How Pharmacists Can Make an Impact When Treating Dedifferentiated Liposarcoma With Brigimadlin

Sarcoma is a rare form of bone and soft tissue cancer, making up approximately 1% of all adult cancers. Liposarcoma is one of the most common subtypes of soft tissue sarcoma (STS) accounting for approximately 20% of adult STS.¹ Liposarcoma can be further differentiated into well-differentiated liposarcoma, dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma, and pleomorphic liposarcoma.¹ DDLPS is an intermediate to high-grade sarcoma with an incidence of less than 0.1 per 1,000,000 each year. Current treatment of localized DDLPS includes surgery, while systemic chemotherapy continues to be the mainstay of therapy for advanced and metastatic disease. Current treatment options include doxorubicin, doxorubicin with ifosfamide (Ifex; Hikma Pharmaceuticals USA Inc), gemcitabine with docetaxel, trabectedin (Yondelis; Johnson & Johnson Innovative Medicine and Pharma Mar SA), eribulin (Halaven; Eisai Co), pazopanib (Votrient; Novartis), or palbociclib (Ibrance; Pfizer).¹

Liposarcoma under a microscope. Image Credit: © Dr_Microbe - stock.adobe.com

DDLPS is characterized by high rates of amplification of MDM2 and CDK4. MDM2 amplification is present in almost 100% of DDLPS patients. MDM2 is an E3 ubiquitin ligase responsible for regulating p53.¹ Amplification of MDM2 leads to increased p53 degradation causing decreased tumor suppression and increased oncogenesis.¹ Due to the high rates of MDM2 amplification and its role in increased oncogenesis, MDM2 is an ideal drug target for DDLS.

Brigimadlin (BI 907828; Boehringer Ingelheim) is an oral MDM2-p53 antagonist that restores normal p53 activity by inhibiting the interaction between MDM2 and p53. This allows for normal cell cycle regulation, DNA repair, and apoptosis. LoRusso et al completed a phase 1a/1b dose escalation and expansion study in patients with solid tumors, including MDM2 amplified advanced and metastatic liposarcoma.² Part a of the study confirmed that brigimadlin has a long half-life (30-60 hours) with an optimal dosing schedule of 45 mg orally once every 3 weeks. Forty-one patients with liposarcoma were included in the study, and it was found that 75% of patients had stable disease.² For patients who received the optimal dosing schedule, brigimadlin was generally well tolerated with nausea being the most common adverse effect (AE) at 74.1%. This was easily managed with antiemetic medications. Of note, 61.1% of patients experienced grade 3 or greater AEs, and most commonly thrombocytopenia (25.9%), neutropenia (24.1%), and anemia (9.3%).² Thephase 1b study is ongoing.

The Brightline-1 study (NCT01723020) is a phase 2/3 trial evaluating the efficacy of brigimadlin compared to single agent doxorubicin as first-line systemic therapy for advance or metastatic DDLPS with positive MDM2 by fluorescence in situ hybridization or MDM2 amplification.³ Phase 2 of the study has 3 arms: brigimadlin at 30 mg every 21 days, brigimadlin at 45 mg every 21 days, and doxorubicin at 75 mg/m² every 21 days, with the primary goal being the identification of the optimal brigimadlin dose.3 The phase 3 portion of the trial will have 2 arms, the selected brigimadlin dose from phase 2 and doxorubicin 75 mg/m² every 21 days (max lifetime dose 450 mg/m²) with a primary outcome of progression free survival (PFS).³ This study is ongoing, and the results will be essential in determining brigimadlin’s place in therapy.

Pharmacists can play an integral role in the management of patients with DDLPS. For patients receiving treatment, pharmacists can provide education to both patients and caregivers. Additionally, they can help manage toxicity by ensuring appropriately dosed regimens and dose reductions based on lab values and patient specific AEs. At time of disease progression, pharmacists can assist the medical team with treatment choices and sequencing based on patient needs. For patients on oral chemotherapy, pharmacists can confirm each patient meets the qualifications for use based on tumor mutation status. Pharmacists can also educate patients on how to take oral medications, potential drug interaction with medications or food, and ensure patients know what to do if they miss a dose. Overall, pharmacists are a valuable part of the medical team as patients face complex diagnoses and treatment.

REFERENCES

1. Zhou MY, Bui NQ, Charville GW, Ganjoo KN, Pan M. Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy. Int J Mol Sci. 2023;24(11):9571. doi:10.3390/ijms24119571

2. 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. doi:10.1158/2159-8290.CD-23-0153

3. Schöffski P, Lahmar M, Lucarelli A, Maki RG. Brightline-1: phase II/III trial of the MDM2-p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS. Future Oncol. 2023;19(9):621-629. doi:10.2217/fon-2022-1291