CHICAGO, Ill. and FORT WORTH, Texas — Actuate Therapeutics, Inc. (NASDAQ: ACTU) (“Actuate” or the “Company”), a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers through the inhibition of glycogen synthase kinase-3 beta (GSK-3β), today announced the publication of new data in Clinical Cancer Research from a Phase II study (NCT05010629) evaluating elraglusib in combination with carboplatin or cisplatin (with or without sequential pembrolizumab priming) in patients with advanced, metastatic salivary gland cancers, including adenoid cystic carcinoma and other subtypes. The peer-reviewed paper (PMID: 41065505), entitled “Elraglusib, a Glycogen Synthase Kinase 3β Inhibitor, plus Chemotherapy with or without Immunotherapy in Patients with Recurrent, Metastatic Salivary Gland Carcinoma,” is available here.
Despite decades of research, there are no approved systemic cytotoxic or targeted therapies available for the treatment of recurrent and metastatic salivary gland cancer. While some treatments have shown modest activity in certain molecular subgroups, such as HER2 (Human Epidermal Growth Factor Receptor 2)-overexpressing, androgen receptor-overexpressing, or NTRK (Neurotrophic Tyrosine Receptor Kinase)-fused tumors, most patients lack actionable therapeutic targets. Exploring new treatment options and novel therapeutic combinations represents a significant priority in salivary gland cancer. This study represents one of the first clinical trials in advanced salivary gland cancer to explore sequential therapy and systemic treatments with varied therapeutic mechanisms in which single-agent approaches have so often yielded limited antitumor activity.
Elraglusib (9-ING-41) is a small-molecule inhibitor of GSK-3β with immune-modifying properties that disrupts multiple cellular signaling pathways, inhibits tumor growth, and increases sensitivity to chemotherapy. This phase II clinical trial evaluated elraglusib combined with platinum chemotherapy in patients with advanced, metastatic salivary gland cancer, including both adenoid cystic carcinoma (ACC) and non-ACC subtypes, with one cohort receiving sequential immune checkpoint inhibitor priming. A key finding in this study was that nuclear GSK-3β (glycogen synthase kinase 3β) expression was significantly higher in responders than non-responders (50% vs. 2%). Across the 32-patient study population, median progression-free survival was 6.4 months, with 27% of patients progression-free at 1 year. Additionally, median overall survival reached 18.6 months for the entire cohort and 27.8 months among non-ACC patients, with 40% of all patients alive at 2 years.
“This study represents an important step in evaluating elraglusib as a treatment and GSK-3β as a therapeutic target for metastatic salivary gland cancer,” said Glenn Hanna, M.D., Director, Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, and Principal Investigator of the study. “Among non-ACC patients who received immune priming followed by cisplatin plus elraglusib, the response rate was 18%. Notably, all three responders had elevated nuclear GSK-3β expression. These novel and promising observations warrant follow-up in future trials.”
Key Highlights and Readouts:
- Both adenoid cystic carcinoma (ACC, 47%) and non-ACC (53%) patients were enrolled, with a total enrollment of 32 patients, in partnership with the Center for Head and Neck Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.
- Median OS was 18.6 months (95% CI, 9.7–29.4). At 1 year, 58% of patients were alive; at 2 years, 40% remained alive. Non-ACC patients had a median OS of 27.8 months.
- Median PFS was 6.4 months (95% CI, 2.3–8.8); 27% of patients remained progression-free at 1 year. Historical PFS for this population is estimated at 4–9 months for ACC and <6 months for non-ACC.
- Three patients, all of whom were non-ACC and had PD-L1 scores <1%, had Partial Responses, indicating responses occurred despite low tumor immunogenicity. The median duration of response was 6.9 months.
- Two of three responders had CDKN2A/B and MTAP co-deletion, a molecular profile that typically predicts poor response to chemotherapy and immunotherapy—suggesting elraglusib may provide added benefit in this subgroup.
- Median nuclear GSK-3β expression was 50% in responders vs. 2% in non-responders. Patients with above-median nGSK-3β expression had longer median PFS (8.5 vs. 4.2 months) and numerically longer OS (not reached vs. 18.6 months).
- The combination was well tolerated: no treatment-related deaths occurred, and only 6% (2 patients) were discontinued due to toxicity. The most common treatment-related adverse events were anemia (69%), nausea (50%), and neutropenia (44%).
“These results mark an important milestone for patients with metastatic salivary gland cancer,” said Dan Schmitt, Chief Executive Officer of Actuate Therapeutics. “This is one of the first trials in this disease to explore sequential therapy combining varied treatment mechanisms (chemotherapy, targeted therapy, and immunotherapy), where single-agent approaches have historically shown limited activity. These findings are promising and provide a foundation for future clinical studies, suggesting that nuclear GSK-3β expression may help identify patients most likely to benefit. We are grateful to the investigators, patients, families, and the Actuate team who made this progress possible, and we remain committed to advancing innovative therapies for those facing this devastating disease.”
About the Phase II Trial
The Phase 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3 Beta (GSK-3β) Inhibitor, Plus Carboplatin in Patients With Advanced, Metastatic Salivary Gland Carcinoma (ClinicalTrials.gov ID NCT05010629) was a single-institution, open-label, non-randomized, parallel cohort Phase II study of elraglusib (9-ING-41) in combination with platinum chemotherapy (carboplatin or cisplatin) for the treatment of adult patients with incurable, recurrent, or metastatic salivary gland carcinoma (SGC). A second cohort received sequential pembrolizumab priming prior to elraglusib plus platinum therapy. The study was conducted at the Center for Head and Neck Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. Actuate Therapeutics supported this research by providing the study drug elraglusib (9-ING-41) and funding. The study has completed enrollment with 32 patients and the results are now published in Clinical Cancer Research.
About Actuate Therapeutics, Inc.
Actuate is a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers. Actuate’s lead investigational drug, elraglusib (a novel GSK-3β inhibitor), targets molecular pathways in cancer that are involved in promoting tumor growth and resistance to conventional cancer drugs such as chemotherapy through the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and DNA Damage Response (DDR). Elraglusib may also mediate anti-tumor immunity through the regulation of multiple immune checkpoints and immune cell function.
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