New Hope for a Rare and Aggressive Cancer

Cholangiocarcinoma, known more commonly as bile duct (or biliary) cancer, has several features that historically have made it difficult to treat.

First, it is a rare cancer, so advances in treatment take longer because clinical trials are smaller and slower to complete. Second, it grows in a pattern along the bile ducts that are shaped like a tree or along the lining of the gallbladder, and therefore may not cause symptoms until late — usually when jaundice develops because of blockage of the main bile duct and at which time it is commonly inoperable. Additionally, it is usually resistant to what we have been using as a mainstay of cancer therapy, chemotherapy.

While the last two decades have seen advances in newer biological cancer therapies, cholangiocarcinoma seemed to have been left behind.

But recently, the tide seems to be turning. The systematic analysis of many tumor types with next-generation DNA sequencing — a much faster (and cheaper) way to decode the genomic aberrations that drive cancers — has illuminated dark secrets for many cancers.

The analysis of proteins encoded by these altered gene can help cancer biologists and chemists fashion customized treatments that disable the cancer machinery for that specific type of cancer.

Some cholangiocarcinomas are now known to harbor fibroblast growth factor receptor 2 (FGFR2) gene fusions and other rearrangements that produce a hyperactive version of this growth factor that can result in malignant transformation. An inhibitor of all four of the FGRF receptors, Lytgobi (futibatinib) blocks the FGFR2 growth-inducing signal, leading to its therapeutic effect as demonstrated in a single-arm trial that enrolled patients who had progressed on prior therapy.

This trial led to the drug’s approval on September 30, 2022.

The revolution in cancer immunotherapy has extended to cholangiocarcinoma. We still are not fully certain of what makes particular cancer types or individual cases more “immunogenic” and likely respond to checkpoint inhibitors, the primary type of immunotherapy. The usual game plan in testing these therapies is to add them to standard chemotherapy, which, in the case of cholangiocarcinoma, for years, has been the combination of gemcitabine and cisplatin.

The TOPAZ-1 randomized trial compared chemotherapy with or without the checkpoint inhibitor Imfinzi (durvalumab) and showed a statistically significant improvement in survival in patients with unresectable/advanced cholangiocarcinoma. This treatment was approved by the Food and Drug Administration on September 2, 2022 — amazingly in the same month and
year as Lytgobi.

This incredible September story is hopefully a harbinger of things to come for rare and resilient cancers, showing that good science, along with creativity in applying and testing it properly, can be successful against all odds.



Professor of Medicine
Chair, Department of Breast Medical Oncology

The University of Texas MD AndersonCancer Center

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