Elraglusib Combo Shows Modest Activity in Select Salivary Gland Cancers

A phase 2 trial (NCT05010629) of elraglusib (9-ING-41), an investigational GSK-3β inhibitor, plus platinum chemotherapy did not meet its primary end point of best overall response rate (ORR) but still showed signals of benefit in select patients with recurrent, metastatic salivary gland carcinomas (SGCs).^1,2

Of 32 total enrolled patients with SGCs including adenoid cystic carcinoma (ACC) and other non-ACC subtypes, the best ORR per RECIST was 9.4% (95% CI, 2%–25%), with 3 partial responses achieved in patients with non-ACC. The median duration of response was 6.9 months, and 59% of patients achieved stable disease.

Although the trial ultimately missed its primary end point, the 3 patients who responded—all of whom had received immunotherapy priming prior to combination therapy—had significantly higher nuclear GSK-3β expression compared to those who did not respond (median, 50% vs 2%), supporting GSK-3β as a promising therapeutic target and potential biomarker of response.

“This study represents an important step in evaluating elraglusib as a treatment and GSK-3β as a therapeutic target for metastatic [SGC],” said Glenn Hanna, MD, Dana-Farber Cancer Institute and Harvard Medical School, in a news release.¹ “Among non-ACC patients who received immune priming followed by cisplatin plus elraglusib, the response rate was 18%. Notably, all [3] responders had elevated nuclear GSK-3β expression. These novel and promising observations warrant follow-up in future trials.”

Survival outcomes compared favorably with historical figures. The median progression-free survival was 6.4 months (95% CI, 2.3–8.8). Among the entire cohort, the median overall survival was 18.6 months (95% CI, 9.7–29.4), which was even longer among patients with non-ACC (27.8 months). At 1 year, 27% of patients were progression-free, and at 2 years, 40% remained alive.

The combination also had a favorable safety profile and was well tolerated by patients. The most frequent treatment-related adverse events included anemia (69%), nausea (50%), and neutropenia (44%). There were no treatment-related deaths.

Elraglusib and the Unmet Need in SGCs

SGCs represent a group of rare and heterogeneous malignancies comprising 3% to 6% of all head and neck cancers.³ As there are no approved systemic or targeted therapies for advanced stages of SGCs, there is an urgent need for more effective treatment options in this setting.

Elraglusib, an intravenously administered small molecule inhibitor with immunomodulatory potential, aims to meet this need by enhancing therapeutic response. It acts by disrupting several cellular signaling pathways, particularly those involving GSK-3β, which is implicated in tumor growth and chemotherapy resistance. It is proposed that inhibiting GSK-3β may suppress tumor growth and increase sensitivity to antitumor therapies.

Study Design and Patient Characteristics

This single-center, nonrandomized, open-label, parallel-cohort trial evaluated the efficacy and safety of elraglusib in combination with investigator’s choice of carboplatin or cisplatin chemotherapy.⁴ Elraglusib was administered intravenously at 15 mg/kg on days 1 and 4 plus chemotherapy every 21 days for up to 2 years. One cohort received 2 cycles of sequential immune checkpoint blockade priming with 200 mg intravenous pembrolizumab (Keytruda) every 21 days prior to the elraglusib combination regimen.

The study involved a total of 32 patients with advanced, metastatic SGCs. Fifteen patients (47%) had ACC and 17 (53%) had other non-ACC subtypes, including adenocarcinoma, mucoepidermoid carcinoma, acinic cell carcinoma, myoepithelial carcinoma, and carcinoma ex pleomorphic adenoma.

The median age of patients was 65 years (range, 37–85), with females representing more than half of the group (63%). More than half (56%) had received 2 or more prior lines of therapy, while 31% had no prior systemic treatment for recurrent or metastatic disease.

REFERENCES

1. Actuate Therapeutics announces publication of positive phase II clinical data for elraglusib combined with platinum chemotherapy and sequential immunotherapy in recurrent, metastatic salivary gland carcinoma. News release. Actuate Therapeutics. December 15, 2025. Accessed December 19, 2025. https://tinyurl.com/3hyptbjn

2. Hanna GJ, Scarfo N, Shin KY, et al. Elraglusib, a glycogen synthase kinase-3β (GSK-3β) inhibitor, plus chemotherapy with or without immunotherapy in patients with recurrent, metastatic salivary gland carcinoma. Clin Cancer Res. Published online October 9, 2025. doi:10.1158/1078-0432.CCR-25-2731

3. Sreenivasan S, Jiwani RA, White R, et al. Advances in targeted and systemic therapy for salivary gland carcinomas: current options and future directions. Curr Oncol. 2025;32(4):232. Published 2025 Apr 16. doi:10.3390/curroncol32040232

4. 9-ING-41 plus carboplatin in salivary gland carcinoma. ClinicalTrials.gov. Updated May 31, 2025. Accessed December 19, 2025. https://www.clinicaltrials.gov/study/NCT05010629