Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive subtype of soft tissue sarcoma, representing approximately 20% of all adult soft tissue sarcomas. Characterized by high rates of MDM2 and CDK4 amplification, DDLPS presents a significant challenge in oncology. Current treatments involve surgery for localized disease and systemic chemotherapy for advanced or metastatic cases, including agents like doxorubicin, gemcitabine, and pazopanib.
Targeting MDM2 in DDLPS
The frequent amplification of MDM2 in DDLPS, present in almost all patients, makes it an attractive therapeutic target. MDM2 is an E3 ubiquitin ligase that regulates p53, a tumor suppressor protein. Amplification of MDM2 leads to increased p53 degradation, reducing tumor suppression and promoting oncogenesis.
Brigimadlin: An MDM2-p53 Antagonist
Brigimadlin (BI 907828; Boehringer Ingelheim) is an oral MDM2-p53 antagonist designed to restore normal p53 activity by inhibiting the interaction between MDM2 and p53. This inhibition allows for normal cell cycle regulation, DNA repair, and apoptosis in cancer cells.
A Phase 1a/1b dose escalation and expansion study by LoRusso et al. evaluated brigimadlin in patients with advanced or metastatic solid tumors, including those with MDM2-amplified liposarcoma. The study established an optimal dosing schedule of 45 mg orally once every three weeks, based on a half-life of 30-60 hours. Among 41 liposarcoma patients, 75% experienced stable disease. While the drug was generally well-tolerated, nausea was a common adverse effect (74.1%), manageable with antiemetics. Grade 3 or greater adverse events occurred in 61.1% of patients, most commonly thrombocytopenia (25.9%), neutropenia (24.1%), and anemia (9.3%).
Brightline-1: A Phase 2/3 Trial
The Brightline-1 study (NCT01723020) is a Phase 2/3 trial assessing the efficacy of brigimadlin compared to single-agent doxorubicin as a first-line systemic therapy for advanced or metastatic DDLPS with MDM2 amplification. Phase 2 includes three arms: brigimadlin at 30 mg every 21 days, brigimadlin at 45 mg every 21 days, and doxorubicin at 75 mg/m2 every 21 days. The primary goal of Phase 2 is to identify the optimal brigimadlin dose.
Phase 3 will compare the selected brigimadlin dose from Phase 2 against doxorubicin at 75 mg/m2 every 21 days (maximum lifetime dose 450 mg/m2), with progression-free survival (PFS) as the primary outcome. This ongoing study is crucial in determining brigimadlin's role in DDLPS treatment.
The Pharmacist's Role
Pharmacists are integral in managing patients with DDLPS. They provide education to patients and caregivers, manage toxicity through appropriate dosing and dose adjustments, and assist in treatment selection based on tumor mutation status. For oral chemotherapies, pharmacists ensure patients meet the qualifications for use and educate them on proper medication administration and potential drug interactions.
