Efficacy and Safety of the MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced Biliary Tract Cancer: A Case Series

Abstract

Background

In patients with advanced biliary tract cancer (BTC), first-line chemotherapy plus immunotherapy has improved outcomes; however, second-line options that reflect the disease’s molecular heterogeneity are still needed. One emerging target is MDM2, amplified in ~5–8% of BTC cases.

Methods

This is a subset analysis of two ongoing Phase Ia/Ib trials assessing patients treated with brigimadlin (BI 907828; a highly potent, oral MDM2–p53 antagonist) ± ezabenlimab (PD-1 inhibitor) ± BI 754111 (anti-LAG-3; n = 1).

Results

Results from 12 patients with BTC are shown (monotherapy: n = 6/combination: n = 6). Six patients achieved partial response (monotherapy: n = 2/combination: n = 4), four had stable disease; responses were durable. Brigimadlin had a manageable safety profile. Seven patients had dose reductions due to adverse events, but no treatment-related adverse events led to treatment discontinuation.

Conclusion

Brigimadlin demonstrated anti-tumor activity in patients with advanced MDM2-amplified BTC, and warrants further investigation.

Plain Language Summary

Biliary tract carcinoma (BTC) is a cancer that affects the bile ducts which are part of the digestive system. Usually, the first treatment for advanced BTC (ie cannot be removed surgically and/or has spread) is chemotherapy in combination with immunotherapy. However, if chemotherapy does not work, or stops working, there are few treatment options available in second-line. Accordingly, intensive research is ongoing to try and find effective drugs. One potential medicine, called brigimadlin (or BI 907828), is a tablet that activates a molecule in tumor cells called p53. The normal function of p53 is to kill cells when they first start to become cancerous. However, if p53 is turned off by genetic mutations, or other mechanisms, then cancer can develop. Although p53 is rarely mutated in BTC tumors, it is inactivated by another molecule called MDM2 which is usually present at abnormally high levels in BTC. Brigimadlin prevents interaction between MDM2 and p53. This activates p53 and causes the cancer to die. Two clinical trials are currently assessing brigimadlin in a range of cancers, including BTC, with the aim of identifying a safe dose that can be examined in more detail in larger trials. So far, 12 patients with BTC have been treated. The patients’ tumors significantly shrank in six of these patients and remained stable in a further four patients. Side effects were as expected and could be tolerated by pausing treatment or lowering the dose. These results show that brigimadlin should be tested further in patients with advanced BTC.

Keywords:

• biliary tract cancer
• MDM2-p53 antagonist
• brigimadlin
• ezabenlimab
• MDM2
• MDM2-amplified

Data Sharing Statement

To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically, one year after the approval has been granted by major Regulatory Authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.

Acknowledgments

The authors thank the patients and their caregivers for making these studies possible. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment related to the development of the manuscript. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Steven Kirkham, PhD, of Ashfield MedComms, an Inizio Company, and funded by Boehringer Ingelheim. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. The study was supported and funded by Boehringer Ingelheim.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Author Disclosures

