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MDM2/p53 Signaling in BTC
Targeting the MDM2/p53 Signaling Pathway in Biliary Tract Cancers: Rationale and Current Status

Released: August 09, 2024

Expiration: August 08, 2025

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Key Takeaways
  • Since biliary tract cancer (BTC) is a molecularly heterogeneous group of malignancies, molecular profiling is very important for patients.
  • For the subset of patients with MDM2-amplifed BTC harboring wild-type p53, blocking the MDM2/p53 signaling pathway represents a potentially novel therapeutic strategy.
  • Brigimadlin is a highly potent, orally bioavailable MDM2/p53 antagonist showing very preliminary promising early evidence of activity in phase I/II trials in advanced BTC.

Biliary tract cancer (BTC) is a heterogenous group of malignancies arising from bile duct epithelial cells. Subtypes of BTC include invasive adenocarcinomas, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. These tumors are very rare with an annual incidence of 12,350 new cases in the United States, accounting for approximately 3% of all adult cancers. Unfortunately, the incidence and mortality rates are increasing largely because of the rise in the incidence of intrahepatic cholangiocarcinoma. For patients with BTC, the median overall survival is approximately 12 months with current standard-of-care first-line therapy, and this decreases to approximately 6 months with second-line therapy.

Molecular profiling is very important in the care of patients with BTC because it is a molecularly heterogeneous disease. In BTC, actionable gene mutations are harbored in 40% to 50% of intrahepatic cholangiocarcinoma, 10% to 30% of extrahepatic cholangiocarcinoma, and approximately 20% to 30% of gallbladder carcinoma. To date, molecular profiling has unveiled many molecular alterations that are now targetable with FDA-approved agents. Targetable alterations with FDA approval for use in BTC include NTRK fusions, BRAF V600E mutations, RET fusions, FGFR fusions or rearrangements, HER2 amplifications or overexpression, IDH1 mutations, and KRAS G12C mutations. There are also many novel targeted therapies that are currently under clinical investigation.

MDM2 in BTC
A pathway of recent clinical interest in BTC is the MDM2/p53 pathway. MDM2 is an E3 ubiquitin ligase with amplifications in MDM2 occurring in approximately 5% to 14% of patients with BTC when testing via next-generation sequencing. MDM2 is a negative regulator of the tumor suppressor gene p53. p53 is very important because when its expression is altered, either via mutations or loss, it can enhance the development and growth of cancer cells. Mutations in p53 occur across all BTC subtypes with a reported incidence ranging from approximately 20% to 47%. Of note, MDM2 amplifications and p53 mutations are mostly mutually exclusive. Alterations in the MDM2 gene can potentially lead to increased tumor development and tumor growth through its regulation of p53. Therefore, the development of drugs that target MDM2 is an important strategy to prevent p53 suppression. Blocking MDM2/p53 signaling in tumors harboring wild-type p53 represents a potentially novel therapeutic approach.

MDM2 inhibitors have emerged as a novel class of therapeutics in clinical oncology. Currently, much of the work with MDM2 inhibitors has focused on MDM2‑amplified soft tissue sarcomas. Milademetan is an MDM2 inhibitor that has been studied in MDM2-amplified advanced solid tumors, and APG-115 is another MDM2 inhibitor that is currently under investigation in locally advanced or metastatic melanomas or solid tumors. Inhibiting MDM2 is a potential therapeutic option, and if these drugs in development are found to be safe and effective, MDM2 inhibitors may become treatment options for patients with these devastating diseases, especially for those disease for which patients have very few available treatment options. For the small subset of patients with MDM2-amplifed BTC, albeit if the tumor also harbors wild-type p53, targeting MDM2 can potentially suppress tumor growth especially in the metastatic setting.

Efficacy and Safety of Brigimadlin in BTC
Brigimadlin is a highly potent, orally bioavailable MDM2/p53 antagonist. It inhibits the interaction between p53 and MDM2 and, thereby, restores p53 tumor suppressor function. The efficacy and safety of brigimadlin in advanced solid tumors harboring wild-type p53 is being investigated in 2 pivotal phase I/II clinical trials either as monotherapy (NCT03449381) or in combination with the anti–PD-1 monoclonal antibody ezabenlimab (NCT03964233). As of October 2023, 23 patients with BTC were enrolled on both trials; 16 of these patients received brigimadlin monotherapy and 7 received brigimadlin plus ezabenlimab. 

Although the number of patients with BTC in these trials was very small, among the 12 evaluable patients in the monotherapy arm, 33% achieved a partial response and 50% achieved stable disease. In the combination arm, 4 patients (57%) achieved a partial response and the remaining 3 patients (43%) achieved stable disease. The most common treatment-related adverse events of all grades with brigimadlin alone or in combination with ezabenlimab were nausea and fatigue, and the most common grade ≥3 treatment-related adverse events were neutropenia and thrombocytopenia. These results are promising especially among this patient population with unresectable, advanced and/or metastatic BTC for whom the prognosis is very poor. If the MDM2/p53 pathway can be effectively targeted in MDM2-amplified BTC harboring wild-type p53, and disease control and enhanced antitumor activity can be achieved, over time, these results may translate into improved progression-free survival and, ultimately, improved overall survival. As yet, it is not clear if the achieved responses in the phase I/II trials will translate into improved survival outcomes and if this response rate would be seen in larger clinical trials.

Clinical Implications and Future Directions
Currently, patients with metastatic BTC have a high likelihood of recurrence after initial treatment, and of importance, novel targeted treatment strategies are gaining a foothold in the field. These are very exciting times in the treatment of BTC, and we will have to wait for long-term results to know the true efficacy of brigimadlin with or without immunotherapy in BTC. As the targeted treatment armamentarium in BTC grows, our excitement for potential new approvals also grows.

For more information on the current management of BTC and the emerging role of MDM2 inhibitors, please see our text module, “Targeting the MDM2-p53 Pathway in Biliary Tract Cancer: Emerging Data and Implications for Future Clinical Practice”.

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