Brigimadlin: A Novel MDM2-Targeted Therapy for Dedifferentiated Liposarcoma

Liposarcomas are rare mesenchymal tumors that arise from lipocytes in soft tissues. These neoplasms can be divided into 5 histological subtypes, with well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) being the most common in the United States. WDLPS are low grade tumors that typically exhibit an indolent clinical course, while DDLPS are higher grade and have a more aggressive phenotype. Since they frequently coexist with one another, WDLPS and DDLPS often share several genetic and histological features.¹ For patients with advanced or metastatic DDLPS, standard treatment includes anthracycline based chemotherapy, which typically produces low objective response rates (ORRs), thus necessitating further treatment options for this patient population.²

Liposarcoma, or soft tissue sarcoma, under a microscope. Image Credit: © Dr_Microbe - stock.adobe.com

MDM2 is amplified in over 90% of WDLPS and DDLPS cases. MDM2 is an E3 ubiquitin ligase that targets the tumor suppressor p53 for proteasomal degradation. There have been several attempts to target MDM2 for advanced solid tumors, but early phase trials have demonstrated limited success. Given the lack of biomarker driven therapeutic options for DDLPS, MDM2 remains an attractive target for patients with advanced or metastatic disease.³

Brigimadlin (BI 907828; Boehringer Ingelheim) is a highly potent oral MDM2-p53 antagonist that has been studied in a phase 1a dose escalation trial. A total of 54 patients with any solid tumor were enrolled, with 29 receiving brigimadlin 10 mg to 80 mg on day 1 of a 21-day cycle (D1 q3w) and 25 receiving brigmadlin 5 mg to 60 mg on days 1 and 8 of a 28-day cycle (D1D8 q4w). The most common tumor type was soft tissue sarcoma (n=46.3%), with 22.2% and 13.0% having DDLPS and WDLPS, respectively. Patients had a median of 2 (range 0-11) prior lines of therapy, and 51.9% of patients had confirmed MDM2 amplification by central assessment.

Safety analysis revealed that all 54 patients had any treatment related adverse event (TRAE), with 61.1% being grade 3 or higher. The most common all grade TRAEs included nausea (74.1%), vomiting (51.9%), fatigue (46.3%) and thrombocytopenia (44.4%). The most common grade 3 or higher TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%), with grade 3 or higher events occurring in 58.6% of the D1 q3w dosing group and 32% of the D1D8 q4W dosing group. From the entire study population, a total of 19 patients required a dose reduction with the most common reasons being neutropenia, thrombocytopenia, and nausea.

Antitumor activity was evaluated, and the ORR was 11.1% for the total patient population (13.8% in the D1 q3W dosing group and 8.0% in D1D8 q4w dosing group) all of which were partial responses (PRs) with 0 patients achieving a complete response (CR). Stable disease occurred in 63% of all evaluable patients, which corresponded to a disease control rate (DCR) of 74.1%. In the preliminary analysis, median progression-free survival (mPFS) was 8.1 months overall; the mPFS in the D1 q3w group was 10.6 months and 8.0 months in the D1D8 q4w group.³

A recent abstract further elucidated the safety and efficacy of brigimadlin in patients with MDM2 amplified, TP53 wildtype (WT) DDLPS in a phase 1b dose escalation study. The results from the phase 1a dose escalation trial established the dose for the expansion to be 45 mg D1 q3w. In 90 patients with DDLPs who received brigimadlin 45 mg q3w, the mPFs was 8.1 months. The ORR was 18.6% (14 PRs and 1 CR) and the DCR was 88.4%. Similar to the phase 1a dose escalation study, the most common TRAEs were nausea (75.0%), fatigue (61.9%), and neutropenia (53.6%), with the most common grade 3 or higher TRAEs being thrombocytopenia (22.6%), neutropenia (22.6%), and anemia (9.5%).⁴

Key Considerations for Pharmacists

Brigimadlin is a promising therapeutic option for DDLPS’s that harbor MDM2 amplifications with WT TP53. The FDA provided fast track designation for the investigation of brigimadlin in DDLPS due to the lack of therapeutic options for these patients.4 While preliminary data shows the efficacy of this agent, important safety concerns should be addressed with prospective patients.

The incidence of all grade nausea with brigimadlin was approximately 75%, with all grade vomiting reaching 51.9% in the phase 1a trial, indicating patients may need aggressive antiemetic therapy.³ Patients should pre-medicate with a 5-HT3 receptor antagonist prior to administration of brigimadlin and continue to take these agents as needed. Additional antiemetics, such as Neurokinin-1 antagonists, phenothiazines, or olanzapine (Zyprexa; Cheplapharm) may be warranted, with appropriate scheduling to avoid excessive dosing of each agent.

A high proportion of patients experienced hematologic toxicity in both the phase 1a and 1b trials, with grade 3 or higher thrombocytopenia and neutropenia occurring in approximately 25% of the total population. Patients should be evaluated for dose reductions/interruptions for high grade hematologic toxicities when taking brigimadlin. Granulocyte colony stimulating factor has classically been utilized to prevent/treat chemotherapy induced neutropenia and can be considered for patients with high grade neutropenia. The use of thrombopoietin receptor agonists can be considered for patients with chemotherapy induced thrombocytopenia, although their utility in MDM2-inhibitor induced thrombocytopenia remains controversial.⁵ Lastly, concomitant use of anticoagulation should be assessed for patients who experience grade 3 or higher thrombocytopenia, with holding parameters being enacted for each agent.

REFERENCES

1. Somaiah N, Tap W. MDM2-p53 in liposarcoma: The need for targeted therapies with novel mechanisms of action. Cancer Treat Rev. 2024;122:102668.
2. Zhu H, Gao H, Ji Y, Qin Z, Du Z et al. Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials. J Hematol Oncol. 2022;15(1):91.
3. LoRusso P, Yamamoto N, Patel MR, et al. The mdm2-p53 antagonist brigimadlin (BI 907828) in patients with advanced or metastatic solid tumors: results of a phase ia, first-in-human, dose-escalation study. Cancer Discov. 2023;13(8):1802-1813.
4. Schöffski P, Lorusso P, Yamamoto N, et al. 56O A phase Ia/Ib study of the MDM2-p53 antagonist brigimadlin (BI 907828): Safety and efficacy in patients with dedifferentiated liposarcom. ESMO Open. 2024;9.
5. DeMatteo R, Sgroe E, Merrill M, Gounder M, Liu D. 674P Response of thrombopoietin receptor agonists in MDM2 inhibitor induced thrombocytopenia. Ann Oncol. 2023;34,S473.