Proteomic analysis in patients with dedifferentiated liposarcoma (DDLPS) in a phase Ia/Ib study of the MDM2–p53 antagonist brigimadlin.
Authors: Yarúa Jaimes, Patricia LoRusso, Gregor Sturm, Mrinal M. Gounder, Noboru Yamamoto, Neeta Somaiah, Iwona A. Lugowska, Victor Moreno, Alexander Peltzer, Michael Teufel, Girish Jayadeva, Patrick Schöffski
Journal: Journal of Clinical Oncology (2024)

11541 Background: The tumor suppressor p53 primarily exerts its suppressive function via the transcriptional regulation of target genes. Both preclinical and clinical studies have demonstrated that restoring p53 activity elevates GDF-15, a p53 target, in plasma; however, the effects of other circulating proteins are not well understood. Brigimadlin (BI 907828), a highly potent, oral MDM2–p53 antagonist, is being investigated in an ongoing Phase Ia/Ib study (NCT03449381) in patients with advanced solid tumors, including DDLPS. To understand the effects of brigimadlin on the circulating proteome, we present data from a longitudinal proteomic analysis of plasma samples from patients with DDLPS who received brigimadlin every 3 weeks in Phase Ib. Methods: The Human DiscoveryMAP assay (Rules-Based Medicine) was used for protein analysis, measuring levels of 204 proteins with the Luminex platform. Plasma samples, collected at baseline and Cycle 3 Day 1 (C3 D1), were used for differential protein expression using a linear model. Proteins that showed a significant differential expression between cycles were further explored by incorporating additional covariates (time on treatment, best overall response, overall survival) into a Cox hazards ratio model. Results: Baseline and C3 D1 plasma samples were available from 37 patients with DDLPS. At baseline, angiopoietin-1, C-C motif chemokine 16, PAI-1, and C-C motif chemokine 5 were higher in DDLPS samples than in other tumor samples (samples from 24 patients in the same study), whereas levels of gamma enolase were lower in DDLPS samples. After patients with DDLPS were treated with brigimadlin (C3 D1), there were significant changes vs baseline in the expression of several proteins (i.e., up- or downregulation), including angiopoietin-1 (down, p = 0.02), LAP_TGF-beta (down, p = 0.02), PAI-1 (down, p = 0.085), thrombomodulin (down, p = 0.062), and serpinA7 (up, p = 0.031). Levels of AXL receptor tyrosine kinase (UFO) were downregulated in patients who achieved a CR or PR (n = 11; p = 0.0092) or SD (n = 23; p = 0.03), according to RECIST. However, in patients with PD (n = 3), baseline UFO levels were higher vs patients achieving CR/PR (mean baseline log 2 expression: 3.6 µg/L vs 3.0 µg/L, respectively) and were not downregulated during treatment. Correlation of changes in thrombomodulin and neutrophil gelatinase-associated lipocalin levels with myelosuppressive events will be shown. Conclusions: These findings provide insight into the proteomic changes associated with brigimadlin treatment in patients with DDLPS and highlight potential biomarkers for treatment response and adverse events. Further investigation is needed to determine their significance and impact on patient outcomes. Clinical trial information: NCT03449381 .