Abstract CT212: Elraglusib, a glycogen synthase kinase 3 beta (GSK 3β) inhibitor, plus chemotherapy with or without immunotherapy for advanced salivary gland cancer
Authors: Glenn J. Hanna, Nicole Scarfo, Kee-Young Shin, Anne ONeill, Michael J. Dennis, Kartik Sehgal, Veronica Bedard, Andrew Mazar, Andrey Ugolkov, Robert I. Haddad
Journal: Cancer Research (2025)

Abstract Background: Salivary gland cancers (SGC) are rare, molecularly rich tumors with limited systemic therapy options. GSK-3β can promote tumor growth and chemoresistance across solid tumors and GSK-3β overexpression is observed in SGC. Elraglusib (9-ING-41) is a potent, small molecule GSK-3β inhibitor. Beyond its role in overcoming chemoresistance, elraglusib (elra) has immunomodulatory properties. We hypothesized that combining elra with platinum chemotherapy and immune priming would be a novel sequential treatment approach to explore in SGC. Methods: This phase 2, non-randomized, clinical trial (NCT05010629) enrolled patients (pts) with advanced SGC (any histology) with measurable disease (RECIST 1.1) and progression in the preceding 12 months (mos) regardless of prior therapies. Pts in cohort 1 received elra (15 mg/kg IV days 1, 4) with carboplatin (AUC 5 IV day 1) or cisplatin (75 mg/m2 IV day 1) every 21-days grouped by adenoid cystic carcinoma (ACC) or non-ACC histology. Pts in cohort 2 received 2-cycles of pembrolizumab (200 mg IV Q3W) priming prior to starting the same elra plus platinum regimen and were grouped similarly. Primary endpoint: overall response rate (ORR): &amp;gt;5 of 32 with CR/PR provided 85% power to detect 25% ORR (one-stage binomial design, alpha=0.1). Secondary endpoints: safety, progression-free survival (PFS), overall survival (OS), and exploratory biomarkers of response (tumor PD-L1, GSK-3β expression). Results: From 9/2021 to 4/2024, 32 pts were enrolled (16 in each cohort). Median age was 65 (range, 37-85), most pts were female (20, 63%); 15 (47%) pts had ACC vs. other SGC and 17 [GH1] (53%) pts had 1 or more prior therapies for advanced SGC. ORR was 9.4% (95%CI, 2-25) with partial responses (PR) in 3 pts (all non-ACC pts, having received pembrolizumab and cisplatin), while 19 (59%) pts had stable disease. Median duration of response: 4.1 mos (range, 2-4); 12 of 19 pts had SD lasting &amp;gt;6 mos[GH2] . Grade 3-4 treatment-related adverse events (TRAEs) occurred in 19 (59%) pts, most commonly cytopenias. Immune-related adverse events occurred in 5 of 16 (31%) pts in cohort 2. Two (7%) pts discontinued treatment for AEs. At median follow-up of 13.8 mos, median PFS was 6.4 mos (95%CI, 2-9), 4.3 vs. 6.6 mos for ACC vs. non-ACC, and 4.3 vs. 7.3 mos in cohort 1 vs. 2; 12-month PFS was 24.5% (95%CI, 10-43). Median OS was 15.6 mos (95%CI, 10-29), 15.3 vs. 15.6 mos for ACC vs. non-ACC, and 17.1 vs. 12.9 mos in cohort 1 vs. 2. All 20 deaths were disease related. Tumor PD-L1 testing was available for 18 (56%); positive (≥1%) in 3 (9%) pts. Aberrant baseline nuclear GSK-3β expression was observed in 20-80% of cancer cells in tumors obtained from 3 pts with PR. Conclusions: Elraglusib with platinum chemotherapy and immune priming was well tolerated. While the primary endpoint was not met, anti-tumor activity was observed among 18% (3/17) of non-ACC pts warranting further investigation. Citation Format: Glenn J. Hanna, Nicole Scarfo, Kee-Young Shin, Anne ONeill, Michael J. Dennis, Kartik Sehgal, Veronica Bedard, Andrew Mazar, Andrey Ugolkov, Robert I. Haddad. Elraglusib, a glycogen synthase kinase 3 beta (GSK 3β) inhibitor, plus chemotherapy with or without immunotherapy for advanced salivary gland cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT212.