Elraglusib Displays Activity in Non-ACC Metastatic Salivary Gland Carcinoma

The addition of elraglusib, a glycogen synthase kinase 3β (GSK-3β) inhibitor, to cisplatin following immune priming treatment exhibited efficacy among patients with metastatic salivary gland carcinoma, particularly among those without adenoid cystic carcinoma (ACC), according to findings from a phase 2 study (NCT05010629) published in Clinical Cancer Research.¹

Although the trial did not meet its primary end point of best overall response rate (ORR) by RECIST v1.1 criteria, a higher nuclear GSK-3β expression was observed among responders to treatment at a median of 50% vs 2% in non-responders, suggesting a potential role for the combination in this GSK-3β–high population.

Among all patients treated on the trial (n = 32), the best ORR was 9.4% (95% CI, 2%-25%), with 3 patients attaining partial responses. Moreover, 56% of patients experienced stable disease, and the remaining 31% had progressive disease. The 3 responders had non-ACC histology, had received pembrolizumab (Keytruda) priming, and received elraglusib with cisplatin. Among these patients, the median time to response was 4.4 months (range, 4.2-9.4), and the median duration of response (DOR) was 6.9 months (range, 2.2-7.3).

After a median follow-up of 18.3 months (range, 2.9-38.0), the median progression-free survival (PFS) among all patients was 6.4 months (95% CI, 2.3-8.8), with 75% experiencing a progression event; the 12-month estimated PFS rate was 26.6% (95% CI, 11.8%-44.1%). Furthermore, the median overall survival (OS) was 18.6 months (95% CI, 9.7-29.4) in this patient population, with 59% of patients having died as of last follow up; the estimated 12- and 24-month rates were 58.1% (95% CI, 39.0%-73.1%) and 39.7% (95% CI, 20.8%-58.1%), respectively.

In the non-ACC vs ACC groups, the median PFS was 6.6 vs 4.3 months. Additionally, the median OS was 27.8 months vs 15.3 months, respectively.

“This study represents an important step in evaluating elraglusib as a treatment and GSK-3β as a therapeutic target for metastatic salivary gland cancer,” Glenn Hanna, MD, director of the Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute and associate professor of Medicine at Harvard Medical School, as well as principal investigator of the study, stated in a news release on the phase 2 study findings.² “Among [patients without] ACC 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.”

Patients 18 years and older with advanced unresectable, recurrent, or metastatic salivary gland cancer and at least 1 measurable lesion were eligible for study enrollment in the single-arm trial. Those included in the trial were required to have documented clinical or radiographic disease progression, and any number of prior lines for advanced disease were permitted.

Patients in cohort 1 received 15 mg/kg of intravenous elraglusib on days 1 and 4 plus carboplatin at area under the curve (AUC) 5 intravenously on day 1 or 75 mg/m² of intravenous cisplatin on day 1 of 21-day cycles in the absence of disease progression, unacceptable toxicity, or withdrawal of consent, or for a maximum of 2 years. Following the completion of cohort 1, patients were assigned to cohort 2 and received initial priming with 2 cycles of single-agent pembrolizumab at 200 mg intravenously every 21 days.

The median age was 65 years (range, 37-85) among all patients in the study, and most were female (63%), White (84%), and non-Hispanic (97%). A total of 59% of patients had an ECOG performance status of 1, 44% had a primary site of disease at the major salivary gland, and 47% had ACC histology. Moreover, 31% and 22% of patients were treatment-naive and treated with 3 or more lines of prior therapy, respectively, and 66% of patients had distant metastases.

Secondary end points of the phase 2 trial included safety and tolerability, PFS, OS, DOR, and quality of life metrics.

A total of 72% of patients on the study experienced grade 3 to 5 adverse effects (AEs). The most common grade 3 treatment-related AEs (TRAEs) included anemia (19%), decreased neutrophil counts (13%), and infusion-related reactions (6%). Notably, no grade 5 TRAEs were observed, and only 1 grade 4 instance of decreased neutrophil count (3%) was reported. AEs leading to treatment discontinuation occurred in 2 patients (6%).

References

1. Hanna GJ, Scarfo N, Shin KY, et al. Elraglusib, a glycogen synthase kinase 3 inhibitor, plus chemotherapy with or without immunotherapy in patients with recurrent, metastatic salivary gland carcinoma. Clin Cancer Res. Published online November 25, 2025. doi:10.1158/1078-0432.CCR-25-2731
2. 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 17, 2025. https://tinyurl.com/mwefpuw8