Treatment options for biliary tract cancer: unmet needs, new targets and opportunities from both physicians' and patients' perspectives

<p>Biliary tract cancer (BTC) is a rare cancer with poor prognosis, characterized by considerable pathophysiological and molecular heterogeneity. While this makes it difficult to treat, it also provides targeted therapy opportunities. Current standard-of-care is chemotherapy ± immunotherapy, but several targeted agents have recently been approved. The current investigational landscape in BTC emphasizes the importance of biomarker testing at diagnosis. MDM2/MDMX are important negative regulators of the tumor suppressor p53 and provide an additional target in BTC (∼5–8% of tumors are <i>MDM2</i>-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.</p> <p>Biliary tract cancer (BTC), an umbrella term for a number of tumor sub-types, is a rare cancer with a poor prognosis (5-year survival rate: 15% [<a href="#CIT00001" target="_blank">1</a>]).</p> <p>It is characterized by considerable pathophysiological and molecular heterogeneity, making it difficult to treat, but providing a number of potentially targetable genetic alterations.</p> <p>No targeted agents are approved in the first-line setting for patients with BTC; chemotherapy-based regimens with or without immunotherapy are the standard of care.</p> <p>Clinical trials into alternative immunochemotherapy regimens and <i>FGFR2</i> inhibitors are ongoing, which may impact on first-line treatment options in the future.</p> <p>Second-line treatment options are largely chemotherapy-based for patients without targetable mutations, or targeted agents against <i>FGFR2</i>, <i>IDH1</i>, <i>HER2</i>, <i>BRAF</i> V600E, <i>NTRK</i>, DNA damage repair genes, <i>KRAS</i> and <i>RET</i> aberrations, some of which are investigational.</p> <p>MDM2 is an endogenous negative regulator of p53, hence aberrations of the <i>MDM2</i> gene can result in inappropriate silencing of wild-type p53, potentially leading to tumorigenesis.</p> <p><i>MDM2</i> amplification is observed in ∼5–8% of BTCs; <i>TP53</i> mutations are largely mutually exclusive.</p> <p>MDM2–p53 antagonists are in clinical development for the treatment of various hematologic and solid tumors.</p> <p>Brigimadlin, an MDM2–p53 antagonist currently in development in patients with BTC, has shown durable responses and no unexpected toxicities across two phase Ia/Ib studies in patients with solid tumors, including a number of patients with BTC.</p> <p>Comprehensive molecular testing is a key recommended in treatment guidelines for BTC.</p> <p>A PDF version of this infographic is available as supplemental material.</p>