Use of lucicebtide (ST101) in glioblastoma patients by antagonism of C/EBPβ-dependent mesenchymal cell transition and immunosuppressive M2 macrophage polarization.

2016 Background: C/EBPβ is a master regulator of the mesenchymal phenotype in GBM and has an essential role in the maintenance of immunosuppressive M2 tumor-associated macrophages (TAMs). Lucicebtide is a first-in-class antagonist of C/EBPβ that has shown direct anti-tumor activity in GBM as well as the ability to reprogram TAMs in the TME toward immunostimulatory M1 macrophages. In a recent recurrent GBM (rGBM) P2 study, lucicebtide was well-tolerated and resulted in disease control in 9/30 patients, including two PRs lasting > 1 year. With strong rationale for targeting C/EBPβ in GBM, additional cohorts we explored in a window-of-opportunity (WoO) study (NCT04478279). 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 analyses including spatial transcriptomics and TME characterization. Results: Lucicebtide was well-tolerated as a single agent and in combination with chemoradiation. Tissue analysis indicates penetration past the BBB and tumor uptake, as well as C/EBPβ target engagement. Lucicebtide + chemoradiation in ndGBM extended PFS beyond historic benchmarks, with the majority of patients remaining on study without progression (7-22+ months). As of January 25, 2025, mOS could not be evaluated, with 8/9 patients alive. In rGBM, lucicebtide improved mPFS to 3.4 months and mOS to at least 11.8 months, exceeding historical data with chemotherapy (historic mPFS ~ 2 months and mOS 5.6-9.8 months). Pathologic evidence of treatment effect, i.e. geographic necrosis, was observed in 5/6 pts including otherwise treatment naïve ndGBM patients. Spatial transcriptomics analysis revealed a significant reduction in the mesenchymal gene signature following lucicebtide, consistent with on-target antagonism of C/EBPβ. Further, immune activation in the TME, as indicated by increased M1/M2 ratio and CD8+ T cell infiltration, was associated with disease control. Conclusions: Lucicebtide is well-tolerated as monotherapy and in combination with SoC. Improvements in PFS and OS in GBM patients following lucicebtide exposure demonstrated penetration across the BBB and target engagement, resulting in 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 mechanistic rationale for continued clinical evaluation of lucicebtide as a novel approach for patients with GBM. Clinical trial information: NCT04478279 .