Brigimadlin versus Doxorubicin in Advanced Dedifferentiated Liposarcoma: Efficacy, Safety, and Translational Data
Patrick Schöffski1,2, Roberta Sanfilippo3, Javier Martín-Broto4,5,6
1Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
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).
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.
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.
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.
Insights
Brigimadlin did not meet its primary endpoint in treating dedifferentiated liposarcoma (DDLPS), showing similar progression-free survival (PFS) to doxorubicin. Further research is needed for MDM2-p53 antagonists in DDLPS treatment.
Area of Science:
- Oncology
- Medical Genetics
- Pharmacology
Background:
- Dedifferentiated liposarcoma (DDLPS) is a rare soft tissue sarcoma.
- MDM2 amplification is a key driver in a subset of DDLPS.
- Targeting the MDM2-p53 interaction is a therapeutic strategy for MDM2-amplified cancers.
Purpose of the Study:
- To evaluate brigimadlin, an MDM2-p53 antagonist, versus doxorubicin as first-line therapy for MDM2-amplified DDLPS.
- To assess progression-free survival (PFS) as the primary endpoint in the Brightline-1 trial.
Main Methods:
- Phase 2/3 randomized controlled trial (Brightline-1, NCT05218499).
- Patients with unresectable, locally advanced/metastatic, progressive DDLPS with MDM2 amplification were enrolled.
- Brigimadlin (45 mg) was compared against doxorubicin (75 mg/m2) every 3 weeks.
Main Results:
- Median PFS was 8.4 months for brigimadlin versus 7.2 months for doxorubicin (HR 0.79, P=0.096), not meeting the primary endpoint.
- Objective response rate was higher with brigimadlin (22.3%) compared to doxorubicin (8.6%).
- Common grade ≥3 adverse events for brigimadlin included neutropenia and thrombocytopenia.
Conclusions:
- Brigimadlin demonstrated activity but did not significantly improve PFS over doxorubicin in this setting.
- The safety profile of brigimadlin was comparable to doxorubicin.
- Translational findings will inform future development of MDM2-p53 antagonists.