Lucicebtide (ST101) plus chemoradiation in newly diagnosed GBM patients: Efficacy, pharmacodynamics, and safety from phase 2 window-of-opportunity study.

2079 Background: Glioblastoma (GBM) is a lethal brain malignancy with no cure. Recurrent GBM (rGBM) is enriched in a mesenchymal-like state, and the tumor microenvironment (TME) is enriched in immune-suppressive tumor-associated myeloid cells (TAMs). C/EBPß is a master regulator of the mesenchymal GBM state and in sustaining immunosuppressive TAMs. Lucicebtide (ST101) is a first-in-class peptide antagonist of C/EBPß with demonstrated anti-tumor activity and TAM reprogramming in preclinical models. Methods: The WoO study enrolled 2 cohorts; 9 pts with rGBM that received 2-4 doses of lucicebtide 500mg QW prior to surgery and resumed lucicebtide after surgery to progression and 9 ndGBM pts that received 2-3 doses of lucicebtide 500mg QW prior to surgery and resumed lucicebtide + chemoradiation after surgery until progression. Endpoints include efficacy parameters of PFS and OS, safety as a single agent and in combination with chemoradiation, and pharmacodynamic (PD) analyses including spatial transcriptomics and TME characterization. Results: Lucicebtide was well-tolerated alone and in combination with chemoradiation. Tissue analysis indicates BBB penetration, tumor uptake, and C/EBPß target engagement. Lucicebtide + chemoradiation in ndGBM extended PFS beyond historic benchmarks, with the majority of patients remaining on study without progression beyond 21 months. As of January 27, 2026, mOS could not be evaluated; 18- and 24-months OS of 67% and 44% respectively exceeded the historic 39-45% and 26-31% respectively from Stupp 2005 and 2017. In rGBM, lucicebtide improved mPFS of 4.0 months and mOS to 12.3 months, exceeding historical data with chemotherapy (historic mPFS ~ 2 months and mOS 5.6-9.8 months). Spatial transcriptomics revealed significant reductions in C/EBPß regulon activity in tumor cells and macrophages, resulting in a dramatic reduction in the mesenchymal signature in tumor cells. Importantly, lucicebtide altered the infiltration patterns and phenotypes of the TME, including increased effector CD8⁺ infiltration and an increase in the M1/M2 ratio that were associated with disease control. Conclusions: Lucicebtide is well-tolerated as monotherapy and in combination with SoC. Improvements in PFS and OS have been seen in GBM patients following lucicebtide exposure. Analysis of tumor resections demonstrate penetration across the BBB and target engagement, and on-target pharmacodynamic activity, including a dramatic reduction in mesenchymal gene signature in tumor cells and a remodeling towards a more permissive immune TME. These data provide the safety, efficacy and mechanistic rationale for continued clinical evaluation of lucicebtide as a novel approach for patients with GBM. Clinical trial information: NCT04478279 .