PublishedOctober 15, 2026
JournalClinical Cancer Research
TrialBrightline-1 (open-label, randomized phase II/III), NCT05218499

Brigimadlin Fails to Significantly Improve Progression-Free Survival Over Doxorubicin in Advanced Dedifferentiated Liposarcoma: Phase II/III Brightline-1 Trial

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Article Summary
  • Brightline-1 randomized patients with MDM2-amplified advanced dedifferentiated liposarcoma to the oral MDM2–p53 antagonist brigimadlin 45 mg or doxorubicin 75 mg/m² every 3 weeks. The primary endpoint, progression-free survival (PFS) by blinded independent central review, was not met: median PFS was 8.4 versus 7.2 months (HR, 0.79; 95% CI, 0.6–1.06; P = 0.0956).
  • Confirmed objective response was 22.3% versus 8.6%, but response and investigator-assessed PFS could not be formally tested under the hierarchical design. Grade ≥3 adverse events occurred in 66.7% versus 61.7%, and adverse events led to discontinuation in 22.4% versus 5.8%. Overall survival data were immature.

Why This Study Matters

Dedifferentiated liposarcoma (DDLPS) is a rare soft tissue sarcoma that accounts for approximately 15% to 20% of liposarcomas and is associated with high rates of local and metastatic recurrence. For nearly five decades, intravenous doxorubicin-based chemotherapy has been the standard-of-care first-line treatment for advanced, unresectable disease. Almost all DDLPS have amplification of MDM2, which suppresses the tumor suppressor p53. Brigimadlin is an oral MDM2–p53 antagonist; in a phase Ia/Ib trial in pretreated patients, 16 of 86 patients with DDLPS (19%) had a complete or partial response and preliminary median PFS was 8.1 months. Brightline-1 tested whether this activity would translate into a first-line advantage over doxorubicin.

1
Primary endpoint not met. Median PFS by blinded independent central review was 8.4 vs 7.2 months (HR, 0.79; 95% CI, 0.6–1.06; P = 0.0956).
2
Higher response rate, not formally tested. Confirmed objective response rate was 22.3% (33 patients) with brigimadlin versus 8.6% (14 patients) with doxorubicin (odds ratio, 2.93; 95% CI, 1.52–5.67).
3
Disease control rate: 86.5% versus 72.2%.
4
Safety: grade ≥3 adverse events in 66.7% versus 61.7%; discontinuation due to adverse events in 22.4% versus 5.8%.
5
Strong comparator. Median PFS with doxorubicin (7.2 months) was substantially longer than the 2–4 months suggested by earlier retrospective data.

Study Design

Brightline-1 was a multinational, open-label, randomized phase II/III trial. In phase II, patients were randomized 1:1:1 to brigimadlin 30 mg, brigimadlin 45 mg, or intravenous doxorubicin 75 mg/m², all every 3 weeks. After a preplanned dose-selection analysis, brigimadlin 45 mg every 3 weeks was carried forward; in phase III patients were randomized 1:1 to brigimadlin 45 mg or doxorubicin 75 mg/m². Randomization was stratified by extent of disease (locally advanced vs metastatic). Doxorubicin was given up to a maximum cumulative dose of 450 mg/m², and patients in the doxorubicin arm could cross over to brigimadlin after centrally confirmed progression.

Trial at a glance

400 patients enrolled; 148 (brigimadlin 45 mg) versus 162 (doxorubicin) analyzed; 107 sites in 21 countries; randomization 1:1:1 (phase II) then 1:1 (phase III); brigimadlin 45 mg and doxorubicin 75 mg/m² every 3 weeks.

Patient Population

Eligible adults had histologically proven, MDM2-amplified, locally advanced or metastatic, unresectable, progressive, or recurrent DDLPS, at least one RECIST 1.1 measurable lesion, ECOG performance status 0 or 1, and no prior systemic or anthracycline-based treatment. Enrollment ran from April 13, 2022 to August 22, 2023. In the analyzed groups, median age was 65.5 years (brigimadlin) and 65 years (doxorubicin); 69.6% and 64.2% of patients, respectively, had metastatic disease; MDM2 amplification was centrally confirmed by FISH in 140 (94.6%) and 145 (89.5%) patients. Data cutoff was May 17, 2024.

Primary Endpoint Results

The primary endpoint was PFS by blinded independent central review. With 86 and 103 events in the brigimadlin and doxorubicin groups, median PFS was 8.4 months versus 7.2 months (HR, 0.79; 95% CI, 0.6–1.06; P = 0.0956). The median time to PFS censoring was 10.6 months (95% CI, 8.5–13.6) and 10.9 months (95% CI, 8.7–12.7). By investigator review, median PFS was 9.4 months versus 7.2 months (HR, 0.69; 95% CI, 0.51–0.93); because of the per-protocol hierarchical ranking of endpoints, investigator-assessed PFS and response could not be formally tested. Overall survival data were immature (41 and 44 events).

