brigimadlin (BI 907828)

P1, N=28, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P2, N=100, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

Real-world evidence in our Caucasian patient population confirmed that a significant number of intrahepatic CCAs showcase MDM2 amplification, qualifying for a personalized therapy option with Brigimadlin. MDM2 amplification must therefore be considered in the context of personalized molecular testing in CCA.

P1, N=34, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Aug 2025 --> Feb 2025

P1, N=267, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P2, N=50, Not yet recruiting, Boehringer Ingelheim

P2, N=103, Recruiting, Boehringer Ingelheim | N=155 --> 103

Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in cancer patients who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.

P3, N=240, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P1, N=28, Recruiting, Boehringer Ingelheim | Trial completion date: Dec 2027 --> Dec 2026 | Trial primary completion date: Nov 2027 --> Nov 2026

P3, N=0, Withdrawn, Boehringer Ingelheim | N=263 --> 0 | Not yet recruiting --> Withdrawn

P2, N=155, Recruiting, Boehringer Ingelheim | Trial completion date: Mar 2027 --> Nov 2026 | Trial primary completion date: Jun 2025 --> Feb 2025

P1, N=32, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

MDM2/MDMX are important negative regulators of the tumor suppressor p53 and provide an additional target in BTC (∼5-8% of tumors are MDM2-amplified). Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown antitumor activity in preclinical studies and promising results in early clinical trials; enrollment is ongoing in a potential registrational trial for patients with BTC.

P2, N=155, Recruiting, Boehringer Ingelheim | Trial primary completion date: Feb 2025 --> Jun 2025

P1, N=13, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P1, N=119, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P3, N=263, Not yet recruiting, Boehringer Ingelheim

P3, N=240, Recruiting, Boehringer Ingelheim | Initiation date: Mar 2023 --> Dec 2023

P3, N=240, Recruiting, Boehringer Ingelheim | Initiation date: Dec 2023 --> Mar 2023

P1, N=140, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1

Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.

P3, N=240, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P2, N=155, Recruiting, Boehringer Ingelheim | Phase classification: P2a/2b --> P2

P1, N=269, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1 | N=204 --> 269

P1, N=16, Recruiting, Boehringer Ingelheim | Trial primary completion date: Feb 2024 --> May 2024

"Burning Rock Biotech Limited...is pleased to announce that the Company and Boehringer Ingelheim officially have signed the Master Service Agreement (MSA) in the field of oncology companion diagnostics. This agreement aims to provide Chinese patients with safer, more efficient, and precise treatment options and diagnostic methods, thereby promoting innovation and development in cancer treatment. This partnership will primarily focus on advancing the clinical trials related to Boehringer Ingelheim's MDM2-p53 antagonist, brigimadlin (BI 907828), and the development of companion diagnostic products in China."

P2, N=120, Not yet recruiting, Institut Bergonié

These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.

P3, N=240, Not yet recruiting, Boehringer Ingelheim

P2/3, N=386, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P1, N=32, Recruiting, Boehringer Ingelheim | N=16 --> 32 | Trial primary completion date: Aug 2023 --> Aug 2024

This mutation analysis represents one of the most robust assessments of longitudinal ctDNA by NGS for TP53 from an MDM2–p53 antagonist trial in liposarcoma. While acquired mutations in TP53 are very common, these data suggest that brigimadlin does not systematically lead to broad acquisition of resistance by inducing alterations in TP53.

As evidence of target engagement, time- and dose-dependent increases in GDF-15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in well-differentiated or dedifferentiated liposarcoma patients (100% and 75% disease control rates, respectively).

While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

Conclusions BI 907828 demonstrated antitumour activity and a manageable safety profile in pts with advanced solid tumours, including those with BTC; dose expansion is ongoing. BI 907828 is being further assessed in pts with BTC in the phase IIa/IIb open-label Brightline-2 trial (NCT05512377).

Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.

Currently, ten patients with BTC had received BI 907828 ± ezabenlimab (an immune checkpoint inhibitor). The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks, or until study discontinuation. As of February 2023, 16 patients have been enrolled.Clinical trial identification: NCT05512377.Editorial acknowledgement: Medical writing assistance, funded by Boehringer Ingelheim, was provided by Jim Sinclair, PhD, of Ashfield MedComms, an Inizio Company, during the preparation of this abstract.Legal entity responsible for the study: Boehringer Ingelheim.

P2a/2b, N=155, Recruiting, Boehringer Ingelheim | Trial completion date: Nov 2026 --> Mar 2027

This mutation analysis represents one of the most comprehensive assessments of longitudinal ctDNA by NGS for TP53 from a clinical trial of an MDM2–p53 antagonist. Preliminary data suggest that BI 907828 does not systematically lead to broad acquisition of resistance by inducing alterations in TP53. Clinical trial information: NCT03449381.

P1, N=16, Recruiting, Boehringer Ingelheim | Trial completion date: Jun 2024 --> Jun 2025