Abstract
PATIENTS AND METHODS
Patients with MDM2-amplified, locally advanced or metastatic, unresectable, progressive, or recurrent DDLPS were eligible. In phase II, patients received oral brigimadlin 30 or 45 mg or intravenous doxorubicin 75 mg/m2 (all once every 3 weeks). Following a preplanned analysis, in phase III patients received brigimadlin 45 mg or doxorubicin 75 mg/m2. The primary endpoint was progression-free survival (PFS) by blinded central independent review.
CONCLUSIONS
Although brigimadlin showed activity in this patient population, the median PFS with doxorubicin was substantially longer than anticipated, and the primary endpoint of PFS was not met. The safety profile of brigimadlin also did not seem to be more manageable than that of doxorubicin. The translational results will guide future clinical investigations of MDM2-p53 antagonists. See related commentary by Shahnam and Gounder, p. 4511.
RESULTS
Between April 13, 2022, and August 22, 2023, 148 patients received brigimadlin 45 mg, and 162 received doxorubicin. At data cutoff, the median PFS was 8.4 months with brigimadlin versus 7.2 months with doxorubicin (hazard ratio, 0.79; 95% confidence interval, 0.6-1.06; P = 0.096); the primary endpoint was not met. The confirmed objective response rate was 22.3% with brigimadlin and 8.6% with doxorubicin. The most common grade ≥3 adverse events with brigimadlin were neutropenia (n = 54, 36.7%) and thrombocytopenia (n = 41, 27.9%). Translational analysis demonstrated that brigimadlin activated the TP53 pathway, but no biomarkers predictive of efficacy were identified.
PURPOSE
The phase II/III Brightline-1 trial (NCT05218499) assessed the mouse double minute 2 homolog (MDM2)-p53 antagonist brigimadlin versus standard-of-care doxorubicin as first-line treatment for MDM2-amplified, locally advanced/metastatic dedifferentiated liposarcoma (DDLPS).