Treatment of patients with dedifferentiated liposarcoma (DDLPS) with the MDM2–p53 antagonist brigimadlin and p53 function: A longitudinal analysis of circulating microRNAs (miRNAs) in a first-in-human phase Ia/Ib study.
Authors: Peltzer Alexander , LoRusso Patricia , Gounder Mrinal M. , Yamamoto Noboru , Somaiah Neeta , Lugowska Iwona A. , Moreno Victor , Teufel Michael , Jayadeva Girish , Hesse Raphael , Sturm Gregor , Schöffski Patrick 
Published: June 2024

11540

Background: The tumor suppressor and transcription factor p53 mainly exerts its function through transcriptional regulation of many target genes, including those involved in the biogenesis of some miRNAs. Brigimadlin (BI 907828) is a highly potent, oral MDM2–p53 antagonist under investigation in an ongoing Phase Ia/b study (NCT03449381) in patients with advanced solid tumors, including DDLPS. Here, we present data from a longitudinal analysis of miRNAs isolated from the plasma of patients with advanced DDLPS treated with brigimadlin in the Phase Ib part of the study. The aim of this analysis was to identify whether baseline miRNA expression and/or longitudinal changes in miRNA may be associated with response to brigimadlin in patients with DDLPS or used as surrogate pharmacodynamic markers. Methods: In Phase Ib, patients received brigimadlin once every 3 weeks; all patients had MDM2-amplified, TP53 wild-type disease. Plasma samples for miRNA analysis were taken longitudinally from patients at baseline and every cycle until the time of the last available sample (LAS). miRNA was purified from plasma and analysed using miRNA-specific next-generation sequencing (NGS; Qiagen QiaSeq on an Illumina NovaSeq sequencer) to identify changes in miRNA expression that may be relevant to describe the mode of action of brigimadlin. Samples with fewer than 200 detected miRNAs were excluded. Analyzed samples contained at least 1% miRNA as a percentage of total RNA content, established as a cut-off on other plasma evaluation samples. Differential miRNA analysis was performed using a linear model; additional predictive analysis was performed with a Cox hazard ratio model. Results: Plasma samples for miRNA analysis were available from 51 patients with DDLPS. For this analysis, baseline plasma samples were available from 26 patients, and samples collected at Cycle 3 or LAS were available from 24 patients. Differential expression analysis revealed that several cancer-related miRNAs, known to regulate p53/p53-related mRNAs, were significantly downregulated upon brigimadlin treatment compared to baseline; specifically, levels of hsa-miR-6131, hsa-miR-92b-3p, hsa-miR-490-5p, hsa-miR-5004-3p, and hsa-miR-548ar-5p were all downregulated. Baseline miRNA profiles that correlated with time on treatment and efficacy of brigimadlin will be presented. Conclusions: We present a comprehensive assessment of a longitudinal miRNA analysis by NGS from samples collected from patients treated with the MDM2–p53 antagonist brigimadlin. These data suggest that restoration of p53 function by brigimadlin may be achieved in patients with DDLPS. A further deconvolution of the analysis results with additional data is underway. Clinical trial information: NCT03449381 .