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Targeting the MDM2–p53 interaction represents a potential therapeutic option in liposarcoma. In an earlier analysis of this phase Ia/Ib study (NCT03449381), brigimadlin, a highly potent, orally available MDM2–p53 antagonist showed promising safety and efficacy in patients (pts) with advanced solid tumours including DDLPS. Here we focus on safety and efficacy in pts with DDLPS. In the phase Ia dose escalation, the recommended dose for expansion was defined as 45 mg on Day 1 of 21-day cycles (q3w; LoRusso et al., Cancer Discovery, 2023). Phase Ib included two cohorts: Cohort 1 (TP53wt, MDM2-amplified advanced sarcoma) and Cohort 2 (other TP53wt, MDM2-amplified advanced solid tumours); both cohorts received brigimadlin q3w. In phase Ib, the primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and grade ≥3 treatment-related adverse events (TRAEs). As of 7 November 2023, 190 pts have been enrolled across phase Ia/Ib to receive brigimadlin q3w (52.6% male; 80.0% white; 55.8%/43.7% ECOG PS 0/1; median 2 prior lines of therapy). In 90 pts with DDLPS who received brigimadlin q3w, median PFS was 8.1 months. In 86 response-evaluable pts, one complete response and 15 partial responses were observed (ORR: 18.6%), and a best response of stable disease was observed in 60 pts (disease control rate: 88.4%). In pts with DDLPS treated in phase Ib (n=84), any-grade TRAEs were reported in 78 (92.9%) pts, most commonly nausea (n=63, 75.0%), fatigue (n=52, 61.9%) and neutropenia (n=45, 53.6%). Grade ≥3 TRAEs were reported in 36 (42.9%) pts, most commonly thrombocytopenia (n=19, 22.6%), neutropenia (n=19, 22.6%) and anaemia (n=8, 9.5%). Adverse events leading to treatment discontinuation occurred in 4 (4.8%) pts. An analysis of radiomic features of tumours will be presented. Brigimadlin q3w demonstrated manageable toxicity and encouraging efficacy with a high rate of disease control in DDLPS pts. Brigimadlin is being evaluated versus doxorubicin as first-line treatment for pts with advanced DDLPS in the phase II/III Brightline-1 study (NCT05218499), for which the FDA has granted a Fast Track Designation.
Schöffski et al. (Fri,) studied this question.