The median PFS with doxorubicin was substantially longer than anticipated when the trial was designed.
— Schöffski et al., Discussion, Clin Cancer Res 2026
Endpoint (intent-to-treat)Brigimadlin 45 mg (N = 148)Doxorubicin (N = 162)
Median PFS, central review8.4 months7.2 months
Confirmed objective response33 (22.3%)14 (8.6%)
Disease control rate86.5%72.2%
Median duration of response9.9 months (95% CI, 9.72–not evaluable)10.0 months (95% CI, 9.9–15.4)
Median total exposure4.9 months (range, 0.03–19.6)3.5 months (range, 0.03–6.1)

Subgroup and Exploratory Analyses

PFS across predefined subgroups is presented only as a forest plot (Figure 2B) in the source; subgroup-level hazard ratios are not specified in the text and are therefore not reproduced here. The text reports the following exploratory results.

AnalysisResult (as reported)
Doxorubicin-arm patients who crossed over to brigimadlin (n = 77)Median PFS 5.3 months by central review
MDM2 copy number (high vs low) and PFS, brigimadlin armHR, 1.0347; 95% CI, 0.9665–1.1077; adjusted P = 0.372
MDM2 copy number (top vs bottom 33%) and PFS, doxorubicin armHR, 1.1026; 95% CI, 1.0205–1.1913; adjusted P = 0.0133
Baseline TP53, JAK-STAT, EGFR pathway activity (brigimadlin arm)Associated with prolonged PFS; high PI3K and MAPK activity associated with shorter PFS (Figure 4A)
PharmacodynamicsSignificant (>2-fold) upregulation of TP53-regulated genes including MDM2, CDKN1A, BBC3, BAX and GDF15; PROGENy p53 pathway activity 25-fold vs 2.3-fold with doxorubicin
Predictive biomarkersNo biomarkers predictive of efficacy were identified

Safety Profile

Safety populations were 147 (brigimadlin) and 154 (doxorubicin). Any-grade adverse events occurred in 99.3% and 99.4%. Hematologic toxicity dominated with brigimadlin: grade 3/4 neutropenia in 54 patients (36.7%) and thrombocytopenia in 41 (27.9%); six patients (4.1%) had grade ≥3 thrombocytopenia with hemorrhage, and 17 (11.6%) received platelet transfusions. One case of febrile neutropenia (grade 3) was reported with no neutropenic sepsis. No cases of myelodysplastic syndrome or leukemia were reported, although follow-up was relatively short. There were three on-study deaths: one assisted suicide and one cerebral infarction (brigimadlin) and one disease progression (doxorubicin).

Adverse event, n (%)Brigimadlin (N = 147)Doxorubicin (N = 154)
Any grade ≥3 AE98 (66.7)95 (61.7)
Any serious AE57 (38.8)42 (27.3)
AE leading to dose reduction71 (48.3)52 (33.8)
AE leading to discontinuation33 (22.4)9 (5.8)
Neutropenia: any grade / grade 3–487 (59.2) / 54 (36.7)84 (54.5) / 70 (45.5)
Thrombocytopenia: any grade / grade 3–483 (56.5) / 41 (27.9)24 (15.6) / 7 (4.5)
Nausea: any grade / grade 3–4112 (76.2) / 3 (2)90 (58.4) / 1 (0.6)
Fatigue: any grade / grade 3–4111 (75.5) / 13 (8.8)104 (67.5) / 12 (7.8)
Anemia: any grade / grade 3–453 (36.1) / 19 (12.9)63 (40.9) / 18 (11.7)
Leukopenia: any grade / grade 3–435 (23.8) / 20 (13.6)41 (26.6) / 25 (16.2)
Alopecia: any grade / grade 3–432 (21.8) / 067 (43.5) / 1 (0.6)

Interpretation and Broader Context

The authors conclude that although brigimadlin showed activity, the primary endpoint was not met, and that the safety profile of brigimadlin did not seem to be more manageable than that of doxorubicin. They note that the doxorubicin median PFS of 7.2 months "represents a new benchmark" relative to historical retrospective estimates of 2 to 4 months, offer possible explanations (earlier treatment start than in routine practice, inclusion of patients with progressive disease after prior nonsystemic therapy, and variable well-differentiated and dedifferentiated tumor components), and point out that the phase III MANTRA study of milademetan as second-line treatment (NCT04979442) also failed to meet its primary endpoint. Patient-reported quality-of-life data showed a consistent trend favoring brigimadlin across EORTC QLQ-C30 domains analyzed. Translational results, according to the authors, "will guide future clinical investigations of MDM2-p53 antagonists," and further optimization of dose and schedule may be important.

Limitations

Limitations noted in the source: overall survival data were immature at cutoff; response and investigator-assessed PFS were not formally testable because of the hierarchical endpoint ranking; follow-up for long-term hematologic safety was short. The trial was open-label, and the source does not specify subgroup-level hazard ratios in the text.

Trial registration

Primary source: DOI 10.1158/1078-0432.CCR-26-0509 · PubMed 42268294 · PMC13669732

References

  1. Schöffski P, Sanfilippo R, Martín-Broto J, Kawai A, Desai J, LoRusso P, et al. Brigimadlin versus Doxorubicin in Advanced Dedifferentiated Liposarcoma: Efficacy, Safety, and Translational Data from Brightline-1, a Randomized Phase II/III Trial. Clin Cancer Res. 2026;32:4538–51. DOI: 10.1158/1078-0432.CCR-26-0509. PMID: 42268294.
  2. ClinicalTrials.gov: NCT05218499 (Brightline-1). Funding: Boehringer Ingelheim.