Reference Detail

Ref Type

Journal Article

PMID

(37269344)

Authors

LoRusso P, Yamamoto N, Patel MR, Laurie SA, Bauer TM, Geng J, Davenport T, Teufel M, Li J, Lahmar M, Gounder MM

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	13	8	2023 Aug 04	1802-1813	Cancer Discov

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MDM2 amp TP53 wild-type	Advanced Solid Tumor	predicted - sensitive	BI 907828	Phase I	Actionable	In a Phase I trial, BI 907828 treatment demonstrated safety and efficacy in patients with advanced solid tumors, resulting in a median progression-free survival of 8.1 months and an overall response rate of 11.1% (6/54, all partial responses (PR), 4 well-differentiated liposarcoma, 1 intrahepatic cholangiocarcinoma, 1 pancreatic cancer), with all PRs occurring in patients harboring an MDM2 amplification (PMID: 37269344; NCT03449381).	37269344
MDM2 amp TP53 wild-type	dedifferentiated liposarcoma	predicted - sensitive	BI 907828	Phase I	Actionable	In a Phase I trial, BI 907828 treatment demonstrated activity in patients with TP53 wild-type, MDM2-amplified dedifferentiated liposarcoma, resulting in a disease control rate (DCR) of 75% (9/12, all stable disease) and progression-free survival (PFS) ranging from 1.5 to 22 months, with PFS greater than 10.5 months in 41.6% (5/12) of patients (PMID: 37269344; NCT03449381).	37269344
MDM2 amp TP53 wild-type	well-differentiated liposarcoma	predicted - sensitive	BI 907828	Phase I	Actionable	In a Phase I trial, BI 907828 treatment demonstrated activity in patients with TP53 wild-type, MDM2-amplified well-differentiated liposarcoma, resulting in a disease control rate of 100%, (7/7, 4 partial responses of at least 12 months, 3 stable disease), and a progression-free survival (PFS) of greater than 7.5 months, with a PFS of at least 14 months or more in 5 patients (PMID: 37269344; NCT03449381).	37269344