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

Abstract

Noboru Yamamoto,1 Anthony Tolcher,2 Navid Hafez,3,4 Iwona Lugowska,5 Rodryg Ramlau,6 Teresa Macarulla,7,8 Junxian Geng,9 Jian Li,9 Michael Teufel,9 Angela Märten,10 Patricia LoRusso3 1Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan; 2NEXT Oncology, San Antonio, TX, USA; 3Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA; 4The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, CA, USA; 5Early Phase Clinical Trials Unit, Maria Skłodowska Curie National Research Institute of Oncology, Warsaw, Poland; 6Institute of Oncology, Poznan University of Medical Sciences, Poznan, Poland; 7Vall d’Hebrón University Hospital, Barcelona, Spain; 8Vall d’Hebrón Institute of Oncology (VHIO), Barcelona, Spain; 9Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 10Boehringer Ingelheim International GmbH, Ingelheim am Rhein, GermanyCorrespondence: Noboru Yamamoto, Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan, Tel + 81-3-3542-2511 ext 7319, Email [email protected]: 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

Keywords

• biliary tract cancer • mdm2–p53 antagonist • brigimadlin • ezabenlimab • mdm2-amplified