61MO Phase Ia/Ib study of the MDM2-p53 antagonist brigimadlin (BI 907828) in advanced solid tumours: Overall safety, and efficacy in patients (pts) with well-differentiated liposarcoma (WDLPS)

Disruption of cell cycle arrest and apoptosis by inactivation of p53 is a key tumour survival and proliferation mechanism and can occur via MDM2 amplification. Thus, inhibiting MDM2 may restore p53 activity in TP53 wild-type tumours. Brigimadlin (BI 907828) is a highly potent, oral MDM2–p53 antagonist that has shown promising preclinical antitumour activity. This phase I study is assessing brigimadlin monotherapy in pts with advanced solid tumours, including WDLPS. Here we report safety data in all pts who received brigimadlin on Day 1 of 21-day cycles (q3w) and updated efficacy data in those with WDLPS. In phase Ia, pts received escalating doses of brigimadlin and the recommended dose for expansion was defined as 45 mg q3w (LoRusso et al., Cancer Discovery, 2023). In phase Ib (dose expansion), pts were enrolled to Cohort 1 (TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). The primary endpoint for phase Ib was progression-free survival (PFS); secondary endpoints included objective response, disease control rate, and grade ≥3 treatment-related adverse events (TRAEs). As of 7 Nov 2023, 217 pts had been enrolled. Of these, 190 pts received brigimadlin q3w: the median age was 61 years (19–83 years); 52.6% were male; and 55.8%/43.7% had an ECOG performance score of 0/1. Among these 190 pts, 169 (88.9%) had a TRAE, the most common being nausea (69.5%) and fatigue (54.2%). The most common grade ≥3 TRAEs were neutropenia (27.4%) and thrombocytopenia (23.7%). Seventy pts (36.8%) experienced an adverse event that led to dose reduction, and 11 pts (5.8%) discontinued treatment due to an adverse event. Of the 190 pts who received brigimadlin q3w, 31 had MDM2-amplified WDLPS, of whom 20 were response-evaluable: 3/20 pts (15%) had a confirmed partial response and 16/20 (80%) had stable disease, giving a disease control rate of 95% (19/20). The preliminary median PFS was 25.1 months. Brigimadlin administered q3w demonstrated a manageable safety profile and encouraging preliminary efficacy in pts with advanced, MDM2-amplified WDLPS.