Brigimadlin (MDM2–p53 antagonist) Misses PFS Endpoint vs Doxorubicin in 1L DDLPS, Despite Higher ORR

Brigimadlin (BI 907828) is an oral small-molecule MDM2 inhibitor that disrupts MDM2–p53 binding to reactivate TP53 signaling, and was tested against standard first-line doxorubicin in Brightline-1 (randomized Phase 2/3; NCT05218499) for MDM2-amplified, unresectable locally advanced/metastatic dedifferentiated liposarcoma (DDLPS). In the Phase 3 dose cohort, 148 patients received brigimadlin 45mg Q3W and 162 received doxorubicin 75mg/m² Q3W; blinded central review median PFS was 8.4 vs 7.2 months (HR 0.79, 95% CI 0.60–1.06; p=0.096), so the primary endpoint was not met even though confirmed ORR was 22.3% vs 8.6% (a higher response rate than typically expected with doxorubicin in many STS contexts). Grade ≥3 neutropenia (36.7%) and thrombocytopenia (27.9%) were the most common severe AEs with brigimadlin—consistent with on-target/class hematologic toxicity for MDM2 inhibitors—while translational work confirmed TP53 pathway activation but did not identify biomarkers predictive of efficacy.