Noboru Yamamoto reports advisory council or committee for Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cmic, Chugai, MERCK, Healios; received honoraria from ONO, Chugai, Daiichi-Sankyo, Eisai; received grants or funds from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic. Anthony Tolcher reports employment with NEXT Oncology; reports consulting or advisory role (recipient: institution) for Nanobiotix, Pierre Fabre, Ascentage Pharma, AbbVie, EMD Serono, BioInvent, Adagene, Agenus, Aximmune, Bayer, HBM Partners, Mekanistic Therapeutics, NBE Therapeutics, Pelican Therapeutics, Pfizer, Immunome, Gilde Healthcare, Immunomet, Mirati Therapeutics, Pieris Pharmaceuticals, Aro Biotherapeutics, Asana Biosciences, Elucida Oncology, Partner Therapeutics, Ryvu Therapeutics, Sotio, Eleven Biotherapeutics, Zymeworks, Mersana, Trillium Therapeutics, Boehringer Ingelheim, Janssen, Aclaris Therapeutics, BluPrint Oncology, Daiichi Sankyo, IDEA Pharma, Immuneering, IMPAC Medical Systems, Karma Oncology, Lengo Therapeutics, Menarini, Seattle Genetics, SK Life Sciences, Spirea, Sunshine Guojian, Transcenta, Zentalis, Transgene, Deka Biosciences, HiberCell, Ikena Oncology, Jazz Pharmaceuticals, Pyxis, Vincerx Pharma, ZielBio, Senti Biosciences, Ocellaris Pharma, Lilly; reports leadership role with Next Oncology; received travel, accommodations, expenses fees (recipient: institution) from Sotio; served as an expert testimony for Immunogen; reports stock and other ownership interests (recipient: institution) from Pyxis; received research fundings (recipient: institution) from AbbVie, Pfizer, Syndax, Asana Biosciences, ADC Therapeutics, Adagene, Aminex, Ascentage Pharma, Arrys Therapeutics, CStone Pharmaceuticals, Deciphera, GlaxoSmithKline, Inhibrx, Innate Pharma, Kiromic, Mersana, Naturewise, NextCure, Nitto BioPharma, Pieris Pharmaceuticals, Symphogen, Tizona Therapeutics, Inc., Zymeworks, Agenus, Amphivena Therapeutics, Astex Pharmaceuticals, Boehringer Ingelheim Basilea, eFFECTOR Therapeutics, EMD Serono, Gilead Sciences, Kechow Pharma, K-Group Beta, Janssen Research & Development, Merck Sharp & Dohme, ORIC Pharmaceuticals, Samumed, Spring Bank, Seattle Genetics, Sunshine Guojian, Synthorx, Bioinvent, Birdie, BJ Bioscience, Boston Biomedical, Daiichi Sankyo, ImmuneOncia, Mirati Therapeutics, NBE Therapeutics, Odonate Therapeutics, Qilu Puget Sound Biotherapeutics, Shanghai HaiHe Pharmaceutical, Takeda, ABL Bio, Apros Therapeutics, Arcellx, ARMO BioSciences, Artios. Iwona Lugowska received honoraria and travel/accommodations/expenses from BMS, Macrogenics, Celon, Janssen, RM, Novartis, MSD, Roche, Boehringer Ingelheim, Amgen. Rodryg Ramlau reports consulting or advisory role for Bristol-Myers Squibb, Boehringer Ingelheim, MSD Oncology, Merck, Roche, Novartis, Takeda, AstraZeneca, Pfizer. Teresa Macarulla reports personal fees from Ability Pharmaceuticals SL, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Incyte, Ipsen Bioscience Inc, Janssen, Lilly, MSD, Novocure, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, and Zymeworks, outside the submitted work. Junxian Geng, Jian Li, Michael Teufel, and Angela Märten report employment with Boehringer Ingelheim. Junxian Geng reports a patent US20230058171A1 pending to Boehringer Ingelheim International GmbH. Patricia LoRusso reports consulting or advisory role for Genentech, CytomX Therapeutics, Roche/Genentech, Halozyme, Five Prime Therapeutics, Agenus, Agios, Cybrexa Therapeutics, Sotio, Abbvie, Genmab, Takeda, Tyme, IQvia, Trial to Reduce IDDM in the Genetically at Risk (TRIGR), Pfizer, ImmunoMet, Black Diamond Therapeutics, GlaxoSmithKline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck Labs, Astellas Pharma, Salarius Pharmaceuticals, Silverback Therapeutics, Macrogenics, Kyowa Kirin International, Kineta, Zentalis, Molecular Templates, Molecular Templates, ABL Bio, SK Life Sciences, ST Cube, Bayer, I-Mab, Seattle Genetics, ImCheck therapeutics, Relay Therapeutics, Stemline Therapeutics, Mekanistic Therapeutics, Compass Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen Therapeutics, Roivant, Neurotrials Research; received travel/accommodations/expenses from Genentech; reports stock and other ownership interests from BAKX Therapeutics; received honoraria from Five Prime Therapeutics; received research funding (recipient: institution) from Genentech.