combination of ziftomenib and imatinib acts via a synthetic lethal mechanism through which ziftomenib targets an epigenetic vulnerability of GIST tumors, creating potent synergy even with KIT inhibitors that are otherwise inactive as monotherapy. Indeed, the activity of ziftomenib appears to be agnostic to the mutational status of KIT in GIST, suggesting an opportunity to explore the combination for all patients, even in the frontline setting."
The combination of ziftomenib and imatinib unexpectedly showed robust and durable antitumor activity in both imatinib-sensitive and imatinib-resistant GIST patient-derived xenograft models, and in all cases was significantly superior to imatinib monotherapy. Mechanistically, the data reveal a KIT-dependent mechanism, with ziftomenib and imatinib combining to sharply reduce KIT expression and/or activity, effectively silencing both the ERK and AKT/mTOR signaling pathways and driving robust cell cycle arrest and apoptosis.
Given that imatinib is well established as the frontline standard of care in patients with GIST, and that generic versions are available, imatinib represents a promising combination partner for ziftomenib.
In August 2024, Kura announced clearance by the U.S. Food and Drug Administration (FDA) of the Investigational New Drug (IND) application for ziftomenib for the treatment of advanced GIST. The Company is now preparing to initiate a proof-of-concept study evaluating ziftomenib and imatinib in patients with advanced GIST after imatinib failure in the first half of 2025. For more information regarding the study, please visit www.clinicaltrials.gov (identifier: NCT06026410).
About GIST
Gastrointestinal stromal tumors (GIST) are the most common form of sarcoma, characterized as KIT-dependent solid tumors. Despite the successful disease control achieved with imatinib in advanced GIST patients, most patients eventually progress due to acquired secondary KIT mutations. TKIs such as sunitinib can target imatinib-resistant genotypes and are approved in later lines, but response rates and long-term outcomes are modest, so new therapeutic options are needed. Previously published data show that the menin-MLL complex regulates KIT expression in GIST cells, and menin inhibitors display additive therapeutic activity in combination with imatinib in imatinib-sensitive GIST models1.
About Ziftomenib
Ziftomenib is a potent, selective and oral menin inhibitor currently in development for the treatment of genetically defined AML patients with high unmet need. In April 2024, ziftomenib received Breakthrough Therapy Designation (BTD) by the FDA for the treatment of relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML) based on data from Kura’s ongoing KOMET-001 clinical trial. Additional information about clinical trials for ziftomenib can be found at kuraoncology.com/clinical-trials/#ziftomenib.