Median overall survival reached 18.6 months across 32 patients with metastatic salivary gland cancers treated with elraglusib plus carboplatin or cisplatin, with 40% alive at two years. Median progression-free survival was 6.4 months, and 27% were progression-free at one year. Three partial responses were observed (all non-ACC), with a median duration of 6.9 months. Safety was manageable, with 6% discontinuations due to toxicity. A pre-specified biomarker signal emerged: responders showed markedly higher nuclear GSK-3β expression (50% vs 2%), and patients with above-median nuclear GSK-3β had longer PFS (8.5 vs 4.2 months) and numerically longer OS.
The core development is the publication in Clinical Cancer Research of a single-institution, non-randomized Phase II trial (NCT05010629) combining the GSK-3β inhibitor elraglusib with platinum chemotherapy, with one cohort receiving sequential pembrolizumab priming, in advanced salivary gland cancers spanning ACC and non-ACC subtypes. In a disease with no approved systemic cytotoxics or targeted agents and modest historical activity from single agents, the study introduces two levers: pathway inhibition via GSK-3β alongside platinum, and a potential predictive biomarker based on nuclear localization of the target.
Strategically, the data are less about headline response rates and more about patient selection. A 9% response rate and PFS in the 6–8 month range are unlikely to anchor a single-arm registrational bid in an ultra-rare setting. However, the nuclear GSK-3β signal provides a plausible enrichment strategy that could convert a broadly modest regimen into a targeted proposition, particularly in non-ACC. The sequential checkpoint priming component suggests a mechanistic bet on immune modulation by GSK-3β inhibition, but also introduces confounding that a future design will need to remove or quantify. Operationally, Actuate is signaling a pivot toward biomarker-defined cohorts, which carries both opportunity and execution risk: developing, validating, and industrializing a nuclear GSK-3β IHC assay will be as determinative as the drug itself.
For stakeholders, sites should anticipate tighter tissue requirements, central pathology, and standardized scoring for nuclear localization, along with discipline around sequencing if the immune priming concept is retained. Sponsors watching rare head and neck spaces will note that biomarker-driven enrichment, not broad expansion, is where regulators and payers are increasingly aligned, but only if the diagnostic is reproducible and prospectively applied. CROs and network sites with rare tumor accrual experience will be essential to scale beyond a single institution, particularly to power a randomized signal-confirmation study in non-ACC. Diagnostic vendors have a clear opening to co-develop a fit-for-purpose IHC assay and digital pathology workflows to reduce inter-reader variability. For patients, the tolerability profile is compatible with platinum backbones, and the observation of responses in PD-L1–low tumors and in CDKN2A/B and MTAP co-deleted cases hints at a niche where standard chemo-IO underperforms.
Next, expect a biomarker-enriched, multi-center study in non-ACC with a fixed platinum backbone, independent response assessment, and prospective nuclear GSK-3β testing, likely without pembrolizumab priming or with a design that isolates its contribution. Key risks include assay standardization, the small absolute number of responders underpinning the biomarker hypothesis, and the need to demonstrate a clinically meaningful delta in ORR or PFS over platinum alone. Watch for assay concordance data, clarification of the registrational intent (randomized Phase 2 vs Phase 3), and whether the MTAP-deleted subgroup is carved out prospectively. The commercial path will depend on turning a suggestive biomarker into a reliable selector that regulators can underwrite and sites can execute at scale.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
