Elraglusib, a Glycogen Synthase Kinase 3β Inhibitor, plus Chemotherapy with or without Immunotherapy in Patients with Recurrent, Metastatic Salivary Gland Carcinoma.

PURPOSE: Glycogen synthase kinase 3β (GSK-3β) is a known therapeutic target in cancer. Aberrant nuclear GSK-3β (nGSK-3β) expression has been shown in some salivary gland cancers. Elraglusib is a small-molecule GSK-3β inhibitor with immunomodulatory potential. We hypothesized that elraglusib plus platinum-based chemotherapy and immunotherapy priming would be a novel treatment approach for salivary gland cancer. PATIENTS AND METHODS: This phase II, open-label trial enrolled patients with recurrent or metastatic salivary gland cancer [adenoid cystic carcinoma (ACC) vs. other subtypes] with disease progression in the preceding year. Cohort 1 received elraglusib (15 mg/kg i.v. on days 1 and 4) plus carboplatin (AUC = 5) or cisplatin (75 mg/m2) every 21 days. Cohort 2 received two cycles of pembrolizumab (200 mg i.v.) every 21 days prior to the same regimen. The primary endpoint included best overall response rate (ORR) by RECIST v1.1 (>5/32 in response to detect 25% ORR). RESULTS: Thirty-two patients were enrolled, including 15 (47%) with ACC and 17 (53%) with non-ACC. The best ORR was 9.4% [3/32; 95% confidence interval (CI), 2-25; three partial responses, all non-ACC]. Nineteen (59%) patients achieved stable disease. The median duration of response was 6.9 months. Common treatment-related adverse events were anemia (22, 69%), nausea (16, 50%), and neutropenia (14, 44%). At the median follow-up of 18.3 months, the median progression-free survival was 6.4 months (95% CI, 2.3-8.8), and the median overall survival was 18.6 months (95% CI, 9.7-29.4) overall. The median nGSK-3β expression was 50% versus 2% for responders versus nonresponders. CONCLUSIONS: The trial did not meet its primary endpoint, although 18% of patients with non-ACC treated with immune priming followed by cisplatin plus elraglusib achieved a response. Higher nGSK-3β expression was observed in tumor samples obtained from responders.