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

• Published in: Cancer discovery 2023-08, Vol.13 (8), p.1802-1813
• Main Authors: LoRusso, Patricia, Yamamoto, Noboru, Patel, Manish R, Laurie, Scott A, Bauer, Todd M, Geng, Junxian, Davenport, Teffany, Teufel, Michael, Li, Jian, Lahmar, Mehdi, Gounder, Mrinal M
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Humans; Liposarcoma - chemically induced; Liposarcoma - drug therapy; Nausea - chemically induced; Neoplasms - drug therapy; Neoplasms - pathology; Neoplasms, Second Primary - chemically induced; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53 - genetics
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-23-0153

Brigimadlin (BI 907828) is an oral MDM2-p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively). We report phase Ia data indicating that the oral MDM2-p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.